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Hire Dr. Tom P.

United Kingdom

USD 150 /hr

Biostatistician & Exprt in R, Stata, Python, Julia, STAN

Profile Summary

I am a biostatistician and R developer with twenty years of experience working at the intersection of medicine, statistics, and software. I help researchers, pharma teams, and NHS data groups turn complex statistical problems into clear, reproducible analyses — and where useful, into reusable tools that outlast a single project. My specialism is causal inference, particularly Mendelian randomisation — using genetic variants as instrumental variables to estimate causal effects in observational data. I have published methodological and applied work in this area for over fifteen years, and have presented at twenty-one international conferences. Alongside MR, I work routinely on epidemiological study design and analysis, missing data methods, and sensitivity analyses for unmeasured confounding. I have several packages on CRAN — bpbounds, mrbayes, OneSampleMR, tmsens, parglm, Statamarkdown, ieugwasr — covering a wide range of topics. OneSampleMR was featured in RStudio's "Top 40 New CRAN Packages" in November 2021. I also maintain and contribute to packages on GitHub, including TwoSampleMR, and have had pull requests accepted in widely used R infrastructure packages such as rmarkdown and rticles. Current and recent work includes designing Docker container images for electronic health records analyses. I have been a co-applicant on several successful research grants and have supervised PhD students through to completion. Technical skills: R (advanced — package development, Shiny, R Markdown, Quarto, unit testing, CI/CD), Stata, Python, Julia, SAS, SPSS, Bash, Git/GitHub, Docker, LaTeX, STAN. I write production-quality, well-documented code and follow functional programming principles. My packages include roxygen-formatted help, pkgdown websites, unit tests, and continuous integration. Education: BSc (Hons), MSc, and PhD from top UK universities. I am comfortable working with research teams, clinical investigators, data engineers, and software engineers. I can take a brief from someone who isn't a statistician, do the work to a standard that holds up in peer review, and explain the result in language the client can use.

Subject Matter Expertise

• ☆ Biostatistics
• ☆ Statistics
• ☆ Applied Statistics
• ☆ STATA
• ☆ R

Services

• Data & AI

Data & AI Statistical Analysis

Work Experience

Senior Lecturer

University of Bristol

February 2020 - Present

Lancaster University

- February 2020

Lecturer in Medical Statistics

Lancaster University

January 2015 - February 2020

Assistant Professor

University of Warwick

January 2013 - December 2014

Research Fellow

University of Bristol

October 2011 - December 2012

Research Associate

University of Bristol

October 2008 - September 2011

Education

PhD (Health Sciences)

University of Leicester

October 2005 - September 2008

MSc in Medical Statistics (Health Sciences)

University of Leicester

October 2004 - September 2005

BSc Mathematics and Economics (joint honours) (School of Mathematics)

University of Nottingham

October 1999 - June 2002

Certifications

• Certification details not provided.

Publications

JOURNAL ARTICLE

A structural mean modelling Mendelian randomization approach to investigate the lifecourse effect of adiposity: applied and methodological considerations @article{d859363ab9534715af01bf1e96446ba1, title = "A structural mean modelling Mendelian randomization approach to investigate the lifecourse effect of adiposity: applied and methodological considerations", author = "Power, {Grace Marion} and Palmer, {Tom M} and Warrington, {Nicole M.} and Heron, {Jon E} and Richardson, {Tom G} and Vanessa Didelez and Tilling, {Kate M} and {Davey Smith}, George and Sanderson, {Eleanor C M}", year = "2024", month = mar, day = "28", doi = "10.1101/2024.03.27.24304961", language = "English", journal = "medRxiv", publisher = "Cold Spring Harbor Laboratory Press", } . medRxiv.

Impact of vaccination on the association of COVID-19 with cardiovascular diseases @article{6e4180a4fc2b4656b2207e4ef57e7102, title = "Impact of vaccination on the association of COVID-19 with cardiovascular diseases: an OpenSAFELY cohort study", abstract = "Infection with SARS-CoV-2 is associated with an increased risk of arterial andvenous thrombotic events, but the implications of vaccination for this increasedrisk are uncertain. With the approval of NHS England, we quantified associationsbetween COVID-19 diagnosis and cardiovascular diseases in different vaccination and variant eras using linked electronic health records for ~40% of theEnglish population. We defined a {\textquoteleft}pre-vaccination{\textquoteright} cohort (18,210,937 people) inthe wild-type/Alpha variant eras (January 2020-June 2021), and {\textquoteleft}vaccinated{\textquoteright} and{\textquoteleft}unvaccinated{\textquoteright} cohorts (13,572,399 and 3,161,485 people respectively) in theDelta variant era (June-December 2021). We showed that the incidence of eacharterial thrombotic, venous thrombotic and other cardiovascular outcomes wassubstantially elevated during weeks 1-4 after COVID-19, compared with beforeor without COVID-19, but less markedly elevated in time periods beyond week 4.Hazard ratios were higher after hospitalised than non-hospitalised COVID-19and higher in the pre-vaccination and unvaccinated cohorts than the vaccinatedcohort. COVID-19 vaccination reduces the risk of cardiovascular events afterCOVID-19 infection. People who had COVID-19 before or without being vaccinated are at higher risk of cardiovascular events for at least two years", author = "Cezard, {Genevieve I} and Denholm, {Rachel E} and Knight, {Rochelle O C} and Yinghui Wei and Lucy Teece and Toms, {Renin M B S} and Forbes, {Harriet J} and Walker, {Alex J} and Louis Fisher and Jon Massey and Hopcroft, {Lisa EM} and Horne, {Elsie M F} and Taylor, {Kurt R} and Palmer, {Tom M} and {AL Arab}, {Marwa M} and {Ignacio Cuitun Coronado}, Jose and Samantha Ip and Simon Davy and Iain Dillingham and Sebastian Bacon and Amir Mehrkar and Morton, {Caroline E} and Felix Greaves and Catherine Hyams and {Davey Smith}, George and John MacLeod and Nishi Chaturvedi and Ben Goldacre and William Whiteley and Wood, {Angela M.} and Sterne, {Jonathan A C} and Walker, {Venexia M}", note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.", year = "2024", month = mar, day = "11", doi = "10.1038/s41467-024-46497-0", language = "English", volume = "15", journal = "Nature Communications", issn = "2041-1723", publisher = "Springer Nature", number = "1", } . Nature Communications.

Challenges in Estimating the Effectiveness of 2 Doses of Covid-19 Vaccine Beyond 6 Months in England @article{34da4e5836074055807e473ff052247f, title = "Challenges in Estimating the Effectiveness of 2 Doses of Covid-19 Vaccine Beyond 6 Months in England", abstract = "Understanding how the effectiveness of coronavirus disease 2019 (COVID-19) vaccine changes over time and in response to new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is crucial to scheduling subsequent doses. In a previous study, Horne et al. (1) quantified vaccine effectiveness (VE) over 6 consecutive 4-week periods from 2 weeks to 26 weeks after the second dose. Waning of hazard ratios (HRs) when comparing vaccinated persons with unvaccinated persons was approximately log-linear over time and was consistent across COVID-19–related outcomes and risk-based subgroups. To investigate waning beyond 26 weeks and in the era of the Omicron variant, we extended follow-up to the earliest of 50 weeks after the second dose or March 31, 2022.", author = "Horne, {Elsie M F} and Hulme, {William J} and Keogh, {Ruth H} and Palmer, {Tom m} and Williamson, {Elizabeth J} and Parker, {Edward P K} and Walker, {Venexia M} and Rochelle Knight and Yinghui Wie and Kurt Taylor and Louis Fisher and Jessica Morley and Amir Mehrkar and Iain Dillingham and Sebastian Bacon and Ben Goldacre and Sterne, {Jonathan A C} and Collaborative, {The opensafely}", note = "Funding Information: A.M. is a member of the NHS Digital Professional Advisory Group (representing the Royal College of General Practitioners), advising on the use of general practice data for COVID-19–related research and planning; until September 2019, he was interim chief medical officer of NHS Digital. B.G. has received research funding from the Laura and John Arnold Foundation, the NIHR, the NIHR School of Primary Care Research, the Good Thinking Foundation, Health Data Research UK, the Health Foundation, the World Health Organization, UKRI, Asthma UK, the British Lung Foundation, and the Longitudinal Health and Wellbeing strand of the National Core Studies Programme. He receives personal income from speaking and writing for lay audiences on the misuse of science; he is also a nonexecutive director of NHS Digital. Funding Information: This work was supported by UK Research and Innovation (UKRI) research councils (grants COV0076 and MR/V015737/1), the Longitudinal Health and Wellbeing strand of the National Core Studies Programme (grants MC_PC_20030 and MC_PC_20059), the National Institute for Health and Care Research (NIHR) Convalescence Study (grant COV-LT-0009), and Asthma UK. The OpenSAFELY data science platform is funded by the Wellcome Trust (grant 222097/Z/20/Z). The work of E.M.F.H. and J.A.C.S. was funded in part by NIHR grant 135073. R.H.K.{\textquoteright}s work was funded by UKRI (Future Leaders Fellowship MR/S017968/1). T.M.P. was supported by the MRC Integrative Epidemiology Unit, which receives funding from the UKRI Medical Research Council and the University of Bristol (grants MC_UU_00011/1 and MC_UU_00011/3). E.J.W. received grants from the Medical Research Council (MRC). The work of E.P.K.P. was funded by UKRI (COVID-19 data analysis secondment MR/W021420/1). Y.W. was supported by a UKRI MRC Fellowship (fellowship MC/W021358/1) and received funding from a UKRI Engineering and Physical Sciences Research Council Impact Acceleration Account (grant EP/X525789/1). B.G.{\textquoteright}s work on better use of data in health care more broadly is currently funded in part by the Bennett Foundation, the Wellcome Trust, the NIHR Oxford Biomedical Research Centre, the NIHR Applied Research Collaboration Oxford and Thames Valley, and the Mohn-Westlake Foundation; all Bennett Institute staff are supported by B.G.{\textquoteright}s grants on this work. J.A.C.S. was additionally supported by the NIHR Bristol Biomedical Research Centre and by Health Data Research UK. Funding Information: This work was supported by UK Research and Innovation (UKRI) research councils (grants COV0076 and MR/V015737/1), the Longitudinal Health and Wellbeing strand of the National Core Studies Programme (grants MC_PC_20030 and MC_PC_20059), the National Institute for Health and Care Research (NIHR) Convalescence Study (grant COV-LT-0009), and Asthma UK. The OpenSAFELY data science platform is funded by the Wellcome Trust (grant 222097/Z/20/Z). The work of E.M.F.H. and J.A.C.S. was funded in part by NIHR grant 135073. R.H.K.'s work was funded by UKRI (Future Leaders Fellowship MR/S017968/1). T.M.P. was supported by the MRC Integrative Epidemiology Unit, which receives funding from the UKRI Medical Research Council and the University of Bristol (grants MC_UU_00011/1 and MC_UU_00011/3). E.J.W. received grants from the Medical Research Council (MRC). The work of E.P.K.P. was funded by UKRI (COVID-19 data analysis secondment MR/W021420/1). Y.W. was supported by a UKRI MRC Fellowship (fellowship MC/W021358/1) and received funding from a UKRI Engineering and Physical Sciences Research Council Impact Acceleration Account (grant EP/X525789/1). B.G.'s work on better use of data in health care more broadly is currently funded in part by the Bennett Foundation, the Wellcome Trust, the NIHR Oxford Biomedical Research Centre, the NIHR Applied Research Collaboration Oxford and Thames Valley, and the Mohn-Westlake Foundation; all Bennett Institute staff are supported by B.G.'s grants on this work. J.A.C.S. was additionally supported by the NIHR Bristol Biomedical Research Centre and by Health Data Research UK. All data were linked, stored, and analyzed securely within the OpenSAFELY platform (https://opensafely. org/). Data included pseudonymized information such as coded diagnoses, medications, and physiological parameters. No free-text data were included. Detailed pseudonymized patient data are potentially reidentifiable and therefore are not shared. Primary-care records managed by the general practitioner software provider, The Phoenix Partnership/EMIS (Egton Medical Information Systems, Leeds, United Kingdom), were linked to COVID-19 test results, hospital admissions, hospital deaths (COVID-19 only), and registered deaths through OpenSAFELY. Data management was performed using Python 3.8.10, with analysis carried out using R, version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria). All software code is shared openly for review and reuse under the MIT License (https://github.com/opensafely/waning-ve-2dose-1year). We are very grateful for all of the support received from the Phoenix Partnership technical operations team throughout this work, and for the generous assistance provided by the information governance and database teams of the National Health Service (NHS) (NHS England and the NHS England Transformation Directorate). A preprint of this letter is available in medRχiv (https://www.medrxiv.org/content/10.1101/2023.01.04.22283762v1). The views expressed in this letter are those of the authors and not necessarily those of the NIHR, NHS England, the UK Health Security Agency, or the UK Department of Health and Social Care. The funders played no role in the consideration of the study design; in the collection, analysis, and interpretation of the data; in the writing of the report; or in the decision to submit the article for publication. A.M. is a member of the NHS Digital Professional Advisory Group (representing the Royal College of General Practitioners), advising on the use of general practice data for COVID-19-related research and planning; until September 2019, he was interim chief medical officer of NHS Digital. B.G. has received research funding from the Laura and John Arnold Foundation, the NIHR, the NIHR School of Primary Care Research, the Good Thinking Foundation, Health Data Research UK, the Health Foundation, the World Health Organization, UKRI, Asthma UK, the British Lung Foundation, and the Longitudinal Health and Wellbeing strand of the National Core Studies Programme. He receives personal income from speaking and writing for lay audiences on the misuse of science; he is also a nonexecutive director of NHS Digital.", year = "2024", month = jan, day = "8", doi = "10.1093/aje/kwad179", language = "English", volume = "193", pages = "227--231", journal = "American Journal of Epidemiology", issn = "0002-9262", publisher = "Oxford University Press", number = "1", } . American Journal of Epidemiology.

Trial arm outcome variance difference after dropout as an indicator of missing-not-at-random bias in randomized controlled trials @article{d4d610df8b3a473098266586d0f9a480, title = "Trial arm outcome variance difference after dropout as an indicator of missing-not-at-random bias in randomized controlled trials", author = "Audinga-Dea Hazewinkel and Tilling, {Kate M} and Wade, {Kaitlin H} and Palmer, {Tom M}", note = "Funding Information: We would like to thank Dr Andrew Vickers and the acupuncture trial team for making the data from “Acupuncture for chronic headache in primary care: large, pragmatic, randomized trial” publicly available. AH, TP and KT were supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/3). KHW is affiliated to the Integrative Cancer Epidemiology Programme (ICEP), and works within the Medical Research Council Integrative Epidemiology Unit. Publisher Copyright: {\textcopyright} 2023 The Authors. Biometrical Journal published by Wiley-VCH GmbH.", year = "2023", month = sep, day = "20", doi = "10.1002/bimj.202200116", language = "English", volume = "65", journal = "Biometrical Journal", issn = "0323-3847", publisher = "Wiley-VCH Verlag", number = "8", } . Biometrical Journal.

Comparative effectiveness of BNT162b2 versus mRNA-1273 covid-19 vaccine boosting in England @article{2f4f4761f7b3403fb19c70933ebe1a92, title = "Comparative effectiveness of BNT162b2 versus mRNA-1273 covid-19 vaccine boosting in England: matched cohort study in OpenSAFELY-TPP", abstract = "Objective To compare the effectiveness of the BNT162b2 mRNA (Pfizer-BioNTech) and mRNA-1273 (Moderna) covid-19 vaccines during the booster programme in England.Design Matched cohort study, emulating a comparative effectiveness trial.Setting Linked primary care, hospital, and covid-19 surveillance records available within the OpenSAFELY-TPP research platform, covering a period when the SARS-CoV-2 delta and omicron variants were dominant.Participants 3 237 918 adults who received a booster dose of either vaccine between 29 October 2021 and 25 February 2022 as part of the national booster programme in England and who received a primary course of BNT162b2 or ChAdOx1.Intervention Vaccination with either BNT162b2 or mRNA-1273 as a booster vaccine dose.Main outcome measures Recorded SARS-CoV-2 positive test, covid-19 related hospital admission, covid-19 related death, and non-covid-19 related death at 20 weeks after receipt of the booster dose.Results 1 618 959 people were matched in each vaccine group, contributing a total 64 546 391 person weeks of follow-up. The 20 week risks per 1000 for a positive SARS-CoV-2 test were 164.2 (95% confidence interval 163.3 to 165.1) for BNT162b2 and 159.9 (159.0 to 160.8) for mRNA-1273; the hazard ratio comparing mRNA-1273 with BNT162b2 was 0.95 (95% confidence interval 0.95 to 0.96). The 20 week risks per 1000 for hospital admission with covid-19 were 0.75 (0.71 to 0.79) for BNT162b2 and 0.65 (0.61 to 0.69) for mRNA-1273; the hazard ratio was 0.89 (0.82 to 0.95). Covid-19 related deaths were rare: the 20 week risks per 1000 were 0.028 (0.021 to 0.037) for BNT162b2 and 0.024 (0.018 to 0.033) for mRNA-1273; hazard ratio 0.83 (0.58 to 1.19). Comparative effectiveness was generally similar within subgroups defined by the primary course vaccine brand, age, previous SARS-CoV-2 infection, and clinical vulnerability. Relative benefit was similar when vaccines were compared separately in the delta and omicron variant eras.Conclusions This matched observational study of adults estimated a modest benefit of booster vaccination with mRNA-1273 compared with BNT162b2 in preventing positive SARS-CoV-2 tests and hospital admission with covid-19 20 weeks after vaccination, during a period of delta followed by omicron variant dominance.", author = "Hulme, {William J} and Horne, {Elsie M F} and Parker, {Edward PK} and Keogh, {Ruth H} and Williamson, {Elizabeth J.} and Walker, {Venexia M} and Palmer, {Tom M} and Curtis, {Helen J} and Walker, {Alex J} and Andrews, {Colm D} and Amir Mehrkar and Jessica Morley and Brian MacKenna and Bacon, {Sebastian CJ} and Ben Goldacre and Hern{\'a}n, {Miguel A} and Sterne, {Jonathan A C}", note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.", year = "2023", month = mar, day = "15", doi = "10.1136/bmj-2022-072808", language = "English", volume = "380", pages = "e072808", journal = "BMJ Medicine", issn = "2754-0413", publisher = "BMJ Publishing Group", } . BMJ Medicine.

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death @article{dbb3ae129da64a36b59377144ea25576, title = "Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A mendelian randomisation study", abstract = "BACKGROUND: Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis.METHODS AND FINDINGS: We performed a mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade.CONCLUSIONS: IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.", author = "Hamilton, {Fergus W} and Matt Thomas and David Arnold and Tom Palmer and Ed Moran and Mentzer, {Alexander J} and Nick Maskell and Kenneth Baillie and Charlotte Summers and Aroon Hingorani and Alasdair MacGowan and Khandaker, {Golam M} and Ruth Mitchell and {Davey Smith}, George and Peter Ghazal and Timpson, {Nicholas J}", note = "Funding Information: expressedarethoseoftheauthorsandnot necessarilythoseoftheNIHR,theNHS,orthe DepartmentofHealthandSocialCare.GDS,FH, RM,TPworkwithintheMRCIntegrative EpidemiologyUnitattheUniversityofBristol, whichissupportedbytheMedicalResearch Council(MC_UU_00011/1).G.M.K.acknowledges fundingsupportfromtheWellcomeTrust(Grant No.201486/Z/16/Z),theMedicalResearchCouncil, UK(GrantNo.MC_UU_00011/1;GrantNo.MR/ S037675/1;andGrantNo.MR/W014416/1),and theNationalInstituteofHealthResearchBristol BiomedicalResearchCentre,UK(GrantNo. NIHR203315).Thefundershadnoroleinstudy design,datacollectionandanalysis,decisionto publish,orpreparationofthemanuscript. Publisher Copyright: Copyright: {\textcopyright} 2023 Hamilton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.", year = "2023", month = jan, day = "30", doi = "10.1371/journal.pmed.1004174", language = "English", volume = "20", journal = "PLoS Medicine", issn = "1549-1277", publisher = "Public Library of Science", number = "1", } . PLoS Medicine.

Maternal vitamin D during pregnancy and offspring autism and autism-associated traits @article{b28ceacb0839419b84c8eb3b1e84c492, title = "Maternal vitamin D during pregnancy and offspring autism and autism-associated traits: a prospective cohort study", abstract = "Background: There has been a growing interest in the association between maternal levels of vitamin D during pregnancy and offspring autism. However, whether any associations reflect causal effects is still inconclusive. Methods: We used data from a UK based pregnancy cohort study (Avon Longitudinal Study of Parents and Children) comprising of 7,689 births between 1991 and 1992 with maternal blood vitamin D levels recorded during pregnancy and at least one recorded outcome measure, including autism diagnosis and autism-associated traits. The association between each outcome with seasonal and gestational age adjusted maternal serum 25-hydroxyvitamin D during pregnancy was estimated using confounder adjusted regression models. Multiple imputation was used to account for missing data and restricted cubic splines were used to investigate non-linear associations. Mendelian randomization was used to strengthen causal inference. Results: No strong evidence of an association between maternal serum 25-hydroxyvitamin D during pregnancy and any offspring autism-associated outcome was found using multivariable regression analysis (autism diagnosis: adjusted OR=0.98, 95%CI= 0.90-1.06), including with multiple imputation (autism diagnosis: adjusted OR=0.99, 95%CI=0.93-1.06), and no evidence of a causal effect was suggested by Mendelian randomization (autism diagnosis: causal OR=1.08, 95%CI=0.46-2.55). Some evidence of increased odds of autism-associated traits at lower levels of maternal serum 25-hydroxyvitamin D was found using spline analysis. Limitations: Our study was potentially limited by low power, particularly for diagnosed autism cases as an outcome. The cohort may not have captured the extreme lows of the distribution of serum 25-hydroxyvitamin D, and our analyses may have been biased by residual confounding and missing data. Conclusions: The present study found no strong evidence of a causal link between maternal vitamin D levels in pregnancy and offspring diagnosis or traits of autism. ", keywords = "Autism, Mendelian randomization, Pregnancy, Vitamin D", author = "Madley-Dowd, {Paul C} and Christina Dardani and Wootton, {Robyn E} and Dack, {Kyle A W} and Palmer, {Tom M} and Rupert Thurston and Havdahl, {Karoline Alexandra} and Jean Golding and Lawlor, {Debbie A} and Dheeraj Rai", note = "Funding Information: The UK Medical Research Council and Wellcome (Grant Ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, and PMD will serve as guarantor for the contents of this paper. This research was funded by the Wellcome Trust [Grant ref: 203776/Z/16/A]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). The MRC funded collection of vitamin D data in ALSPAC (G0701603) and Wellcome funded maternal GWAS data (WT088806). Child GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. PMD, TP and DAL work in or are affiliated to a unit that receives support from the University of Bristol (MC_UU_00011/3 and MC_UU_00011/1), and DAL is an NIHR Senior investigatory (NF-0616-10102). REW is supported by a postdoctoral fellowship from the South-Eastern Norway Regional Health Authority (2020024). KD is supported by a Ph.D. studentship from the MRC Integrative Epidemiology Unit at the University of Bristol (faculty matched place for MRC and Peter and Jean James Scholarship). CD is supported by the Wellcome Trust [215379/Z/19/Z]. DR is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (Grant ref: BRC-1215-2011). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care or any other funder. The funders had no role in the study design, analyses or interpretation of results. Publisher Copyright: {\textcopyright} 2022, The Author(s).", year = "2022", month = nov, day = "12", doi = "10.1186/s13229-022-00523-4", language = "English", volume = "13", journal = "Molecular Autism", issn = "2040-2392", publisher = "BioMed Central", number = "1", } . Molecular Autism.

Using allele scores to identify confounding by reverse causation @article{30b94b6e946444a6b2319a9891c0d37c, title = "Using allele scores to identify confounding by reverse causation: studies of alcohol consumption as an exemplar", abstract = "BackgroundMendelian randomization (MR) is a form of instrumental variable analysis used to investigate causality using observational data. Another important, although less frequently applied, use of this technique is to investigate confounding due to reverse causality.MethodsWe used a form of reverse MR and data from UK Biobank in a proof-of-principle study to investigate confounding due to reverse causation. Here we focus on the association between alcohol consumption (exposure) and outcomes including educational attainment, and physical and mental health. First, we examined the observational relationship between alcohol consumption and these outcomes. Allele scores were then derived for educational attainment, and physical and mental health, and the association with alcohol consumption (as the outcome) was explored. Sample sizes ranged from 114 941–336 473 in observational analyses and 142 093–336 818 in genetic analyses.ResultsConventional observational analyses indicated associations between alcohol consumption and a number of outcomes (e.g. neuroticism, body mass index, educational attainment). Analyses using allele scores suggested evidence of reverse causation for several of these relationships (in particular physical health and educational attainment).ConclusionAllele scores allow us to investigate reverse causation in observational studies. Our findings suggest that observed associations implying beneficial effects of alcohol consumption may be due to confounding by reverse causation in many cases.", author = "Sallis, {Hannah M} and Palmer, {Tom M} and Tilling, {Kate M} and {Davey Smith}, George and Munafo, {Marcus R}", year = "2022", month = aug, day = "18", doi = "10.1093/ije/dyac165", language = "English", journal = "International Journal of Epidemiology", issn = "0300-5771", publisher = "Oxford University Press", } . International Journal of Epidemiology.

Waning effectiveness of BNT162b2 and ChAdOx1 covid-19 vaccines over six months since second dose @article{5696c662da71449385bbe7f57bbd9b16, title = "Waning effectiveness of BNT162b2 and ChAdOx1 covid-19 vaccines over six months since second dose: OpenSAFELY cohort study using linked electronic health records", abstract = "Objective To estimate waning of covid-19 vaccine effectiveness over six months after second dose.Design Cohort study, approved by NHS England.Setting Linked primary care, hospital, and covid-19 records within the OpenSAFELY-TPP database.Participants Adults without previous SARS-CoV-2 infection were eligible, excluding care home residents and healthcare professionals.Exposures People who had received two doses of BNT162b2 or ChAdOx1 (administered during the national vaccine rollout) were compared with unvaccinated people during six consecutive comparison periods, each of four weeks.Main outcome measures Adjusted hazard ratios for covid-19 related hospital admission, covid-19 related death, positive SARS-CoV-2 test, and non-covid-19 related death comparing vaccinated with unvaccinated people. Waning vaccine effectiveness was quantified as ratios of adjusted hazard ratios per four week period, separately for subgroups aged ≥65 years, 18-64 years and clinically vulnerable, 40-64 years, and 18-39 years.Results 1 951 866 and 3 219 349 eligible adults received two doses of BNT162b2 and ChAdOx1, respectively, and 2 422 980 remained unvaccinated. Waning of vaccine effectiveness was estimated to be similar across outcomes and vaccine brands. In the ≥65 years subgroup, ratios of adjusted hazard ratios for covid-19 related hospital admission, covid-19 related death, and positive SARS-CoV-2 test ranged from 1.19 (95% confidence interval 1.14 to 1.24)to 1.34 (1.09 to 1.64) per four weeks. Despite waning vaccine effectiveness, rates of covid-19 related hospital admission and death were substantially lower among vaccinated than unvaccinated adults up to 26 weeks after the second dose, with estimated vaccine effectiveness ≥80% for BNT162b2, and ≥75% for ChAdOx1. By weeks 23-26, rates of positive SARS-CoV-2 test in vaccinated people were similar to or higher than in unvaccinated people (adjusted hazard ratios up to 1.72 (1.11 to 2.68) for BNT162b2 and 1.86 (1.79 to 1.93) for ChAdOx1).Conclusions The rate at which estimated vaccine effectiveness waned was consistent for covid-19 related hospital admission, covid-19 related death, and positive SARS-CoV-2 test and was similar across subgroups defined by age and clinical vulnerability. If sustained to outcomes of infection with the omicron variant and to booster vaccination, these findings will facilitate scheduling of booster vaccination.", author = "Horne, {Elsie M F} and Hulme, {William J} and Keogh, {Ruth H} and Palmer, {Tom M} and Williamson, {Elizabeth J.} and Parker, {Edward PK} and Amelia Green and Walker, {Venexia M} and Walker, {Alex J} and Curtis, {Helen J} and Louis Fisher and Brian MacKenna and Richard Croker and Hopcroft, {Lisa EM} and Park, {Robin Y} and Jon Massey and Jessica Morley and Amir Mehrkar and Sebastian Bacon and David Evans and Peter Inglesby and Morton, {Caroline E} and George Hickman and Simon Davy and Tom Ward and Iain Dillingham and Ben Goldacre and Hern{\'a}n, {Miguel A} and Sterne, {Jonathan A C}", note = "Funding Information: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: funding for this work from the Longitudinal Health and Wellbeing COVID-19 National Core Study, Asthma UK, and the NIHR; BG has received research funding from the Laura and John Arnold Foundation, the NIHR, the NIHR School of Primary Care Research, the NIHR Oxford Biomedical Research Centre, the Mohn-Westlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, the Wellcome Trust, the Good Thinking Foundation, Health Data Research UK, the Health Foundation, the World Health Organization, UKRI, Asthma UK, the British Lung Foundation, and the Longitudinal Health and Wellbeing strand of the National Core Studies programme; he receives personal income from speaking and writing for lay audiences on the misuse of science; he is also a non-executive director of NHS Digital; AM is on the NHS Digital Professional Advisory Group (representing the Royal College of General Practitioners), advising on the use of general practice data for covid-19 related research and planning; until September 2019 he was interim chief medical officer of NHS Digital. Funding Information: Funding: This work was supported by the Longitudinal Health and Wellbeing COVID-19 National Core Study (UK Research and Innovation (UKRI) Medical Research Council (MRC) MC_PC_20030 and MC_PC_20059), Asthma UK, and National Institute for Health Research (NIHR) grant MR/V015737/1. The OpenSAFELY software platform is funded by Wellcome and by the Data and Connectivity COVID-19 National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UKRI (grant ref MC_PC_20058). TPP provided technical expertise and infrastructure within their data centre pro bono in the context of a national emergency. BG{\textquoteright}s work on better use of data in healthcare more broadly is funded in part by NIHR Oxford Biomedical Research Centre, NIHR Applied Research Collaboration Oxford and Thames Valley, the Mohn-Westlake Foundation, NHS England, and the Health Foundation; all DataLab staff are supported by BG{\textquoteright}s grants on this work. RHK was funded by UKRI (Future Leaders Fellowship MR/S017968/1). VW and TMP were supported by the MRC Integrative Epidemiology Unit, which receives funding from the UKRI Medical Research Council and the University of Bristol (MC_UU_00011/1 and MC_UU_00011/3). EPKP was funded by UKRI (covid-19 data analysis secondment MR/W021420/1). EW holds grants from the MRC. JACS is supported by the NIHR Bristol Biomedical Research Centre and by Health Data Research UK. The views expressed are those of the authors and not necessarily those of the NIHR, NHS England, Public Health England, or the Department of Health and Social Care. The funders had no role in considering the study design or in the collection, analysis, and interpretation of data, writing of the report, or decision to submit the article for publication. Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.", year = "2022", month = jul, day = "20", doi = "10.1136/bmj-2022-071249", language = "English", volume = "378", pages = "e071249", journal = "BMJ", issn = "0959-8138", publisher = "BMJ Publishing Group", } . BMJ.

Comparative effectiveness of ChAdOx1 versus BNT162b2 covid-19 vaccines in health and social care workers in England @article{048552152aba4a98867215d71b1f5c05, title = "Comparative effectiveness of ChAdOx1 versus BNT162b2 covid-19 vaccines in health and social care workers in England: cohort study using OpenSAFELY", abstract = "Objective To compare the effectiveness of the BNT162b2 mRNA (Pfizer-BioNTech) and the ChAdOx1 (Oxford-AstraZeneca) covid-19 vaccines against infection and covid-19 disease in health and social care workers.Design Cohort study, emulating a comparative effectiveness trial, on behalf of NHS England.Setting Linked primary care, hospital, and covid-19 surveillance records available within the OpenSAFELY-TPP research platform, covering a period when the SARS-CoV-2 Alpha variant was dominant.Participants 317 341 health and social care workers vaccinated between 4 January and 28 February 2021, registered with a general practice using the TPP SystmOne clinical information system in England, and not clinically extremely vulnerable.Interventions Vaccination with either BNT162b2 or ChAdOx1 administered as part of the national covid-19 vaccine roll-out.Main outcome measures Recorded SARS-CoV-2 positive test, or covid-19 related attendance at an accident and emergency (A&E) department or hospital admission occurring within 20 weeks of receipt of the first vaccine dose.Results Over the duration of 118 771 person-years of follow-up there were 6962 positive SARS-CoV-2 tests, 282 covid-19 related A&E attendances, and 166 covid-19 related hospital admissions. The cumulative incidence of each outcome was similar for both vaccines during the first 20 weeks after vaccination. The cumulative incidence of recorded SARS-CoV-2 infection 20 weeks after first-dose vaccination with BNT162b2 was 21.7 per 1000 people (95% confidence interval 20.9 to 22.4) and with ChAdOx1 was 23.7 (21.8 to 25.6), representing a difference of 2.04 per 1000 people (0.04 to 4.04). The difference in the cumulative incidence per 1000 people of covid-19 related A&E attendance at 20 weeks was 0.06 per 1000 people (95% CI −0.31 to 0.43). For covid-19 related hospital admission, this difference was 0.11 per 1000 people (−0.22 to 0.44).Conclusions In this cohort of healthcare workers where we would not anticipate vaccine type to be related to health status, we found no substantial differences in the incidence of SARS-CoV-2 infection or covid-19 disease up to 20 weeks after vaccination. Incidence dropped sharply at 3-4 weeks after vaccination, and there were few covid-19 related hospital attendance and admission events after this period. This is in line with expected onset of vaccine induced immunity and suggests strong protection against Alpha variant covid-19 disease for both vaccines in this relatively young and healthy population of healthcare workers.We will share information and interpretation of our findings through press releases, social media channels, and plain language summary on the OpenSAFELY website (https://opensafely.org/research/).", author = "Hulme, {William J.} and Williamson, {Elizabeth J.} and Green, {Amelia C.A.} and Krishnan Bhaskaran and McDonald, {Helen I.} and Rentsch, {Christopher T.} and Anna Schultze and John Tazare and Curtis, {Helen J.} and Walker, {Alex J.} and Tomlinson, {Laurie A.} and Tom Palmer and Horne, {Elsie M.F.} and Brian MacKenna and Morton, {Caroline E.} and Amir Mehrkar and Jessica Morley and Louis Fisher and Bacon, {Sebastian C.J.} and David Evans and Peter Inglesby and George Hickman and Simon Davy and Tom Ward and Richard Croker and Eggo, {Rosalind M.} and Wong, {Angel Y.S.} and Rohini Mathur and Kevin Wing and Harriet Forbes and Grint, {Daniel J.} and Douglas, {Ian J.} and Evans, {Stephen J.W.} and Liam Smeeth and Chris Bates and Jonathan Cockburn and John Parry and Frank Hester and Sam Harper and Sterne, {Jonathan A.C.} and Hern{\'a}n, {Miguel A.} and Ben Goldacre", note = "Funding Information: Funding This work was supported by the UKRI (COV0076;MR/V015737/1) NIHR and Asthma UK-BLF and the Longitudinal Health and wellbeing strand of the National Core Studies programme (UKRI MRC MC_PC_20030 and MC_PC_20059). The OpenSAFELY platform is funded by the Wellcome Trust (222097/Z/20/Z). TPP provided technical expertise and infrastructure within their data centre pro bono in the context of a national emergency. BG{\textquoteright}s work on clinical informatics is supported by the NIHR Oxford Biomedical Research Centre and the NIHR Applied Research Collaboration Oxford and Thames Valley. BG{\textquoteright}s work on better use of data in healthcare more broadly is currently funded in part by: NIHR Oxford Biomedical Research Centre, NIHR Applied Research Collaboration Oxford and Thames Valley, the Mohn-Westlake Foundation, NHS England, and the Health Foundation; all DataLab staff are supported by BG{\textquoteright}s grants on this work. LS reports grants from Wellcome, MRC, NIHR, UKRI, British Council, GSK, British Heart Foundation, and Diabetes UK outside this work. KB holds a Wellcome Senior Research Fellowship (220283/Z/20/Z). HIM is funded by the NIHR Health Protection Research Unit in Immunisation, a partnership between Public Health England and London School of Hygiene and Tropical Medicine. AYSW holds a fellowship from the British Heart Foundation. EJW holds grants from MRC. RM holds a Sir Henry Wellcome Fellowship funded by the Wellcome Trust (201375/Z/16/Z). HF holds a UKRI fellowship. IJD holds grants from NIHR and GSK. TP receives support from the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/4). Funders had no role in the study design, collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Funding Information: Competing interests: All authors have completed the ICMJE uniform disclosure form and declare the following: BG has received research funding from Health Data Research UK (HDRUK), the Laura and John Arnold Foundation, the Wellcome Trust, the NIHR Oxford Biomedical Research Centre, the NHS National Institute for Health Research School of Primary Care Research, the Mohn-Westlake Foundation, the Good Thinking Foundation, the Health Foundation, and the World Health Organisation; he also receives personal income from speaking and writing for lay audiences on the misuse of science. IJD holds shares in GlaxoSmithKline (GSK). Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.", year = "2022", month = jul, day = "20", doi = "10.1101/2021.10.13.21264937", language = "English", volume = "378", journal = "BMJ", issn = "0959-8138", publisher = "BMJ Publishing Group", } . BMJ.

Effects of general and central adiposity on circulating lipoprotein, lipid, and metabolite levels in UK Biobank @article{076c7034fad44bd29ac632894197e278, title = "Effects of general and central adiposity on circulating lipoprotein, lipid, and metabolite levels in UK Biobank: A multivariable Mendelian randomization study", abstract = "Background: The direct effects of general adiposity (body mass index (BMI)) and central adiposity (waist-to-hip-ratio (WHR)) on circulating lipoproteins, lipids, and metabolites are unknown.Methods: We used new metabolic data from UK Biobank (N=109,532, a five-fold higher N over previous studies). EDTA-plasma was used to quantify 249 traits with nuclear-magnetic-resonance spectroscopy including subclass-specific lipoprotein concentrations and lipid content, plus preglycemic and inflammatory metabolites. We used univariable and multivariable two-stage leastsquares regression models with genetic risk scores for BMI and WHR as instruments to estimate total (unadjusted) and direct (mutually-adjusted) effects of BMI and WHR on metabolic traits; plus effects on statin use and interaction by sex, statin use, and age (proxy for medication use).Findings: Higher BMI decreased apolipoprotein B and low-density lipoprotein cholesterol (LDL-C) before and after WHR-adjustment, whilst BMI increased triglycerides only before WHR-adjustment. These effects of WHR were larger and BMI-independent. Direct effects differed markedly by sex, e.g., triglycerides increased only with BMI among men, and only with WHR among women.Adiposity measures increased statin use and showed metabolic effects which differed by statin use and age. Among the youngest (38-53y, statins-5%), BMI and WHR (per-SD) increased LDL-C (total effects: 0.04-SD, 95%CI=-0.01,0.08 and 0.10-SD, 95%CI=0.02,0.17 respectively), but only WHR directly. Among the oldest (63-73y, statins-29%), BMI and WHR directly lowered LDL-C (-0.19-SD, 95%CI=-0.27,-0.11 and -0.05-SD, 95%CI=-0.16,0.06 respectively).Interpretation: Excess adiposity likely raises atherogenic lipid and metabolite levels exclusively via adiposity stored centrally, particularly among women. Apparent effects of adiposity on lowering LDL-C are likely explained by an effect of adiposity on statin use.", keywords = "Bristol Population Health Science Institute, Adiposity, BMI, WHR, Metabolism, NMR, Mendelian randomization, Epidemiology, UK Biobank", author = "Bell, {Joshua A} and Richardson, {Tom G} and Qin Wang and Sanderson, {Eleanor C M} and Palmer, {Tom M} and Walker, {Venexia M} and O'Keefe, {Linda Marie} and Timpson, {Nicholas John} and Anna Cichonska and Heli Julkunen and Peter Wurtz and Holmes, {Michael V} and {Davey Smith}, George", note = "Funding Information: JAB, TGR, ES, VMW, TP, and GDS work in a unit funded by the UK MRC (MC_UU_00011/1; MC_UU_00011/3; MC_UU_00011/4) and the University of Bristol. QW is funded by a Novo Nordisk postdoctoral fellowship (NNF17OC0027034) and during this work began employment with GSK. VMW is supported by the COVID-19 Longitudinal Health and Wellbeing National Core Study, which is funded by the Medical Research Council (MC_PC_20030; MC_PC_20059). LMOK is supported by a Health Research Board (HRB) of Ireland Emerging Investigator Award (Grant ref: EIA-FA-2019-007 SCaRLeT. MVH works in a unit that receives funding from the UK MRC and is supported by a BHF Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre; and towards completion of this work began employment with 23andMe. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-20011), the MRC Integrative Epidemiology Unit (MC_UU_00011/1) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). This publication is the work of the authors and JAB is the guarantor for its contents. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2022 The Author(s)", year = "2022", month = jul, day = "6", doi = "10.1016/j.lanepe.2022.100457", language = "English", volume = "21", journal = "The Lancet Regional Health - Europe", issn = "2666-7762", publisher = "Elsevier Limited", } . The Lancet Regional Health - Europe.

Sensitivity to missing not at random dropout in clinical trials @article{c7ee91b4d54243d1a0a9c2a895a6b236, title = "Sensitivity to missing not at random dropout in clinical trials: Use and interpretation of the trimmed means estimator", abstract = "Outcome values in randomized controlled trials (RCTs) may be missing not at random (MNAR), if patients with extreme outcome values are more likely to drop out (eg, due to perceived ineffectiveness of treatment, or adverse effects). In such scenarios, estimates from complete case analysis (CCA) and multiple imputation (MI) will be biased. We investigate the use of the trimmed means (TM) estimator for the case of univariable missingness in one continuous outcome. The TM estimator operates by setting missing values to the most extreme value, and then {"}trimming{"} away equal fractions of both groups, estimating the treatment effect using the remaining data. The TM estimator relies on two assumptions, which we term the {"}strong MNAR{"} and {"}location shift{"} assumptions. We derive formulae for the TM estimator bias resulting from the violation of these assumptions for normally distributed outcomes. We propose an adjusted TM estimator, which relaxes the location shift assumption and detail how our bias formulae can be used to establish the direction of bias of CCA and TM estimates, to inform sensitivity analyses. The TM approach is illustrated in a sensitivity analysis of the CoBalT RCT of cognitive behavioral therapy (CBT) in 469 individuals with 46 months follow-up. Results were consistent with a beneficial CBT treatment effect, with MI estimates closer to the null and TM estimates further from the null than the CCA estimate. We propose using the TM estimator as a sensitivity analysis for data where extreme outcome value dropout is plausible.", keywords = "trimmed means, dropout, randomized controlled trials, missing not at random, sensitivity analyses, bias quantification", author = "Audinga-Dea Hazewinkel and Jack Bowden and Wade, {Kaitlin H} and Tom Palmer and Wiles, {Nicola J} and Kate Tilling", note = "Funding Information: The CoBalT trial was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Audinga‐Dea Hazewinkel, Tom Palmer, and Kate Tilling were supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/3). Jack Bowden's research at the University of Exeter is funded by a UKRI Expanding Excellence in England (E3) award. Kaitlin H. Wade was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund [204813/Z/16/Z] and is now affiliated to the Integrative Cancer Epidemiology Programme (ICEP), and works within the Medical Research Council Integrative Epidemiology Unit. Nicola J. Wiles: The CoBalT trial was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme (project number 06/404/02). Funding Information: information Health Technology Assessment Programme, 06/404/02; Medical Research Council, MC_UU_0011/3; UK Research and Innovation, E3; Wellcome Trust, 204813/Z/16/ZThe CoBalT trial was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Audinga-Dea Hazewinkel, Tom Palmer, and Kate Tilling were supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/3). Jack Bowden's research at the University of Exeter is funded by a UKRI Expanding Excellence in England (E3) award. Kaitlin H. Wade was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund [204813/Z/16/Z] and is now affiliated to the Integrative Cancer Epidemiology Programme (ICEP), and works within the Medical Research Council Integrative Epidemiology Unit. Nicola J. Wiles: The CoBalT trial was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme (project number 06/404/02). Funding Information: Health Technology Assessment Programme, 06/404/02; Medical Research Council, MC_UU_0011/3; UK Research and Innovation, E3; Wellcome Trust, 204813/Z/16/Z Funding information Publisher Copyright: {\textcopyright} 2022 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.", year = "2022", month = apr, day = "15", doi = "10.1101/2021.03.05.21252334", language = "English", volume = "41", pages = "1462--1481", journal = "Statistics in Medicine", issn = "0277-6715", publisher = "John Wiley & Sons, Ltd.", number = "8", } . Statistics in Medicine.

Murphy M, Scott A, Wong G et al. The consultation open and close study: A feasibility study of a complex intervention [version 1; peer review: 1 approved, 1 approved with reservations] NIHR Open Res 2022, 2:29 (https://doi.org/10.3310/nihropenres.13267.1) .

The consultation open and close study: A feasibility study of a complex intervention @article{e9544a1172594947b9b4ddd7d02dff27, title = "The consultation open and close study: A feasibility study of a complex intervention", abstract = "Use of telephone, video and online consultations in general practice is increasing. This can lead to transactional consultations which make it harder for patients to describe how symptoms affect their lives, and confusion about plans for future care. The aim of this study was to test the feasibility of a randomised control trial (RCT ) for a complex intervention designed to address patients{\textquoteright} concerns more comprehensively and help them remember advice from general practitioners (GPs). ", author = "C Murphy and Scott, {Anne P} and Chris Salisbury and Walter, {Scott R} and Palmer, {Tom M}", year = "2022", month = apr, day = "14", doi = "10.3310/nihropenres.13267.1", language = "English", pages = "1 --58", journal = "NIHR Open Research", issn = "2633-4402", publisher = "NIHR Journals Library", } . NIHR Open Research.

A review of group-based methods for teaching statistics in Higher Education @article{4d0438b54d2547e1bb6cc2701fe1c14b, title = "A review of group-based methods for teaching statistics in Higher Education", abstract = "The teaching of statistics in higher education in the UK is still largely lecture based. This is despite recommendations such as those given by the American Statistical Association{\textquoteright}s Guidelines for Assessment and Instruction in Statistics Education report that more emphasis should be placed on active learning strategies where students take more responsibility for their own learning. One possible model is that of collaborative learning, where students learn in groups through carefully crafted {\textquoteleft}problems{\textquoteright}, which has long been suggested as a strategy for teaching statistics. In this article, we review two specific approaches that fall under the collaborative learning model: problem- and team-based learning. We consider the evidence for changing to this model of teaching in statistics, as well as give practical suggestions on how this could be implemented in typical statistics classes in higher education.", author = "Elinor Jones and Tom Palmer", year = "2022", month = mar, day = "31", doi = "10.1093/teamat/hrab002", language = "English", volume = "41", pages = "69--86", journal = "Teaching Mathematics and its Applications", issn = "0268-3679", publisher = "Oxford University Press", number = "1", } . Teaching Mathematics and its Applications.

A review of group-based methods for teaching statistics in higher education @article{6e82b39f1957475f9e9a1556fc15cefa, title = "A review of group-based methods for teaching statistics in higher education", abstract = "The teaching of statistics in higher education in the UK is still largely lecture based. This is despite recommendations such as those given by the American Statistical Association{\textquoteright}s Guidelines for Assessment and Instruction in Statistics Education report that more emphasis should be placed on active learning strategies where students take more responsibility for their own learning. One possible model is that of collaborative learning, where students learn in groups through carefully crafted {\textquoteleft}problems{\textquoteright}, which has long been suggested as a strategy for teaching statistics. In this article, we review two specific approaches that fall under the collaborative learning model: problem- and team-based learning. We consider the evidence for changing to this model of teaching in statistics, as well as give practical suggestions on how this could be implemented in typical statistics classes in higher education.", author = "Jones, {Elinor M} and Palmer, {Tom M}", note = "Publisher Copyright: {\textcopyright} 2021 The Author(s). Published by Oxford University Press on behalf of The Institute of Mathematics and its Applications. All rights reserved.", year = "2022", month = mar, day = "1", doi = "10.1093/teamat/hrab002", language = "English", volume = "41", pages = "69--86", journal = "Teaching Mathematics and Its Application", issn = "0268-3679", publisher = "Oxford University Press", number = "1", } . Teaching Mathematics and Its Application.

Mendelian randomization @article{69a2049269f143d097ccfd7b9a15fbbc, title = "Mendelian randomization", abstract = "Mendelian randomization (MR) is a term that applies to the use of genetic variation to address causal questions about how modifiable exposures influence different outcomes. The principles of MR are based on Mendel{\textquoteright}s laws of inheritance and instrumental variable estimation methods, which enable the inference of causal effects in the presence of unobserved confounding. In this Primer, we outline the principles of MR, the instrumental variable conditions underlying MR estimation and some of the methods used for estimation. We go on to discuss how the assumptions underlying an MR study can be assessed and describe methods of estimation that are robust to certain violations of these assumptions. We give examples of a range of studies in which MR has been applied, the limitations of current methods of analysis and the outlook for MR in the future. The differences between the assumptions required for MR analysis and other forms of epidemiological studies means that MR can be used as part of a triangulation across multiple sources of evidence for causal inference.", author = "Eleanor Sanderson and Glymour, {M. Maria} and Holmes, {Michael V.} and Hyunseung Kang and Jean Morrison and Munaf{\`o}, {Marcus R.} and Tom Palmer and Schooling, {C. Mary} and Chris Wallace and Qingyuan Zhao and {Davey Smith}, George", note = "Funding Information: E.S., M.R.M., T.P. and G.D.S. are members of the UK Medical Research Council (MRC) Integrative Epidemiology unit, which is funded by the MRC (MC_UU_00011/1, MC_UU_00011/3 and MC_UU_00011/7) and the University of Bristol. M.M.G. is supported by the National Institutes of Health/National Institute on Aging (NIH/NIA) grant R01AG057869. M.V.H. works in a unit that receives funding from the MRC and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. H.K. is supported by the National Science Foundation grant DMS-1811414. C.W. is funded by the MRC (MC UU 00002/4, MC UU 00002/13) and the Wellcome Trust (WT107881). Publisher Copyright: {\textcopyright} 2022, Springer Nature Limited.", year = "2022", month = feb, day = "10", doi = "10.1038/s43586-021-00092-5", language = "English", volume = "2", journal = "Nature Reviews Methods Primers", issn = "2662-8449", publisher = "Springer Nature [academic journals on nature.com]", number = "1", } . Nature Reviews Methods Primers.

Changes in presentations with features potentially indicating cancer in primary care during the COVID-19 pandemic @article{97889a971562477ea7ebc722e08b9775, title = "Changes in presentations with features potentially indicating cancer in primary care during the COVID-19 pandemic: a retrospective cohort study", abstract = "Objectives To investigate how the COVID-19 pandemic affected the number of people aged 50+ presenting to primary care with features which could potentially indicate cancer, and to explore how reporting differed by patient characteristics and in face-to-face vs. remote consultations. Design, Setting and Participants A retrospective cohort study of GP, nurse, and paramedic primary-care consultations in 21 practices in South-West England covering 123,947 patients. The models compared potential cancer indicators reported in April – July 2019 with April – July 2020. Main outcome measures Potential indicators of cancer were identified using code lists for symptoms, signs, test results and diagnoses listed in the National Institute for Health and Care Excellence (NICE) suspected-cancer referral guidance (NG12). Results During April-July 2019, 17% of registered patients aged 50+ years reported a potential cancer indicator in a consultation with a GP or nurse. During April-July 2020 this reduced to 11% (IRR 0.64, 95% CI 0.62 to 0.67, p<0.001). Reductions in potential cancer indicators were stable across age group, sex, ethnicity, index of multiple deprivation (IMD) quintile, and shielding status, but less marked in patients with mental health conditions than without (IRR=0.75, 95% CI 0.72 to 0.79, interaction p<0.001). Proportions of GP consultations with potential indicators of cancer reduced between 2019 and 2020 for face-to-face consultations (IRR=0.84, 95% CI 0.76 to 0.92, p<0.001) and increased for remote consultations (IRR=1.17, 95% CI 1.07 to 1.29, p=0.001), though it remained lower in remote consulting than face-to-face in April-July 2020. This difference was greater for nurse/paramedic consultations (face-to-face: IRR=0.61, 95% CI 0.44 to 0.83, p=0.002; remote: IRR=1.60, 95% CI 1.10 to 2.333, p=0.014). Conclusion The number of patients consulting with presentations that could potentially indicate cancer reduced during the first-wave of the COVID-19 pandemic. Patients should be encouraged to continue contacting primary care for persistent signs and symptoms, and GPs and nurses should be encouraged to probe patients for further information during remote consulting, in the absence of non-verbal cues. ", keywords = "COVID-19, General practice, CANCER", author = "Scott, {Lauren J} and C Murphy and Sarah Price and Horwood, {Jeremy P} and Denholm, {Rachel E} and Rhys Lewis and Palmer, {Tom M} and Chris Salisbury", note = "Funding Information: Twitter Mairead Murphy @mairead_murf, Jeremy Horwood @JPHorwood and Chris Salisbury @prof_tweet Acknowledgements The authors would like to thank all the participants in this study, Bristol North Somerset and South Gloucestershire Clinical Commissioning Group, One Care for providing the data extract, the NIHR Clinical Research Network for adopting the study on the NIHR portfolio and the NIHR SPCR for funding the research. The authors would also like to thank Willie Hamilton for his work on developing the potential cancer indicator lists (alongside author Sarah Price). Funding Information: Funding This study was funded by the National Institute for Health Research (NIHR) School for Primary Care Research. Additional funding for staff time was provided by the Applied Research Collaboration West (ARC West) at University Hospitals Bristol and Weston NHS Foundation Trust and One Care. CS is a NIHR Senior Investigator. SP is funded by the NIHR Policy Research Programme via the Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis, PR-PRU-1217-21601. TP is supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1 and MC_UU_00011/3) Disclaimer The funder had no role in the study design, collection and analysis of data, or the writing of the manuscript. The views expressed are those of the authors and not necessarily those of, the NIHR or the Department of Health and Social Care. Publisher Copyright: {\textcopyright} 2021 Author(s). Published by BMJ.", year = "2021", month = may, day = "24", doi = "10.1136/bmjopen-2021-050131", language = "English", volume = "11", journal = "BMJ Open", issn = "2044-6055", publisher = "BMJ Publishing Group", number = "5", } . BMJ Open.

To Adjust or Not to Adjust? @article{9afd13c35daf4718a96d39a6337afbad, title = "To Adjust or Not to Adjust?: When a {"}Confounder{"} Is Only Measured After Exposure", abstract = "Advice regarding the analysis of observational studies of exposure effects usually is against adjustment for factors that occur after the exposure, as they may be caused by the exposure (or mediate the effect of exposure on outcome), so potentially leading to collider stratification bias. However, such factors could also be caused by unmeasured confounding factors, in which case adjusting for them will also remove some of the bias due to confounding. We derive expressions for collider stratification bias when conditioning and confounding bias when not conditioning on the mediator, in the presence of unmeasured confounding (assuming that all associations are linear and there are no interactions). Using simulations, we show that generally neither the conditioned nor the unconditioned estimate is unbiased, and the trade-off between them depends on the magnitude of the effect of the exposure that is mediated relative to the effect of the unmeasured confounders and their relations with the mediator. We illustrate the use of the bias expressions via three examples: neuroticism and mortality (adjusting for the mediator appears the least biased option), glycated hemoglobin levels and systolic blood pressure (adjusting gives smaller bias), and literacy in primary school pupils (not adjusting gives smaller bias). Our formulae and simulations can inform quantitative bias analysis as well as analysis strategies for observational studies in which there is a potential for unmeasured confounding. ", keywords = "Bias, Confounding, Mediation, Observational study", author = "R.H.H. Groenwold and T.M. Palmer and K. Tilling", year = "2021", month = mar, day = "31", doi = "10.1097/EDE.0000000000001312", language = "English", volume = "32", pages = "194--201", journal = "Epidemiology", issn = "1531-5487", publisher = "NLM (Medline)", number = "2", } . Epidemiology.

To Adjust or Not to Adjust? When a "Confounder" Is Only Measured After Exposure @article{071d43384dc149ccb92845245db765f7, title = "To Adjust or Not to Adjust? When a {"}Confounder{"} Is Only Measured After Exposure", abstract = "Advice regarding the analysis of observational studies of exposure effects usually is against adjustment for factors that occur after the exposure, as they may be caused by the exposure (or mediate the effect of exposure on outcome), so potentially leading to collider stratification bias. However, such factors could also be caused by unmeasured confounding factors, in which case adjusting for them will also remove some of the bias due to confounding. We derive expressions for collider stratification bias when conditioning and confounding bias when not conditioning on the mediator, in the presence of unmeasured confounding (assuming that all associations are linear and there are no interactions). Using simulations, we show that generally neither the conditioned nor the unconditioned estimate is unbiased, and the trade-off between them depends on the magnitude of the effect of the exposure that is mediated relative to the effect of the unmeasured confounders and their relations with the mediator. We illustrate the use of the bias expressions via three examples: neuroticism and mortality (adjusting for the mediator appears the least biased option), glycated hemoglobin levels and systolic blood pressure (adjusting gives smaller bias), and literacy in primary school pupils (not adjusting gives smaller bias). Our formulae and simulations can inform quantitative bias analysis as well as analysis strategies for observational studies in which there is a potential for unmeasured confounding.", author = "Groenwold, {Rolf H H} and Palmer, {Tom M} and Tilling, {Kate M}", note = "Publisher Copyright: {\textcopyright} 2021 Lippincott Williams and Wilkins. All rights reserved.", year = "2021", month = mar, day = "1", doi = "10.1097/EDE.0000000000001312", language = "English", volume = "32", pages = "194--201", journal = "Epidemiology", issn = "1044-3983", publisher = "Lippincott Williams and Wilkins", number = "2", } . Epidemiology.

Software Application Profile @article{1f5657ee0720440ea8a4f2eb48adf07b, title = "Software Application Profile: Bayesian estimation of inverse variance weighted and MR-Egger models for two-sample Mendelian randomization studies-mrbayes", abstract = "Motivation: We present our package, mrbayes, for the open source software environment R. The package implements Bayesian estimation for inverse variance weighted (IVW) and MR-Egger models, including the radial MR-Egger model, for summary-level data in Mendelian randomization (MR) analyses. Implementation: We have implemented a choice of prior distributions for the model parameters, namely; weakly informative, non-informative, a joint prior for the MR-Egger model slope and intercept, and an informative prior (pseudo-horseshoe prior), or the user can specify their own prior distribution. General features: Users have the option of fitting the models using either JAGS or Stan software packages with similar prior distributions; the option for the user-defined prior distribution is only in our JAGS functions. We show how to use the package through an applied example investigating the causal effect of body mass index (BMI) on acute ischaemic stroke. Availability: The package is freely available, under the GNU General Public License v3.0, on GitHub [https://github.com/okezie94/mrbayes] or CRAN [https://CRAN.R-project.org/package=mrbayes]. ", keywords = "Inverse variance weighted, JAGS, Mendelian randomization, MR-Egger model, R, Stan", author = "O. Uche-Ikonne and F. Dondelinger and T. Palmer", year = "2021", month = feb, day = "28", doi = "10.1093/ije/dyaa191", language = "English", volume = "50", pages = "43--49", journal = "International Journal of Epidemiology", issn = "0300-5771", publisher = "Oxford University Press", number = "1", } . International Journal of Epidemiology.

Software aplpication profile: Bayesian estimation of inverse variance weighted and MR-Egger models for two-sample Mendelian randomization studies - mrbayes @article{1e9b4f96611b4d9f98b898fac77a5d15, title = "Software aplpication profile: Bayesian estimation of inverse variance weighted and MR-Egger models for two-sample Mendelian randomization studies - mrbayes", author = "Okezie Uche-Ikonne and Frank Dondelinger and Tom Palmer", year = "2021", month = feb, day = "1", doi = "10.1101/19005868", language = "English", volume = "50", pages = "43--49", journal = "International Journal of Epidemiology", issn = "0300-5771", publisher = "Oxford University Press", number = "1", } . International Journal of Epidemiology.

Sex differences in the risk of coronary heart disease associated with type 2 diabetes @article{99503141d2b247409832fdca4112da7e, title = "Sex differences in the risk of coronary heart disease associated with type 2 diabetes: a Mendelian Randomization analysis", abstract = "OBJECTIVE Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding.RESEARCH DESIGN AND METHODS Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment.RESULTS MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08–1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17–1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs.CONCLUSIONS This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.", author = "Tricia Peters and Holmes, {Michael V} and Brent Richards and Palmer, {Tom M} and Vincenzo Forgetta and Lindgren, {Cecilia M} and Asselbergs, {Folkert W} and Nelson, {Christopher P.} and Samani, {Nilesh J.} and McCarthy, {Mark I} and Anubha Mahajan and {Davey Smith}, George and Mark Woodward and O'Keeffe, {Linda M} and Peters, {Sanne A}", note = "Funding Information: (University of Oxford), did not accept any personal payment. J.B.R. has served as an advisor to GlaxoSmithKline. M.I.M. has served on advisory panels for Pfizer, Novo Nordisk, and Zoe Global; has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly; and has received research funding from AbbVie, AstraZeneca, Boehringer Ingelheim,EliLilly,Janssen,Merck,NovoNordisk, Pfizer, Roche, Sanofi Aventis, SERVIER, and Takeda. As of June 2019, M.I.M. is an employee of Genentech and a holder of Roche stock. As of January 2020, A.M. is an employee of Genentech and a holder of Roche stock. No other potential conflicts of interest relevant to this article were reported. Author Contributions. T.M.P. analyzed the data, wrote the manuscript, and contributed to the study design and conception. M.V.H., J.B.R., M.W.,andL.M.O.contributedtothestudydesign and reviewed/edited the manuscript. T.P. con-tributedtothestudydesignanddataanalysisand reviewed the manuscript. V.F. contributed to the data analysis and reviewed the manuscript. C.M.L., F.W.A., C.P.N., N.J.S., and G.D.S reviewed/edited the manuscript. M.I.M. and A.M. contributed data and reviewed/edited the manuscript. S.A.E.P. contributed to the study design and data analysis and wrote the manuscript. T.M.P. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Funding Information: This research is supported by the Lady Davis Institute for Medical Research and the Department of Medicine, Jewish General Hospital (T.M.P.); the UK Medical Research Council; British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512); and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (M.V.H.). J.B.R. is supported by the Canadian Institutes of Health Research (CIHR), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK, the Fonds de Recherche Qu?ebec Sant?e (FRQS), and an FRQS Clinical Research Scholarship. C.M.L. is supported by the Li Ka Shing Foundation, the NIHR Oxford Biomedical Research Centre, National Institutes of Health grants CRR00070 CR00.01 and 5P50-HD-028138-27, WT-SSI/John Fell funds, and Widenlife. F.W.A. is supported by University College London Hospitals NIHR Biomedical Research Centre. C.P.N. and N.J.S. are supported by the British Heart Foundation. M.I.M. is supported by Wellcome Trust grants 090532, 098381, 203141, and 212259 and National Institute of Diabetes and Digestive and Kidney Diseases grant U01-DK-105535 and was a Wellcome investigator and an NIHR senior investigator. L.M.O. is supported by a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1). S.A.E.P. is supported by a UK Medical Research Council Skills Development Fellowship (MR/P014550/1). Funding Information: European DIAMANTE investigators for making data available. This research has been conducted using the UK Biobank resource under application number 24281. Funding. This research is supported by the Lady Davis Institute for Medical Research and the Department of Medicine, Jewish General Hospital (T.M.P.); the UK Medical Research Council; British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512); and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (M.V.H.). J.B.R. is supported by the Canadian Institutes of Health Research (CIHR), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK, the Fonds de Recherche Qu{\'e}bec Sant{\'e} (FRQS), and an FRQS Clinical Research Scholarship. C.M.L. is supported by the Li Ka Shing Foundation, the NIHR Oxford Biomedical Research Centre, National Institutes of Health grants CRR00070 CR00.01 and 5P50-HD-028138-27,WT-SSI/JohnFellfunds,andWidenlife.F.W.A. is supported by University College London Hospitals NIHR Biomedical Research Centre. C.P.N. and N.J.S. are supported by the British Heart Foundation. M.I.M. is supported by Wellcome Trust grants 090532, 098381, 203141, and 212259 and National Institute of Diabetes and Digestive and Kidney Diseases grant U01-DK-105535 and was a Wellcome investigator and an NIHR senior investigator. L.M.O. is supported by a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1). S.A.E.P. is supported by a UK Medical Research Council Skills Development Fellowship (MR/P014550/1). Publisher Copyright: {\textcopyright} 2020 by the American Diabetes Association.", year = "2021", month = feb, doi = "10.2337/dc20-1137", language = "English", volume = "44", pages = "556--562", journal = "Diabetes Care", issn = "0149-5992", publisher = "American Diabetes Association Inc.", number = "2", } . Diabetes Care.

The role of combinatorial health technologies in supporting older people with long-term conditions: Responsibilisation or co-management of healthcare? @article{9d2e3f6f22cf4dff9d748e968a4484b4, title = "The role of combinatorial health technologies in supporting older people with long-term conditions: Responsibilisation or co-management of healthcare?", abstract = "Neoliberalism, austerity and health responsibilisation are increasingly informing policies and practices designed to encourage older patients to take responsibility for the management of their own healthcare. Combined with an ageing population, novel ways to address the increasing healthcare needs of older people have become a priority, with the emergence in recent years of new models of integrated care enhanced by combinatorial health technologies (CHTs). This paper presents qualitative findings from the evaluation of one programme, the Lancashire and Cumbria Innovation Alliance (LCIA) Test Bed, a programme funded by NHS England and conducted in England between 2016 and 2018.Drawing on data from patients, family carers, and staff members involved in the programme, this paper explores the extent to which CHTs, as part of the LCIA Test Bed programme, contributed to health responsibilisation amongst older people with complex health conditions. Through this programme, we find that relationships between patients, family carers and healthcare professionals combined to create a sense of reassurance and shared responsibility for all parties. Our findings suggest the need for a more nuanced approach to responsibilisation and self-management for older people living with complex health conditions. By focusing on co-management – and recognising the potential of CHTs to facilitate this approach – there is potential to increase patient confidence in managing their health condition, reduce carer burden, and enhance clinician satisfaction in their work roles. While neoliberal agendas are focused on self-management and self-responsibility of one's own health care, with technology as a facilitator of this, our findings suggest that the successful use of CHTs for older people with complex health conditions may instead be rooted in co-management. This paper argues that co-management may be a more successful model of care for patients, carers and clinicians.", keywords = "Ageing, Co-management, Healthcare, Health technologies, Neoliberalism, Responsibilisation, Self-management", author = "Varey, {Sandra Elaine} and Mandy Dixon and Alejandra Hernandez and Ceu Mateus and Palmer, {Tom M} and Christine Milligan", note = "Funding Information: Within a landscape of neoliberalism, austerity and an ageing population, the responsibilisation agenda is continuing to strengthen, with ?the responsibility for the prevention and management of health shift[ing] increasingly onto patients (as consumers) and to technological systems? (Rich et al., 2019, p.34). In the UK, for example, one of the aims of the ?Personalised Health and Care 2020? strategy (NHS Digital, 2020a) is to ?to help people better manage their health and care? and ?take greater control of their health? (NHS Digital, 2020b). Ways to address the increasing healthcare needs of older people have also become a priority, with a focus on facilitating older people's ability to better self-manage their health care needs at home. One strategy developed by NHS England has been a focus on the potential of health technologies to support the provision of new models of care (NHS England, 2020). The NHS England Test Bed programme has been designed to encourage the trialling of combinatorial health technologies (CHTs), in which new models of care are supported by digital health technologies across a number of areas in the UK. This paper presents findings from the qualitative evaluation of one such programme, the Lancashire and Cumbria Innovation Alliance (LCIA) Test Bed (hereafter referred to as ?the programme?). Drawing on data from patients, family carers, and staff members, this paper explores the extent to which CHTs, as part of the programme, contributed to health responsibilisation amongst older people with complex health conditions. In doing so, this work contributes to the conversation regarding the responsibilisation agenda within healthcare and suggests the need for a more nuanced approach to responsibilisation and self-management for older people living with complex health conditions.This evaluation was funded by NHS England. The authors wish to thank all patients, family carers and staff members who took part in and supported the study. Thank you to members of the Evaluation Advisory Group who provided invaluable advice and guidance throughout the LCIA Test Bed programme. Special thanks are due to Professor Maggie Mort, with whom a conversation about co-monitoring marked the beginnings of this paper. Funding Information: This evaluation was funded by NHS England. The authors wish to thank all patients, family carers and staff members who took part in and supported the study. Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd", year = "2021", month = jan, day = "1", doi = "10.1016/j.socscimed.2020.113545", language = "English", volume = "269", journal = "Social Science and Medicine", issn = "0277-9536", publisher = "Elsevier", } . Social Science and Medicine.

Collider bias undermines our understanding of COVID-19 disease risk and severity @article{ccd6500fedf04cb9809d4bc05d63975a, title = "Collider bias undermines our understanding of COVID-19 disease risk and severity", abstract = "Numerous observational studies have attempted to identify risk factors for infection with SARS-CoV-2 and COVID-19 disease outcomes. Studies have used datasets sampled from patients admitted to hospital, people tested for active infection, or people who volunteered to participate. Here, we highlight the challenge of interpreting observational evidence from such non-representative samples. Collider bias can induce associations between two or more variables which affect the likelihood of an individual being sampled, distorting associations between these variables in the sample. Analysing UK Biobank data, compared to the wider cohort the participants tested for COVID-19 were highly selected for a range of genetic, behavioural, cardiovascular, demographic, and anthropometric traits. We discuss the mechanisms inducing these problems, and approaches that could help mitigate them. While collider bias should be explored in existing studies, the optimal way to mitigate the problem is to use appropriate sampling strategies at the study design stage.", keywords = "selection, sample, coronavirus, epidemiology", author = "Griffith, {Gareth J} and Morris, {Tim T} and Tudball, {Matthew J} and Annie Herbert and Giulia Mancano and Lindsey Pike and Sharp, {Gemma C} and Jonathan Sterne and Palmer, {Tom M} and {Davey Smith}, George and Kate Tilling and Luisa Zuccolo and Davies, {Neil M} and Gibran Hemani", year = "2020", month = nov, day = "12", doi = "10.1038/s41467-020-19478-2", language = "English", volume = "11", journal = "Nature Communications", issn = "2041-1723", publisher = "Springer Nature", } . Nature Communications.

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals @article{35abdb95069140ba82676d67313ec17d, title = "Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals", abstract = "Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health. ", keywords = "ABC transporter A1, ADAM protein, biological marker, caspase 8, chemokine receptor CCR2, chemokine receptor CCR5, chitinase 3 like protein 1, creatinine, CXCL16 chemokine, epidermal growth factor, galanin, growth differentiation factor 15, high density lipoprotein cholesterol, interleukin 16, macrophage elastase, macrophage inflammatory protein 1alpha, myoglobin, pregnancy associated plasma protein A, programmed death 1 ligand 1, protein kinase, RANTES, somatomedin binding protein, spondin 1, triacylglycerol, tribbles homolog 1, tumor necrosis factor, unclassified drug, Article, atherosclerosis, atopy, bioinformatics, body mass, bone density, cardiovascular disease, cardiovascular risk, clinical article, clinical outcome, cohort analysis, enzyme linked immunosorbent assay, estimated glomerular filtration rate, gene expression, genetic analysis, genetic regulation, genetic susceptibility, genome-wide association study, genotype, haplotype, human, human tissue, IC50, lipid metabolism, machine learning, Mendelian randomization analysis, meta analysis, metabolite, observational study, personalized medicine, phenotype, pleiotropy, priority journal, quantitative trait locus, risk factor, single nucleotide polymorphism", author = "L. Folkersen and S. Gustafsson and Q. Wang and D.H. Hansen and {\AA}.K. Hedman and A. Schork and K. Page and D.V. Zhernakova and Y. Wu and J. Peters and N. Eriksson and S.E. Bergen and T.S. Boutin and A.D. Bretherick and S. Enroth and A. Kalnapenkis and J.R. G{\aa}din and B.E. Suur and Y. Chen and L. Matic and J.D. Gale and J. Lee and W. Zhang and A. Quazi and M. Ala-Korpela and S.H. Choi and A. Claringbould and J. Danesh and {Davey Smith}, G. and {de Masi}, F. and S. Elmst{\aa}hl and G. Engstr{\"o}m and E. Fauman and C. Fernandez and L. Franke and P.W. Franks and V. Giedraitis and C. Haley and A. Hamsten and A. Ingason and {\AA}. Johansson and P.K. Joshi and L. Lind and C.M. Lindgren and S. Lubitz and T. Palmer and E. Macdonald-Dunlop and M. Magnusson and O. Melander and K. Michaelsson and A.P. Morris and R. M{\"a}gi and M.W. Nagle and P.M. Nilsson and J. Nilsson and M. Orho-Melander and O. Polasek and B. Prins and E. P{\aa}lsson and T. Qi and M. Sj{\"o}gren and J. Sundstr{\"o}m and P. Surendran and U. V{\~o}sa and T. Werge and R. Wernersson and H.-J. Westra and J. Yang and A. Zhernakova and J. {\"A}rnl{\"o}v and J. Fu and J.G. Smith and T. Esko and C. Hayward and U. Gyllensten and M. Landen and A. Siegbahn and J.F. Wilson and L. Wallentin and A.S. Butterworth and M.V. Holmes and E. Ingelsson and A. M{\"a}larstig", year = "2020", month = oct, day = "16", doi = "10.1038/s42255-020-00287-2", language = "English", volume = "2", pages = "1135--1148", journal = "Nature Metabolism", number = "10", } . Nature Metabolism.

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals @article{606bf60f93384b5bb48b584b5bfbef3b, title = "Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals", abstract = "Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.", author = "Lasse Folkersen and Stefan Gustafsson and Qin Wang and Hansen, {Daniel Hvidberg} and Hedman, {{\AA}sa K.} and Andrew Schork and Karen Page and Zhernakova, {Daria V.} and Yang Wu and James Peters and Niclas Eriksson and Bergen, {Sarah E.} and Boutin, {Thibaud S.} and Bretherick, {Andrew D.} and Stefan Enroth and Anette Kalnapenkis and G{\aa}din, {Jesper R.} and Suur, {Bianca E.} and Yan Chen and Ljubica Matic and Gale, {Jeremy D.} and Julie Lee and Weidong Zhang and Amira Quazi and Mika Ala-Korpela and Choi, {Seung Hoan} and Annique Claringbould and John Danesh and {Davey Smith}, George and {de Masi}, Federico and S{\"o}lve Elmst{\aa}hl and Gunnar Engstr{\"o}m and Eric Fauman and Celine Fernandez and Lude Franke and Franks, {Paul W.} and Vilmantas Giedraitis and Chris Haley and Anders Hamsten and Andres Ingason and {\AA}sa Johansson and Joshi, {Peter K.} and Lars Lind and Lindgren, {Cecilia M.} and Steven Lubitz and Tom Palmer and Erin Macdonald-Dunlop and Martin Magnusson and Olle Melander and Karl Michaelsson and Morris, {Andrew P.} and Reedik M{\"a}gi and Nagle, {Michael W.} and Nilsson, {Peter M.} and Jan Nilsson and Marju Orho-Melander and Ozren Polasek and Bram Prins and Erik P{\aa}lsson and Ting Qi and Marketa Sj{\"o}gren and Johan Sundstr{\"o}m and Praveen Surendran and Urmo V{\~o}sa and Thomas Werge and Rasmus Wernersson and Harm-Jan Westra and Jian Yang and Alexandra Zhernakova and Johan {\"A}rnl{\"o}v and Jingyuan Fu and Smith, {J. Gustav} and T{\~o}nu Esko and Caroline Hayward and Ulf Gyllensten and Mikael Landen and Agneta Siegbahn and Wilson, {James F.} and Lars Wallentin and Butterworth, {Adam S.} and Holmes, {Michael V.} and Erik Ingelsson and Anders M{\"a}larstig", year = "2020", month = oct, day = "16", doi = "10.1038/s42255-020-00287-2", language = "English", volume = "2", pages = "1135–1148 (2020)", journal = "Nature Metabolism", issn = "2522-5812", publisher = "Nature Research", } . Nature Metabolism.

The MRC IEU OpenGWAS data infrastructure @article{0c8ddf0084d84505b226f9cf75c87772, title = "The MRC IEU OpenGWAS data infrastructure", abstract = "Data generated by genome-wide association studies (GWAS) are growing fast with the linkage of biobank samples to health records, and expanding capture of high-dimensional molecular phenotypes. However the utility of these efforts can only be fully realised if their complete results are collected from their heterogeneous sources and formats, harmonised and made programmatically accessible.Here we present the OpenGWAS database, an open source, open access, scalable and high-performance cloud-based data infrastructure that imports and publishes complete GWAS summary datasets and metadata for the scientific community. Our import pipeline harmonises these datasets against dbSNP and the human genome reference sequence, generates summary reports and standardises the format of results and metadata. Users can access the data via a website, an application programming interface, R and Python packages, and also as downloadable files that can be rapidly queried in high performance computing environments.OpenGWAS currently contains 126 billion genetic associations from 14,582 complete GWAS datasets representing a range of different human phenotypes and disease outcomes across different populations. We developed R and Python packages to serve as conduits between these GWAS data sources and a range of available analytical tools, enabling Mendelian randomization, genetic colocalisation analysis, fine mapping, genetic correlation and locus visualisation.OpenGWAS is freely accessible at https://gwas.mrcieu.ac.uk, and has been designed to facilitate integration with third party analytical tools.Competing Interest StatementTRG, GH and GDS have received research funding from GlaxoSmithKline and Biogen for projects that use the MRC IEU OpenGWAS database. VH has previously been supported by funding from GlaxoSmithKline. Neither company had any input into or control over the contents of this manuscript. Oracle have provided cloud resources to host the OpenGWAS database.", author = "Ben Elsworth and Matthew Lyon and Tessa Alexander and Yi Liu and Peter Matthews and Jon Hallett and Phil Bates and Tom Palmer and Valeriia Haberland and Smith, {George Davey} and Jie Zheng and Philip Haycock and Gaunt, {Tom R} and Gibran Hemani", year = "2020", month = aug, day = "10", doi = "10.1101/2020.08.10.244293", language = "English", journal = "bioRxiv", publisher = "Cold Spring Harbor Laboratory", } . bioRxiv.

Assessment of a causal relationship between body mass index and atopic dermatitis @article{4827a373016743f18b831d914e00a290, title = "Assessment of a causal relationship between body mass index and atopic dermatitis", abstract = "[No abstract]", keywords = "atopic dermatitis, body mass index, eczema, causality, genetic risk score, obesity, Mendelian randomization", author = "Ashley Budu-Aggrey and Watkins, {Sarah H} and Brumpton, {Ben M} and Mari L{\o}set and Jess Tyrrell and Modalsli, {Ellen H.} and Vie, {Gunnhild {\AA}berge} and Tom Palmer and Fritsche, {Lars G} and Nielsen, {Jonas Bille} and Romundstad, {P{\aa}l Richard} and {Davey Smith}, George and {\AA}svold, {Bj{\o}rn Olav} and Lavinia Paternoster and Brown, {Sara J}", year = "2020", month = apr, day = "17", doi = "10.1016/j.jaci.2020.04.050", language = "English", volume = "147", pages = "400--403", journal = "Journal of Allergy and Clinical Immunology", issn = "0091-6749", publisher = "Elsevier Inc.", number = "1", } . Journal of Allergy and Clinical Immunology.

Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: @article{a4757afed71c4533b00a9a7ffe856aac, title = "Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease:: A multivariable Mendelian randomisation analysis", abstract = "BACKGROUND: Circulating lipoprotein lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. Using genetic instruments for lipoprotein lipid traits implemented through multivariable Mendelian randomisation (MR), we sought to compare their causal roles in the aetiology of CHD.METHODS AND FINDINGS: We conducted a genome-wide association study (GWAS) of circulating non-fasted lipoprotein lipid traits in the UK Biobank (UKBB) for low-density lipoprotein (LDL) cholesterol, triglycerides, and apolipoprotein B to identify lipid-associated single nucleotide polymorphisms (SNPs). Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable MR analyses. Similar GWAS and MR analyses were conducted for high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I. The GWAS of lipids and apolipoproteins in the UKBB included between 393,193 and 441,016 individuals in whom the mean age was 56.9 y (range 39-73 y) and of whom 54.2% were women. The mean (standard deviation) lipid concentrations were LDL cholesterol 3.57 (0.87) mmol/L and HDL cholesterol 1.45 (0.38) mmol/L, and the median triglycerides was 1.50 (IQR = 1.11) mmol/L. The mean (standard deviation) values for apolipoproteins B and A-I were 1.03 (0.24) g/L and 1.54 (0.27) g/L, respectively. The GWAS identified multiple independent SNPs associated at P < 5 × 10-8 for LDL cholesterol (220), apolipoprotein B (n = 255), triglycerides (440), HDL cholesterol (534), and apolipoprotein A-I (440). Between 56%-93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWASs. Almost half (46%) of these SNPs were associated at P < 5 × 10-8 with more than one lipid-related trait. Assessed individually using MR, LDL cholesterol (odds ratio [OR] 1.66 per 1-standard-deviation-higher trait; 95% CI: 1.49-1.86; P < 0.001), triglycerides (OR 1.34; 95% CI: 1.25-1.44; P < 0.001) and apolipoprotein B (OR 1.73; 95% CI: 1.56-1.91; P < 0.001) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95% CI: 1.31-2.81; P < 0.001) retained a robust effect, with the estimate for LDL cholesterol (OR 0.85; 95% CI: 0.57-1.27; P = 0.44) reversing and that of triglycerides (OR 1.12; 95% CI: 1.02-1.23; P = 0.01) becoming weaker. Individual MR analyses showed a 1-standard-deviation-higher HDL cholesterol (OR 0.80; 95% CI: 0.75-0.86; P < 0.001) and apolipoprotein A-I (OR 0.83; 95% CI: 0.77-0.89; P < 0.001) to lower the risk of CHD, but these effect estimates attenuated substantially to the null on accounting for apolipoprotein B. A limitation is that, owing to the nature of lipoprotein metabolism, measures related to the composition of lipoprotein particles are highly correlated, creating a challenge in making exclusive interpretations on causation of individual components.CONCLUSIONS: These findings suggest that apolipoprotein B is the predominant trait that accounts for the aetiological relationship of lipoprotein lipids with risk of CHD.", author = "Richardson, {Tom G} and Eleanor Sanderson and Palmer, {Tom M} and Mika Ala-Korpela and Ference, {Brian A} and {Davey Smith}, George and Holmes, {Michael V}", year = "2020", month = mar, day = "23", doi = "10.1371/journal.pmed.1003062", language = "English", volume = "17", pages = "e1003062", journal = "PLoS Medicine", issn = "1549-1277", publisher = "Public Library of Science", number = "3", } . PLoS Medicine.

A review of group-based methods for teaching statistics in Higher Education @article{06333e68b854484a9a77d0b70889087f, title = "A review of group-based methods for teaching statistics in Higher Education", author = "Elinor Jones and Tom Palmer", year = "2019", month = oct, day = "1", language = "English", journal = "arXiv", } . arXiv.

Apolipoprotein B underlies the causal relationship of circulating blood lipids with coronary heart disease @article{ee89c7926a4844018ef29cffe254b178, title = "Apolipoprotein B underlies the causal relationship of circulating blood lipids with coronary heart disease", abstract = "Background: Circulating blood lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. We sought to explore the causal relationships of blood lipid traits with risk of CHD using multivariable Mendelian randomization. Methods: We conducted GWAS of circulating blood lipid traits in UK Biobank (up to n=440,546) for LDL cholesterol, triglycerides and apolipoprotein B to identify lipid57 associated SNPs. Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable Mendelian randomization (MR) analyses. Similar analyses were conducted for HDL cholesterol and apolipoprotein A-I. Findings: GWAS identified multiple independent SNPs associated at P<5x10-8 62 for LDL cholesterol (220), apolipoprotein B (n=255), triglycerides (440), HDL cholesterol (534) and apolipoprotein AI (440). Between 56-93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWAS. Almost half (46%) of these SNPs were associated at P<5x10-8 with more than one lipid related trait. Assessed individually using MR, each of LDL cholesterol (OR 1.66 per 1 standard deviation higher trait; 95%CI: 1.49; 1.86; P=2.4x10-19), triglycerides (OR 1.34; 95%CI: 1.25, 1.44; P=9.1x10-16 68 ) and apolipoprotein B (OR 1.73; 95%CI: 1.56, 1.91; P=1.5x10-25 69 ) had effect estimates (which was consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95%CI: 1.31, 2.81; P=7.5x10-4 71 ) retained a robust effect with the estimate for LDL cholesterol (OR 0.85; 95%CI: 0.57; 1.27; P=0.44) reversing and that of triglycerides (OR 1.12; 95%CI: 1.02, 1.23; P=0.01) becoming markedly weaker. Individual MR analyses showed a 1-SD higher HDL-C (OR 0.80; 95%CI: 0.75, 0.86; P=1.7x10-10) and apolipoprotein A-I (OR 0.83; 95%CI: 0.77, 0.89; P=1.0x10-6) to lower the risk of CHD but these effect estimates weakened to include the null on accounting for apolipoprotein B. Conclusions: Apolipoprotein B is of fundamental causal relevance in the aetiology of CHD, and underlies the relationship of LDL cholesterol and triglycerides with CHD.", author = "Richardson, {Tom G} and Eleanor Sanderson and Palmer, {Tom M} and Mika Ala-Korpela and Ference, {Brian A} and {Davey Smith}, George and Holmes, {Michael V}", year = "2019", month = aug, day = "29", doi = "10.1101/19004895", language = "English", journal = "medRxiv", publisher = "Cold Spring Harbor Laboratory Press", } . medRxiv.

Apolipoprotein B underlies the causal relationship of circulating blood lipids with coronary heart disease @article{382e607ab26144a1b10cfcea77121923, title = "Apolipoprotein B underlies the causal relationship of circulating blood lipids with coronary heart disease", abstract = "Background: Circulating blood lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. We sought to explore the causal relationships of blood lipid traits with risk of CHD using multivariable Mendelian randomization. Methods: We conducted GWAS of circulating blood lipid traits in UK Biobank (up to n=440,546) for LDL cholesterol, triglycerides and apolipoprotein B to identify lipid-associated SNPs. Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable Mendelian randomization (MR) analyses. Similar analyses were conducted for HDL cholesterol and apolipoprotein A-I. Findings: GWAS identified multiple independent SNPs associated at P<5x10-8 for LDL cholesterol (220), apolipoprotein B (n=255), triglycerides (440), HDL cholesterol (534) and apolipoprotein AI (440). Between 56-93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWAS. Almost half (46%) of these SNPs were associated at P<5x10-8 with more than one lipid related trait. Assessed individually using MR, each of LDL cholesterol (OR 1.66 per 1 standard deviation higher trait; 95%CI: 1.49; 1.86; P=2.4x10-19), triglycerides (OR 1.34; 95%CI: 1.25, 1.44; P=9.1x10-16) and apolipoprotein B (OR 1.73; 95%CI: 1.56, 1.91; P=1.5x10-25) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95%CI: 1.31, 2.81; P=7.5x10-4) retained a robust effect with the estimate for LDL cholesterol (OR 0.85; 95%CI: 0.57; 1.27; P=0.44) reversing and that of triglycerides (OR 1.12; 95%CI: 1.02, 1.23; P=0.01) becoming markedly weaker. Individual MR analyses showed a 1-SD higher HDL-C (OR 0.80; 95%CI: 0.75, 0.86; P=1.7x10-10) and apolipoprotein A-I (OR 0.83; 95%CI: 0.77, 0.89; P=1.0x10-6) to lower the risk of CHD but these effect estimates weakened to include the null on accounting for apolipoprotein B. Conclusions: Apolipoprotein B is of fundamental causal relevance in the aetiology of CHD, and underlies the relationship of LDL cholesterol and triglycerides with CHD.Competing Interest StatementBAF reported receiving personal fees from Merck & Co., Amgen, Regeneron, Sanofi, Pfizer, CiVi BioPhama, and KrKA Phamaceuticals, and grants from Merck & Co., Amgen, Novartis and Esperion Therapeutics. All other authors report no potential conflicts of interest. Funding StatementTGR, ES and GDS work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1 and MC_UU-00011/2). TGR is a UKRI Innovation Research Fellow (MR/S003886/1). MAK is supported by a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia (APP1158958) and a research grant from the Sigrid Juselius Foundation, Finland. The Baker Institute is supported in part by the Victorian Government{\textquoteright}s Operational Infrastructure Support Program. BAF is supported by the National Institute for Health Research Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust. MVH works in a unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author DeclarationsAll relevant ethical guidelines have been followed and any necessary IRB and/or ethics committee approvals have been obtained.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesAny clinical trials involved have been registered with an ICMJE-approved registry such as ClinicalTrials.gov and the trial ID is included in the manuscript.Not ApplicableI have followed all appropriate research reporting guidelines and uploaded the relevant Equator, ICMJE or other checklist(s) as supplementary files, if applicable.Not ApplicableGWAS data will become available once the manuscript is In Press", author = "Richardson, {Tom G} and Eleanor Sanderson and Palmer, {Tom M} and Mika Ala-Korpela and Ference, {Brian A} and {Davey Smith}, George and Holmes, {Michael V}", year = "2019", month = aug, day = "29", doi = "10.1101/19004895", language = "English", journal = "medRxiv", publisher = "Cold Spring Harbor Laboratory Press", } . medRxiv.

Associations of mortality with own blood pressure using son's blood pressure as an instrumental variable @article{73a17c5ccc1a4c5d8ba94432f27c7730, title = "Associations of mortality with own blood pressure using son's blood pressure as an instrumental variable", abstract = "High systolic blood pressure (SBP) causes cardiovascular disease (CVD) and is associated with mortality from other causes, but conventional multivariably-adjusted results may be confounded. Here we used a son{\textquoteright}s SBP (>1 million Swedish men) as an instrumental variable for parental SBP and examined associations with parents{\textquoteright} cause-specific mortality, avoiding reverse causation. The hazard ratio for CVD mortality per SD (10.80 mmHg) of SBP was 1.49 (95% CI: 1.43, 1.56); SBP was positively associated with coronary heart disease and stroke. SBP was also associated positively with all-cause, diabetes and kidney cancer mortality, and negatively with external causes. Negative associations with respiratory-related mortality were probably confounded by smoking. Hazard ratios for other causes were imprecise or null. Diastolic blood pressure gave similar results to SBP. CVD hazard ratios were intermediate between those from conventional multivariable studies and Mendelian randomization and stronger than those from clinical trials, approximately consistent with an effect of exposure duration on effect sizes. Plots of parental mortality against offspring SBP were approximately linear, supporting calls for lower SBP targets. Results suggest that conventional multivariable analyses of mortality and SBP are not substantially confounded by reverse causation and confirm positive effects of SBP on all-cause, CVD and diabetes mortality.", author = "David Carslake and Abigail Fraser and Margaret May and Tom Palmer and Karri Silventoinen and Per Tynelius and Debbie Lawlor and Smith, {George Davey}", year = "2019", month = jun, day = "20", doi = "10.1038/s41598-019-45391-w", language = "English", volume = "9", journal = "Scientific Reports", issn = "2045-2322", publisher = "Nature Publishing Group", } . Scientific Reports.

Associations of mortality with own blood pressure using son's blood pressure as an instrumental variable @article{8b0f3e4e5f8645c38bd6e28530813eb5, title = "Associations of mortality with own blood pressure using son's blood pressure as an instrumental variable", abstract = "High systolic blood pressure (SBP) causes cardiovascular disease (CVD) and is associated with mortality from other causes, but conventional multivariably-adjusted results may be confounded. Here we used a son{\textquoteright}s SBP (>1 million Swedish men) as an instrumental variable for parental SBP and examined associations with parents{\textquoteright} cause-specific mortality, avoiding reverse causation. The hazard ratio for CVD mortality per SD (10.80 mmHg) of SBP was 1.49 (95% CI: 1.43, 1.56); SBP was positively associated with coronary heart disease and stroke. SBP was also associated positively with all-cause, diabetes and kidney cancer mortality, and negatively with external causes. Negative associations with respiratory-related mortality were probably confounded by smoking. Hazard ratios for other causes were imprecise or null. Diastolic blood pressure gave similar results to SBP. CVD hazard ratios were intermediate between those from conventional multivariable studies and Mendelian randomization and stronger than those from clinical trials, approximately consistent with an effect of exposure duration on effect sizes. Plots of parental mortality against offspring SBP were approximately linear, supporting calls for lower SBP targets. Results suggest that conventional multivariable analyses of mortality and SBP are not substantially confounded by reverse causation and confirm positive effects of SBP on all-cause, CVD and diabetes mortality.", author = "David Carslake and Abigail Fraser and Margaret May and Tom Palmer and Karri Silventoinen and Per Tynelius and Debbie Lawlor and Smith, {George Davey}", year = "2019", month = jun, day = "20", doi = "10.1038/s41598-019-45391-w", language = "English", volume = "9", journal = "Scientific Reports", issn = "2045-2322", publisher = "Springer Nature", number = "1", } . Scientific Reports.

Evidence of a causal relationship between body mass index and psoriasis: A mendelian randomization study @article{24eab52e2f9a4e4e83302546b2c39679, title = "Evidence of a causal relationship between body mass index and psoriasis: A mendelian randomization study", abstract = "In a mendelian randomization study, Ashley Budu-Aggrey and co-workers study the influence of body mass index on psoriasis.", author = "Ashley Budu-Aggrey and Ben Brumpton and Jess Tyrrell and Sarah Watkins and Modalsli, {Ellen H.} and Carlos Celis-Morales and Ferguson, {Lyn D.} and Vie, {Gunnhild {\AA}berge} and Tom Palmer and Fritsche, {Lars G.} and Mari L{\o}set and Nielsen, {Jonas Bille} and Wei Zhou and Tsoi, {Lam C.} and Wood, {Andrew R.} and Jones, {Samuel E.} and Robin Beaumont and Marit Saunes and Romundstad, {P{\aa}l Richard} and Stefan Siebert and McInnes, {Iain B.} and Elder, {James T.} and {Davey Smith}, George and Frayling, {Timothy M.} and {\AA}svold, {Bj{\o}rn Olav} and Brown, {Sara J.} and Naveed Sattar and Lavinia Paternoster", year = "2019", month = jan, day = "31", doi = "10.1371/journal.pmed.1002739", language = "English", volume = "16", journal = "PLoS Medicine", issn = "1549-1277", publisher = "Public Library of Science", number = "1", } . PLoS Medicine.

Evidence of a causal relationship between body mass index and psoriasis @article{315eb315e48047a08184083ed426a1aa, title = "Evidence of a causal relationship between body mass index and psoriasis: A mendelian randomization study", abstract = " Background: Psoriasis is a common inflammatory skin disease that has been reported to be associated with obesity. We aimed to investigate a possible causal relationship between body mass index (BMI) and psoriasis. Methods and findings: Following a review of published epidemiological evidence of the association between obesity and psoriasis, mendelian randomization (MR) was used to test for a causal relationship with BMI. We used a genetic instrument comprising 97 single-nucleotide polymorphisms (SNPs) associated with BMI as a proxy for BMI (expected to be much less confounded than measured BMI). One-sample MR was conducted using individual-level data (396,495 individuals) from the UK Biobank and the Nord-Tr{\o}ndelag Health Study (HUNT), Norway. Two-sample MR was performed with summary-level data (356,926 individuals) from published BMI and psoriasis genome-wide association studies (GWASs). The one-sample and two-sample MR estimates were meta-analysed using a fixed-effect model. To test for a potential reverse causal effect, MR analysis with genetic instruments comprising variants from recent genome-wide analyses for psoriasis were used to test whether genetic risk for this skin disease has a causal effect on BMI. Published observational data showed an association of higher BMI with psoriasis. A mean difference in BMI of 1.26 kg/m 2 (95% CI 1.02-1.51) between psoriasis cases and controls was observed in adults, while a 1.55 kg/m 2 mean difference (95% CI 1.13-1.98) was observed in children. The observational association was confirmed in UK Biobank and HUNT data sets. Overall, a 1 kg/m 2 increase in BMI was associated with 4% higher odds of psoriasis (meta-analysis odds ratio [OR] = 1.04; 95% CI 1.03-1.04; P = 1.73 × 10 −60 ). MR analyses provided evidence that higher BMI causally increases the odds of psoriasis (by 9% per 1 unit increase in BMI; OR = 1.09 (1.06-1.12) per 1 kg/m 2 ; P = 4.67 × 10 −9 ). In contrast, MR estimates gave little support to a possible causal effect of psoriasis genetic risk on BMI (0.004 kg/m 2 change in BMI per doubling odds of psoriasis (−0.003 to 0.011). Limitations of our study include possible misreporting of psoriasis by patients, as well as potential misdiagnosis by clinicians. In addition, there is also limited ethnic variation in the cohorts studied. Conclusions: Our study, using genetic variants as instrumental variables for BMI, provides evidence that higher BMI leads to a higher risk of psoriasis. This supports the prioritization of therapies and lifestyle interventions aimed at controlling weight for the prevention or treatment of this common skin disease. Mechanistic studies are required to improve understanding of this relationship.", keywords = "Scorpions, Palaeobiology, Phylogenetics, Terrestrialization, Molecular clocks, Arachnids", author = "Ashley Budu-Aggrey and Ben Brumpton and Jess Tyrrell and Sarah Watkins and Modalsli, {Ellen H.} and Carlos Celis-Morales and Ferguson, {Lyn D.} and Vie, {Gunnhild {\AA}berge} and Tom Palmer and Fritsche, {Lars G.} and Mari L{\o}set and Nielsen, {Jonas Bille} and Wei Zhou and Tsoi, {Lam C.} and Wood, {Andrew R.} and Jones, {Samuel E.} and Robin Beaumont and Marit Saunes and Romundstad, {P{\aa}l Richard} and Stefan Siebert and McInnes, {Iain B.} and Elder, {James T.} and {Davey Smith}, George and Frayling, {Timothy M.} and {\AA}svold, {Bj{\o}rn Olav} and Brown, {Sara J.} and Naveed Sattar and Lavinia Paternoster", year = "2019", month = jan, doi = "10.1371/journal.pmed.1002739", language = "English", volume = "19", pages = "71--86", journal = "PLoS Medicine", issn = "1549-1277", publisher = "Public Library of Science", number = "1", } . PLoS Medicine.

Budu-Aggrey, A., Brumpton, B., Tyrrell, J., Watkins, S., Modalsli, E.H., Celis-Morales, C., Ferguson, L.D., Vie, G.&#197;., Palmer, T., Fritsche, L.G., et al.(2019). Evidence of a causal relationship between body mass index and psoriasis: A mendelian randomization study . PLoS Medicine. 16. (1).

Carslake, D., Fraser, A., May, M.T., Palmer, T., Silventoinen, K., Tynelius, P., Lawlor, D.A., Davey Smith, G., Carslake, D., Fraser, A., et al.(2019). Associations of mortality with own blood pressure using son’s blood pressure as an instrumental variable . Scientific Reports. 9. (1).

Older people with long term conditions using technologies supporting home based care @article{df7e997893524301a1233983d5d4df1e, title = "Older people with long term conditions using technologies supporting home based care", author = "C. Mateus and A. Hernandez and T. Palmer and S. Varey and C. Milligan", year = "2018", month = oct, doi = "10.1016/j.jval.2018.09.1309", language = "English", volume = "21", pages = "S220--S220", journal = "Value in Health", issn = "1098-3015", publisher = "Elsevier Inc.", number = "Suppl. 3", } . Value in Health.

Software Application Profile @article{415d5f53ff9f4477ad8130d028764a05, title = "Software Application Profile: mrrobust - A Tool For Performing Two-Sample Summary Mendelian Randomization Analyses", author = "Wesley Spiller and Neil Davies and Palmer, {Thomas Michael}", note = "This is a pre-copy-editing, author-produced PDF of an article accepted for publication in International Journal of Epidemiology following peer review. The definitive publisher-authenticated version Wes Spiller, Neil M Davies, Tom M Palmer; Software application profile: mrrobust—a tool for performing two-sample summary Mendelian randomization analyses, International Journal of Epidemiology, , dyy195, https://doi.org/10.1093/ije/dyy195 is available online at: [url]", year = "2018", month = sep, day = "12", doi = "10.1101/142125", language = "English", journal = "International Journal of Epidemiology", issn = "0300-5771", publisher = "Oxford University Press", } . International Journal of Epidemiology.

Software Application Profile @article{2b9bf91ae75c4dbcaab02bcc1f4b658b, title = "Software Application Profile: mrrobust - a tool for performing two-sample summary Mendelian randomization analyses", abstract = "Motivation: In recent years Mendelian randomization analysis using summary data from genome-wide association studies has become a popular approach for investigating causal relationships in epidemiology. The mrrobust Stata package implements several of the recently developed methods.Implementation: mrrobust is freely available as a Stata package.General Features: The package includes inverse variance weighted estimation, as well as a range of median, modal and MR-Egger estimation methods. Using mrrobust, plots can be constructed visualising each estimate either individually or simultaneously. The package also provides statistics such as I_GX^2, which are useful in assessing attenuation bias in causal estimates.Availability: The software is freely available from GitHub [https://raw.github.com/remlapmot/mrrobust/master/].", keywords = "summary MR, MR-Egger, IVW, weighted median, Mendelian randomization, Stata", author = "Wes Spiller and Neil Davies and Palmer, {Tom M}", year = "2018", month = sep, day = "12", doi = "10.1093/ije/dyy195", language = "English", journal = "International Journal of Epidemiology", issn = "0300-5771", publisher = "Oxford University Press", } . International Journal of Epidemiology.

Attachment and therapeutic alliance in psychological therapy for people with recent onset psychosis who use cannabis @article{46f7bb8cd509488a820fa8f74b90f1fc, title = "Attachment and therapeutic alliance in psychological therapy for people with recent onset psychosis who use cannabis", abstract = "We examine associations between client attachment style and therapeutic alliance in a 3-arm randomized controlled trial of brief motivational interviewing and cognitive–behavioural therapy compared with longer term motivational interviewing and cognitive–behavioural therapy or standard care alone. Client self-report measures of attachment style were completed at baseline, and both clients and therapists in the treatment arms of the trial completed alliance measures 1 month into therapy. We found that insecure–anxious attachment was positively associated with therapist-rated alliance, whereas clients with insecure–avoidant attachment were more likely to report poorer bond with therapist. There was no evidence that client attachment significantly predicted clinical or substance misuse outcomes either directly or indirectly via alliance. Nor evidence that the length of therapy offered interacted with attachment to predict alliance.", keywords = "alliance, attachment, cognitive–behavioural therapy, motivational interviewing, psychosis, substance misuse", author = "Katherine Berry and Palmer, {Thomas Michael} and Lynsey Gregg and Christine Barrowclough and Lobban, {Anne Fiona}", note = "This is the peer reviewed version of the following article: Berry K, Palmer T, Gregg L, Barrowclough C, Lobban F. Attachment and therapeutic alliance in psychological therapy for people with recent onset psychosis who use cannabis. Clin Psychol Psychother. 2018;25:440–445. https://doi.org/10.1002/cpp.2178 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/cpp.2178/abstract This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.", year = "2018", month = jun, day = "6", doi = "10.1002/cpp.2178", language = "English", volume = "25", pages = "440--445", journal = "Clinical Psychology and Psychotherapy", issn = "1063-3995", publisher = "John Wiley and Sons Ltd", number = "3", } . Clinical Psychology and Psychotherapy.

UK families with children with rare chromosome disorders @article{a93a5183a51047cc92bae1f82657623f, title = "UK families with children with rare chromosome disorders: Changing experiences of diagnosis and counselling (2003-2013)", abstract = "The latest United Kingdom (UK) strategy for rare diseases emphasises the need to empower affected populations to improve diagnosis, intervention, and coordination of care. Families who have a child with a rare chromosome disorder (RCD) are a challenging group to include. We report the findings of 2 large-scale surveys, undertaken by the UK RCD Support Group Unique, of these families' experiences over a 10-year period. Seven stages of the patient journey were examined. From pre-testing, through diagnosis, genetics consultation, clinical follow-up and peer support. Overall, 1158 families replied; 36.4% response rate (2003) and 53.6% (2013). Analysis of responses identifies significant differences (P <.001) over time with a decrease in results reported face to face (76%-62%), doubling by telephone (12%-22%), improved explanation of chromosome disorder (57%-75%), and increased signposting to peer support group (34%-62%). However, conduct of the consultation raises a number of important questions. Overall, 28 aspects of the patient journey are recognised as requiring improvement; only 12/28 are currently incorporated in UK service specifications. Involvement of RCD families has identified key service improvements. This approach can empower those affected by such extremely rare disorders, and also enable professionals to design improved services in partnership with “expert families.” Further surveys are planned.", keywords = "clinical genetics services, evidence-based clinical guidelines, families' experiences, national surveys, patient reported outcomes (PROs), rare chromosome disorders", author = "A. Szczepura and S. Wynn and B. Searle and Khan, {A. J.} and T. Palmer and D. Biggerstaff and J. Elliott and Hult{\'e}n, {M. A.}", year = "2018", month = may, day = "1", doi = "10.1111/cge.13207", language = "English", volume = "93", pages = "972--981", journal = "Clinical Genetics", issn = "0009-9163", publisher = "Munksgaard International Publishers", number = "5", } . Clinical Genetics.

Attachment and therapeutic alliance in psychological therapy for people with recent onset psychosis who use cannabis @article{d58644face58436daf96dc742c071587, title = "Attachment and therapeutic alliance in psychological therapy for people with recent onset psychosis who use cannabis", abstract = "We examine associations between client attachment style and therapeutic alliance in a 3-arm randomized controlled trial of brief motivational interviewing and cognitive–behavioural therapy compared with longer term motivational interviewing and cognitive–behavioural therapy or standard care alone. Client self-report measures of attachment style were completed at baseline, and both clients and therapists in the treatment arms of the trial completed alliance measures 1 month into therapy. We found that insecure–anxious attachment was positively associated with therapist-rated alliance, whereas clients with insecure–avoidant attachment were more likely to report poorer bond with therapist. There was no evidence that client attachment significantly predicted clinical or substance misuse outcomes either directly or indirectly via alliance. Nor evidence that the length of therapy offered interacted with attachment to predict alliance.", keywords = "alliance, attachment, cognitive–behavioural therapy, motivational interviewing, psychosis, substance misuse", author = "Katherine Berry and Tom Palmer and Lynsey Gregg and Christine Barrowclough and Fiona Lobban", year = "2018", month = may, day = "1", doi = "10.1002/cpp.2178", language = "English", volume = "25", pages = "440--445", journal = "Clinical Psychology and Psychotherapy", issn = "1063-3995", publisher = "John Wiley & Sons, Ltd.", number = "3", } . Clinical Psychology and Psychotherapy.

UK Families with Children with Rare Chromosome Disorders @article{f3316971c9b641998fa6db6fb0e28ccb, title = "UK Families with Children with Rare Chromosome Disorders: Changing Experiences of Diagnosis and Counseling (2003 to 2013)", abstract = "The latest United Kingdom (UK) strategy for rare diseases emphasises the need to empower affected populations to improve diagnosis, intervention, and coordination of care. Families who have a child with a rare chromosome disorder (RCD) are a challenging group to include. We report the findings of 2 large-scale surveys, undertaken by the UK RCD Support Group Unique, of these families' experiences over a 10-year period. Seven stages of the patient journey were examined. From pre-testing, through diagnosis, genetics consultation, clinical follow-up and peer support. Overall, 1158 families replied; 36.4% response rate (2003) and 53.6% (2013). Analysis of responses identifies significant differences (P <.001) over time with a decrease in results reported face to face (76%-62%), doubling by telephone (12%-22%), improved explanation of chromosome disorder (57%-75%), and increased signposting to peer support group (34%-62%). However, conduct of the consultation raises a number of important questions. Overall, 28 aspects of the patient journey are recognised as requiring improvement; only 12/28 are currently incorporated in UK service specifications. Involvement of RCD families has identified key service improvements. This approach can empower those affected by such extremely rare disorders, and also enable professionals to design improved services in partnership with expert families. Further surveys are planned.", author = "Ala Szczepura and Sarah Wynn and Beverly Searle and Amir Khan and Palmer, {Thomas Michael} and Deborah Biggerstaff and Josh Elliott and Maj Hulten", note = "This is the peer reviewed version of the following article: Szczepura A, Wynn S, Searle B, et al. UK families with children with rare chromosome disorders: Changing experiences of diagnosis and counselling (2003‐2013). Clin Genet. 2018;93:972–981. https://doi.org/10.1111/cge.13207 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/cge.13207/abstract This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.", year = "2018", month = may, doi = "10.1111/cge.13207", language = "English", volume = "93", pages = "972--981", journal = "Clinical Genetics", issn = "0009-9163", publisher = "Wiley-Blackwell", number = "5", } . Clinical Genetics.

Instrumental variable methods for a binary outcome were used to informatively address noncompliance in a randomized trial in surgery @article{dc4f9655b95c4245b7bf7b40c347ea00, title = "Instrumental variable methods for a binary outcome were used to informatively address noncompliance in a randomized trial in surgery", abstract = "Objectives: Randomization can be used as an instrumental variable (IV) to account for unmeasured confounding when seeking to assess the impact of noncompliance with treatment allocation in a randomized trial. We present and compare different methods to calculate the treatment effect on a binary outcome as a rate ratio in a randomized surgical trial. Study Design and Setting: The effectiveness of peeling versus not peeling the internal limiting membrane of the retina as part of the surgery for a full thickness macular hole. We compared the IV-based estimates (nonparametric causal bound and two-stage residual inclusion approach [2SRI]) with standard treatment effect measures (intention to treat, per protocol and treatment received [TR]). Compliance was defined in two ways (initial and up to the time point of interest). Poisson regression was used for the model-based approaches with robust standard errors to calculate the risk ratio (RR) with 95% confidence intervals. Results: Results were similar for 1-month macular hole status across methods. For 3- and 6-month macular hole status, nonparametric causal bounds provided a narrower range of uncertainty than other methods, though still had substantial imprecision. For 3-month macular hole status, the TR estimate was substantially different from the other point estimates. Conclusion: Nonparametric causal bound approaches are a useful addition to an IV estimation approach, which tend to have large levels of uncertainty. Methods which allow RRs to be calculated when addressing noncompliance in randomized trials exist and may be superior to standard estimates. Further research is needed to explore the properties of different IV methods in a broad range of randomized controlled trial scenarios.", keywords = "Binary, Causal modeling, Instrumental variable, Noncompliance, RCT, Risk ratio", author = "Cook, {Jonathan A.} and MacLennan, {Graeme S.} and Tom Palmer and Noemi Lois and Richard Emsley", year = "2018", month = apr, day = "1", doi = "10.1016/j.jclinepi.2017.11.011", language = "English", volume = "96", pages = "126--132", journal = "Journal of Clinical Epidemiology", issn = "0895-4356", publisher = "Elsevier Inc.", } . Journal of Clinical Epidemiology.

Instrumental variable methods for a binary outcome were used to informatively address non-compliance in a randomised trial in surgery @article{459a46851d3a4573824bca6e4dbd1482, title = "Instrumental variable methods for a binary outcome were used to informatively address non-compliance in a randomised trial in surgery", abstract = "Objectives Randomisation can be used as an instrumental variable (IV) to account for unmeasured confounding when seeking to assess the impact of non-compliance with treatment allocation in a randomised trial. We present and compare different methods to calculate the treatment effect on a binary outcome as a rate ratio in a randomised surgical trial. Study design and setting The effectiveness of peeling versus not peeling the internal limiting membrane of the retina as part of the surgery for a full thickness macular hole. We compared IV based estimates (non-parametric causal bound, and two stage residual inclusion approach [2SRI] with standard treatment effect measures (intention to treat [ITT], per protocol [PP] and treatment received [TR]). Compliance was defined in two ways (initial and up to time point of interest). Poisson regression was used for the model based approaches with robust standard errors to calculate the risk ratio with 95% confidence intervals. Results Results were similar for 1-month macular hole status across methods. For 3- and 6-month macular hole status, non-parametric causal bounds provided a narrower range of uncertainty than other methods, though still had substantial imprecision. For 3-month macular hole status, the TR estimate was substantially different from the other point estimates. Conclusion Non-parametric causal bound approaches are a useful addition to an IV estimation approach, which tend to have large levels of uncertainty. Methods which allow risk ratios to be calculated when addressing non-compliance in randomised trials exist and may be superior to standard estimates. Further research is needed to explore the properties of different IV methods in a broad range of RCT scenarios.", keywords = "Instrumental variable, RCT, non-compliance, binary, causal modelling, risk ratio", author = "J.A. Cook and G.S. Maclennan and T. Palmer and N. Lois and R. Emsley", year = "2018", month = apr, doi = "10.1016/j.jclinepi.2017.11.011", language = "English", volume = "96", pages = "126--132", journal = "Journal of Clinical Epidemiology", issn = "0895-4356", publisher = "Elsevier Inc.", } . Journal of Clinical Epidemiology.

Reading comprehension difficulties in children with rolandic epilepsy @article{8f9462e84f3e4794b4dbb34b64401724, title = "Reading comprehension difficulties in children with rolandic epilepsy", abstract = "Aim: Difficulties in reading comprehension can arise from either word reading or listening comprehension difficulties, or a combination of the two. We sought to determine whether children with rolandic epilepsy had poor reading comprehension relative to typically developing comparison children, and whether such difficulties were associated with word reading and/or general language comprehension difficulties. Method: In this cross-sectional study, children with rolandic epilepsy (n=25; 16 males, 9 females; mean age 9y 1mo, SD 1y 7mo) and a comparison group (n=39; 25 males, 14 females; mean age 9y 1mo, SD 1y 3mo) completed assessments of reading comprehension, listening comprehension, word/non-word reading, speech articulation, and Non-verbal IQ. Results: Reading comprehension and word reading were worse in children with rolandic epilepsy (F1,61=6.89, p=0.011, n2p =0.10 and F1,61=6.84, p=0.011, n2p =0.10 respectively), with listening comprehension being marginal (F1,61=3.81, p=0.055, n2p =0.06). Word reading and listening comprehension made large and independent contributions to reading comprehension, explaining 70% of the variance. Interpretation: Children with rolandic epilepsy may be at risk of reading comprehension difficulties. Thorough assessment of individual children is required to ascertain whether the difficulties lie with decoding text, or with general comprehension skills, or both. What this paper adds: Children with rolandic epilepsy may be at risk of poor reading comprehension. This was related to poor word reading, poor listening comprehension, or both. Reading comprehension interventions should be tailored to the profile of difficulties.", author = "Currie, {Nicola K.} and Lew, {Adina R.} and Palmer, {Tom M.} and Helen Basu and {De Goede}, Christian and Anand Iyer and Kate Cain", year = "2018", month = mar, day = "1", doi = "10.1111/dmcn.13628", language = "English", volume = "60", pages = "275--282", journal = "Developmental Medicine and Child Neurology", issn = "0012-1622", publisher = "Wiley-Blackwell", number = "3", } . Developmental Medicine and Child Neurology.

Reading comprehension difficulties in children with rolandic epilepsy @article{e328587436314118a6bf7bf96af32090, title = "Reading comprehension difficulties in children with rolandic epilepsy", abstract = "AimDifficulties in reading comprehension can arise from either word reading or listening comprehension difficulties, or a combination of the two. We sought to determine whether children with rolandic epilepsy had poor reading comprehension relative to typically developing comparison children, and whether such difficulties were associated with word reading and/or general language comprehension difficulties.MethodIn this cross-sectional study, children with rolandic epilepsy (n=25; 16 males, 9 females; mean age 9y 1mo, SD 1y 7mo) and a comparison group (n=39; 25 males, 14 females; mean age 9y 1mo, SD 1y 3mo) completed assessments of reading comprehension, listening comprehension, word/non-word reading, speech articulation, and Non-verbal IQ.ResultsReading comprehension and word reading were worse in children with rolandic epilepsy (F1,61=6.89, p=0.011, math formula=0.10 and F1,61=6.84, p=0.011, math formula=0.10 respectively), with listening comprehension being marginal (F1,61=3.81, p=0.055, math formula=0.06). Word reading and listening comprehension made large and independent contributions to reading comprehension, explaining 70% of the variance.InterpretationChildren with rolandic epilepsy may be at risk of reading comprehension difficulties. Thorough assessment of individual children is required to ascertain whether the difficulties lie with decoding text, or with general comprehension skills, or both.What this paper addsChildren with rolandic epilepsy may be at risk of poor reading comprehension.This was related to poor word reading, poor listening comprehension, or both.Reading comprehension interventions should be tailored to the profile of difficulties.", author = "Currie, {Nicola Kate} and Lew, {Adina Raquel} and Palmer, {Thomas Michael} and Helen Basu and {De Goede}, Christian and Anand Ayer and Kate Cain", note = "This is the peer reviewed version of the following article:Currie, N. K., Lew, A. R., Palmer, T. M., Basu, H., De Goede, C., Iyer, A. and Cain, K. (2018), Reading comprehension difficulties in children with rolandic epilepsy. Dev Med Child Neurol, 60: 275–282. doi:10.1111/dmcn.13628 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/dmcn.13628/abstract This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving. ", year = "2018", month = mar, doi = "10.1111/dmcn.13628", language = "English", volume = "60", pages = "275--282", journal = "Developmental Medicine and Child Neurology", issn = "0012-1622", publisher = "Wiley-Blackwell", number = "3", } . Developmental Medicine and Child Neurology.

How effective and cost effective are innovative combinatorial technologies and practices for supporting older people with long-term conditions to remain well in the community? @article{a7f32b3b03634166aeefb67097cc9c0a, title = "How effective and cost effective are innovative combinatorial technologies and practices for supporting older people with long-term conditions to remain well in the community?", abstract = "Introduction: The Lancashire and Cumbria Innovation Alliance (LCIA) Test Bed is a partnership between National Health Services in England (NHS), industry (led by Philips) and Lancaster University. Through the implementation of a combination of innovative health technologies and practices, it aims to determine the most effective and cost effective ways of supporting frail older people with long-term conditions to remain well in the community. Among the Test Bed{\textquoteright}s objectives are to: improve patient activation and the ability of older people to self-care at home; reduce healthcare system utilisation; and deliver increased workforce productivity. Methods and Analysis: Patients aged 55 years and over are recruited to four cohorts defined by their risk of hospital admission, with long-term conditions including COPD, dementia, diabetes and heart failure. The programme is determined on an individual basis, with a range of technologies available. The evaluation is adopting a two-phase approach: Phase 1 includes a bespoke patient survey and a mass matched control analysis; and Phase 2 is using observational interviews with patients, and weekly diaries, action learning meetings and focus groups with members of staff and other key stakeholders. Phase 1 data analysis consists of a statistical evaluation of the effectiveness of the programme. A health economic analysis of its costs and associated cost changes will be undertaken. Phase 2 data will be analysed thematically with the aid of Atlas.ti qualitative software. The evaluation is located within a logic model framework, to consider the processes, management and participation that may have implications for the Test Bed{\textquoteright}s success. Ethics and Dissemination: The LCIA Test Bed evaluation has received ethical approval from the Health Research Authority and Lancaster University{\textquoteright}s Faculty of Health and Medicine Research Ethics Committee. A range of dissemination methods are adopted including deliberative panels to validate findings and develop outcomes for policy and practice.", author = "Varey, {Sandra Elaine} and {Hernandez Huerta}, {Maria Alejandra} and Palmer, {Thomas Michael} and Ceu Mateus and Joann Wilkinson and Dixon, {Mandy Patricia} and Christine Milligan", note = "M1 - e017268", year = "2018", month = feb, day = "28", doi = "10.1136/bmjopen-2017-017268", language = "English", volume = "8", journal = "BMJ Open", issn = "2044-6055", publisher = "BMJ Publishing Group", number = "2", } . BMJ Open.

How effective and cost effective are innovative combinatorial technologies and practices for supporting older people with long-term conditions to remain well in the community? @article{39f64e485e3d4b949bdf79b433bbb558, title = "How effective and cost effective are innovative combinatorial technologies and practices for supporting older people with long-term conditions to remain well in the community?: An evaluation protocol for an NHS Test Bed in North West England", abstract = "Introduction: The Lancashire and Cumbria Innovation Alliance (LCIA) Test Bed is a partnership between National Health Services in England (NHS), industry (led by Philips) and Lancaster University. Through the implementation of a combination of innovative health technologies and practices, it aims to determine the most effective and cost effective ways of supporting frail older people with long-term conditions to remain well in the community. Among the Test Bed{\textquoteright}s objectives are to: improve patient activation and the ability of older people to self-care at home; reduce healthcare system utilisation; and deliver increased workforce productivity. Methods and Analysis: Patients aged 55 years and over are recruited to four cohorts defined by their risk of hospital admission, with long-term conditions including COPD, dementia, diabetes and heart failure. The programme is determined on an individual basis, with a range of technologies available. The evaluation is adopting a two-phase approach: Phase 1 includes a bespoke patient survey and a mass matched control analysis; and Phase 2 is using observational interviews with patients, and weekly diaries, action learning meetings and focus groups with members of staff and other key stakeholders. Phase 1 data analysis consists of a statistical evaluation of the effectiveness of the programme. A health economic analysis of its costs and associated cost changes will be undertaken. Phase 2 data will be analysed thematically with the aid of Atlas.ti qualitative software. The evaluation is located within a logic model framework, to consider the processes, management and participation that may have implications for the Test Bed{\textquoteright}s success. Ethics and Dissemination: The LCIA Test Bed evaluation has received ethical approval from the Health Research Authority and Lancaster University{\textquoteright}s Faculty of Health and Medicine Research Ethics Committee. A range of dissemination methods are adopted including deliberative panels to validate findings and develop outcomes for policy and practice. ", author = "Varey, {Sandra Elaine} and {Hernandez Huerta}, {Maria Alejandra} and Palmer, {Thomas Michael} and Ceu Mateus and Joann Wilkinson and Dixon, {Mandy Patricia} and Christine Milligan", year = "2018", month = feb, day = "28", doi = "10.1136/bmjopen-2017-017268", language = "English", volume = "8", journal = "BMJ Open", issn = "2044-6055", publisher = "BMJ Publishing Group Ltd", number = "2", } . BMJ Open.

Cook, J.A., MacLennan, G.S., Palmer, T., Lois, N., Emsley, R., Cook, J.A., MacLennan, G.S., Palmer, T., Lois, N., Emsley, R.(2018). Instrumental variable methods for a binary outcome were used to informatively address noncompliance in a randomized trial in surgery . Journal of Clinical Epidemiology. 96. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 126-132.

Currie, N.K., Lew, A.R., Palmer, T.M., Basu, H., De Goede, C., Iyer, A., Cain, K., Currie, N.K., Lew, A.R., Palmer, T.M., et al.(2018). Reading comprehension difficulties in children with rolandic epilepsy . Developmental Medicine and Child Neurology. 60. (3). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 275-282.

Varey, S., Hern&#225;ndez, A., Palmer, T.M., Mateus, C., Wilkinson, J., Dixon, M., Milligan, C., Varey, S., Hern&#225;ndez, A., Palmer, T.M., et al.(2018). How effective and cost-effective are innovative combinatorial technologies and practices for supporting older people with long-term conditions to remain well in the community? An evaluation protocol for an NHS Test Bed in North West England . BMJ Open. 8. (2).

Szczepura, A., Wynn, S., Searle, B., Khan, A.J., Palmer, T., Biggerstaff, D., Elliott, J., Hult&#233;n, M.A., Szczepura, A., Wynn, S., et al.(2018). UK families with children with rare chromosome disorders: Changing experiences of diagnosis and counselling (2003-2013) . Clinical Genetics. 93. (5). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 972-981.

Berry, K., Palmer, T., Gregg, L., Barrowclough, C., Lobban, F., Berry, K., Palmer, T., Gregg, L., Barrowclough, C., Lobban, F.(2018). Attachment and therapeutic alliance in psychological therapy for people with recent onset psychosis who use cannabis . Clinical Psychology and Psychotherapy. 25. (3). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 440-445.

Correcting the standard errors of two-stage residual inclusion estimators for Mendelian randomization studies @article{82cc5d21949c45daa1001649349b3485, title = "Correcting the standard errors of two-stage residual inclusion estimators for Mendelian randomization studies", abstract = "Mendelian randomization studies use genotypes as instrumental variables to test for and estimate the causal effects of modifiable risk factors on outcomes. Two-stage residual inclusion (TSRI) estimators have been used when researchers are willing to make parametric assumptions. However, researchers are currently reporting uncorrected or heteroskedasticity robust standard errors (SEs) for these estimates.We compare several different forms of the SE for linear and logistic TSRI estimates in simulations and in real data examples. Amongst others we consider SEs modified from the approach of Newey (1987), Terza (2016), and bootstrapping.In our simulations Newey, Terza, bootstrap, and corrected two-stage least squares (in the linear case) standard errors gave the best results in terms of coverage and type I error. In the real data examples the Newey SEs were 0.5% and 2% larger than the unadjusted standard errors for the linear and logistic TSRI estimators respectively.We show that TSRI estimators with modified SEs have correct type I error under the null. Researchers should report TSRI estimates with modified SEs instead of reporting unadjusted or heteroskedasticity robust SEs.", keywords = "Causal inference, instrumental variables, Mendelian randomization, two-stage predictor substitution estimators, two-stage residual inclusion estimators", author = "Palmer, {Thomas Michael} and Holmes, {Michael V.} and Keating, {Brendan J.} and Sheehan, {Nuala A.}", note = "This is a pre-copy-editing, author-produced PDF of an article accepted for publication in American Journal of Epidemiology following peer review. The definitive publisher-authenticated version Tom M Palmer, Michael V Holmes, Brendan J Keating, Nuala A Sheehan; Correcting the Standard Errors of 2-Stage Residual Inclusion Estimators for Mendelian Randomization Studies, American Journal of Epidemiology, Volume 186, Issue 9, 1 November 2017, Pages 1104–1114, https://doi.org/10.1093/aje/kwx175 is available online at: https://academic.oup.com/aje/article/186/9/1104/3860090", year = "2017", month = nov, day = "1", doi = "10.1093/aje/kwx175", language = "English", volume = "186", pages = "1104--1114", journal = "American Journal of Epidemiology", issn = "0002-9262", publisher = "Oxford University Press", number = "9", } . American Journal of Epidemiology.

Correcting the Standard Errors of 2-Stage Residual Inclusion Estimators for Mendelian Randomization Studies @article{707fc4df280a44239ee384d2e71c0474, title = "Correcting the Standard Errors of 2-Stage Residual Inclusion Estimators for Mendelian Randomization Studies", abstract = "Mendelian randomization studies use genotypes as instrumental variables to test for and estimate the causal effects of modifiable risk factors on outcomes. Two-stage residual inclusion (TSRI) estimators have been used when researchers are willing to make parametric assumptions. However, researchers are currently reporting uncorrected or heteroscedasticity-robust standard errors for these estimates. We compared several different forms of the standard error for linear and logistic TSRI estimates in simulations and in real-data examples. Among others, we consider standard errors modified from the approach of Newey (1987), Terza (2016), and bootstrapping. In our simulations Newey, Terza, bootstrap, and corrected 2-stage least squares (in the linear case) standard errors gave the best results in terms of coverage and type I error. In the real-data examples, the Newey standard errors were 0.5% and 2% larger than the unadjusted standard errors for the linear and logistic TSRI estimators, respectively. We show that TSRI estimators with modified standard errors have correct type I error under the null. Researchers should report TSRI estimates with modified standard errors instead of reporting unadjusted or heteroscedasticity-robust standard errors.", keywords = "2-stage predictor substitution estimators, 2-stage residual inclusion estimators, causal inference, instrumental variables, Mendelian randomization", author = "Palmer, {Tom M.} and Holmes, {Michael V.} and Keating, {Brendan J.} and Sheehan, {Nuala A.}", year = "2017", month = nov, day = "1", doi = "10.1093/aje/kwx175", language = "English", volume = "186", pages = "1104--1114", journal = "American Journal of Epidemiology", issn = "0002-9262", publisher = "Oxford University Press", number = "9", } . American Journal of Epidemiology.

Education and coronary heart disease @article{dc56d24916e241a887435f2ded4a8e86, title = "Education and coronary heart disease: mendelian randomisation study", abstract = "Objective: To determine whether educational attainment is a causal risk factor in the development of coronary heart disease. Design: Mendelian randomisation study, using genetic data as proxies for education to minimise confounding. Setting: The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries. Findings from mendelian randomisation analyses were then compared against results from traditional observational studies (164 170 participants). Finally, genetic data from six additional consortia were analysed to investigate whether longer education can causally alter the common cardiovascular risk factors. Participants: The main analysis was of 543 733 men and women (from CARDIoGRAMplusC4D and SSGAC), predominantly of European origin. Exposure: A one standard deviation increase in the genetic predisposition towards higher education (3.6 years of additional schooling), measured by 162 genetic variants that have been previously associated with education. Main outcome measure: Combined fatal and non-fatal coronary heart disease (63 746 events in CARDIoGRAMplusC4D). Results: Genetic predisposition towards 3.6 years of additional education was associated with a one third lower risk of coronary heart disease (odds ratio 0.67, 95% confidence interval 0.59 to 0.77; P=3×10(-8)). This was comparable to findings from traditional observational studies (prevalence odds ratio 0.73, 0.68 to 0.78; incidence odds ratio 0.80, 0.76 to 0.83). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely, although this remains an untestable possibility. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favourable blood lipid profile. Conclusions: This mendelian randomisation study found support for the hypothesis that low education is a causal risk factor in the development of coronary heart disease. Potential mechanisms could include smoking, body mass index, and blood lipids. In conjunction with the results from studies with other designs, these findings suggest that increasing education may result in substantial health benefits.", author = "Taavi Tillmann and Julien Vaucher and Aysu Okbay and Hynek Pikhart and Anne Peasey and Ruzena Kubinova and Andrzej Pajak and Abdonas Tamosiunas and Sofia Malyutina and Hartwig, {Fernando Pires} and Krista Fischer and Giovanni Veronesi and Tom Palmer and Jack Bowden and {Davey Smith}, George and Martin Bobak and Holmes, {Michael V}", year = "2017", month = aug, day = "30", doi = "10.1136/bmj.j3542", language = "English", volume = "358", journal = "BMJ", issn = "0959-8138", publisher = "BMJ Publishing Group", } . BMJ.

Education and coronary heart disease: mendelian randomisation study @article{84f82ed550634f38a5af2b2a7bf3730a, title = "Education and coronary heart disease: mendelian randomisation study", abstract = "Objective To determine whether educational attainment is a causal risk factor in the development of coronary heart disease.Design Mendelian randomisation study, using genetic data as proxies for education to minimise confounding.Setting The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries. Findings from mendelian randomisation analyses were then compared against results from traditional observational studies (164 170 participants). Finally, genetic data from six additional consortia were analysed to investigate whether longer education can causally alter the common cardiovascular risk factors.Participants The main analysis was of 543 733 men and women (from CARDIoGRAMplusC4D and SSGAC), predominantly of European origin.Exposure A one standard deviation increase in the genetic predisposition towards higher education (3.6 years of additional schooling), measured by 162 genetic variants that have been previously associated with education.Main outcome measure Combined fatal and non-fatal coronary heart disease (63 746 events in CARDIoGRAMplusC4D).Results Genetic predisposition towards 3.6 years of additional education was associated with a one third lower risk of coronary heart disease (odds ratio 0.67, 95% confidence interval 0.59 to 0.77; P=3×10−8). This was comparable to findings from traditional observational studies (prevalence odds ratio 0.73, 0.68 to 0.78; incidence odds ratio 0.80, 0.76 to 0.83). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely, although this remains an untestable possibility. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favourable blood lipid profile.Conclusions This mendelian randomisation study found support for the hypothesis that low education is a causal risk factor in the development of coronary heart disease. Potential mechanisms could include smoking, body mass index, and blood lipids. In conjunction with the results from studies with other designs, these findings suggest that increasing education may result in substantial health benefits.", author = "Taavi Tillmann and Julien Vaucher and Aysu Okbay and Hynek Pikhart and Anne Peasey and Ruzena Kubinova and Andrzej Pajak and Abdonas Tamosiunas and Sofia Malyutina and Hartwig, {Fernando Pires} and Krista Fischer and Giovanni Veronesi and Tom Palmer and Jack Bowden and {Davey Smith}, George and Martin Bobak and Holmes, {Michael V}", year = "2017", month = aug, day = "30", doi = "10.1136/bmj.j3542", language = "English", volume = "358", journal = "BMJ", issn = "0959-8138", publisher = "British Medical Association", } . BMJ.

Taller height as a risk factor for venous thromboembolism @article{9b2f775239f74a9899b01e93221f85c2, title = "Taller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis", abstract = "Essentials Observational data suggest taller people have a higher risk of venous thromboembolism (VTE). We used Mendelian randomization techniques to further explore this association in three studies. Risk of VTE increased by 30–40% for each 10 cm increment in height. Height was more strongly associated with deep vein thrombosis than with pulmonary embolism. Summary: Background Taller height is associated with a greater risk of venous thromboembolism (VTE). Objectives To use instrumental variable (IV) techniques (Mendelian randomization) to further explore this relationship. Methods Participants of European ancestry were included from two cohort studies (Atherosclerosis Risk in Communities [ARIC] study and Cardiovascular Health Study [CHS]) and one case–control study (Mayo Clinic VTE Study [Mayo]). We created two weighted genetic risk scores (GRSs) for height; the full GRS included 668 single-nucleotide polymorphisms (SNPs) from a previously published meta-analysis, and the restricted GRS included a subset of 362 SNPs not associated with weight independently of height. Standard logistic regression and IV models were used to estimate odds ratios (ORs) for VTE per 10-cm increment in height. ORs were pooled across the three studies by the use of inverse variance-weighted random effects meta-analysis. Results Among 9143 ARIC and 3180 CHS participants free of VTE at baseline, there were 367 and 109 incident VTE events. There were 1143 VTE cases and 1292 controls included from Mayo. The pooled ORs from non-IV models and models using the full and restricted GRSs as IVs were 1.27 (95% confidence interval [CI] 1.11–1.46), 1.34 (95% CI 1.04–1.73) and 1.45 (95% CI 1.04–2.01) per 10-cm greater height, respectively. Conclusions Taller height is associated with an increased risk of VTE in adults of European ancestry. Possible explanations for this association, including taller people having a greater venous surface area, a higher number of venous valves, or greater hydrostatic pressure, need to be explored further.", keywords = "body height, genetics, Mendelian randomization analysis, meta-analysis, venous thromboembolism", author = "Roetker, {N. S.} and Armasu, {S. M.} and Pankow, {J. S.} and Lutsey, {P. L.} and W. Tang and Rosenberg, {M. A.} and Palmer, {T. M.} and MacLehose, {R. F.} and Heckbert, {S. R.} and M. Cushman and {de Andrade}, M. and Folsom, {A. R.}", year = "2017", month = jul, day = "1", doi = "10.1111/jth.13719", language = "English", volume = "15", pages = "1334--1343", journal = "Journal of Thrombosis and Haemostasis", issn = "1538-7933", publisher = "Wiley-Blackwell", number = "7", } . Journal of Thrombosis and Haemostasis.

Taller height as a risk factor for venous thromboembolism @article{62237da8a60540478311ff7ac2d4941f, title = "Taller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis", abstract = "BackgroundTaller height is associated with greater risk of venous thromboembolism (VTE).ObjectivesWe used instrumental variable (IV) techniques (Mendelian randomization) to further explore this relationshipMethodsParticipants of European ancestry were included from two cohort studies [Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS)] and one case-control study [Mayo Clinic VTE Study (Mayo)]. We created two weighted genetic risk scores (GRS) for height; the full GRS included 668 single nucleotide polymorphisms (SNPs) from a previously published meta-analysis and the restricted GRS included a subset of 362 SNPs not associated with weight independently of height. Standard logistic regression and IV models were used to estimate odds ratios (ORs) for VTE per 10 cm increment in height. ORs were pooled across the three studies using inverse variance weighted random effects meta-analysisResultsAmong 9143 ARIC and 3180 CHS participants free of VTE at baseline, there were 367 and 109 incident VTE events. There were 1143 VTE cases and 1292 controls included from Mayo. The pooled ORs from non-IV models and models using the full and restricted GRSs as IVs were 1.27 (95% CI: 1.11, 1.46), 1.34 (95% CI: 1.04, 1.73), and 1.45 (95% CI: 1.04, 2.01) per 10 cm greater height, respectively.ConclusionsTaller height is associated with an increased risk of VTE in adults of European ancestry. Possible explanations for this association, including that taller people may have greater venous surface area, greater number of venous valves, or greater hydrostatic pressure, need to be explored further.", author = "Nicholas Roetker and Armasu, {S. M.} and Pankow, {J. S.} and Lutsey, {P. L.} and W. Tang and Rosenberg, {M. A.} and Palmer, {Thomas Michael} and MacLehose, {R. F.} and Heckbert, {S. R.} and M. Cushman and {de Andrade}, M. and Folsom, {A. R.}", note = "This is the peer reviewed version of the following article: Roetker NS, Armasu SM, Pankow JS, Lutsey PL, Tang W, Rosenberg MA, Palmer TM, MacLehose RF, Heckbert SR, Cushman M, de Andrade M, Folsom AR. Taller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis. J Thromb Haemost 2017; 15: 1334–43. which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/jth.13719/abstract This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.", year = "2017", month = jul, doi = "10.1111/jth.13719", language = "English", volume = "15", pages = "1334--1343", journal = "Journal of Thrombosis and Haemostasis", issn = "1538-7836", publisher = "Wiley", number = "7", } . Journal of Thrombosis and Haemostasis.

Causal Associations of Adiposity and Body Fat Distribution With Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus @article{ac3c309e64c34fc1b9eff593d378f57e, title = "Causal Associations of Adiposity and Body Fat Distribution With Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus: A Mendelian Randomization Analysis", abstract = "Background: Implications of different adiposity measures on cardiovascular disease aetiology remain unclear. In this paper we quantify and contrast causal associations of central adiposity (waist:hip ratio adjusted for BMI (WHRadjBMI)) and general adiposity (body mass index (BMI)) with cardiometabolic disease. Methods: 97 independent single nucleotide polymorphisms (SNPs) for BMI and 49 SNPs for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with CHD data from CARDIoGRAMplusC4D (combined total 66,842 cases), stroke from METASTROKE (12,389 ischaemic stroke cases), type 2 diabetes (T2D) from DIAGRAM (34,840 cases), and lipids from GLGC (213,500 participants) consortia. Primary outcomes were CHD, T2D, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits. Results: Each one standard deviation (SD) higher WHRadjBMI (1SD~0.08 units) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD: 1.48; 95%CI: 1.28-1.71), similar to findings for BMI (1SD~4.6kg/m2; OR for CHD: 1.36; 95%CI: 1.22-1.52). Only WHRadjBMI increased risk of ischaemic stroke (OR 1.32; 95%CI 1.03-1.70). For T2D we find OR 1.82 (95%CI 1.38-2.42) per 1SD WHRadjBMI and OR 1.98 (95%CI 1.41-2.78) per 1SD BMI. Both WHRadjBMI and BMI were associated with increased left ventricular hypertrophy, glycaemic traits, interleukin-6, and circulating lipids. WHRadjBMI was associated with carotid intima-media thickness (37%; 95%CI: 7%-74% per 1SD).Conclusions: Both general and central adiposity have causal effects on CHD and T2D. Central adiposity may have a stronger effect on stroke risk. Future estimates of adiposity burden on health should include measures of central and general adiposity.", keywords = "adiposity, body fat distribution, body mass index, coronary artery disease, Mendelian randomization analysis, stroke, waist-hip ratio", author = "Dale, {Caroline E} and Ghazaleh Fatemifar and Palmer, {Tom M} and Jon White and David Prieto-Merino and Delilah Zabaneh and Engmann, {Jorgen E L} and Tina Shah and Andrew Wong and Warren, {Helen R} and Stela McLachlan and Stella Trompet and Max Moldovan and Morris, {Richard W} and Reecha Sofat and Meena Kumari and Elina Hypp{\"o}nen and Jefferis, {Barbara J} and Tom Gaunt and Yoav Ben-Shlomo and Ang Zhou and Aleksandra Gentry-Maharaj and Andy Ryan and {UCLEB Consortium} and {METASTROKE consortium} and {de Mutsert}, Ren{\'e}e and Raymond Noordam and Caulfield, {Mark J} and Jukema, {J Wouter} and Bradford Worrall and Munroe, {Patricia B} and Usha Menon and Chris Power and Kuh, {Diana J L} and Lawlor, {Debbie A} and Humphries, {Steve E} and Mook-Kanamori, {Dennis O} and {Davey Smith}, George and Naveed Sattar and Kivimaki, {Mika J} and Price, {Jacqueline F} and Frank Dudridge and Aroon Hingorani and Holmes, {Michael V} and Cass, {Juan P}", year = "2017", month = jun, day = "13", doi = "10.1161/CIRCULATIONAHA.116.026560", language = "English", volume = "135", pages = "2373--2388", journal = "Circulation", issn = "0009-7322", publisher = "Lippincott Williams and Wilkins", number = "24", } . Circulation.

Causal Associations of Adiposity and Body Fat Distribution with Coronary Heart Disease, Stroke Subtypes and Type 2 Diabetes @article{8234eb46080943908de741933c89f57f, title = "Causal Associations of Adiposity and Body Fat Distribution with Coronary Heart Disease, Stroke Subtypes and Type 2 Diabetes: A Mendelian randomization analysis", abstract = "Background—Implications of different adiposity measures on cardiovascular disease aetiology remain unclear. In this paper we quantify and contrast causal associations of central adiposity (waist:hip ratio adjusted for BMI (WHRadjBMI)) and general adiposity (body mass index (BMI)) with cardiometabolic disease.Methods—97 independent single nucleotide polymorphisms (SNPs) for BMI and 49 SNPs for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with CHD data from CARDIoGRAMplusC4D (combined total 66,842 cases), stroke from METASTROKE (12,389 ischaemic stroke cases), type 2 diabetes (T2D) from DIAGRAM (34,840 cases), and lipids from GLGC (213,500 participants) consortia. Primary outcomes were CHD, T2D, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits.Results—Each one standard deviation (SD) higher WHRadjBMI (1SD~0.08 units) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD: 1.48; 95%CI: 1.28-1.71), similar to findings for BMI (1SD~4.6kg/m2; OR for CHD: 1.36; 95%CI: 1.22-1.52). Only WHRadjBMI increased risk of ischaemic stroke (OR 1.32; 95%CI 1.03-1.70). For T2D, both measures had large effects: OR 1.82 (95%CI 1.38-2.42) and OR 1.98 (95%CI 1.41-2.78) per 1SD higher WHRadjBMI and BMI respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycaemic traits, interleukin-6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95%CI: 9%-77% per 1SD).Conclusions—Both general and central adiposity have causal effects on CHD and T2D. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity.", author = "Caroline Dale and Ghazaleh Fatemifar and Tom Palmer and Jonathan White and David Prieto-Merino and Delilah Zabaneh and Engmann, {Jorgen E. L.} and Tina Shah and Andrew Wong and Warren, {Helen R.} and Stela McLachlan and Stella Trompet and Max Moldovan and Morris, {Richard W.} and Reecha Sofat and Meena Kumari and Elina Hypp{\"o}nen and Jefferis, {Barbara J.} and Gaunt, {Tom R.} and Yoav Ben-Shlomo and Ang Zhou and Aleksandra Gentry-Maharaj and Andy Ryan and {de Mutsert}, Ren{\'e}e and Raymond Noordam and Caulfield, {Mark J.} and Jukema, {J. Wouter} and Worrall, {Bradford B.} and Munroe, {Patricia B.} and Usha Menon and Chris Power and Diana Kuh and Lawlor, {Debbie A.} and Humphries, {Steve E.} and Mook-Kanamori, {Dennis O.} and {Davey Smith}, George and Naveed Sattar and Mika Kivimaki and Price, {Jacqueline F.} and Frank Dudbridge and Hingorani, {Aroon D.} and Holmes, {Michael V.} and Juan-Pablo Casas", note = "{\textcopyright}2017 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited", year = "2017", month = jun, day = "13", doi = "10.1161/CIRCULATIONAHA.116.026560", language = "English", volume = "135", pages = "2373--2388", journal = "Circulation", issn = "0009-7322", publisher = "Lippincott Williams and Wilkins", number = "24", } . Circulation.

Using genetic variation to explore the causal effect of maternal pregnancy adiposity on future offspring adiposity @article{9569362c4d98400ca606b4851368dd15, title = "Using genetic variation to explore the causal effect of maternal pregnancy adiposity on future offspring adiposity: a Mendelian randomisation study", abstract = "BackgroundIt has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intrauterine mechanisms. Our aim was to use Mendelian randomisation (MR) to investigate the causal effect of intrauterine exposure to greater maternal body mass index (BMI) on offspring BMI and fat mass from childhood to early adulthood.Methods and FindingsWe used maternal genetic variants as instrumental variables (IVs) to test the causal effect of maternal BMI in pregnancy on offspring fatness (BMI and dual-energy X-ray absorptiometry [DXA] determined fat mass index [FMI]) in a MR approach. This was investigated, with repeat measurements, from ages 7 to 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 2,521 to 3,720 for different ages). We then sought to replicate findings with results for BMI at age 6 in Generation R (n = 2,337 for replication sample; n = 6,057 for total pooled sample).In confounder-adjusted multivariable regression in ALSPAC, a 1 standard deviation (SD, equivalent of 3.7 kg/m2) increase in maternal BMI was associated with a 0.25 SD (95% CI 0.21–0.29) increase in offspring BMI at age 7, with similar results at later ages and when FMI was used as the outcome.A weighted genetic risk score was generated from 32 genetic variants robustly associated with BMI (minimum F-statistic = 45 in ALSPAC). The MR results using this genetic risk score as an IV in ALSPAC were close to the null at all ages (e.g., 0.04 SD (95% CI -0.21–0.30) at age 7 and 0.03 SD (95% CI -0.26–0.32) at age 18 per SD increase in maternal BMI), which was similar when a 97 variant generic risk score was used in ALSPAC.When findings from age 7 in ALSPAC were meta-analysed with those from age 6 in Generation R, the pooled confounder-adjusted multivariable regression association was 0.22 SD (95% CI 0.19–0.25) per SD increase in maternal BMI and the pooled MR effect (pooling the 97 variant score results from ALSPAC with the 32 variant score results from Generation R) was 0.05 SD (95%CI -0.11–0.21) per SD increase in maternal BMI (p-value for difference between the two results = 0.05). A number of sensitivity analyses exploring violation of the MR results supported our main findings. However, power was limited for some of the sensitivity tests and further studies with relevant data on maternal, offspring, and paternal genotype are required to obtain more precise (and unbiased) causal estimates.ConclusionsOur findings provide little evidence to support a strong causal intrauterine effect of incrementally greater maternal BMI resulting in greater offspring adiposity.", author = "Rebecca Richmond and Timpson, {Nicholas J.} and Janine Felix and Palmer, {Thomas Michael} and Romy Gaillard and George McMahon and {Davey Smith}, George and Vincent Jaddoe and Lawlor, {Debbie A.}", year = "2017", month = jan, day = "24", doi = "10.1371/journal.pmed.1002221", language = "English", volume = "14", journal = "PLoS Medicine", issn = "1549-1277", publisher = "Public Library of Science", number = "1", } . PLoS Medicine.

Using genetic variation to explore the causal effect of maternal pregnancy adiposity on future offspring adiposity @article{21c46cd36d93445fb4415647cd46be73, title = "Using genetic variation to explore the causal effect of maternal pregnancy adiposity on future offspring adiposity: a Mendelian randomization study", abstract = "BackgroundIt has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intra-uterine mechanisms. Our aim was to use Mendelian randomizationto investigate the causal effect of intra-uterine exposure to greater maternal body mass index (BMI) on offspring BMI and fat mass from childhood to early adulthood.Methods and FindingsWe used maternal genetic variants as instrumental variables to test the causal effect of maternal BMI in pregnancy on offspring fatness (BMI and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI)) in a Mendelian randomization approach. This was investigated, with repeat measurements, from age 7 to 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 2,521 to 3,720 for different ages). We then sought to replicate findings with results for BMI at age 6 in Generation R (N = 2,337 for replication sample; N= 6,057 for total pooled sample).In confounder adjusted multivariable regression in ALSPAC, a 1 SD (equivalent of 3.7 kg/m2) increase in maternal BMI was associated with a 0.25 SD (95% confidence interval (CI) = 0.21, 0.29) increase in offspring BMI at age 7, with similar results at later ages and when FMI was used as the outcome.A weighted genetic risk score was generated from 32 genetic variants robustly associated with BMI (minimum F-statistic = 45 in ALSPAC). The Mendelian randomization results using this genetic risk score as an instrumental variable in ALSPAC were close to the null at all ages (e.g. 0.04 SD (95% CI -0.21, 0.30) at age 7 and 0.03 SD (95% CI -0.26, 0.32) at age 18 per SD increase in maternal BMI), which was similar when a 97 variant generic risk score was used in ALSPAC.When findings from age 7 in A 52 LSPAC were meta-analysed with those from age 6 in Generation R, the pooled confounder adjusted multivariable regression association was 0.22 SD (95%CI: 0.19, 0.25) per SD increase in maternal BMI and the pooled Mendelian randomization effect (pooling the 97 variant score results from ALSPAC with the 32 variant score results from Generation R) was 0.05 SD (95%CI: -0.11, 0.21) per SD increase in maternal BMI (p-value for difference between the two results = 0.05). A number of sensitivity analyses exploring violation of the Mendelian randomization results supported our main findings. However, power was limited for some of the sensitivity tests and further studies with relevant data on maternal, offspring (and paternal) genotype are required to obtain more precise (and unbiased) causal estimates.ConclusionsOur findings provide little evidence to support a strong causal intrauterine effect of incrementally greater maternal BMI resulting in greater offspring adiposity.", keywords = "Mendelian randomization, developmental overnutrition, ALSPAC, Generation R, meta-analysis, inter-generational", author = "Rebecca Richmond and Nicholas Timpson and Felix, {Janine F} and Palmer, {Tom M} and Romy Gaillard and George McMahon and {Davey Smith}, George and Jaddoe, {Vincent W V} and Debbie Lawlor", year = "2017", month = jan, day = "24", doi = "10.1371/journal.pmed.1002221", language = "English", volume = "14", journal = "PLoS Medicine", issn = "1549-1277", publisher = "Public Library of Science", number = "1", } . PLoS Medicine.

Dale, C.E., Fatemifar, G., Palmer, T.M., White, J., Prieto-Merino, D., Zabaneh, D., Engmann, J.E.L., Shah, T., Wong, A., Warren, H.R., et al.(2017). Causal Associations of Adiposity and Body Fat Distribution with Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus: A Mendelian Randomization Analysis . Circulation. 135. (24). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 2373-2388.

Richmond, R.C., Timpson, N.J., Felix, J.F., Palmer, T., Gaillard, R., McMahon, G., Davey Smith, G., Jaddoe, V.W., Lawlor, D.A., Richmond, R.C., et al.(2017). Using Genetic Variation to Explore the Causal Effect of Maternal Pregnancy Adiposity on Future Offspring Adiposity: A Mendelian Randomisation Study . PLoS Medicine. 14. (1).

Tillmann, T., Vaucher, J., Okbay, A., Pikhart, H., Peasey, A., Kubinova, R., Pajak, A., Tamosiunas, A., Malyutina, S., Hartwig, F.P., et al.(2017). Education and coronary heart disease: Mendelian randomisation study . BMJ (Online). 358.

Roetker, N.S., Armasu, S.M., Pankow, J.S., Lutsey, P.L., Tang, W., Rosenberg, M.A., Palmer, T.M., MacLehose, R.F., Heckbert, S.R., Cushman, M., et al.(2017). Taller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis . Journal of Thrombosis and Haemostasis. 15. (7). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1334-1343.

Palmer, T.M., Holmes, M.V., Keating, B.J., Sheehan, N.A., Palmer, T.M., Holmes, M.V., Keating, B.J., Sheehan, N.A.(2017). Correcting the Standard Errors of 2-Stage Residual Inclusion Estimators for Mendelian Randomization Studies . American Journal of Epidemiology. 186. (9). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1104-1114.

Adult height, coronary heart disease and stroke @article{91bf01760dcd4bbeb06aa2059ef549cf, title = "Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis", abstract = "Background: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis.Methods: We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D.Results: IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index (P ", author = "Eveline N{\"u}esch and Caroline Dale and Palmer, {Tom M.} and Jon White and Keating, {Brendan J.} and {van Iperen}, {Erik P. A.} and Anuj Goel and Sandosh Padmanabhan and Asselbergs, {Folkert W.} and {EPIC-Netherland Investigators} and Verschuren, {W. M.} and C. Wijmenga and {Van der Schouw}, {Y. T.} and Onland-Moret, {N. C.} and Lange, {Leslie A.} and Hovingh, {G. Kees} and Suthesh Sivapalaratnam and Morris, {Richard W.} and Whincup, {Peter H.} and Wannamethe, {Goya S.} and Gaunt, {Tom R.} and Shah Ebrahim and Laura Steel and Nikhil Nair and Reiner, {Alexander P.} and Charles Kooperberg and Wilson, {James F.} and Bolton, {Jennifer L.} and Stela McLachlan and Price, {Jacqueline F.} and Strachan, {Mark W. J.} and Robertson, {Christine M.} and Kleber, {Marcus E.} and Graciela Delgado and Winfried M{\"a}rz and Olle Melander and Dominiczak, {Anna F.} and Martin Farrall and Hugh Watkins and Maarten Leusink and {Maitland-van der Zee}, {Anke H.} and {de Groot}, {Mark C. H.} and Frank Dudbridge and Aroon Hingorani and Yoav Ben-Shlomo and Lawlor, {Debbie A.} and {UCLEB Investigators} and A. Amuzu and M. Caufield and A. Cavadino and J. Cooper and Davies, {T. L.} and {IN Day}", year = "2016", month = dec, doi = "10.1093/ije/dyv074", language = "English", volume = "45", pages = "1927--1937", journal = "International Journal of Epidemiology", issn = "0300-5771", publisher = "Oxford University Press", number = "6", } . International Journal of Epidemiology.

Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization @article{1bbec454e325404cbe5c385b6c3adfd1, title = "Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: genetic variants as instruments for circulating levels", abstract = "Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N∼900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs high (≥ 7) Gleason grade, localised vs advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/ml) on risk of high vs low grade disease as 1.14 (95% CI 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker. This article is protected by copyright. All rights reserved.", author = "Carolina Bonilla and Lewis, {Sarah J.} and Mari-Anne Rowlands and Gaunt, {Tom R.} and Smith, {George Davey} and David Gunnell and Tom Palmer and Donovan, {Jenny L.} and Hamdy, {Freddie C.} and Neal, {David E.} and Rosalind Eeles and Doug Easton and Zsofia Kote-Jarai and Olama, {Ali Amin Al} and Sara Benlloch and Kenneth Muir and Giles, {Graham G.} and Fredrik Wiklund and Henrik Gronberg and Haiman, {Christopher A.} and Johanna Schleutker and Nordestgaard, {B{\o}rge G.} and Travis, {Ruth C.} and Nora Pashayan and Kay-Tee Khaw and Stanford, {Janet L.} and Blot, {William J.} and Stephen Thibodeau and Christiane Maier and Kibel, {Adam S.} and Cezary Cybulski and Lisa Cannon-Albright and Hermann Brenner and Jong Park and Radka Kaneva and Jyotsna Batra and Teixeira, {Manuel R.} and Hardev Pandha and Mark Lathrop and Martin, {Richard M.} and Holly, {Jeff M. P.} and {PRACTICAL consortium}", note = "This is the peer reviewed version of the following article: Bonilla, C., Lewis, S. J., Rowlands, M.-A., Gaunt, T. R., Davey Smith, G., Gunnell, D., Palmer, T., Donovan, J. L., Hamdy, F. C., Neal, D. E., Eeles, R., Easton, D., Kote-Jarai, Z., Al Olama, A. A., Benlloch, S., Muir, K., Giles, G. G., Wiklund, F., Gr{\"o}nberg, H., Haiman, C. A., Schleutker, J., Nordestgaard, B. G., Travis, R. C., Pashayan, N., Khaw, K.-T., Stanford, J. L., Blot, W. J., Thibodeau, S., Maier, C., Kibel, A. S., Cybulski, C., Cannon-Albright, L., Brenner, H., Park, J., Kaneva, R., Batra, J., Teixeira, M. R., Pandha, H., the PRACTICAL consortium, Lathrop, M., Martin, R. M. and Holly, J. M. P. (2016), Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels. Int. J. Cancer, 139: 1520–1533. doi: 10.1002/ijc.30206 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/jpim.12206/abstract This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.", year = "2016", month = oct, day = "1", doi = "10.1002/ijc.30206", language = "English", volume = "139", pages = "1520--1533", journal = "International Journal of Cancer", issn = "0020-7136", publisher = "John Wiley and Sons Inc.", number = "7", } . International Journal of Cancer.

Antipsychotic prescribing in care homes before and after launch of a national dementia strategy @article{49a8b655270341309cca6efda3280409, title = "Antipsychotic prescribing in care homes before and after launch of a national dementia strategy: an observational study in English institutions over a 4-year period", abstract = "OBJECTIVES: To assess associations between the launch of the National Dementia Strategy (NDS) and antipsychotic prescribing in long-term residential care (LTC) in England.SETTING AND PARTICIPANTS: Retrospective analysis of prescribing patterns in 616 LTC institutions (31 619 residents) following launch of the NDS, using information from electronic medicines management system.PRIMARY AND SECONDARY OUTCOME MEASURES: Antipsychotic prescribing point prevalence (PP) for all residents in a cross section of LTC settings over a 4-year period following NDS launch. Secondary outcomes included dosages, length of treatment and use of recommended second-generation antipsychotics (SGAs) versus first-generation antipsychotics (FGAs). Associations between facility-level PP values and institutional characteristics, resident demographics were explored. Variations across geographical areas examined. Prescription net ingredient costs calculated.RESULTS: No statistically significant difference was observed in overall prescribing rates over the 4-year period (Kolmogorov-Smirnov (KS) test p=0.60), and there was no significant shift towards newer SGAs (KS test p=0.32). Dosages were above the maximum indicated in only 1.3% of cases, but duration of prescribing was excessive in 69.7% of cases. Care homes in the highest prescribing quintile were more likely to be located in a deprived area (rate ratio (Q5/Q1) RR=5.89, 95% CI 4.35 to 7.99), registered for dementia (RR=3.38, 95% CI 3.06 to 3.73) and those in the lowest quintile were more likely to be served by a single general practitioner (GP) practice (RR=0.48; 95% CI 0.37 to 0.63); p<0.001 all. A sixfold variation in PP levels was observed between geographical areas. The average annual expenditure on antipsychotics was £65.6 per person resident (2012 prices).CONCLUSIONS: The NDS in England was not associated with reduced PP levels or the types of antipsychotic prescribing in care homes. Further research is needed to explore why. Clear standards specifying recommended agents, dosages and length of treatment, together with routine monitoring and greater accountability for antipsychotic prescribing, may be required.", keywords = "GERIATRIC MEDICINE, PRIMARY CARE, PUBLIC HEALTH", author = "Ala Szczepura and Deidre Wild and Khan, {Amir J.} and Owen, {David W.} and Thomas Palmer and Tariq Muhammad and Clark, {Michael D.} and Clive Bowman", year = "2016", month = sep, day = "20", doi = "10.1136/bmjopen-2015-009882", language = "English", volume = "6", pages = "e009882", journal = "BMJ Open", issn = "2044-6055", publisher = "BMJ Publishing Group", number = "9", } . BMJ Open.

Antipsychotic prescribing in care homes before and after launch of a national dementia strategy @article{1cd8e589163643c48266e950f26686f5, title = "Antipsychotic prescribing in care homes before and after launch of a national dementia strategy: an observational study in English institutions over a 4-year period", abstract = "Objectives To assess associations between the launch of the National Dementia Strategy (NDS) and antipsychotic prescribing in long-term residential care (LTC) in England. Setting and participants Retrospective analysis of prescribing patterns in 616 LTC institutions (31 619 residents) following launch of the NDS, using information from electronic medicines management system. Primary and secondary outcome measures Antipsychotic prescribing point prevalence (PP) for all residents in a cross section of LTC settings over a 4-year period following NDS launch. Secondary outcomes included dosages, length of treatment and use of recommended second-generation antipsychotics (SGAs) versus first-generation antipsychotics (FGAs). Associations between facility-level PP values and institutional characteristics, resident demographics were explored. Variations across geographical areas examined. Prescription net ingredient costs calculated. Results No statistically significant difference was observed in overall prescribing rates over the 4-year period (Kolmogorov-Smirnov (KS) test p=0.60), and there was no significant shift towards newer SGAs (KS test p=0.32). Dosages were above the maximum indicated in only 1.3% of cases, but duration of prescribing was excessive in 69.7% of cases. Care homes in the highest prescribing quintile were more likely to be located in a deprived area (rate ratio (Q5/Q1) RR=5.89, 95% CI 4.35 to 7.99), registered for dementia (RR=3.38, 95% CI 3.06 to 3.73) and those in the lowest quintile were more likely to be served by a single general practitioner (GP) practice (RR=0.48; 95% CI 0.37 to 0.63); p<0.001 all. A sixfold variation in PP levels was observed between geographical areas. The average annual expenditure on antipsychotics was £65.6 per person resident (2012 prices). Conclusions The NDS in England was not associated with reduced PP levels or the types of antipsychotic prescribing in care homes. Further research is needed to explore why. Clear standards specifying recommended agents, dosages and length of treatment, together with routine monitoring and greater accountability for antipsychotic prescribing, may be required.", author = "Ala Szczepura and Diedre Wild and Amir Khan and David Owen and Palmer, {Thomas Michael} and Tariq Muhammad and Michael Clark and Clive Bowman", year = "2016", month = sep, day = "20", doi = "10.1136/bmjopen-2015-009882", language = "English", volume = "6", journal = "BMJ Open", issn = "2044-6055", publisher = "BMJ Publishing Group Ltd", number = "9", } . BMJ Open.

Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk @article{530be558f095474c82ca480d9b69b3f3, title = "Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk", abstract = "Therapeutic interventions that lower LDL-cholesterol effectively reduce the risk of coronary artery disease (CAD). However, statins, the most widely prescribed LDL-cholesterol lowering drugs, increase diabetes risk. We used genome-wide association study (GWAS) data in the public domain to investigate the relationship of LDL-C and diabetes and identify loci encoding potential drug targets for LDL-cholesterol modification without causing dysglycemia. We obtained summary-level GWAS data for LDL-C from GLGC, glycemic traits from MAGIC, diabetes from DIAGRAM and CAD from CARDIoGRAMplusC4D consortia. Mendelian randomization analyses identified a one standard deviation (SD) increase in LDL-C caused an increased risk of CAD (odds ratio [OR] 1.63 (95 % confidence interval [CI] 1.55, 1.71), which was not influenced by removing SNPs associated with diabetes. LDL-C/CAD-associated SNPs showed consistent effect directions (binomial P = 6.85 × 10−5). Conversely, a 1-SD increase in LDL-C was causally protective of diabetes (OR 0.86; 95 % CI 0.81, 0.91), however LDL-cholesterol/diabetes-associated SNPs did not show consistent effect directions (binomial P = 0.15). HMGCR, our positive control, associated with LDL-C, CAD and a glycemic composite (derived from GWAS meta-analysis of four glycemic traits and diabetes). In contrast, PCSK9, APOB, LPA, CETP, PLG, NPC1L1 and ALDH2 were identified as “druggable” loci that alter LDL-C and risk of CAD without displaying associations with dysglycemia. In conclusion, LDL-C increases the risk of CAD and the relationship is independent of any association of LDL-C with diabetes. Loci that encode targets of emerging LDL-C lowering drugs do not associate with dysglycemia, and this provides provisional evidence that new LDL-C lowering drugs (such as PCSK9 inhibitors) may not influence risk of diabetes.", author = "Vinicius Tragante and Asselbergs, {Folkert W.} and Swerdlow, {Daniel I.} and Palmer, {Tom M.} and Moore, {Jason H.} and {de Bakker}, {Paul I.W.} and Keating, {Brendan J.} and Holmes, {Michael V.}", year = "2016", month = may, day = "1", doi = "10.1007/s00439-016-1647-9", language = "English", volume = "135", pages = "453--467", journal = "Human Genetics", issn = "0340-6717", publisher = "Springer Berlin Heidelberg", number = "5", } . Human Genetics.

Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk @article{8f223b45c6934bdeaa461197a92bb93c, title = "Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk", abstract = "Therapeutic interventions that lower LDL-cholesterol effectively reduce the risk of coronary artery disease (CAD). However, statins, the most widely prescribed LDL-cholesterol lowering drugs, increase diabetes risk. We used genome-wide association study (GWAS) data in the public domain to investigate the relationship of LDL-C and diabetes and identify loci encoding potential drug targets for LDL-cholesterol modification without causing dysglycemia. We obtained summary-level GWAS data for LDL-C from GLGC, glycemic traits from MAGIC, diabetes from DIAGRAM and CAD from CARDIoGRAMplusC4D consortia. Mendelian randomization analyses identified a one standard deviation (SD) increase in LDL-C caused an increased risk of CAD (odds ratio [OR] 1.63 (95 % confidence interval [CI] 1.55, 1.71), which was not influenced by removing SNPs associated with diabetes. LDL-C/CAD-associated SNPs showed consistent effect directions (binomial P = 6.85 × 10−5). Conversely, a 1-SD increase in LDL-C was causally protective of diabetes (OR 0.86; 95 % CI 0.81, 0.91), however LDL-cholesterol/diabetes-associated SNPs did not show consistent effect directions (binomial P = 0.15). HMGCR, our positive control, associated with LDL-C, CAD and a glycemic composite (derived from GWAS meta-analysis of four glycemic traits and diabetes). In contrast, PCSK9, APOB, LPA, CETP, PLG, NPC1L1 and ALDH2 were identified as “druggable” loci that alter LDL-C and risk of CAD without displaying associations with dysglycemia. In conclusion, LDL-C increases the risk of CAD and the relationship is independent of any association of LDL-C with diabetes. Loci that encode targets of emerging LDL-C lowering drugs do not associate with dysglycemia, and this provides provisional evidence that new LDL-C lowering drugs (such as PCSK9 inhibitors) may not influence risk of diabetes.", author = "Vinicius Tragante and Asselbergs, {Folkert W.} and Swerdlow, {Daniel I.} and Palmer, {Tom M.} and Moore, {Jason H.} and Bakker, {Paul I. W.} and Keating, {Brendan J.} and Holmes, {Michael V.}", note = "{\textcopyright} The Author(s) 2016. This article is published with open access at Springerlink.com", year = "2016", month = may, doi = "10.1007/s00439-016-1647-9", language = "English", volume = "135", pages = "453--467", journal = "Human Genetics", issn = "1432-1203", publisher = "Springer Science and Business Media Deutschland GmbH", number = "5", } . Human Genetics.

Plasma urate concentration and risk of coronary heart disease @article{45f95314bb13447bb8600276dfc96172, title = "Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis", abstract = "SummaryBackgroundIncreased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis.MethodsWe first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy.FindingsIn the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04–1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08–1·29), 1·10 (1·00–1·22), and 1·05 (0·92–1·20), respectively, per 1 SD increment in plasma urate.InterpretationConventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions.", author = "Jon White and Reecha Sofat and Gibran Hemani and Tina Shah and Jorgen Engmann and Caroline Dale and Sonia Shah and Kruger, {Felix A.} and Claudia Giambartolomei and Swerdlow, {Daniel I.} and Tom Palmer and Stela McLachlan and Claudia Langenberg and Delilah Zabaneh and Ruth Lovering and Alana Cavadino and Barbara Jefferis and Chris Finan and Andrew Wong and Antoinette Amuzu and Ken Ong and Gaunt, {Tom R.} and Helen Warren and Teri-Louise Davies and Fotios Drenos and Jackie Cooper and Shah Ebrahim and Lawlor, {Debbie A.} and Talmud, {Philippa J.} and Humphries, {Steve E.} and Christine Power and Elina Hypponen and Marcus Richards and Rebecca Hardy and Diana Kuh and Nicholas Wareham and Yoav Ben-Shlomo and Day, {Ian N.} and Peter Whincup and Richard Morris and Strachan, {Mark W. J.} and Jacqueline Price and Meena Kumari and Mika Kivimaki and Vincent Plagnol and Whittaker, {John C.} and Smith, {George Davey} and Frank Dudbridge and Casas, {Juan P.} and Holmes, {Michael V.} and Hingorani, {Aroon D.}", note = "{\textcopyright} White et al. Open Access article distributed under the terms of CC BY.", year = "2016", month = apr, doi = "10.1016/S2213-8587(15)00386-1", language = "English", volume = "4", pages = "327--336", journal = "The Lancet Diabetes and Endocrinology", issn = "2213-8587", publisher = "Elsevier Limited", number = "4", } . The Lancet Diabetes and Endocrinology.

Plasma urate concentration and risk of coronary heart disease @article{594f41bd52f54ab6b62f90a548818d31, title = "Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis", abstract = "BACKGROUND: Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis.METHODS: We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy.FINDINGS: In the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04-1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08-1·29), 1·10 (1·00-1·22), and 1·05 (0·92-1·20), respectively, per 1 SD increment in plasma urate.INTERPRETATION: Conventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions.FUNDING: UK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.", author = "Jon White and Reecha Sofat and Gibran Hemani and Tina Shah and Jorgen Engmann and Caroline Dale and Sonia Shah and Kruger, {Felix A} and Claudia Giambartolomei and Swerdlow, {Daniel I} and Tom Palmer and Stela McLachlan and Claudia Langenberg and Delilah Zabaneh and Ruth Lovering and Alana Cavadino and Barbara Jefferis and Chris Finan and Andrew Wong and Antoinette Amuzu and Ken Ong and Gaunt, {Tom R} and Helen Warren and Teri-Louise Davies and Fotios Drenos and Jackie Cooper and Shah Ebrahim and Lawlor, {Debbie A} and Talmud, {Philippa J} and Humphries, {Steve E} and Christine Power and Elina Hypponen and Marcus Richards and Rebecca Hardy and Diana Kuh and Nicholas Wareham and Yoav Ben-Shlomo and Day, {Ian N} and Peter Whincup and Richard Morris and Strachan, {Mark W J} and Jacqueline Price and Meena Kumari and Mika Kivimaki and Vincent Plagnol and Whittaker, {John C} and Smith, {George Davey} and Frank Dudbridge and Casas, {Juan P} and Holmes, {Michael V} and {UCLEB (University College London-London School of Hygiene & Tropical Medicine-Edinburgh-Bristol Consortium}", note = "Copyright {\textcopyright} 2016 White et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.", year = "2016", month = apr, doi = "10.1016/S2213-8587(15)00386-1", language = "English", volume = "4", pages = "327--336", journal = "Lancet Diabetes and Endocrinology", issn = "2213-8587", publisher = "Lancet Publishing Group", number = "4", } . Lancet Diabetes and Endocrinology.

Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight @article{b448900c2db24c228a2dbef07f0ccc8b, title = "Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight", abstract = "ImportanceNeonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.ObjectiveTo test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.Design, Setting, and ParticipantsMendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30 487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.ExposuresGenetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.Main Outcome and MeasureOffspring birth weight from 18 studies.ResultsAmong the 30 487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10−14) and −4 g (95% CI, −6 to −2g) per SBP-raising allele (P = 1×10−5), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, −394 to −21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.Conclusions and RelevanceIn this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.", author = "Jessica Tyrrell and Richmond, {Rebecca C} and Palmer, {Tom M} and Bjarke Feenstra and Janani Rangarajan and Sarah Metrusky and Alana Cavadino and Lavinia Paternoster and Armstrong, {Loren L} and {De Silva}, {N M G} and Wood, {Andrew R} and Momoko Horikoshi and Frank Geller and Ronnie Myhre and Bradfield, {Jonathan P} and Eskil Kreiner-M{\o}ller and Ville Huikari and Painter, {Jodie N} and Hottenga, {Jouke Jan} and Catherine Allard and Berry, {Diane J} and Luigi Bouchard and Shikta Das and Evans, {David M} and Hakon Hakonarson and Hayes, {M Geoffrey} and Jani Heikkinen and Albert Hofman and Knight, {Bridget A} and Lind, {Penelope A} and McCarthy, {Mark I} and George McMahon and Medland, {Sarah E} and Mads Melbye and Morris, {Andrew P} and Michael Nodzenski and Christoph Reichetzeder and Ring, {Susan M} and Sylvain Sebed and Verena Sengpiel and Sorensen, {Thorkild I A} and Gonneke Willemsen and {de Geus}, {Eco J C} and Martin, {Nicholas G} and Spector, {Tim D} and Christine Power and Marjo-Riitta J{\"a}rvelin and Hans Bisgaard and Grant, {Struan F A} and Nohr, {Ellen Aagaard} and VW Jaddoe and Bo Jacobsson and Murray, {Jeffrey C} and Berthold Hocher and Hattersley, {Andrew T} and Scholtens, {Denise M} and {Davey Smith}, George and Marie-France Hivert and Felix, {Janine F} and Elina Hypp{\"o}nen and Lowe, {William L.} and Frayling, {Timothy M} and Lawlor, {Debbie A} and Freathy, {Rachel M}", year = "2016", month = mar, day = "15", doi = "10.1001/jama.2016.1975", language = "English", volume = "315", pages = "1129--1140", journal = "JAMA - Journal of the American Medical Association", issn = "0098-7484", publisher = "American Medical Association", number = "11", } . JAMA - Journal of the American Medical Association.

Genetic evidence for causal relationships between maternal obesity-related traits and birth weight @article{923db04c8e324160a067b7bc20eefc1d, title = "Genetic evidence for causal relationships between maternal obesity-related traits and birth weight", abstract = "Importance  Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.Objective  To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.Design, Setting, and Participants  Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30 487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. Exposures  Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.Main Outcome and Measure  Offspring birth weight from 18 studies.Results  Among the 30 487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10−14) and −4 g (95% CI, −6 to −2g) per SBP-raising allele (P = 1×10−5), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, −394 to −21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.Conclusions and Relevance  In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.", author = "J. Tyrrell and Richmond, {R. C.} and Tom Palmer", year = "2016", month = mar, day = "15", doi = "10.1001/jama.2016.1975", language = "English", volume = "315", pages = "1129--1140", journal = "Journal of the American Medical Association", issn = "0098-7484", publisher = "American Medical Association", number = "11", } . Journal of the American Medical Association.

Lipids, obesity and gallbladder disease in women @article{df3cb580c28447c6a216d249c2c6b188, title = "Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array", abstract = "Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, gender, population, obesity and diabetes, and represents a major economic burden. Although gallstones are composed of cholesterol by-products and are associated with obesity, presumed causal pathways remain unproven, although BMI reduction is typically recommended. We performed genetic studies to discover candidate genes and define pathways involved in GBD. We genotyped 15 241 women of European ancestry from three cohorts, including 3216 with GBD, using the Human cardiovascular disease (HumanCVD) BeadChip containing up to ~53 000 single-nucleotide polymorphisms (SNPs). Effect sizes with P-values for development of GBD were generated. We identify two new loci associated with GBD, GCKR rs1260326:T>C (P=5.88 × 10(-7), {\ss}=-0.146) and TTC39B rs686030:C>A (P=6.95x10(-7), {\ss}=0.271) and detect four independent SNP effects in ABCG8 rs4953023:G>A (P=7.41 × 10(-47), {\ss}=0.734), ABCG8 rs4299376:G(>)T (P=2.40 × 10(-18), {\ss}=0.278), ABCG5 rs6544718:T>C (P=2.08 × 10(-14), {\ss}=0.044) and ABCG5 rs6720173:G>C (P=3.81 × 10(-12), {\ss}(=)0.262) in conditional analyses taking genotypes of rs4953023:G>A as a covariate. We also delineate the risk effects among many genotypes known to influence lipids. These data, from the largest GBD genetic study to date, show that specific, mainly hepatocyte-centred, components of lipid metabolism are important to GBD risk in women. We discuss the potential pharmaceutical implications of our findings.European Journal of Human Genetics advance online publication, 29 April 2015; doi:10.1038/ejhg.2015.63.", author = "Santiago Rodriguez and Gaunt, {Tom R} and Yiran Guo and Jie Zheng and Barnes, {Michael R} and Weihang Tang and Fazal Danish and Andrew Johnson and Castillo, {Berta A} and Li, {Yun R} and Hakon Hakonarson and Buxbaum, {Sarah G} and Tom Palmer and Tsai, {Michael Y} and Lange, {Leslie A} and Shah Ebrahim and {Davey Smith}, George and Lawlor, {Debbie A} and Folsom, {Aaron R} and Ron Hoogeveen and Alex Reiner and Brendan Keating and Day, {Ian Nm}", year = "2016", month = jan, doi = "10.1038/ejhg.2015.63", language = "English", volume = "24", pages = "106--112", journal = "European Journal of Human Genetics", issn = "1018-4813", publisher = "Springer Nature", number = "1", } . European Journal of Human Genetics.

Lipids, obesity and gallbladder disease in women @article{47060b2fafda47928781ce59ad54f9b5, title = "Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array", abstract = "Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, gender, population, obesity and diabetes, and represents a major economic burden. Although gallstones are composed of cholesterol by-products and are associated with obesity, presumed causal pathways remain unproven, although BMI reduction is typically recommended. We performed genetic studies to discover candidate genes and define pathways involved in GBD. We genotyped 15 241 women of European ancestry from three cohorts, including 3216 with GBD, using the Human cardiovascular disease (HumanCVD) BeadChip containing up to ~53 000 single-nucleotide polymorphisms (SNPs). Effect sizes with P-values for development of GBD were generated. We identify two new loci associated with GBD, GCKR rs1260326:T>C (P=5.88 × 10(-7), {\ss}=-0.146) and TTC39B rs686030:C>A (P=6.95x10(-7), {\ss}=0.271) and detect four independent SNP effects in ABCG8 rs4953023:G>A (P=7.41 × 10(-47), {\ss}=0.734), ABCG8 rs4299376:G(>)T (P=2.40 × 10(-18), {\ss}=0.278), ABCG5 rs6544718:T>C (P=2.08 × 10(-14), {\ss}=0.044) and ABCG5 rs6720173:G>C (P=3.81 × 10(-12), {\ss}(=)0.262) in conditional analyses taking genotypes of rs4953023:G>A as a covariate. We also delineate the risk effects among many genotypes known to influence lipids. These data, from the largest GBD genetic study to date, show that specific, mainly hepatocyte-centred, components of lipid metabolism are important to GBD risk in women. We discuss the potential pharmaceutical implications of our findings.European Journal of Human Genetics advance online publication, 29 April 2015; doi:10.1038/ejhg.2015.63.", author = "Santiago Rodriguez and Gaunt, {Tom R.} and Yiran Guo and Jie Zheng and Barnes, {Michael R.} and Weihang Tang and Fazal Danish and Andrew Johnson and Castillo, {Berta A.} and Li, {Yun R.} and Hakon Hakonarson and Buxbaum, {Sarah G.} and Tom Palmer and Tsai, {Michael Y.} and Lange, {Leslie A.} and Shah Ebrahim and {Davey Smith}, George and Lawlor, {Debbie A.} and Folsom, {Aaron R.} and Ron Hoogeveen and Alex Reiner and Brendan Keating and Day, {Ian Nm}", year = "2016", month = jan, doi = "10.1038/ejhg.2015.63", language = "English", volume = "24", pages = "106--112", journal = "European Journal of Human Genetics", issn = "1018-4813", publisher = "Springer Nature", number = "1", } . European Journal of Human Genetics.

Rodriguez, S., Gaunt, T.R., Guo, Y., Zheng, J., Barnes, M.R., Tang, W., Danish, F., Johnson, A., Castillo, B.A., Li, Y.R., et al.(2016). Lipids, obesity and gallbladder disease in women: Insights from genetic studies using the cardiovascular gene-centric 50K SNP array . European Journal of Human Genetics. 24. (1). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 106-112.

White, J., Sofat, R., Hemani, G., Shah, T., Engmann, J., Dale, C., Shah, S., Kruger, F.A., Giambartolomei, C., Swerdlow, D.I., et al.(2016). Plasma urate concentration and risk of coronary heart disease: A Mendelian randomisation analysis . The Lancet Diabetes and Endocrinology. 4. (4). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 327-336.

Tyrrell, J., Richmond, R.C., Palmer, T.M., Feenstra, B., Rangarajan, J., Metrustry, S., Cavadino, A., Paternoster, L., Armstrong, L.L., De Silva, N.M.G., et al.(2016). Genetic evidence for causal relationships between maternal obesity-related traits and birth weight . JAMA - Journal of the American Medical Association. 315. (11). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1129-1140.

Tyrrell, J., Richmond, R.C., Palmer, T.M., Tyrrell, J., Richmond, R.C., Palmer, T.M.(2016). Erratum: Genetic evidence for causal relationships between maternal obesity-related traits and birth weight (JAMA (2016) 315:11 (1129-1140) 10.1001/JAMA.2016.1975)) . JAMA - Journal of the American Medical Association. 315. (15). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1661.

Szczepura, A., Wild, D., Khan, A.J., Owen, D.W., Palmer, T., Muhammad, T., Clark, M.D., Bowman, C., Szczepura, A., Wild, D., et al.(2016). Antipsychotic prescribing in care homes before and after launch of a national dementia strategy: an observational study in English institutions over a 4-year period . BMJ open. 6. (9). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString e009882.

Tragante, V., Asselbergs, F.W., Swerdlow, D.I., Palmer, T.M., Moore, J.H., de Bakker, P.I.W., Keating, B.J., Holmes, M.V., Tragante, V., Asselbergs, F.W., et al.(2016). Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk . Human Genetics. 135. (5). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 453-467.

Bonilla, C., Lewis, S.J., Rowlands, M.-A., Gaunt, T.R., Davey Smith, G., Gunnell, D., Palmer, T., Donovan, J.L., Hamdy, F.C., Neal, D.E., et al.(2016). Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels . International Journal of Cancer. 139. (7). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1520-1533.

N&#252;esch, E., Dale, C., Palmer, T.M., White, J., Keating, B.J., van Iperen, E.P.A., Goel, A., Padmanabhan, S., Asselbergs, F.W., Verschuren, W.M., et al.(2016). Adult height, coronary heart disease and stroke: A multi-locus Mendelian randomization meta-analysis . International Journal of Epidemiology. 45. (6). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1927-1937.

Effect of smoking on physical and cognitive capability in later life @article{5b4fcd35aad240b4b6ee0aab50d50978, title = "Effect of smoking on physical and cognitive capability in later life: a multicohort study using observational and genetic approaches", abstract = "Objectives The observed associations between smoking and functional measures at older ages are vulnerable to bias and confounding. Mendelian randomisation (MR) uses genotype as an instrumental variable to estimate unconfounded causal associations. We conducted a meta-analysis of the observational associations and implemented an MR approach using the smoking-related single nucleotide polymorphism rs16969968 to explore their causal nature.Setting 9 British cohorts belonging to the HALCyon collaboration.Participants Individual participant data on N=26 692 individuals of European ancestry (N from earliest phase analysed per study) of mean ages 50–79 years were available for inclusion in observational meta-analyses of the primary outcomes.Primary outcomes Physical capability, cognitive capability and cognitive decline. The smoking exposures were cigarettes per day, current versus ex-smoker, current versus never smoker and ever versus never smoker.Results In observational analyses current and ever smoking were generally associated with poorer physical and cognitive capability. For example, current smokers had a general fluid cognition score which was 0.17 z-score units (95% CI −0.221 to −0.124) lower than ex-smokers in cross-sectional analyses. Current smokers had a walk speed which was 0.25 z-score units lower than never smokers (95% CI −0.338 to −0.170). An MR instrumental variable approach for current versus ex-smoker and number of cigarettes smoked per day produced CIs which neither confirmed nor refuted the observational estimates. The number of genetic associations stratified by smoking status were consistent with type I error.Conclusions Our observational analysis supports the hypothesis that smoking is detrimental to physical and cognitive capability. Further studies are needed for a suitably powered MR approach.", author = "Teri-Louise North and Palmer, {Tom M.} and Lewis, {Sarah J.} and Rachel Cooper and Chris Power and Alison Pattie and Starr, {John M.} and Deary, {Ian J.} and Martin, {Richard M.} and {Aihie Sayer}, Avan and Meena Kumari and Cyrus Cooper and Mika Kivimaki and Diana Kuh and Yoav Ben-Shlomo and Day, {Ian N. M.}", year = "2015", month = dec, day = "15", doi = "10.1136/bmjopen-2015-008393", language = "English", volume = "5", journal = "BMJ Open", issn = "2044-6055", publisher = "BMJ Publishing Group Ltd", number = "12", } . BMJ Open.

A Mendelian randomization study of circulating uric acid and type 2 diabetes @article{f092618587334884b6ae72eb9280af3c, title = "A Mendelian randomization study of circulating uric acid and type 2 diabetes", abstract = "We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid associated loci. We used data of the EPIC-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident type 2 diabetes cases were ascertained. Higher uric acid associated with higher diabetes risk following adjustment for confounders, with a HR of 1.20 (95%CI: 1.11,1.30) per 59.48 µmol/L (1 mg/dL) uric acid. The genetic score raised uric acid by 17 µmol/L (95%CI: 15,18) per SD increase, and explained 4% of uric acid variation. Using the genetic score to estimate the unconfounded effect found that a 59.48 µmol/L higher uric acid concentration did not have a causal effect on diabetes (HR 1.01, 95%CI: 0.87,1.16). Including data from DIAGRAM consortium, increasing our dataset to 41,508 diabetes cases, the summary OR estimate was 0.99 (95%CI: 0.92, 1.06). In conclusion, our study does not support a causal effect of circulating uric acid on diabetes risk. Uric acid lowering therapies may therefore not be beneficial in reducing diabetes risk.", author = "Ivonne Sluijs and Holmes, {Michael V.} and {van der Schouw}, {Yvonne T.} and Beulens, {Joline W. J.} and Asselbergs, {Folkert W.} and Huerta, {Jos{\'e} Mar{\'i}a} and Palmer, {Tom M.} and Larraitz Arriola and Beverley Balkau and Aurelio Barricarte and Heiner Boeing and Fran{\c c}oise Clavel-Chapelon and Guy Fagherazzi and Franks, {Paul W.} and Diana Gavrila and Rudolf Kaaks and Khaw, {Kay Tee} and Tilman K{\"u}hn and Esther Molina-Montes and Mortensen, {Lotte Maxild} and Nilsson, {Peter M.} and Kim Overvad and Domenico Palli and Salvatore Panico and Quir{\'o}s, {J. Ram{\'o}n} and Olov Rolandsson and Carlotta Sacerdote and N{\'u}ria Sala and Schmidt, {Julie A.} and Scott, {Robert A.} and Sabina Sieri and Nadia Slimani and Spijkerman, {Annemieke Mw} and Anne Tjonneland and {Travis Dphil}, {Ruth C.} and Rosario Tumino and {van der A}, {Daphne L.} and Sharp, {Stephen J.} and Forouhi, {Nita G.} and Claudia Langenberg and Elio Riboli and Wareham, {Nicholas J.} and {InterAct consortium}", note = "This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http://diabetes.diabetesjournals.org/content/64/8/3028", year = "2015", month = aug, doi = "10.2337/db14-0742", language = "English", volume = "64", pages = "3028--3036", journal = "Diabetes", issn = "0012-1797", publisher = "American Diabetes Association Inc.", number = "8", } . Diabetes.

A Mendelian randomization study of circulating uric acid and type 2 diabetes @article{5744ec56db6c45a79c2c60c7c07b9ad8, title = "A Mendelian randomization study of circulating uric acid and type 2 diabetes", abstract = "We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid associated loci. We used data of the EPIC-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident type 2 diabetes cases were ascertained. Higher uric acid associated with higher diabetes risk following adjustment for confounders, with a HR of 1.20 (95%CI: 1.11,1.30) per 59.48 µmol/L (1 mg/dL) uric acid. The genetic score raised uric acid by 17 µmol/L (95%CI: 15,18) per SD increase, and explained 4% of uric acid variation. Using the genetic score to estimate the unconfounded effect found that a 59.48 µmol/L higher uric acid concentration did not have a causal effect on diabetes (HR 1.01, 95%CI: 0.87,1.16). Including data from DIAGRAM consortium, increasing our dataset to 41,508 diabetes cases, the summary OR estimate was 0.99 (95%CI: 0.92, 1.06). In conclusion, our study does not support a causal effect of circulating uric acid on diabetes risk. Uric acid lowering therapies may therefore not be beneficial in reducing diabetes risk.", author = "Ivonne Sluijs and Holmes, {Michael V.} and {van der Schouw}, {Yvonne T.} and Beulens, {Joline W. J.} and Asselbergs, {Folkert W.} and Huerta, {Jos{\'e} Mar{\'i}a} and Palmer, {Tom M.} and Larraitz Arriola and Beverley Balkau and Aurelio Barricarte and Heiner Boeing and Fran{\c c}oise Clavel-Chapelon and Guy Fagherazzi and Franks, {Paul W.} and Diana Gavrila and Rudolf Kaaks and Khaw, {Kay Tee} and Tilman K{\"u}hn and Esther Molina-Montes and Mortensen, {Lotte Maxild} and Nilsson, {Peter M.} and Kim Overvad and Domenico Palli and Salvatore Panico and Quir{\'o}s, {J. Ram{\'o}n} and Olov Rolandsson and Carlotta Sacerdote and N{\'u}ria Sala and Schmidt, {Julie A.} and Scott, {Robert A.} and Sabina Sieri and Nadia Slimani and Spijkerman, {Annemieke Mw} and Anne Tjonneland and {Travis Dphil}, {Ruth C.} and Rosario Tumino and {van der A}, {Daphne L.} and Sharp, {Stephen J.} and Forouhi, {Nita G.} and Claudia Langenberg and Elio Riboli and Wareham, {Nicholas J.} and InterAct consortium", note = "This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http://diabetes.diabetesjournals.org/content/64/8/3028", year = "2015", month = aug, doi = "10.2337/db14-0742", language = "English", volume = "64", pages = "3028--3036", journal = "Diabetes", issn = "0012-1797", publisher = "American Diabetes Association Inc.", number = "8", } . Diabetes.

Dmitry Shungin, Marilyn C. Cornelis, Kimon Divaris, Birte Holtfreter, John R. Shaffer, Yau-Hua Yu, Silvana P Barros, James D. Beck, Reiner Biffar, Eric A. Boerwinkle, et al.(2015). Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium . International Journal of Epidemiology. 44. (2). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 638--650. Oxford University Press

Adult height, coronary heart disease and stroke @article{2c62c1419d95425692bf38e7b4e207b0, title = "Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis", abstract = "BACKGROUND: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis.METHODS: We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D.RESULTS: IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index (P < 0.001), triglycerides (P < 0.001), non high-density (non-HDL) cholesterol (P < 0.001), C-reactive protein (P = 0.042), and systolic blood pressure (P = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity (P < 0.001 for both).CONCLUSIONS: Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure.", author = "Eveline N{\"u}esch and Caroline Dale and Palmer, {Tom M} and Jon White and Keating, {Brendan J} and {van Iperen}, {Erik Pa} and Anuj Goel and Sandosh Padmanabhan and Asselbergs, {Folkert W} and Verschuren, {W M} and C Wijmenga and {Van der Schouw}, {Y T} and Onland-Moret, {N C} and Lange, {Leslie A} and Hovingh, {G K} and Suthesh Sivapalaratnam and Morris, {Richard W} and Whincup, {Peter H} and Wannamethe, {Goya S} and Gaunt, {Tom R} and Shah Ebrahim and Laura Steel and Nikhil Nair and Reiner, {Alexander P} and Charles Kooperberg and Bolton, {Jennifer L} and Stela McLachlan and Price, {Jacqueline F} and Strachan, {Mark Wj} and Robertson, {Christine M} and Kleber, {Marcus E} and Graciela Delgado and Yoav Ben-Shlomo and Lawlor, {Debbie A} and J Cooper and Davies, {T L} and F Drenos and M Kivimaki and S Shah and H Warren and A Wong and {Davey Smith}, George and Leon, {David A} and {EPIC-Netherland Investigators}", note = "{\textcopyright} The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.", year = "2015", month = may, day = "15", doi = "10.1093/ije/dyv074", language = "English", journal = "International Journal of Epidemiology", issn = "0300-5771", publisher = "Oxford University Press", } . International Journal of Epidemiology.

Using genetics to test the causal relationship of total adiposity and periodontitis @article{03618e21d6e34f0f9cffe52672b4e906, title = "Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium", abstract = "BACKGROUND: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI).METHODS: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49,066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17,672/31,394 with/without periodontitis); 68,761 participants with BMI and genotype data; and 57,871 participants (18,881/38,990 with/without periodontitis) with data on BMI and periodontitis.RESULTS: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI:1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data.CONCLUSIONS: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals.", keywords = "Adiposity, Adult, Age Distribution, Aged, Body Mass Index, Cohort Studies, Female, Genotype, Humans, Life Style, Male, Membrane Proteins, Mendelian Randomization Analysis, Middle Aged, Obesity, Periodontitis, Polymorphism, Single Nucleotide, Proteins, Receptor, Melanocortin, Type 4, Young Adult, Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't", author = "Dmitry Shungin and Cornelis, {Marilyn C} and Kimon Divaris and Birte Holtfreter and Shaffer, {John R} and Yau-Hua Yu and Barros, {Silvana P} and Beck, {James D} and Reiner Biffar and Boerwinkle, {Eric A} and Crout, {Richard J} and Andrea Ganna and Goran Hallmans and George Hindy and Hu, {Frank B} and Peter Kraft and McNeil, {Daniel W} and Olle Melander and Moss, {Kevin L} and North, {Kari E} and Marju Orho-Melander and Pedersen, {Nancy L} and Ridker, {Paul M} and Rimm, {Eric B} and Rose, {Lynda M} and Gull Rukh and Alexander Teumer and Weyant, {Robert J} and Chasman, {Daniel I} and Kaumudi Joshipura and Thomas Kocher and Magnusson, {Patrik K E} and Marazita, {Mary L} and Peter Nilsson and Steve Offenbacher and {Davey Smith}, George and Pernilla Lundberg and Palmer, {Tom M} and Timpson, {Nicholas J} and Ingegerd Johansson and Franks, {Paul W}", note = "{\textcopyright} The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.", year = "2015", month = apr, doi = "10.1093/ije/dyv075", language = "English", volume = "44", pages = "638--50", journal = "International Journal of Epidemiology", issn = "0300-5771", publisher = "Oxford University Press", number = "2", } . International Journal of Epidemiology.

Mendelian randomization of blood lipids for coronary heart disease @article{1ac01fb1eae5433b8607a2baaa4e055d, title = "Mendelian randomization of blood lipids for coronary heart disease", abstract = "AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.", keywords = "Lipids, Heart disease, Mendelian randomization, Aetiology, Epidemiology", author = "Holmes, {Michael V.} and Asselbergs, {Folkert W.} and Palmer, {Tom M.} and Fotios Drenos and Lanktree, {Matthew B.} and Nelson, {Christopher P.} and Dale, {Caroline E.} and Sandosh Padmanabhan and Chris Finan and Swerdlow, {Daniel I.} and Vinicius Tragante and {van Iperen}, {Erik P. A.} and Suthesh Sivapalaratnam and Sonia Shah and Elbers, {Clara C.} and Tina Shah and Jorgen Engmann and Claudia Giambartolomei and Jon White and Delilah Zabaneh and Reecha Sofat and Stela McLachlan and Doevendans, {Pieter A.} and Balmforth, {Anthony J.} and Hall, {Alistair S.} and North, {Kari E.} and Berta Almoguera and Hoogeveen, {Ron C.} and Mary Cushman and Myriam Fornage and Patel, {Sanjay R.} and Susan Redline and Siscovick, {David S.} and Tsai, {Michael Y.} and Karczewski, {Konrad J.} and Hofker, {Marten H.} and Verschuren, {W. Monique} and Bots, {Michiel L.} and {van der Schouw}, {Yvonne T.} and Olle Melander and Dominiczak, {Anna F.} and Richard Morris and Yoav Ben-Shlomo and Jackie Price and Meena Kumari and Jens Baumert and Annette Peters and Barbara Thorand and Wolfgang Koenig and Gaunt, {Tom R.} and {UCLEB Consortium}", note = " {\textcopyright} The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.", year = "2015", month = mar, day = "1", doi = "10.1093/eurheartj/eht571", language = "English", volume = "36", pages = "539--550", journal = "European Heart Journal", issn = "0195-668X", publisher = "Oxford University Press", number = "9", } . European Heart Journal.

Systematic review and metaanalysis of genetic association studies of urinary symptoms and prolapse in women @article{7044aebdbf3e457e99a18427f6aefd87, title = "Systematic review and metaanalysis of genetic association studies of urinary symptoms and prolapse in women", abstract = "Objective Family studies and twin studies demonstrate that lower urinary tract symptoms and pelvic organ prolapse are heritable. This review aimed to identify genetic polymorphisms tested for an association with lower urinary tract symptoms or prolapse, and to assess the strength, consistency, and risk of bias among reported associations. Study Design PubMed and HuGE Navigator were searched up to May 1, 2014, using a combination of genetic and phenotype key words, including {"}nocturia,{"} {"}incontinence,{"} {"}overactive bladder,{"} {"}prolapse,{"} and {"}enuresis.{"} Major genetics, urology, and gynecology conference abstracts were searched from 2005 through 2013. We screened 889 abstracts, and retrieved 78 full texts. In all, 27 published and 7 unpublished studies provided data on polymorphisms in or near 32 different genes. Fixed and random effects metaanalyses were conducted using codominant models of inheritance. We assessed the credibility of pooled associations using the interim Venice criteria. Results In pooled analysis, the rs4994 polymorphism of the ADRB3 gene was associated with overactive bladder (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.7-3.6; n = 419). The rs1800012 polymorphism of the COL1A1 gene was associated with prolapse (OR, 1.3; 95% CI, 1.0-1.7; n = 838) and stress urinary incontinence (OR, 2.1; 95% CI, 1.4-3.2; n = 190). Other metaanalyses, including those for polymorphisms of COL3A1, LAMC1, MMP1, MMP3, and MMP9 did not show significant effects. Many studies were at high risk of bias from genotyping error or population stratification. Conclusion These metaanalyses provide moderate epidemiological credibility for associations of variation in ADRB3 with overactive bladder, and variation of COL1A1 with prolapse. Clinical testing for any of these polymorphisms cannot be recommended based on current evidence.", keywords = "genetics, incontinence, lower urinary tract symptoms, overactive bladder, prolapse, systematic review", author = "Rufus Cartwright and Kirby, {Anna C.} and Tikkinen, {Kari A.O.} and Altaf Mangera and Gans Thiagamoorthy and Prabhakar Rajan and Jori Pesonen and Chris Ambrose and Juan Gonzalez-Maffe and Phillip Bennett and Tom Palmer and Andrew Walley and J{\"a}rvelin, {Marjo Riitta} and Chris Chapple and Vik Khullar", year = "2015", month = feb, day = "1", doi = "10.1016/j.ajog.2014.08.005", language = "English", volume = "212", pages = "199.e1--199.e24", journal = "American Journal of Obstetrics and Gynecology", issn = "0002-9378", publisher = "Elsevier Inc.", number = "2", } . American Journal of Obstetrics and Gynecology.

Systematic review and metaanalysis of genetic association studies of urinary symptoms and prolapse in women @article{c621d6ad0c934f5e958bed3afa5c466e, title = "Systematic review and metaanalysis of genetic association studies of urinary symptoms and prolapse in women", abstract = "OBJECTIVE: Family studies and twin studies demonstrate that lower urinary tract symptoms and pelvic organ prolapse are heritable. This review aimed to identify genetic polymorphisms tested for an association with lower urinary tract symptoms or prolapse, and to assess the strength, consistency, and risk of bias among reported associations.STUDY DESIGN: PubMed and HuGE Navigator were searched up to May 1, 2014, using a combination of genetic and phenotype key words, including {"}nocturia,{"} {"}incontinence,{"} {"}overactive bladder,{"} {"}prolapse,{"} and {"}enuresis.{"} Major genetics, urology, and gynecology conference abstracts were searched from 2005 through 2013. We screened 889 abstracts, and retrieved 78 full texts. In all, 27 published and 7 unpublished studies provided data on polymorphisms in or near 32 different genes. Fixed and random effects metaanalyses were conducted using codominant models of inheritance. We assessed the credibility of pooled associations using the interim Venice criteria.RESULTS: In pooled analysis, the rs4994 polymorphism of the ADRB3 gene was associated with overactive bladder (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.7-3.6; n = 419). The rs1800012 polymorphism of the COL1A1 gene was associated with prolapse (OR, 1.3; 95% CI, 1.0-1.7; n = 838) and stress urinary incontinence (OR, 2.1; 95% CI, 1.4-3.2; n = 190). Other metaanalyses, including those for polymorphisms of COL3A1,LAMC1,MMP1,MMP3, and MMP9 did not show significant effects. Many studies were at high risk of bias from genotyping error or population stratification.CONCLUSION: These metaanalyses provide moderate epidemiological credibility for associations of variation in ADRB3 with overactive bladder, and variation of COL1A1 with prolapse. Clinical testing for any of these polymorphisms cannot be recommended based on current evidence.", keywords = "Female, Genetic Association Studies, Genotype, Humans, Lower Urinary Tract Symptoms, Odds Ratio, Pelvic Organ Prolapse", author = "Rufus Cartwright and Kirby, {Anna C.} and Tikkinen, {Kari A. O.} and Altaf Mangera and Gans Thiagamoorthy and Prabhakar Rajan and Jori Pesonen and Chris Ambrose and Juan Gonzalez-Maffe and Phillip Bennett and Tom Palmer and Andrew Walley and Marjo-Riitta J{\"a}rvelin and Chris Chapple and Vik Khullar", note = " Copyright {\textcopyright} 2015 The Authors. Published by Elsevier Inc. All rights reserved.", year = "2015", month = feb, doi = "10.1016/j.ajog.2014.08.005", language = "English", volume = "212", pages = "199.e1--24", journal = "American Journal of Obstetrics and Gynecology", issn = "0002-9378", publisher = "Elsevier Inc.", number = "2", } . American Journal of Obstetrics and Gynecology.

Improving health outcomes for young people with long term conditions @article{735bb96557264b9aaccc627c5e4b7a1c, title = "Improving health outcomes for young people with long term conditions", abstract = "BackgroundYoung people living with long term conditions are vulnerable to health service disengagement. This endangers their long term health. Studies report requests for digital forms of communication? email, text, social media ? with their health care team. Digital clinical communication is troublesome for the UK NHS.AimIn this article we aim to present the research protocol for evaluating the impacts and outcomes of digital clinical communications for young people living with long term conditions and provide critical analysis of their use, monitoring and evaluation by NHS providers (LYNC study: Long term conditions, Young people, Networked Communications).MethodsThe research involves: (a) patient and public involvement activities with 16?24 year olds with and without long term health conditions; (b) six literature reviews; (c) case studies ? the main empirical part of the study ? and (d) synthesis and a consensus meeting. Case studies use a mixed methods design. Interviews and non-participant observation of practitioners and patients communicating in up to 20 specialist clinical settings will be combined with data, aggregated at the case level (non-identifiable patient data) on a range of clinical outcomes meaningful within the case and across cases. We will describe the use of digital clinical communication from the perspective of patients, clinical staff, support staff and managers, interviewing up to 15 young people and 15 staff per case study. Outcome data includes emergency admissions, A&E attendance and DNA (did not attend) rates. Case studies will be analysed to understand impacts of digital clinical communication on patient health outcomes, health care costs and consumption, ethics and patient safety.", author = "Griffiths, {Frances E} and Helen Atherton and Barker, {Jack R} and Cave, {Jonathan AK} and Kathryn Dennick and Peter Dowdall and Joe Fraser and Caroline Huxley and Sung-Wook Kim and Madan, {Jason J} and Harjit Matharu and Luhanga Musumadi and Palmer, {Tom M} and Moli Paul and Sailesh Sankaranarayanan and Anne-Marie Slowther and Sujan, {Mark A} and Sutcliffe, {Paul A} and Jackie Sturt", year = "2015", month = jan, day = "1", doi = "10.1177/2055207615593698", language = "English", volume = "1", journal = "Digital Health", issn = "2055-2076", publisher = "SAGE Publications Ltd", } . Digital Health.

Fitting fixed-and random-effects meta-analysis models using structural equation modeling with the sem and gsem commands @article{541a0fd7fd7c468393434f10183eaf00, title = "Fitting fixed-and random-effects meta-analysis models using structural equation modeling with the sem and gsem commands", abstract = "In this article, we demonstrate how to fit fixed-and random-effects meta-analysis, meta-regression, and multivariate outcome meta-analysis models under the structural equation modeling framework using the sem and gsem commands. While all of these models can be fit using existing user-written commands, formulating the models in the structural equation modeling framework provides deeper insight into how they work. Further, the heterogeneity test for metaregression and multivariate meta-analysis is readily available from this output.", keywords = "gsem, Meta-analysis, Meta-regression, metan, metareg, mvmeta, sem, st0398, Structural equation modeling", author = "Palmer, {Tom M.} and Sterne, {Jonathan A.C.}", year = "2015", month = jan, day = "1", language = "English", volume = "15", pages = "645--671", journal = "Stata Journal", issn = "1536-867X", publisher = "DPC Nederland", number = "3", } . Stata Journal.

Improving health outcomes for young people with long term conditions @article{50278e3b59994b53b066e410d6bda647, title = "Improving health outcomes for young people with long term conditions: The role of digital communication in current and future patient–clinician communication for NHS providers of specialist clinical services for young people – LYNC study protocol", abstract = "BackgroundYoung people living with long term conditions are vulnerable to health service disengagement. This endangers their long term health. Studies report requests for digital forms of communication? email, text, social media ? with their health care team. Digital clinical communication is troublesome for the UK NHS.AimIn this article we aim to present the research protocol for evaluating the impacts and outcomes of digital clinical communications for young people living with long term conditions and provide critical analysis of their use, monitoring and evaluation by NHS providers (LYNC study: Long term conditions, Young people, Networked Communications).MethodsThe research involves: (a) patient and public involvement activities with 16?24 year olds with and without long term health conditions; (b) six literature reviews; (c) case studies ? the main empirical part of the study ? and (d) synthesis and a consensus meeting. Case studies use a mixed methods design. Interviews and non-participant observation of practitioners and patients communicating in up to 20 specialist clinical settings will be combined with data, aggregated at the case level (non-identifiable patient data) on a range of clinical outcomes meaningful within the case and across cases. We will describe the use of digital clinical communication from the perspective of patients, clinical staff, support staff and managers, interviewing up to 15 young people and 15 staff per case study. Outcome data includes emergency admissions, A&E attendance and DNA (did not attend) rates. Case studies will be analysed to understand impacts of digital clinical communication on patient health outcomes, health care costs and consumption, ethics and patient safety.", author = "Griffiths, {Frances E} and Helen Atherton and Barker, {Jack R} and Cave, {Jonathan AK} and Kathryn Dennick and Peter Dowdall and Joe Fraser and Caroline Huxley and Sung-Wook Kim and Madan, {Jason J} and Harjit Matharu and Luhanga Musumadi and Palmer, {Tom M} and Moli Paul and Sailesh Sankaranarayanan and Anne-Marie Slowther and Sujan, {Mark A} and Sutcliffe, {Paul A} and Jackie Sturt", year = "2015", month = jan, day = "1", doi = "10.1177/2055207615593698", language = "English", volume = "1", journal = "DIGITAL HEALTH", issn = "2055-2076", publisher = "SAGE Publications Ltd", } . DIGITAL HEALTH.

Paul S Clarke, Tom M Palmer, Frank Windmeijer(2015). Estimating Structural Mean Models with Multiple Instrumental Variables using the Generalised Method of Moments . Statistical Science. 30. (1). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 96--117. Institute of Mathematical Statistics

Clarke, P.S., Palmer, T.M., Windmeijer, F., Clarke, P.S., Palmer, T.M., Windmeijer, F.(2015). Estimating structural mean models with multiple instrumental variables using the generalised method of moments . Statistical Science. 30. (1). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 96-117.

Holmes, M.V., Asselbergs, F.W., Palmer, T.M., Drenos, F., Lanktree, M.B., Nelson, C.P., Dale, C.E., Padmanabhan, S., Finan, C., Swerdlow, D.I., et al.(2015). Mendelian randomization of blood lipids for coronary heart disease . European Heart Journal. 36. (9). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 539-550.

Tom Palmer, Jonathan A. C. Sterne(2015). Fitting fixed- and random-effects meta-analysis models using structural equation modeling with the sem and gsem commands . Stata Journal. 15. (3). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 645--671. SAGE Publications Inc.

Shungin, D., Cornelis, M.C., Divaris, K., Holtfreter, B., Shaffer, J.R., Yu, Y.-H., Barros, S.P., Beck, J.D., Biffar, R., Boerwinkle, E.A., et al.(2015). Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium . International Journal of Epidemiology. 44. (2). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 638-650.

Paul Clarke, Thomas Michael Palmer, Frank Windmeijer(2015). Estimating structural mean models with multiple instrumental variables using the generalised method of moments . Statistical Science. 30. (1). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 96--117. Institute of Mathematical Statistics

North, T.-L., Palmer, T.M., Lewis, S.J., Cooper, R., Power, C., Pattie, A., Starr, J.M., Deary, I.J., Martin, R.M., Sayer, A.A., et al.(2015). Effect of smoking on physical and cognitive capability in later life: A multicohort study using observational and genetic approaches . BMJ Open. 5. (12).

Cartwright, R., Kirby, A.C., Tikkinen, K.A.O., Mangera, A., Thiagamoorthy, G., Rajan, P., Pesonen, J., Ambrose, C., Gonzalez-Maffe, J., Bennett, P., et al.(2015). Systematic review and metaanalysis of genetic association studies of urinary symptoms and prolapse in women . American Journal of Obstetrics and Gynecology. 212. (2). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 199.e1-199.e24.

Palmer, T.M., Sterne, J.A.C., Palmer, T.M., Sterne, J.A.C.(2015). Fitting fixed-and random-effects meta-analysis models using structural equation modeling with the sem and gsem commands . Stata Journal. 15. (3). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 645-671.

Sluijs, I., Holmes, M.V., Van Der Schouw, Y.T., Beulens, J.W.J., Asselbergs, F.W., Huerta, J.M., Palmer, T.M., Arriola, L., Balkau, B., Barricarte, A., et al.(2015). A Mendelian randomization study of circulating uric acid and type 2 diabetes . Diabetes. 64. (8). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 3028-3036.

Teri-Louise North, Tom M Palmer, Sarah J Lewis, Rachel Cooper, Chris Power, Alison Pattie, John M Starr, Ian J Deary, Richard M Martin, Avan Aihie Sayer, et al.(2015). Effect of smoking on physical and cognitive capability in later life . BMJ Open. 5. (12). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString e008393. BMJ Publishing Group

Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study @article{896b570e985f492eb9a8db627d35c7d1, title = "Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study: Application to alcohol and cardiovascular traits", abstract = "Background: Mendelian randomization studies have so far restricted attention to linear associations relating the genetic instrument to the exposure, and the exposure to the outcome. In some cases, however, observational data suggest a non-linear association between exposure and outcome. For example, alcohol consumption is consistently reported as having a U-shaped association with cardiovascular events. In principle, Mendelian randomization could address concerns that the apparent protective effect of light-to-moderate drinking might reflect 'sick-quitters' and confounding. Methods: The Alcohol-ADH1B Consortium was established to study the causal effects of alcohol consumption on cardiovascular events and biomarkers, using the single nucleotide polymorphism rs1229984 in ADH1B as a genetic instrument. To assess non-linear causal effects in this study, we propose a novel method based on estimating local average treatment effects for discrete levels of the exposure range, then testing for a linear trend in those effects. Our method requires an assumption that the instrument has the same effect on exposure in all individuals. We conduct simulations examining the robustness of the method to violations of this assumption, and apply the method to the Alcohol-ADH1B Consortium data. Results: Our method gave a conservative test for non-linearity under realistic violations of the key assumption. We found evidence for a non-linear causal effect of alcohol intake on several cardiovascular traits. Conclusions: We believe our method is useful for inferring departure from linearity when only a binary instrument is available. We estimated non-linear causal effects of alcohol intake which could not have been estimated through standard instrumental variable approaches.", keywords = "Alcohol consumption, Cardiovascular disease, Causal inference, Instrumental variables, Local average treatment effects, Mendelian randomization", author = "Silverwood, {Richard J.} and Holmes, {Michael V.} and Dale, {Caroline E.} and Lawlor, {Debbie A.} and Whittaker, {John C.} and Smith, {George Davey} and Leon, {David A.} and Tom Palmer and Keating, {Brendan J.} and Luisa Zuccolo and Casas, {Juan P.} and Frank Dudbridge", year = "2014", month = dec, day = "1", doi = "10.1093/ije/dyu187", language = "English", volume = "43", pages = "1781--1790", journal = "International Journal of Epidemiology", issn = "0300-5771", publisher = "Oxford University Press", number = "6", } . International Journal of Epidemiology.

Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study @article{237a16d8e49a4218b2d058ba2b45aa94, title = "Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study: application to alcohol and cardiovascular traits", abstract = "BACKGROUND: Mendelian randomization studies have so far restricted attention to linear associations relating the genetic instrument to the exposure, and the exposure to the outcome. In some cases, however, observational data suggest a non-linear association between exposure and outcome. For example, alcohol consumption is consistently reported as having a U-shaped association with cardiovascular events. In principle, Mendelian randomization could address concerns that the apparent protective effect of light-to-moderate drinking might reflect 'sick-quitters' and confounding.METHODS: The Alcohol-ADH1B Consortium was established to study the causal effects of alcohol consumption on cardiovascular events and biomarkers, using the single nucleotide polymorphism rs1229984 in ADH1B as a genetic instrument. To assess non-linear causal effects in this study, we propose a novel method based on estimating local average treatment effects for discrete levels of the exposure range, then testing for a linear trend in those effects. Our method requires an assumption that the instrument has the same effect on exposure in all individuals. We conduct simulations examining the robustness of the method to violations of this assumption, and apply the method to the Alcohol-ADH1B Consortium data.RESULTS: Our method gave a conservative test for non-linearity under realistic violations of the key assumption. We found evidence for a non-linear causal effect of alcohol intake on several cardiovascular traits.CONCLUSIONS: We believe our method is useful for inferring departure from linearity when only a binary instrument is available. We estimated non-linear causal effects of alcohol intake which could not have been estimated through standard instrumental variable approaches.", keywords = "Mendelian randomization, instrumental variables, causal inference, local average treatment effects, alcohol consumption, cardiovascular disease", author = "Silverwood, {Richard J.} and Holmes, {Michael V.} and Dale, {Caroline E.} and Lawlor, {Debbie A.} and Whittaker, {John C.} and Smith, {George Davey} and Leon, {David A.} and Tom Palmer and Keating, {Brendan J.} and Luisa Zuccolo and Casas, {Juan P.} and Frank Dudbridge and {Alcohol-ADH1B Consortium}", note = "{\textcopyright} The Author 2014; Published by Oxford University Press on behalf of the International Epidemiological Association.", year = "2014", month = dec, doi = "10.1093/ije/dyu187", language = "English", volume = "43", pages = "1781--1790", journal = "International Journal of Epidemiology", issn = "0300-5771", publisher = "Oxford University Press", number = "6", } . International Journal of Epidemiology.

Systematic review and meta-analysis of candidate gene association studies of lower urinary tract symptoms in men @article{0e9d911f724340cc82aa8c5c17590b18, title = "Systematic review and meta-analysis of candidate gene association studies of lower urinary tract symptoms in men", abstract = "CONTEXT: Although family studies have shown that male lower urinary tract symptoms (LUTS) are highly heritable, no systematic review exists of genetic polymorphisms tested for association with LUTS.OBJECTIVE: To systematically review and meta-analyze studies assessing candidate polymorphisms/genes tested for an association with LUTS, and to assess the strength, consistency, and potential for bias among pooled associations.EVIDENCE ACQUISITION: A systematic search of the PubMed and HuGE databases as well as abstracts of major urologic meetings was performed through to January 2013. Case-control studies reporting genetic associations in men with LUTS were included. Reviewers independently and in duplicate screened titles, abstracts, and full texts to determine eligibility, abstracted data, and assessed the credibility of pooled associations according to the interim Venice criteria. Authors were contacted for clarifications if needed. Meta-analyses were performed for variants assessed in more than two studies.EVIDENCE SYNTHESIS: We identified 74 eligible studies containing data on 70 different genes. A total of 35 meta-analyses were performed with statistical significance in five (ACE, ELAC2, GSTM1, TERT, and VDR). The heterogeneity was high in three of these meta-analyses. The rs731236 variant of the vitamin D receptor had a protective effect for LUTS (odds ratio: 0.64; 95% confidence interval, 0.49-0.83) with moderate heterogeneity (I(2)=27.2%). No evidence for publication bias was identified. Limitations include wide-ranging phenotype definitions for LUTS and limited power in most meta-analyses to detect smaller effect sizes.CONCLUSIONS: Few putative genetic risk variants have been reliably replicated across populations. We found consistent evidence of a reduced risk of LUTS associated with the common rs731236 variant of the vitamin D receptor gene in our meta-analyses.PATIENT SUMMARY: Combining the results from all previous studies of genetic variants that may cause urinary symptoms in men, we found significant variants in five genes. Only one, a variant of the vitamin D receptor, was consistently protective across different populations.", author = "Rufus Cartwright and Altaf Mangera and Tikkinen, {Kari A. O.} and Prabhakar Rajan and Jori Pesonen and Kirby, {Anna C.} and Ganesh Thiagamoorthy and Chris Ambrose and Juan Gonzalez-Maffe and Bennett, {Phillip R.} and Tom Palmer and Andrew Walley and Marjo-Riitta J{\"a}rvelin and Vik Khullar and Chris Chapple", note = " Copyright {\textcopyright} 2014 The Authors. Published by Elsevier B.V. All rights reserved.", year = "2014", month = oct, doi = "10.1016/j.eururo.2014.01.007", language = "English", volume = "66", pages = "752--768", journal = "European Urology", issn = "0302-2838", publisher = "Elsevier BV", number = "4", } . European Urology.

Alcohol consumption and cognitive performance @article{41fdf006255d4a92b5cac276a953d27d, title = "Alcohol consumption and cognitive performance: A mendelian randomization study", abstract = "Aims: To use Mendelian randomization to assess whether alcohol intake was causally associated with cognitive function. Design: Mendelian randomization using a genetic variant related to alcohol intake (ADH1B rs1229984) was used to obtain unbiased estimates of the association between alcohol intake and cognitive performance. Setting: Europe. Participants: More than 34000 adults. Measurements: Any versus no alcohol intake and units of intake in the previous week was measured by questionnaire. Cognitive function was assessed in terms of immediate and delayed word recall, verbal fluency and processing speed. Findings: Having consumed any versus no alcohol was associated with higher scores by 0.17 standard deviations (SD) [95% confidence interval (CI)=0.15, 0.20] for immediate recall, 0.17 SD (95% CI=0.14, 0.19) for delayed recall, 0.17 SD (95% CI=0.14, 0.19) for verbal fluency and 0.12 SD (95% CI=0.09, 0.15) for processing speed. The minor allele of rs1229984 was associated with reduced odds of consuming any alcohol (odds ratio=0.87; 95% CI=0.80, 0.95; P=0.001; R2=0.1%; F-statistic=47). In Mendelian randomization analysis, the minor allele was not associated with any cognitive test score, and instrumental variable analysis suggested no causal association between alcohol consumption and cognition: -0.74 SD (95% CI=-1.88, 0.41) for immediate recall, -1.09 SD (95% CI=-2.38, 0.21) for delayed recall, -0.63 SD (95% CI=-1.78, 0.53) for verbal fluency and -0.16 SD (95% CI=-1.29, 0.97) for processing speed. Conclusions: The Mendelian randomization analysis did not provide strong evidence of a causal association between alcohol consumption and cognitive ability.", keywords = "ADH1B, Alcohol intake, Cognition, Memory, Processing speed, Verbal fluency", author = "Meena Kumari and Holmes, {Michael V.} and Dale, {Caroline E.} and Hubacek, {Jaroslav A.} and Palmer, {Tom M.} and Hynek Pikhart and Anne Peasey and Annie Britton and Pia Horvat and Ruzena Kubinova and Sofia Malyutina and Andrzej Pajak and Abdonas Tamosiunas and Aparna Shankar and Archana Singh-Manoux and Mikhail Voevoda and Mika Kivimaki and Hingorani, {Aroon D.} and Marmot, {Michael G.} and Casas, {Juan P.} and Martin Bobak", year = "2014", month = sep, day = "1", doi = "10.1111/add.12568", language = "English", volume = "109", pages = "1462--1471", journal = "Addiction", issn = "0965-2140", publisher = "Wiley", number = "9", } . Addiction.

Alcohol consumption and cognitive performance @article{6e992320c6784966ad3b6431881942af, title = "Alcohol consumption and cognitive performance: a Mendelian randomization study", abstract = "AIMS: To use Mendelian randomization to assess whether alcohol intake was causally associated with cognitive function.DESIGN: Mendelian randomization using a genetic variant related to alcohol intake (ADH1B rs1229984) was used to obtain unbiased estimates of the association between alcohol intake and cognitive performance.SETTING: Europe.PARTICIPANTS: More than 34 000 adults.MEASUREMENTS: Any versus no alcohol intake and units of intake in the previous week was measured by questionnaire. Cognitive function was assessed in terms of immediate and delayed word recall, verbal fluency and processing speed.FINDINGS: Having consumed any versus no alcohol was associated with higher scores by 0.17 standard deviations (SD) [95% confidence interval (CI) = 0.15, 0.20] for immediate recall, 0.17 SD (95% CI = 0.14, 0.19) for delayed recall, 0.17 SD (95% CI = 0.14, 0.19) for verbal fluency and 0.12 SD (95% CI = 0.09, 0.15) for processing speed. The minor allele of rs1229984 was associated with reduced odds of consuming any alcohol (odds ratio = 0.87; 95% CI = 0.80, 0.95; P = 0.001; R(2)  = 0.1%; F-statistic = 47). In Mendelian randomization analysis, the minor allele was not associated with any cognitive test score, and instrumental variable analysis suggested no causal association between alcohol consumption and cognition: -0.74 SD (95% CI = -1.88, 0.41) for immediate recall, -1.09 SD (95% CI = -2.38, 0.21) for delayed recall, -0.63 SD (95% CI = -1.78, 0.53) for verbal fluency and -0.16 SD (95% CI = -1.29, 0.97) for processing speed.CONCLUSIONS: The Mendelian randomization analysis did not provide strong evidence of a causal association between alcohol consumption and cognitive ability.", keywords = "ADH1B, alcohol intake, cognition, memory, processing speed, verbal fluency", author = "Meena Kumari and Holmes, {Michael V.} and Dale, {Caroline E.} and Hubacek, {Jaroslav A.} and Palmer, {Tom M.} and Hynek Pikhart and Anne Peasey and Annie Britton and Pia Horvat and Ruzena Kubinova and Sofia Malyutina and Andrzej Pajak and Abdonas Tamosiunas and Aparna Shankar and Archana Singh-Manoux and Mikhail Voevoda and Mika Kivimaki and Hingorani, {Aroon D.} and Marmot, {Michael G.} and Casas, {Juan P.} and Martin Bobak", note = " {\textcopyright} 2014 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.", year = "2014", month = sep, doi = "10.1111/add.12568", language = "English", volume = "109", pages = "1462--1471", journal = "Addiction", issn = "0965-2140", publisher = "Wiley-Blackwell", number = "9", } . Addiction.

Association between alcohol and cardiovascular disease @article{3d93e89d4da0484a9009e1d9e151519e, title = "Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data", abstract = "OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.", author = "Holmes, {Michael V} and Dale, {Caroline E} and Luisa Zuccolo and Silverwood, {Richard J} and Yiran Guo and Zheng Ye and David Prieto-Merino and Abbas Dehghan and Stella Trompet and Andrew Wong and Alana Cavadino and Dagmar Drogan and Sandosh Padmanabhan and Shanshan Li and Ajay Yesupriya and Maarten Leusink and Johan Sundstrom and Hubacek, {Jaroslav A} and Hynek Pikhart and Swerdlow, {Daniel I} and Panayiotou, {Andrie G} and Borinskaya, {Svetlana A} and Chris Finan and Sonia Shah and Kuchenbaecker, {Karoline B} and Tina Shah and Jorgen Engmann and Lasse Folkersen and Per Eriksson and Fulvio Ricceri and Olle Melander and Carlotta Sacerdote and Gamble, {Dale M} and Sruti Rayaprolu and Ross, {Owen A} and Stela McLachlan and Olga Vikhireva and Scott, {Robert A} and Meena Kumari and Shah Ebrahim and Gaunt, {Tom R} and Norman, {Paul E} and Richard Morris and Johnson, {Andrew D} and Mika Kivimaki and Lawlor, {Debbie A} and {Davey Smith}, George and Wilson, {James G} and Leon, {David A} and Palmer, {Tom M} and {InterAct Consortium}", note = "{\textcopyright} Holmes et al 2014.", year = "2014", month = jul, day = "10", doi = "10.1136/bmj.g4164", language = "English", volume = "349", pages = "g4164", journal = "BMJ", issn = "0959-8138", publisher = "BMJ Publishing Group", } . BMJ.

Association between alcohol and cardiovascular disease @article{e5cd63ce57a34026acde5da77bf60b12, title = "Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data", abstract = "OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.", keywords = "Adult, Aged, Alcohol Dehydrogenase, Alcohol Drinking, Biological Markers, Coronary Disease, Female, Genetic Markers, Genotype, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Models, Statistical, Polymorphism, Single Nucleotide, Stroke", author = "Holmes, {Michael V} and Dale, {Caroline E} and Luisa Zuccolo and Silverwood, {Richard J} and Yiran Guo and Zheng Ye and David Prieto-Merino and Abbas Dehghan and Stella Trompet and Andrew Wong and Alana Cavadino and Dagmar Drogan and Sandosh Padmanabhan and Shanshan Li and Ajay Yesupriya and Maarten Leusink and Johan Sundstrom and Hubacek, {Jaroslav A} and Hynek Pikhart and Swerdlow, {Daniel I} and Panayiotou, {Andrie G} and Borinskaya, {Svetlana A} and Chris Finan and Sonia Shah and Kuchenbaecker, {Karoline B} and Tina Shah and Jorgen Engmann and Lasse Folkersen and Per Eriksson and Fulvio Ricceri and Olle Melander and Carlotta Sacerdote and Gamble, {Dale M} and Sruti Rayaprolu and Ross, {Owen A} and Stela McLachlan and Olga Vikhireva and Ivonne Sluijs and Scott, {Robert A} and Vera Adamkova and Leon Flicker and Bockxmeer, {Frank M van} and Christine Power and Pedro Marques-Vidal and Tom Meade and Marmot, {Michael G} and Ferro, {Jose M} and Sofia Paulos-Pinheiro and Humphries, {Steve E} and Palmer, {Tom M.} and {InterAct Consortium}", note = " {\textcopyright} Holmes et al 2014.", year = "2014", month = jul, day = "10", doi = "10.1136/bmj.g4164", language = "English", volume = "349", journal = "BMJ", issn = "0959-8138", publisher = "British Medical Association", } . BMJ.

Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood @article{8ff06423a80b49c9a15cc4ca5b0a07cd, title = "Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study", abstract = "Background Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach. Methods and Findings We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m2, p  = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects. Conclusions Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century.", author = "Raquel Granell and Henderson, {A J W} and David Evans and {Davey Smith}, George and Ness, {Andy R} and Lewis, {Sarah P} and Palmer, {Tom M.} and Sterne, {Jonathan A C}", year = "2014", month = jul, day = "1", doi = "10.1371/journal.pmed.1001669", language = "English", volume = "11", journal = "PLoS Medicine", issn = "1549-1277", publisher = "Public Library of Science", number = "7", } . PLoS Medicine.

Lack of identification in semiparametric instrumental variable models with binary outcomes @article{e0d086523b1a4a4489d3b9ceef5989f2, title = "Lack of identification in semiparametric instrumental variable models with binary outcomes", abstract = "A parameter in a statistical model is identified if its value can be uniquely determined from the distribution of the observable data. We consider the context of an instrumental variable analysis with a binary outcome for estimating a causal risk ratio. The semiparametric generalized method of moments and structural mean model frameworks use estimating equations for parameter estimation. In this paper, we demonstrate that lack of identification can occur in either of these frameworks, especially if the instrument is weak. In particular, the estimating equations may have no solution or multiple solutions. We investigate the relationship between the strength of the instrument and the proportion of simulated data sets for which there is a unique solution of the estimating equations. We see that this proportion does not appear to depend greatly on the sample size, particularly for weak instruments (ρ2 ≤ 0.01). Poor identification was observed in a considerable proportion of simulated data sets for instruments explaining up to 10% of the variance in the exposure with sample sizes up to 1 million. In an applied example considering the causal effect of body mass index (weight (kg)/height (m)2) on the probability of early menarche, estimates and standard errors from an automated optimization routine were misleading.", keywords = "Avon Longitudinal Study of Parents and Children, generalized method of moments, identifiability, identification, instrumental variables, semiparametric methods, structural mean model, weak instruments", author = "Stephen Burgess and Raquel Granell and Palmer, {Tom M.} and Sterne, {Jonathan A C} and Vanessa Didelez", year = "2014", month = jul, day = "1", doi = "10.1093/aje/kwu107", language = "English", volume = "180", pages = "111--119", journal = "American Journal of Epidemiology", issn = "0002-9262", publisher = "Oxford University Press", number = "1", } . American Journal of Epidemiology.

Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood @article{8ff06423a80b49c9a15cc4ca5b0a07cd, title = "Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study", abstract = "Background Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach. Methods and Findings We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m2, p  = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects. Conclusions Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century.", author = "Raquel Granell and Henderson, {A J W} and David Evans and {Davey Smith}, George and Ness, {Andy R} and Lewis, {Sarah P} and Palmer, {Tom M.} and Sterne, {Jonathan A C}", year = "2014", month = jul, day = "1", doi = "10.1371/journal.pmed.1001669", language = "English", volume = "11", journal = "PLoS Medicine", issn = "1549-1277", publisher = "Public Library of Science", number = "7", } . PLoS Medicine.

Effects of BMI, fat mass, and lean mass on asthma in childhood @article{32b2dacf9e5e438f803c3b5bba21e4f5, title = "Effects of BMI, fat mass, and lean mass on asthma in childhood: a Mendelian randomization study", abstract = "BACKGROUND: Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.METHODS AND FINDINGS: We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38-4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16-2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19-3.03) than for atopic asthma (1.37, 95% CI 0.89-2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11-1.79) per 0.5 kg and 2.25 (95% CI 1.23-4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.CONCLUSIONS: Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century. Please see later in the article for the Editors' Summary.", author = "Raquel Granell and Henderson, {A. John} and Evans, {David M.} and Smith, {George Davey} and Ness, {Andrew R.} and Sarah Lewis and Palmer, {Tom M.} and Sterne, {Jonathan A. C.}", year = "2014", month = jul, day = "1", doi = "10.1371/journal.pmed.1001669", language = "English", volume = "11", journal = "PLoS Medicine", issn = "1549-1277", publisher = "Public Library of Science", number = "7", } . PLoS Medicine.

Lack of identification in semiparametric instrumental variable models with binary outcomes @article{280d07fd7adc43fda3dfd7e52c139708, title = "Lack of identification in semiparametric instrumental variable models with binary outcomes", abstract = "A parameter in a statistical model is identified if its value can be uniquely determined from the distribution of the observable data. We consider the context of an instrumental variable analysis with a binary outcome for estimating a causal risk ratio. The semiparametric generalized method of moments and structural mean model frameworks use estimating equations for parameter estimation. In this paper, we demonstrate that lack of identification can occur in either of these frameworks, especially if the instrument is weak. In particular, the estimating equations may have no solution or multiple solutions. We investigate the relationship between the strength of the instrument and the proportion of simulated data sets for which there is a unique solution of the estimating equations. We see that this proportion does not appear to depend greatly on the sample size, particularly for weak instruments (ρ(2) ≤ 0.01). Poor identification was observed in a considerable proportion of simulated data sets for instruments explaining up to 10% of the variance in the exposure with sample sizes up to 1 million. In an applied example considering the causal effect of body mass index (weight (kg)/height (m)(2)) on the probability of early menarche, estimates and standard errors from an automated optimization routine were misleading.", keywords = "Adolescent, Age Factors, Asthma, Body Mass Index, Causality, Child, Data Interpretation, Statistical, Female, Humans, Menarche, Models, Statistical, Odds Ratio, Sample Size", author = "Stephen Burgess and Raquel Granell and Palmer, {Tom M.} and Sterne, {Jonathan A. C.} and Vanessa Didelez", note = "{\textcopyright} The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.", year = "2014", month = jul, day = "1", doi = "10.1093/aje/kwu107", language = "English", volume = "180", pages = "111--119", journal = "American Journal of Epidemiology", issn = "0002-9262", publisher = "Oxford University Press", number = "1", } . American Journal of Epidemiology.

Genetic variants at chromosome 9p21 and risk of first versus subsequent coronary heart disease events @article{ab96cec24c584de2b664794210d10e0e, title = "Genetic variants at chromosome 9p21 and risk of first versus subsequent coronary heart disease events: A systematic review and meta-analysis", abstract = "Objectives The purpose of this analysis was to compare the association between variants at the chromosome 9p21 locus (Ch9p21) and risk of first versus subsequent coronary heart disease (CHD) events through systematic review and meta-analysis. Background Ch9p21 is a recognized risk factor for a first CHD event. However, its association with risk of subsequent events in patients with established CHD is less clear. Methods We searched PubMed and EMBASE for prospective studies reporting association of Ch9p21 with incident CHD events and extracted information on cohort type (individuals without prior CHD or individuals with established CHD) and effect estimates for risk of events. Results We identified 31 cohorts reporting on 193,372 individuals. Among the 16 cohorts of individuals without prior CHD (n = 168,209), there were 15,664 first CHD events. Ch9p21 was associated with a pooled hazard ratio (HR) of a first event of 1.19 (95% confidence interval: 1.17 to 1.22) per risk allele. In individuals with established CHD (n = 25,163), there were 4,436 subsequent events providing >99% and 91% power to detect a per-allele HR of 1.19 or 1.10, respectively. The pooled HR for subsequent events was 1.01 (95% confidence interval: 0.97 to 1.06) per risk allele. There was strong evidence of heterogeneity between the effect estimates for first and subsequent events (p value for heterogeneity = 5.6 × 10-11). We found no evidence for biases to account for these findings. Conclusions Ch9p21 shows differential association with risk of first versus subsequent CHD events. This has implications for genetic risk prediction in patients with established CHD and for mechanistic understanding of how Ch9p21 influences risk of CHD.", keywords = "9p21, coronary heart disease, genomics, incident, subsequent", author = "Patel, {Riyaz S.} and Asselbergs, {Folkert W.} and Quyyumi, {Arshed A.} and Palmer, {Tom M.} and Finan, {Chris I.} and Vinicius Tragante and John Deanfield and Harry Hemingway and Hingorani, {Aroon D.} and Holmes, {Michael V.}", year = "2014", month = jun, day = "3", doi = "10.1016/j.jacc.2014.01.065", language = "English", volume = "63", pages = "2234--2245", journal = "Journal of the American College of Cardiology", issn = "0735-1097", publisher = "Elsevier Inc.", number = "21", } . Journal of the American College of Cardiology.

Genetic variants at chromosome 9p21 and risk of first versus subsequent coronary heart disease events @article{4a94513f3a9d45c9862285f4e9d839ea, title = "Genetic variants at chromosome 9p21 and risk of first versus subsequent coronary heart disease events: a systematic review and meta-analysis", abstract = "OBJECTIVES: The purpose of this analysis was to compare the association between variants at the chromosome 9p21 locus (Ch9p21) and risk of first versus subsequent coronary heart disease (CHD) events through systematic review and meta-analysis.BACKGROUND: Ch9p21 is a recognized risk factor for a first CHD event. However, its association with risk of subsequent events in patients with established CHD is less clear.METHODS: We searched PubMed and EMBASE for prospective studies reporting association of Ch9p21 with incident CHD events and extracted information on cohort type (individuals without prior CHD or individuals with established CHD) and effect estimates for risk of events.RESULTS: We identified 31 cohorts reporting on 193,372 individuals. Among the 16 cohorts of individuals without prior CHD (n = 168,209), there were 15,664 first CHD events. Ch9p21 was associated with a pooled hazard ratio (HR) of a first event of 1.19 (95% confidence interval: 1.17 to 1.22) per risk allele. In individuals with established CHD (n = 25,163), there were 4,436 subsequent events providing >99% and 91% power to detect a per-allele HR of 1.19 or 1.10, respectively. The pooled HR for subsequent events was 1.01 (95% confidence interval: 0.97 to 1.06) per risk allele. There was strong evidence of heterogeneity between the effect estimates for first and subsequent events (p value for heterogeneity = 5.6 × 10(-11)). We found no evidence for biases to account for these findings.CONCLUSIONS: Ch9p21 shows differential association with risk of first versus subsequent CHD events. This has implications for genetic risk prediction in patients with established CHD and for mechanistic understanding of how Ch9p21 influences risk of CHD.", keywords = "Animals, Chromosomes, Human, Pair 9, Coronary Disease, Genetic Predisposition to Disease, Genetic Variation, Humans, Polymorphism, Single Nucleotide, Risk Factors", author = "Patel, {Riyaz S.} and Asselbergs, {Folkert W.} and Quyyumi, {Arshed A.} and Palmer, {Tom M.} and Finan, {Chris I.} and Vinicius Tragante and John Deanfield and Harry Hemingway and Hingorani, {Aroon D.} and Holmes, {Michael V.}", note = " Copyright {\textcopyright} 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.", year = "2014", month = jun, day = "3", doi = "10.1016/j.jacc.2014.01.065", language = "English", volume = "63", pages = "2234--2245", journal = "Journal of the American College of Cardiology", publisher = "Elsevier USA", number = "21", } . Journal of the American College of Cardiology.

Causal effects of body mass index on cardiometabolic traits and events @article{77a2b03be1ce41d1a47dc0d1f2054a2b, title = "Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis", abstract = "Elevated body mass index (BMI) associates with cardiometabolic traits on observational analysis, yet the underlying causal relationships remain unclear. We conducted Mendelian randomization analyses by using a genetic score (GS) comprising 14 BMI-associated SNPs from a recent discovery analysis to investigate the causal role of BMI in cardiometabolic traits and events. We used eight population-based cohorts, including 34,538 European-descent individuals (4,407 type 2 diabetes (T2D), 6,073 coronary heart disease (CHD), and 3,813 stroke cases). A 1 kg/m(2) genetically elevated BMI increased fasting glucose (0.18 mmol/l; 95% confidence interval (CI) = 0.12-0.24), fasting insulin (8.5%; 95% CI = 5.9-11.1), interleukin-6 (7.0%; 95% CI = 4.0-10.1), and systolic blood pressure (0.70 mmHg; 95% CI = 0.24-1.16) and reduced high-density lipoprotein cholesterol (-0.02 mmol/l; 95% CI = -0.03 to -0.01) and low-density lipoprotein cholesterol (LDL-C; -0.04 mmol/l; 95% CI = -0.07 to -0.01). Observational and causal estimates were directionally concordant, except for LDL-C. A 1 kg/m(2) genetically elevated BMI increased the odds of T2D (odds ratio [OR] = 1.27; 95% CI = 1.18-1.36) but did not alter risk of CHD (OR 1.01; 95% CI = 0.94-1.08) or stroke (OR = 1.03; 95% CI = 0.95-1.12). A meta-analysis incorporating published studies reporting 27,465 CHD events in 219,423 individuals yielded a pooled OR of 1.04 (95% CI = 0.97-1.12) per 1 kg/m(2) increase in BMI. In conclusion, we identified causal effects of BMI on several cardiometabolic traits; however, whether BMI causally impacts CHD risk requires further evidence.", keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Blood Glucose, Blood Pressure, Body Mass Index, Cholesterol, HDL, Cholesterol, LDL, Coronary Disease, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Fasting, Female, Genetic Association Studies, Humans, Insulin, Interleukin-6, Longitudinal Studies, Male, Mendelian Randomization Analysis, Meta-Analysis as Topic, Middle Aged, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Selection, Genetic, Sensitivity and Specificity, Stroke, Young Adult", author = "Holmes, {Michael V.} and Lange, {Leslie A.} and Tom Palmer and Lanktree, {Matthew B.} and North, {Kari E.} and Berta Almoguera and Sarah Buxbaum and Chandrupatla, {Hareesh R.} and Elbers, {Clara C.} and Yiran Guo and Hoogeveen, {Ron C.} and Jin Li and Li, {Yun R.} and Swerdlow, {Daniel I.} and Mary Cushman and Price, {Tom S.} and Curtis, {Sean P.} and Myriam Fornage and Hakon Hakonarson and Patel, {Sanjay R.} and Susan Redline and Siscovick, {David S.} and Tsai, {Michael Y.} and Wilson, {James G.} and {van der Schouw}, {Yvonne T.} and FitzGerald, {Garret A.} and Hingorani, {Aroon D.} and Casas, {Juan P.} and {de Bakker}, {Paul I. W.} and Rich, {Stephen S.} and Schadt, {Eric E.} and Asselbergs, {Folkert W.} and Reiner, {Alex P.} and Keating, {Brendan J.}", note = "Copyright {\textcopyright} 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.", year = "2014", month = feb, day = "6", doi = "10.1016/j.ajhg.2013.12.014", language = "English", volume = "94", pages = "198--208", journal = "American Journal of Human Genetics", issn = "0002-9297", publisher = "Cell Press", number = "2", } . American Journal of Human Genetics.

Causal effects of body mass index on cardiometabolic traits and events @article{32e0f8c7536649dd8908577a36258a4e, title = "Causal effects of body mass index on cardiometabolic traits and events: A Mendelian randomization analysis", abstract = "Elevated body mass index (BMI) associates with cardiometabolic traits on observational analysis, yet the underlying causal relationships remain unclear. We conducted Mendelian randomization analyses by using a genetic score (GS) comprising 14 BMI-associated SNPs from a recent discovery analysis to investigate the causal role of BMI in cardiometabolic traits and events. We used eight population-based cohorts, including 34,538 European-descent individuals (4,407 type 2 diabetes (T2D), 6,073 coronary heart disease (CHD), and 3,813 stroke cases). A 1 kg/m2 genetically elevated BMI increased fasting glucose (0.18 mmol/l; 95% confidence interval (CI) = 0.12-0.24), fasting insulin (8.5%; 95% CI = 5.9-11.1), interleukin-6 (7.0%; 95% CI = 4.0-10.1), and systolic blood pressure (0.70 mmHg; 95% CI = 0.24-1.16) and reduced high-density lipoprotein cholesterol (-0.02 mmol/l; 95% CI = -0.03 to -0.01) and low-density lipoprotein cholesterol (LDL-C; -0.04 mmol/l; 95% CI = -0.07 to -0.01). Observational and causal estimates were directionally concordant, except for LDL-C. A 1 kg/m2 genetically elevated BMI increased the odds of T2D (odds ratio [OR] = 1.27; 95% CI = 1.18-1.36) but did not alter risk of CHD (OR 1.01; 95% CI = 0.94-1.08) or stroke (OR = 1.03; 95% CI = 0.95-1.12). A meta-analysis incorporating published studies reporting 27,465 CHD events in 219,423 individuals yielded a pooled OR of 1.04 (95% CI = 0.97-1.12) per 1 kg/m2 increase in BMI. In conclusion, we identified causal effects of BMI on several cardiometabolic traits; however, whether BMI causally impacts CHD risk requires further evidence.", author = "Holmes, {Michael V.} and Lange, {Leslie A.} and Tom Palmer and Lanktree, {Matthew B.} and North, {Kari E.} and Berta Almoguera and Sarah Buxbaum and Chandrupatla, {Hareesh R.} and Elbers, {Clara C.} and Yiran Guo and Hoogeveen, {Ron C.} and Jin Li and Li, {Yun R.} and Swerdlow, {Daniel I.} and Mary Cushman and Price, {Tom S.} and Curtis, {Sean P.} and Myriam Fornage and Hakon Hakonarson and Patel, {Sanjay R.} and Susan Redline and Siscovick, {David S.} and Tsai, {Michael Y.} and Wilson, {James G.} and {Van Der Schouw}, {Yvonne T.} and Fitzgerald, {Garret A.} and Hingorani, {Aroon D.} and Casas, {Juan P.} and {De Bakker}, {Paul I.W.} and Rich, {Stephen S.} and Schadt, {Eric E.} and Asselbergs, {Folkert W.} and Reiner, {Alex P.} and Keating, {Brendan J.}", year = "2014", month = feb, day = "6", doi = "10.1016/j.ajhg.2013.12.014", language = "English", volume = "94", pages = "198--208", journal = "American Journal of Human Genetics", issn = "0002-9297", publisher = "Cell Press", number = "2", } . American Journal of Human Genetics.

Mendelian randomization of blood lipids for coronary heart disease @article{ea630f3f9fcf49e3905385bbfa0c02a3, title = "Mendelian randomization of blood lipids for coronary heart disease", abstract = "AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.", author = "Holmes, {Michael V} and Asselbergs, {Folkert W} and Palmer, {Tom M} and Fotios Drenos and Lanktree, {Matthew B} and Nelson, {Christopher P} and Dale, {Caroline E} and Sandosh Padmanabhan and Chris Finan and Swerdlow, {Daniel I} and Vinicius Tragante and {van Iperen}, {Erik P A} and Suthesh Sivapalaratnam and Sonia Shah and Elbers, {Clara C} and Tina Shah and Jorgen Engmann and Claudia Giambartolomei and Jon White and Delilah Zabaneh and Reecha Sofat and Stela McLachlan and Doevendans, {Pieter A} and Balmforth, {Anthony J} and Hall, {Alistair S} and North, {Kari E} and Berta Almoguera and Hoogeveen, {Ron C} and Mary Cushman and Myriam Fornage and Patel, {Sanjay R} and Susan Redline and Siscovick, {David S} and Tsai, {Michael Y} and Karczewski, {Konrad J} and Hofker, {Marten H} and Verschuren, {W Monique} and Bots, {Michiel L} and {van der Schouw}, {Yvonne T} and Olle Melander and Dominiczak, {Anna F} and Richard Morris and Yoav Ben-Shlomo and Jackie Price and Meena Kumari and Jens Baumert and Gaunt, {Tom R} and Wilson, {James G} and {Davey Smith}, George and Lawlor, {Debbie A} and {UCLEB Consortium}", year = "2014", month = jan, day = "27", doi = "10.1093/eurheartj/eht571", language = "English", volume = "36", pages = "539--550", journal = "European Heart Journal", issn = "0195-668X", publisher = "Oxford University Press", number = "9", } . European Heart Journal.

Effects of promoting longer-term and exclusive breastfeeding on cardiometabolic risk factors at age 11.5 years @article{901a33e163f24a16abfe3ac10a020e9b, title = "Effects of promoting longer-term and exclusive breastfeeding on cardiometabolic risk factors at age 11.5 years: a cluster-randomized, controlled trial", abstract = "BACKGROUND: The duration and exclusivity of breastfeeding in infancy have been inversely associated with future cardiometabolic risk. We investigated the effects of an experimental intervention to promote increased duration of exclusive breastfeeding on cardiometabolic risk factors in childhood.METHODS AND RESULTS: We followed-up children in the Promotion of Breastfeeding Intervention Trial, a cluster-randomized trial of a breastfeeding promotion intervention based on the World Health Organization/United Nations Children's Fund Baby-Friendly Hospital Initiative. In 1996 to 1997, 17 046 breastfeeding mother-infant pairs were enrolled from 31 Belarusian maternity hospitals and affiliated polyclinics (16 intervention versus 15 control sites); 13 879 (81.4%) children were followed up at 11.5 years, with 13 616 (79.9%) who had fasted and did not have diabetes mellitus. The outcomes were blood pressure; fasting insulin, adiponectin, glucose, and apolipoprotein A1; and the presence of metabolic syndrome. Analysis was by intention to treat, accounting for clustering within hospitals/clinics. The intervention substantially increased breastfeeding duration and exclusivity in comparison with the control arm (43% versus 6% and 7.9% versus 0.6% exclusively breastfed at 3 and 6 months, respectively). Cluster-adjusted mean differences at 11.5 years between experimental versus control groups were as follows: 1.0 mm Hg (95% confidence interval, -1.1 to 3.1) for systolic and 0.8 mm Hg (-0.6 to 2.3) for diastolic blood pressure; -0.1 mmol/L (-0.2 to 0.1) for glucose; 8% (-3% to 34%) for insulin; -0.3 μg/mL (-1.5 to 0.9) for adiponectin; and 0.0 g/L (-0.1 to 0.1) for apolipoprotein A1. The cluster-adjusted odds ratio for metabolic syndrome, comparing experimental versus control groups, was 1.21 (0.85 to 1.72).CONCLUSIONS: An intervention to improve breastfeeding duration and exclusivity among healthy term infants did not influence cardiometabolic risk factors in childhood.CLINICAL TRIAL REGISTRATION: Current Controlled Trials: ISRCTN37687716 (http://www.controlled-trials.com/ISRCTN37687716). URL: http://clinicaltrials.gov. Unique identifier: NCT01561612.", keywords = "Breast Feeding, Cardiovascular Diseases, Child, Cluster Analysis, Female, Follow-Up Studies, Health Promotion, Humans, Infant, Insulin Resistance, Male, Metabolic Diseases, Republic of Belarus, Risk Factors, World Health Organization", author = "Martin, {Richard M.} and Rita Patel and Kramer, {Michael S.} and Konstantin Vilchuck and Natalia Bogdanovich and Natalia Sergeichick and Nina Gusina and Ying Foo and Tom Palmer and Jennifer Thompson and Gillman, {Matthew W.} and Smith, {George Davey} and Emily Oken", year = "2014", month = jan, day = "21", doi = "10.1161/CIRCULATIONAHA.113.005160", language = "English", volume = "129", pages = "321--329", journal = "Circulation", issn = "0009-7322", publisher = "Lippincott Williams and Wilkins", number = "3", } . Circulation.

Effects of Promoting Longer-Term and Exclusive Breastfeeding on Cardiometabolic Risk Factors at Age 11.5 Years A Cluster-Randomized, Controlled Trial @article{4c1588cde366455e92f940db9abe59c0, title = "Effects of Promoting Longer-Term and Exclusive Breastfeeding on Cardiometabolic Risk Factors at Age 11.5 Years A Cluster-Randomized, Controlled Trial", abstract = "Background The duration and exclusivity of breastfeeding in infancy have been inversely associated with future cardiometabolic risk. We investigated the effects of an experimental intervention to promote increased duration of exclusive breastfeeding on cardiometabolic risk factors in childhood.Methods and Results We followed-up children in the Promotion of Breastfeeding Intervention Trial, a cluster-randomized trial of a breastfeeding promotion intervention based on the World Health Organization/United Nations Children's Fund Baby-Friendly Hospital Initiative. In 1996 to 1997, 17 046 breastfeeding mother-infant pairs were enrolled from 31 Belarusian maternity hospitals and affiliated polyclinics (16 intervention versus 15 control sites); 13 879 (81.4%) children were followed up at 11.5 years, with 13 616 (79.9%) who had fasted and did not have diabetes mellitus. The outcomes were blood pressure; fasting insulin, adiponectin, glucose, and apolipoprotein A1; and the presence of metabolic syndrome. Analysis was by intention to treat, accounting for clustering within hospitals/clinics. The intervention substantially increased breastfeeding duration and exclusivity in comparison with the control arm (43% versus 6% and 7.9% versus 0.6% exclusively breastfed at 3 and 6 months, respectively). Cluster-adjusted mean differences at 11.5 years between experimental versus control groups were as follows: 1.0 mm Hg (95% confidence interval, -1.1 to 3.1) for systolic and 0.8 mm Hg (-0.6 to 2.3) for diastolic blood pressure; -0.1 mmol/L (-0.2 to 0.1) for glucose; 8% (-3% to 34%) for insulin; -0.3 g/mL (-1.5 to 0.9) for adiponectin; and 0.0 g/L (-0.1 to 0.1) for apolipoprotein A1. The cluster-adjusted odds ratio for metabolic syndrome, comparing experimental versus control groups, was 1.21 (0.85 to 1.72).Conclusions An intervention to improve breastfeeding duration and exclusivity among healthy term infants did not influence cardiometabolic risk factors in childhood.Clinical Trial Registration Current Controlled Trials: ISRCTN37687716 (http://www.controlled-trials.com/ISRCTN37687716). URL: http://clinicaltrials.gov. Unique identifier: NCT01561612.", keywords = "adiponectin, blood pressure, breast feeding, fasting, glucose, lactation, lipids, insulins, randomized controlled trial, BLOOD-PRESSURE, INSULIN-RESISTANCE, METABOLIC SYNDROME, APOLIPOPROTEIN-B, YOUNG ADULTHOOD, LATER LIFE, CHILDHOOD, INFANT, GROWTH, COHORT", author = "Martin, {Richard M.} and Rita Patel and Kramer, {Michael S.} and Konstantin Vilchuck and Natalia Bogdanovich and Natalia Sergeichick and Nina Gusina and Ying Foo and Tom Palmer and Jennifer Thompson and Gillman, {Matthew W.} and Smith, {George Davey} and Emily Oken", year = "2014", month = jan, day = "21", doi = "10.1161/CIRCULATIONAHA.113.005160", language = "English", volume = "129", pages = "321--329", journal = "Circulation", issn = "0009-7322", publisher = "Lippincott Williams and Wilkins", number = "3", } . Circulation.

Tom Palmer, K. H. Wade, O. Skugarevsky, Michael S. Kramer, Shital R. Patel, Natalia Bogdanovich, K Vilchuck, N Sergeichick, R. Richmond, George Davey Smith, et al.(2014). Prospective associations of parental smoking, alcohol use, marital status, maternal satisfaction, and parental and childhood body mass index at 6.5 years with later problematic eating attitudes . Nutrition and Diabetes. 4. Nature Publishing Group

Systematic review and meta-analysis of candidate gene association studies of lower urinary tract symptoms in men @article{189de50aa661492b98d8eeb9547fb78c, title = "Systematic review and meta-analysis of candidate gene association studies of lower urinary tract symptoms in men", abstract = "Context Although family studies have shown that male lower urinary tract symptoms (LUTS) are highly heritable, no systematic review exists of genetic polymorphisms tested for association with LUTS. Objective To systematically review and meta-analyze studies assessing candidate polymorphisms/genes tested for an association with LUTS, and to assess the strength, consistency, and potential for bias among pooled associations. Evidence acquisition A systematic search of the PubMed and HuGE databases as well as abstracts of major urologic meetings was performed through to January 2013. Case-control studies reporting genetic associations in men with LUTS were included. Reviewers independently and in duplicate screened titles, abstracts, and full texts to determine eligibility, abstracted data, and assessed the credibility of pooled associations according to the interim Venice criteria. Authors were contacted for clarifications if needed. Meta-analyses were performed for variants assessed in more than two studies. Evidence synthesis We identified 74 eligible studies containing data on 70 different genes. A total of 35 meta-analyses were performed with statistical significance in five (ACE, ELAC2, GSTM1, TERT, and VDR). The heterogeneity was high in three of these meta-analyses. The rs731236 variant of the vitamin D receptor had a protective effect for LUTS (odds ratio: 0.64; 95% confidence interval, 0.49-0.83) with moderate heterogeneity (I 2 = 27.2%). No evidence for publication bias was identified. Limitations include wide-ranging phenotype definitions for LUTS and limited power in most meta-analyses to detect smaller effect sizes. Conclusions Few putative genetic risk variants have been reliably replicated across populations. We found consistent evidence of a reduced risk of LUTS associated with the common rs731236 variant of the vitamin D receptor gene in our meta-analyses. Patient summary Combining the results from all previous studies of genetic variants that may cause urinary symptoms in men, we found significant variants in five genes. Only one, a variant of the vitamin D receptor, was consistently protective across different populations.", keywords = "Benign prostatic hyperplasia, BPH, Genetics, Genomics, Incontinence, male, Lower urinary tract symptoms, LUTS, Overactive bladder", author = "Rufus Cartwright and Altaf Mangera and Tikkinen, {Kari A.O.} and Prabhakar Rajan and Jori Pesonen and Kirby, {Anna C.} and Ganesh Thiagamoorthy and Chris Ambrose and Juan Gonzalez-Maffe and Bennett, {Phillip R.} and Tom Palmer and Andrew Walley and J{\"a}rvelin, {Marjo Riitta} and Vik Khullar and Chris Chapple", year = "2014", month = jan, day = "1", doi = "10.1016/j.eururo.2014.01.007", language = "English", volume = "66", pages = "752--768", journal = "European Urology", issn = "0302-2838", publisher = "Elsevier B.V.", number = "4", } . European Urology.

Tom Palmer, Corrie Macdonald-Wallis, Debbie Lawlor, Kate Tilling(2014). Estimating adjusted associations between random effects from multilevel models . Stata Journal. 14. (1). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 119--140. SAGE Publications Inc.

Martin, R.M., Martin, R.M., Patel, R., Kramer, M.S., Patel, R., Vilchuck, K., Kramer, M.S., Bogdanovich, N., Vilchuck, K., Sergeichick, N., et al.(2014). Effects of promoting longer-term and exclusive breastfeeding on cardiometabolic risk factors at age 11.5 years: A cluster-randomized, controlled trial . Circulation. 129. (3). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 321-329.

Kaitlin H Wade, O Skugarevsky, M S Kramer, R Patel, N Bogdanovich, K Vilchuck, N Sergeichick, R Richmond, T Palmer, G Davey Smith, et al.(2014). Prospective associations of parental smoking, alcohol use, marital status, maternal satisfaction, and parental and childhood body mass index at 6.5 years with later problematic eating attitudes . Nutrition and Diabetes. 4. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1--8. Springer Nature

Holmes, M.V., Lange, L.A., Palmer, T., Holmes, M.V., Lanktree, M.B., Lange, L.A., North, K.E., Palmer, T., Almoguera, B., Buxbaum, S., et al.(2014). Causal effects of body mass index on cardiometabolic traits and events: A Mendelian randomization analysis . American Journal of Human Genetics. 94. (2). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 198-208.

Holmes, M.V., Lange, L.A., Palmer, T., Lanktree, M.B., North, K.E., Almoguera, B., Buxbaum, S., Chandrupatla, H.R., Elbers, C.C., Guo, Y., et al.(2014). Erratum: Causal effects of body mass index on cardiometabolic traits and events: A mendelian randomization analysis (American Journal of Human Genetics (2014) 94 (198-208)) . American Journal of Human Genetics. 94. (2). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 312.

Burgess, S., Granell, R., Palmer, T.M., Sterne, J.A.C., Didelez, V., Burgess, S., Granell, R., Palmer, T.M., Sterne, J.A.C., Didelez, V.(2014). Lack of identification in semiparametric instrumental variable models with binary outcomes . American Journal of Epidemiology. 180. (1). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 111-119.

Cartwright, R., Mangera, A., Tikkinen, K.A.O., Rajan, P., Pesonen, J., Kirby, A.C., Thiagamoorthy, G., Ambrose, C., Gonzalez-Maffe, J., Bennett, P.R., et al.(2014). Systematic review and meta-analysis of candidate gene association studies of lower urinary tract symptoms in men . European Urology. 66. (4). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 752-768.

Wade, K.H., Skugarevsky, O., Kramer, M.S., Patel, R., Bogdanovich, N., Vilchuck, K., Sergeichick, N., Richmond, R., Palmer, T., Smith, G.D., et al.(2014). Prospective associations of parental smoking, alcohol use, marital status, maternal satisfaction, and parental and childhood body mass index at 6.5 years with later problematic eating attitudes . Nutrition and Diabetes. 4. (JANUARY).

Patel, R.S., Asselbergs, F.W., Quyyumi, A.A., Palmer, T.M., Finan, C.I., Tragante, V., Deanfield, J., Hemingway, H., Hingorani, A.D., Holmes, M.V., et al.(2014). Genetic variants at chromosome 9p21 and risk of first versus subsequent coronary heart disease events: A systematic review and meta-analysis . Journal of the American College of Cardiology. 63. (21). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 2234-2245.

Holmes, M.V., Dale, C.E., Zuccolo, L., Silverwood, R.J., Guo, Y., Ye, Z., Prieto-Merino, D., Dehghan, A., Trompet, S., Wong, A., et al.(2014). Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data . BMJ (Online). 349.

Tom Palmer, Corrie Macdonald-Wallis, Debbie Lawlor, Kate Tilling(2014). Estimating adjusted associations between random effects from multilevel models . Stata Journal. 14. (1). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 119--140. DPC Nederland

Kumari, M., Holmes, M.V., Dale, C.E., Hubacek, J.A., Palmer, T.M., Pikhart, H., Peasey, A., Britton, A., Horvat, P., Kubinova, R., et al.(2014). Alcohol consumption and cognitive performance: A mendelian randomization study . Addiction. 109. (9). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1462-1471.

Granell, R., Henderson, A.J., Evans, D.M., Smith, G.D., Ness, A.R., Lewis, S., Palmer, T.M., Sterne, J.A.C., Granell, R., Henderson, A.J., et al.(2014). Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study . PLoS Medicine. 11. (7).

Silverwood, R.J., Holmes, M.V., Dale, C.E., Lawlor, D.A., Whittaker, J.C., Smith, G.D., Leon, D.A., Palmer, T., Keating, B.J., Zuccolo, L., et al.(2014). Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study: Application to alcohol and cardiovascular traits . International Journal of Epidemiology. 43. (6). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1781-1790.

Secretory phospholipase A(2)-IIA and cardiovascular disease @article{f697571987ef4253b0758c4689a87ae0, title = "Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study", abstract = "OBJECTIVES: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.BACKGROUND: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.METHODS: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.RESULTS: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.CONCLUSIONS: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.", keywords = "Alleles, Cardiovascular Diseases, DNA, Gene Expression Regulation, Global Health, Humans, Incidence, Mendelian Randomization Analysis, Phospholipases A2, Secretory", author = "Holmes, {Michael V.} and Tabassome Simon and Exeter, {Holly J.} and Lasse Folkersen and Asselbergs, {Folkert W.} and Montse Guardiola and Cooper, {Jackie A.} and Jutta Palmen and Hubacek, {Jaroslav A.} and Carruthers, {Kathryn F.} and Horne, {Benjamin D.} and Brunisholz, {Kimberly D.} and Mega, {Jessica L.} and {van Iperen}, {Erik P. A.} and Mingyao Li and Maarten Leusink and Stella Trompet and Verschuren, {Jeffrey J. W.} and Hovingh, {G. Kees} and Abbas Dehghan and Nelson, {Christopher P.} and Salma Kotti and Nicolas Danchin and Markus Scholz and Haase, {Christiane L.} and Dietrich Rothenbacher and Swerdlow, {Daniel I.} and Kuchenbaecker, {Karoline B.} and Eleonora Staines-Urias and Anuj Goel and {van 't Hooft}, Ferdinand and Karl Gertow and {de Faire}, Ulf and Panayiotou, {Andrie G.} and Elena Tremoli and Damiano Baldassarre and Fabrizio Veglia and Holdt, {Lesca M.} and Frank Beutner and Gansevoort, {Ron T.} and Navis, {Gerjan J.} and {Mateo Leach}, Irene and Breitling, {Lutz P.} and Hermann Brenner and Joachim Thiery and Dhayana Dallmeier and Anders Franco-Cereceda and Boer, {Jolanda M. A.} and Stephens, {Jeffrey W.} and Hofker, {Marten H.} and Alain Tedgui and Albert Hofman and Uitterlinden, {Andr{\'e} G.} and Vera Adamkova and Jan Pitha and Onland-Moret, {N. Charlotte} and Cramer, {Maarten J.} and Nathoe, {Hendrik M.} and Wilko Spiering and Klungel, {Olaf H.} and Meena Kumari and Whincup, {Peter H.} and Morrow, {David A.} and Braund, {Peter S.} and Hall, {Alistair S.} and Olsson, {Anders G.} and Doevendans, {Pieter A.} and Trip, {Mieke D.} and Tobin, {Martin D.} and Anders Hamsten and Hugh Watkins and Wolfgang Koenig and Nicolaides, {Andrew N.} and Daniel Teupser and Day, {Ian N. M.} and Carlquist, {John F.} and Gaunt, {Tom R.} and Ian Ford and Naveed Sattar and Sotirios Tsimikas and Schwartz, {Gregory G.} and Lawlor, {Debbie A.} and Morris, {Richard W.} and Sandhu, {Manjinder S.} and Rudolf Poledne and {Maitland-van der Zee}, {Anke H.} and Kay-Tee Khaw and Keating, {Brendan J.} and {van der Harst}, Pim and Price, {Jackie F.} and Mehta, {Shamir R.} and Salim Yusuf and Witteman, {Jaqueline C. M.} and Franco, {Oscar H.} and Jukema, {J. Wouter} and {de Knijff}, Peter and Anne Tybjaerg-Hansen and Rader, {Daniel J.} and Martin Farrall and Samani, {Nilesh J.} and Mika Kivimaki and Fox, {Keith A. A.} and Humphries, {Steve E.} and Anderson, {Jeffrey L.} and Boekholdt, {S. Matthijs} and Palmer, {Tom M.} and Per Eriksson and Guillaume Par{\'e} and Hingorani, {Aroon D.} and Sabatine, {Marc S.} and Ziad Mallat and Casas, {Juan P.} and Talmud, {Philippa J.}", note = "Copyright {\textcopyright} 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.", year = "2013", month = nov, day = "19", doi = "10.1016/j.jacc.2013.06.044", language = "English", volume = "62", pages = "1966--1976", journal = "Journal of the American College of Cardiology", publisher = "Elsevier USA", number = "21", } . Journal of the American College of Cardiology.

Secretory phospholipase A2-IIA and cardiovascular disease @article{8eea386ad9fa4115a2ba3e30a32ae018, title = "Secretory phospholipase A2-IIA and cardiovascular disease: A mendelian randomization study", abstract = "Objectives This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Background Higher circulating levels of sPLA2-IIA mass or sPLA 2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. Methods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. Results PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA 2 enzyme activity and MVE. Conclusions Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.", keywords = "cardiovascular diseases, drug development, epidemiology, genetics, Mendelian randomization", author = "Holmes-paper and Holmes, {Michael V.} and Tabassome Simon and Exeter, {Holly J.} and Lasse Folkersen and Asselbergs, {Folkert W.} and Montse Guardiola and Cooper, {Jackie A.} and Jutta Palmen and Hubacek, {Jaroslav A.} and Carruthers, {Kathryn F.} and Horne, {Benjamin D.} and Brunisholz, {Kimberly D.} and Mega, {Jessica L.} and {Van Iperen}, {Erik P.A.} and Mingyao Li and Maarten Leusink and Stella Trompet and Verschuren, {Jeffrey J.W.} and Hovingh, {G. Kees} and Abbas Dehghan and Nelson, {Christopher P.} and Salma Kotti and Nicolas Danchin and Markus Scholz and Haase, {Christiane L.} and Dietrich Rothenbacher and Swerdlow, {Daniel I.} and Kuchenbaecker, {Karoline B.} and Eleonora Staines-Urias and Anuj Goel and {Van 'T Hooft}, Ferdinand and Karl Gertow and {De Faire}, Ulf and Panayiotou, {Andrie G.} and Elena Tremoli and Damiano Baldassarre and Fabrizio Veglia and Holdt, {Lesca M.} and Frank Beutner and Meena Kumari and Tobin, {Martin D.} and Day, {Ian N.M.} and Gaunt, {Tom R.} and Naveed Sattar and Schwartz, {Gregory G.} and Lawlor, {Debbie A.} and Morris, {Richard W.} and Mika Kivimaki and Anderson, {Jeffrey L.} and Palmer, {Tom M.}", year = "2013", month = nov, day = "19", doi = "10.1016/j.jacc.2013.06.044", language = "English", volume = "62", pages = "1966--1976", journal = "Journal of the American College of Cardiology", issn = "0735-1097", publisher = "Elsevier Inc.", number = "21", } . Journal of the American College of Cardiology.

Effects of an intervention to promote breastfeeding on maternal adiposity and blood pressure at 11.5 y postpartum @article{ad12008355194e47b49ad75d8e0a4f63, title = "Effects of an intervention to promote breastfeeding on maternal adiposity and blood pressure at 11.5 y postpartum: results from the Promotion of Breastfeeding Intervention Trial, a cluster-randomized controlled trial", abstract = "BACKGROUND: Differences between mothers who do and do not succeed in breastfeeding are likely to confound associations of lactation with later maternal adiposity.OBJECTIVE: We compared adiposity and blood pressure (BP) in women randomly assigned to an intervention to promote prolonged and exclusive breastfeeding or usual care.DESIGN: We performed a cluster-randomized trial at 31 hospitals in Belarus in 1996-1997.RESULTS: Of 17,046 women enrolled at delivery, we assessed 11,867 women (69.6%) at 11.5 y postpartum. The prevalence of exclusive breastfeeding ≥3 mo was 44.5% in 6321 women in the intervention group and 7.1% in 5546 women in the control group. At 11.5 y postpartum, mean (±SD) body mass index (BMI; in kg/m(2)) was 26.5 ± 5.5, the percentage of body fat was 33.6% ± 8.3%, and systolic BP was 124.6 ± 14.6 mm Hg. On intention-to-treat analysis (without imputation) with adjustment for clustering by hospital, mean outcomes were lower in intervention compared with control mothers for BMI (mean difference: -0.27; 95% CI: -0.91, 0.37), body fat (-0.49%; 95% CI: -1.25%, 0.27%), and systolic BP (-0.81 mm Hg; 95% CI: -3.33, 1.71 mm Hg), but effect sizes were small, CIs were wide, and results were attenuated further toward the null after adjustment for baseline characteristics. Results were similar in sensitivity analyses [ie, by using conventional observational analyses disregarding treatment assignment, instrumental variable analyses to estimate the causal effect of breastfeeding, and multiple imputation to account for missing outcome measures (n = 17,046)].CONCLUSION: In women who initiated breastfeeding, an intervention to promote longer breastfeeding duration did not result in an important lowering of adiposity or BP. This trial was registered at clinicaltrials.gov as NCT01561612 and at Current Controlled Trials as ISRCTN37687716.", keywords = "Adiposity, Adult, Blood Pressure, Body Mass Index, Breast Feeding, Female, Follow-Up Studies, Health Promotion, Humans, Lactation, Maternal Welfare, Pregnancy, Quality Assurance, Health Care, Republic of Belarus, Time Factors", author = "Emily Oken and Rita Patel and Guthrie, {Lauren B.} and Konstantin Vilchuck and Natalia Bogdanovich and Natalia Sergeichick and Palmer, {Tom M.} and Kramer, {Michael S.} and Martin, {Richard M.}", year = "2013", month = oct, doi = "10.3945/ajcn.113.065300", language = "English", volume = "98", pages = "1048--1056", journal = "American Journal of Clinical Nutrition", issn = "0002-9165", publisher = "Elsevier BV", number = "4", } . American Journal of Clinical Nutrition.

Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts @article{8b660759bf244aeca7cce6536ebeb074, title = "Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts", abstract = "To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index.", author = "Palmer, {Tom M} and Nordestgaard, {B{\o}rge G} and Marianne Benn and Anne Tybj{\ae}rg-Hansen and {Davey Smith}, George and Lawlor, {Debbie A} and Timpson, {Nicholas J}", year = "2013", month = jul, day = "18", doi = "10.1136/bmj.f4262", language = "English", volume = "347", journal = "BMJ", issn = "0959-8138", publisher = "BMJ Publishing Group", } . BMJ.

Association of plasma uric acid with ischaemic heart disease and blood pressure @article{f3ef166f8bc64d08b5fcd140b80b9b65, title = "Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts", abstract = "OBJECTIVES: To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index.DESIGN: Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index).SETTING: Two large, prospective cohort studies in Denmark.PARTICIPANTS: We measured levels of uric acid and related covariables in 58,072 participants from the Copenhagen General Population Study and 10,602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively.MAIN OUTCOME: Blood pressure and prospectively assessed ischaemic heart disease.RESULTS: Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%).CONCLUSION: By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions.", keywords = "Adult, Aged, Blood Pressure, Body Mass Index, Denmark, Female, Humans, Hyperuricemia, Male, Mendelian Randomization Analysis, Middle Aged, Myocardial Ischemia, Prospective Studies, Regression Analysis, Uric Acid", author = "Palmer, {Tom M.} and Nordestgaard, {B{\o}rge G.} and Marianne Benn and Anne Tybj{\ae}rg-Hansen and {Davey Smith}, George and Lawlor, {Debbie A.} and Timpson, {Nicholas J.}", year = "2013", month = jul, day = "18", language = "English", volume = "347", journal = "BMJ", issn = "0959-8138", publisher = "British Medical Association", } . BMJ.

Associations of mortality with own height using son's height as an instrumental variable @article{eee26e3de0ee4783ab8409f6e41a1b89, title = "Associations of mortality with own height using son's height as an instrumental variable", abstract = "Height is associated with mortality from many diseases, but it remains unclear whether the association is causal or due to confounding by social factors, genetic pleiotropy,(1) or existing ill-health. The authors investigated whether the association of height with mortality is causal by using a son's height as an instrumental variable (IV) for parents' height among the parents of a cohort of 1,036,963 Swedish men born between 1951 and 1980 who had their height measured at military conscription, aged around 18, between 1969 and 2001. In a two-sample IV analysis adjusting for son's age at examination and secular trends in height, as well as parental age, and socioeconomic position, the hazard ratio (HR) for all-cause paternal mortality per standard deviation (SD, 6.49cm) of height was 0.96 (95% confidence interval (CI): 0.95, 0.96). The results of IV analyses of mortality from all causes, cardiovascular disease (CVD), respiratory disease, cancer, external causes and suicide were comparable to those obtained using son's height as a simple proxy for own height and to conventional analyses of own height in the present data and elsewhere, suggesting that such conventional analyses are not substantially confounded by existing ill-health.", keywords = "Adolescent, Adult, Body Height, Cause of Death, Confidence Intervals, Confounding Factors (Epidemiology), Female, Humans, Longitudinal Studies, Male, Nuclear Family, Proportional Hazards Models, Sweden, Young Adult", author = "David Carslake and Abigail Fraser and {Davey Smith}, George and Margaret May and Tom Palmer and Jonathan Sterne and Karri Silventoinen and Per Tynelius and Lawlor, {Debbie A.} and Finn Rasmussen", note = " Copyright {\textcopyright} 2012 Elsevier B.V. All rights reserved.", year = "2013", month = jul, doi = "10.1016/j.ehb.2012.04.003", language = "English", volume = "11", pages = "351--359", journal = "Economics and Human Biology", publisher = "Elsevier BV", number = "3", } . Economics and Human Biology.

Associations of mortality with own height using son's height as an instrumental variable @article{804b1b2778ae4e4cb1129b2d8f0d3027, title = "Associations of mortality with own height using son's height as an instrumental variable", abstract = "Height is associated with mortality from many diseases, but it remains unclear whether the association is causal or due to confounding by social factors, genetic pleiotropy,(1) or existing ill-health. The authors investigated whether the association of height with mortality is causal by using a son's height as an instrumental variable (IV) for parents' height among the parents of a cohort of 1,036,963 Swedish men born between 1951 and 1980 who had their height measured at military conscription, aged around 18, between 1969 and 2001. In a two-sample IV analysis adjusting for son's age at examination and secular trends in height, as well as parental age, and socioeconomic position, the hazard ratio (HR) for all-cause paternal mortality per standard deviation (SD, 6.49 cm) of height was 0.96 (95% confidence interval (CI): 0.95, 0.96). The results of IV analyses of mortality from all causes, cardiovascular disease (CVD), respiratory disease, cancer, external causes and suicide were comparable to those obtained using son's height as a simple proxy for own height and to conventional analyses of own height in the present data and elsewhere, suggesting that such conventional analyses are not substantially confounded by existing ill-health. (C) 2012 Elsevier B.V. All rights reserved.", keywords = "Body height, Mortality, Confounding factor, Causality, Cohort studies, CORONARY-HEART-DISEASE, BODY-MASS INDEX, ADULT HEIGHT, CANCER-MORTALITY, LUNG-FUNCTION, RISK-FACTORS, CARDIORESPIRATORY DISEASE, CARDIOVASCULAR-DISEASE, GLASGOW-UNIVERSITY, FINNISH TWINS", author = "David Carslake and Abigail Fraser and Smith, {George Davey} and Margaret May and Tom Palmer and Jonathan Sterne and Karri Silventoinen and Per Tynelius and Lawlor, {Debbie A.} and Finn Rasmussen", year = "2013", month = jul, doi = "10.1016/j.ehb.2012.04.003", language = "English", volume = "11", pages = "351--359", journal = "Economics and Human Biology", issn = "1570-677X", publisher = "Elsevier Science", number = "3", } . Economics and Human Biology.

Severity of bias of a simple estimator of the causal odds ratio in Mendelian randomization studies @article{9562c843352345169dfeea33fadd65fc, title = "Severity of bias of a simple estimator of the causal odds ratio in Mendelian randomization studies", abstract = "Mendelian randomization studies estimate causal effects using genetic variants as instruments. Instrumental variable methods are straightforward for linear models, but epidemiologists often use odds ratios to quantify effects. Also, odds ratios are often the quantities reported in meta-analyses. Many applications of Mendelian randomization dichotomize genotype and estimate the population causal log odds ratio for unit increase in exposure by dividing the genotype-disease log odds ratio by the difference in mean exposure between genotypes. This 'Wald-type' estimator is biased even in large samples, but whether the magnitude of bias is of practical importance is unclear. We study the large-sample bias of this estimator in a simple model with a continuous normally distributed exposure, a single unobserved confounder that is not an effect modifier, and interpretable parameters. We focus on parameter values that reflect scenarios in which we apply Mendelian randomization, including realistic values for the degree of confounding and strength of the causal effect. We evaluate this estimator and the causal odds ratio using numerical integration and obtain approximate analytic expressions to check results and gain insight. A small simulation study examines finite sample bias and mild violations of the normality assumption. For our simple data-generating model, we find that the Wald estimator is asymptotically biased with a bias of around 10% in fairly typical Mendelian randomization scenarios but which can be larger in more extreme situations. Recently developed methods such as structural mean models require fewer untestable assumptions and we recommend their use when the individual-level data they require are available. The Wald-type estimator may retain a role as an approximate method for meta-analysis based on summary data.", keywords = "Bias (Epidemiology), Biostatistics, Causality, Humans, Mendelian Randomization Analysis, Meta-Analysis as Topic, Models, Statistical, Odds Ratio", author = "Harbord, {Roger M.} and Vanessa Didelez and Palmer, {Tom M.} and Sha Meng and Sterne, {Jonathan A. C.} and Sheehan, {Nuala A.}", note = " Copyright {\textcopyright} 2012 John Wiley & Sons, Ltd.", year = "2013", month = mar, day = "30", doi = "10.1002/sim.5659", language = "English", volume = "32", pages = "1246--1258", journal = "Statistics in Medicine", issn = "0277-6715", publisher = "John Wiley and Sons Ltd", number = "7", } . Statistics in Medicine.

Severity of bias of a simple estimator of the causal odds ratio in Mendelian randomization studies @article{18dddc3df7e24e35a9478b0aff0dc304, title = "Severity of bias of a simple estimator of the causal odds ratio in Mendelian randomization studies", abstract = "Mendelian randomization studies estimate causal effects using genetic variants as instruments. Instrumental variable methods are straightforward for linear models, but epidemiologists often use odds ratios to quantify effects. Also, odds ratios are often the quantities reported in meta-analyses. Many applications of Mendelian randomization dichotomize genotype and estimate the population causal log odds ratio for unit increase in exposure by dividing the genotype-disease log odds ratio by the difference in mean exposure between genotypes. This Wald-type' estimator is biased even in large samples, but whether the magnitude of bias is of practical importance is unclear. We study the large-sample bias of this estimator in a simple model with a continuous normally distributed exposure, a single unobserved confounder that is not an effect modifier, and interpretable parameters. We focus on parameter values that reflect scenarios in which we apply Mendelian randomization, including realistic values for the degree of confounding and strength of the causal effect. We evaluate this estimator and the causal odds ratio using numerical integration and obtain approximate analytic expressions to check results and gain insight. A small simulation study examines finite sample bias and mild violations of the normality assumption. For our simple data-generating model, we find that the Wald estimator is asymptotically biased with a bias of around 10% in fairly typical Mendelian randomization scenarios but which can be larger in more extreme situations. Recently developed methods such as structural mean models require fewer untestable assumptions and we recommend their use when the individual-level data they require are available. The Wald-type estimator may retain a role as an approximate method for meta-analysis based on summary data. Copyright (c) 2012 John Wiley & Sons, Ltd.", keywords = "Mendelian randomization, instrumental variables, causal inference, binary outcomes, odds ratios, INSTRUMENTAL-VARIABLE ESTIMATION, CORONARY-HEART-DISEASE, OBSERVATIONAL EPIDEMIOLOGY, PLASMA-FIBRINOGEN, BAYESIAN METHODS, MODELS, INFERENCE, METAANALYSIS, RISK, ASSOCIATION", author = "Harbord, {Roger M.} and Vanessa Didelez and Palmer, {Tom M.} and Sha Meng and Sterne, {Jonathan A. C.} and Sheehan, {Nuala A.}", year = "2013", month = mar, day = "30", doi = "10.1002/sim.5659", language = "English", volume = "32", pages = "1246--1258", journal = "Statistics in Medicine", issn = "0277-6715", publisher = "John Wiley & Sons, Ltd.", number = "7", } . Statistics in Medicine.

Effects of promoting longer-term and exclusive breastfeeding on adiposity and insulin-like growth factor-I at age 11.5 years: a randomized trial @article{e3bdce8c95a74f32a6eafe163331a740, title = "Effects of promoting longer-term and exclusive breastfeeding on adiposity and insulin-like growth factor-I at age 11.5 years: a randomized trial", abstract = "Importance Evidence that longer-term and exclusive breastfeeding reduces child obesity risk is based on observational studies that are prone to confounding.Objective To investigate effects of an intervention to promote increased duration and exclusivity of breastfeeding on child adiposity and circulating insulin-like growth factor (IGF)-I, which regulates growth.Design, Setting, and Participants Cluster-randomized controlled trial in 31 Be-larusian maternity hospitals and their affiliated clinics, randomized into 1 of 2 groups: breastfeeding promotion intervention (n=16) or usual practices (n=15). Participants were 17 046 breastfeeding mother-infant pairs enrolled in 1996 and 1997, of whom 13 879 (81.4%) were followed up between January 2008 and December 2010 at a median age of 11.5 years.Intervention Breastfeeding promotion intervention modeled on the WHO/UNICEF Baby-Friendly Hospital Initiative (World Health Organization/United Nations Children's Fund).Main Outcome Measures Body mass index (BMI), fat and fat-free mass indices (FMI and FFMI), percent body fat, waist circumference, triceps and subscapular skinfold thicknesses, overweight and obesity, and whole-blood IGF-I. Primary analysis was based on modified intention-to-treat (without imputation), accounting for clustering within hospitals and clinics.Results The experimental intervention substantially increased breastfeeding duration and exclusivity when compared with the control (43% vs 6% exclusively breast-fed at 3 months and 7.9% vs 0.6% at 6 months). Cluster-adjusted mean differences in outcomes at 11.5 years of age between experimental vs control groups were: 0.19 (95% CI, -0.09 to 0.46) for BMI; 0.12 (-0.03 to 0.28) for FMI; 0.04 (-0.11 to 0.18) for FFMI; 0.47% (-0.11% to 1.05%) for percent body fat; 0.30 cm (-1.41 to 2.01) for waist circumference; -0.07 mm (-1.71 to 1.57) for triceps and -0.02 mm (-0.79 to 0.75) for subscapular skinfold thicknesses; and -0.02 standard deviations (-0.12 to 0.08) for IGF-I. The cluster-adjusted odds ratio for overweight/obesity (BMI >= 85th vs = 95th vs Conclusions and Relevance Among healthy term infants in Belarus, an intervention that succeeded in improving the duration and exclusivity of breastfeeding did not prevent overweight or obesity, nor did it affect IGF-I levels at age 11.5 years. Breastfeeding has many advantages but population strategies to increase the duration and exclusivity of breastfeeding are unlikely to curb the obesity epidemic.", keywords = "Young Adult, Obesity, Intervention Studies, Breast Feeding, Adiposity, Humans, Infant, Newborn, Overweight, Child, Insulin-Like Growth Factor I, Pregnancy, Health Promotion, Infant, Hospitals, Maternity, Adult, Follow-Up Studies, Time Factors, Male, Female, Republic of Belarus", author = "Martin, {Richard M} and Rita Patel and Kramer, {Michael S} and Lauren Guthrie and Konstantin Vilchuck and Natalia Bogdanovich and Natalia Sergeichick and Nina Gusina and Ying Foo and Palmer, {Tom M} and Rifas-Shiman, {Sheryl L} and Gillman, {Matthew W} and {Davey Smith}, George and Emily Oken", year = "2013", month = mar, day = "13", doi = "10.1001/jama.2013.167", language = "English", volume = "309", pages = "1005--1013", journal = "JAMA - Journal of the American Medical Association", issn = "0098-7484", publisher = "American Medical Association", number = "10", } . JAMA - Journal of the American Medical Association.

Effects of promoting increased duration and exclusivity of breastfeeding on adiposity and insulin-like growth factor-I at age 11.5 years @article{56ebd4d6b3fb4e0386209f8e58bd4ab5, title = "Effects of promoting increased duration and exclusivity of breastfeeding on adiposity and insulin-like growth factor-I at age 11.5 years: a randomized trial", abstract = "IMPORTANCE: Evidence that increased duration and exclusivity of breastfeeding reduces child obesity risk is based on observational studies that are prone to confounding. OBJECTIVE: To investigate effects of an intervention to promote increased duration and exclusivity of breastfeeding on child adiposity and circulating insulin-like growth factor (IGF)-I (which regulates growth). DESIGN: Cluster-randomized controlled trial. SETTING: 31 Belarusian maternity hospitals and their affiliated polyclinics, randomized to usual practices (n=15) or a breastfeeding promotion intervention (n=16). PARTICIPANTS: 17,046 breastfeeding mother-infant pairs enrolled in 1996/7, of whom 13,879 (81.4%) were followed-up between January 2008 and December 2010 at a median age of 11.5 years. INTERVENTION: Breastfeeding promotion intervention modeled on the WHO/UNICEF Baby Friendly Hospital Initiative. MAIN OUTCOME MEASURES: Body mass index (BMI), fat and fat-free mass indices (FMI and FFMI), percent body fat, waist circumference, triceps and subscapular skinfold thicknesses, overweight and obesity, and whole-blood IGF-I. Primary analysis was based on modified intention-to-treat (without imputation), accounting for clustering within hospitals/clinics. RESULTS: The experimental intervention substantially increased breastfeeding duration and exclusivity (43% vs. 6% and 7.9% vs. 0.6% exclusively breastfed at 3 and 6 months, respectively) versus the control intervention. Cluster-adjusted mean differences in outcomes at 11.5 years between experimental vs. control groups were: 0.19 kg/m(2) (95% 4 CI: −0.09, 0.46) for BMI; 0.12 kg/m(2) (−0.03, 0.28) for FMI; 0.04 kg/m(2) (−0.11, 0.18) for FFMI; 0.47% (−0.11, 1.05) for % body fat; 0.30 cm (−1.41, 2.01) for waist circumference; −0.07 mm (−1.71, 1.57) for triceps and −0.02 mm (−0.79, 0.75) for subscapular skinfold thicknesses; and −0.02 standard deviations (−0.12, 0.08) for IGF-I. The cluster-adjusted odds ratio for overweight / obesity (BMI ≥85(th) percentile vs ", author = "Martin, {Richard M.} and Rita Patel and Kramer, {Michael S.} and Lauren Guthrie and Konstantin Vilchuck and Natalia Bogdanovich and Natalia Sergeichick and Nina Gusina and Ying Foo and Tom Palmer and Rifas-Shiman, {Sheryl L.} and Gillman, {Matthew W.} and {Davey Smith}, George and Emily Oken", year = "2013", month = mar, day = "13", doi = "10.1001/jama.2013.167", language = "English", volume = "309", pages = "1005--1013", journal = "Journal of the American Medical Association", issn = "0098-7484", publisher = "American Medical Association", number = "10", } . Journal of the American Medical Association.

Holmes, M.V., Simon, T., Exeter, H.J., Folkersen, L., Asselbergs, F.W., Guardiola, M., Cooper, J.A., Palmen, J., Hubacek, J.A., Carruthers, K.F., et al.(2013). Secretory phospholipase A <inf>2</inf> -IIA and cardiovascular disease: A mendelian randomization study . Journal of the American College of Cardiology. 62. (21). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1966-1976.

Palmer, T.M., Nordestgaard, B.G., Benn, M., Tybjarg-Hansen, A., Smith, G.D., Lawlor, D.A., Timpson, N.J., Palmer, T.M., Nordestgaard, B.G., Benn, M., et al.(2013). Association of plasma uric acid with ischaemic heart disease and blood pressure: Mendelian randomization analysis of two large cohorts . BMJ (Online). 347. (7919).

Martin, R.M., Patel, R., Kramer, M.S., Guthrie, L., Vilchuck, K., Bogdanovich, N., Sergeichick, N., Martin, R.M., Gusina, N., Patel, R., et al.(2013). Effects of promoting longer-term and exclusive breastfeeding on adiposity and insulin-like growth factor-I at age 11.5 years: A randomized trial . JAMA - Journal of the American Medical Association. 309. (10). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1005-1013.

Carslake, D., Fraser, A., Davey Smith, G., May, M., Palmer, T., Sterne, J., Silventoinen, K., Tynelius, P., Lawlor, D.A., Rasmussen, F., et al.(2013). Associations of mortality with own height using son's height as an instrumental variable . Economics and Human Biology. 11. (3). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 351-359.

Harbord, R.M., Didelez, V., Palmer, T.M., Meng, S., Sterne, J.A.C., Sheehan, N.A., Harbord, R.M., Didelez, V., Palmer, T.M., Meng, S., et al.(2013). Severity of bias of a simple estimator of the causal odds ratio in Mendelian randomization studies . Statistics in Medicine. 32. (7). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1246-1258.

Oken, E., Patel, R., Guthrie, L.B., Vilchuck, K., Bogdanovich, N., Sergeichick, N., Palmer, T.M., Kramer, M.S., Martin, R.M., Oken, E., et al.(2013). Effects of an intervention to promote breastfeeding on maternal adiposity and blood pressure at 11.5 y postpartum: Results from the promotion of breastfeeding intervention trial, a cluster-randomized controlled trial . American Journal of Clinical Nutrition. 98. (4). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1048-1056.

Multivariate multilevel spline models for parallel growth processes @article{379555ce277b42d2940cefe651502066, title = "Multivariate multilevel spline models for parallel growth processes: application to weight and mean arterial pressure in pregnancy", author = "Corrie Macdonald-Wallis and Lawlor, {Debbie A} and Tom Palmer and Kate Tilling", year = "2012", month = nov, day = "20", doi = "10.1002/sim.5385", language = "English", volume = "31", pages = "3147--3164", journal = "Statistics in Medicine", issn = "0277-6715", publisher = "John Wiley & Sons, Ltd.", number = "26", } . Statistics in Medicine.

Multivariate multilevel spline models for parallel growth processes @article{ce163f73a3b14d5abf4513a8aa143b70, title = "Multivariate multilevel spline models for parallel growth processes: application to weight and mean arterial pressure in pregnancy", abstract = "Growth models are commonly used in life course epidemiology to describe growth trajectories and their determinants or to relate particular patterns of change to later health outcomes. However, methods to analyse relationships between two or more change processes occurring in parallel, in particular to assess evidence for causal influences of change in one variable on subsequent changes in another, are less developed. We discuss linear spline multilevel models with a multivariate response and show how these can be used to relate rates of change in a particular time period in one variable to later rates of change in another variable by using the variances and covariances of individual-level random effects for each of the splines. We describe how regression coefficients can be calculated for these associations and how these can be adjusted for other parameters such as random effect variables relating to baseline values or rates of change in earlier time periods, and compare different methods for calculating the standard errors of these regression coefficients. We also show that these models can equivalently be fitted in the structural equation modelling framework and apply each method to weight and mean arterial pressure changes during pregnancy, obtaining similar results for multilevel and structural equation models. This method improves on the multivariate linear growth models, which have been used previously to model parallel processes because it enables nonlinear patterns of change to be modelled and the temporal sequence of multivariate changes to be determined, with adjustment for change in earlier time periods.", keywords = "Adult, Biometry, Blood Pressure, Databases, Factual, Female, Growth, Humans, Infant, Newborn, Linear Models, Male, Models, Biological, Models, Statistical, Multivariate Analysis, Pregnancy, Weight Gain, Young Adult", author = "Corrie Macdonald-Wallis and Lawlor, {Debbie A.} and Tom Palmer and Kate Tilling", note = "Copyright {\textcopyright} 2012 John Wiley & Sons, Ltd.", year = "2012", month = nov, day = "20", doi = "10.1002/sim.5385", language = "English", volume = "31", pages = "3147--3164", journal = "Statistics in Medicine", issn = "0277-6715", publisher = "John Wiley and Sons Ltd", number = "26", } . Statistics in Medicine.

Re: "credible mendelian randomization studies @article{3452296179434dc3b460aced43581108, title = "Re: {"}credible mendelian randomization studies: approaches for evaluating the instrumental variable assumptions{"}", keywords = "Causality, Epidemiologic Research Design, Humans, Mendelian Randomization Analysis", author = "Palmer, {Tom M.} and Ramsahai, {Roland R.} and Lawlor, {Debbie A.} and Sheehan, {Nuala A.} and Vanessa Didelez", year = "2012", month = sep, day = "1", doi = "10.1093/aje/kws250", language = "English", volume = "176", pages = "457--458; author reply 458", journal = "American Journal of Epidemiology", issn = "0002-9262", publisher = "Oxford University Press", number = "5", } . American Journal of Epidemiology.

Instrumental variable estimation of the causal effect of plasma 25-hydroxy-vitamin D on colorectal cancer risk @article{07496b75209f4b339cb326d12a475a9a, title = "Instrumental variable estimation of the causal effect of plasma 25-hydroxy-vitamin D on colorectal cancer risk: a mendelian randomization analysis", abstract = "Vitamin D deficiency has been associated with several common diseases, including cancer and is being investigated as a possible risk factor for these conditions. We reported the striking prevalence of vitamin D deficiency in Scotland. Previous epidemiological studies have reported an association between low dietary vitamin D and colorectal cancer (CRC). Using a case-control study design, we tested the association between plasma 25-hydroxy-vitamin D (25-OHD) and CRC (2,001 cases, 2,237 controls). To determine whether plasma 25-OHD levels are causally linked to CRC risk, we applied the control function instrumental variable (IV) method of the mendelian randomization (MR) approach using four single nucleotide polymorphisms (rs2282679, rs12785878, rs10741657, rs6013897) previously shown to be associated with plasma 25-OHD. Low plasma 25-OHD levels were associated with CRC risk in the crude model (odds ratio (OR): 0.76, 95% Confidence Interval (CI): 0.71, 0.81, p: 1.4×10(-14)) and after adjusting for age, sex and other confounding factors. Using an allele score that combined all four SNPs as the IV, the estimated causal effect was OR 1.16 (95% CI 0.60, 2.23), whilst it was 0.94 (95% CI 0.46, 1.91) and 0.93 (0.53, 1.63) when using an upstream (rs12785878, rs10741657) and a downstream allele score (rs2282679, rs6013897), respectively. 25-OHD levels were inversely associated with CRC risk, in agreement with recent meta-analyses. The fact that this finding was not replicated when the MR approach was employed might be due to weak instruments, giving low power to demonstrate an effect (<0.35). The prevalence and degree of vitamin D deficiency amongst individuals living in northerly latitudes is of considerable importance because of its relationship to disease. To elucidate the effect of vitamin D on CRC cancer risk, additional large studies of vitamin D and CRC risk are required and/or the application of alternative methods that are less sensitive to weak instrument restrictions.", keywords = "25-Hydroxyvitamin D 2, Adult, Aged, Case-Control Studies, Chromatography, Liquid, Colorectal Neoplasms, Female, Genotype, Humans, Likelihood Functions, Male, Mendelian Randomization Analysis, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Risk Factors, Scotland, Tandem Mass Spectrometry, Vitamin D Deficiency", author = "Evropi Theodoratou and Tom Palmer and Lina Zgaga and Farrington, {Susan M} and Paul McKeigue and Din, {Farhat V. N.} and Albert Tenesa and George Davey-Smith and Dunlop, {Malcolm G.} and Harry Campbell", year = "2012", month = jun, day = "6", doi = "10.1371/journal.pone.0037662", language = "English", volume = "7", journal = "PLoS ONE", issn = "1932-6203", publisher = "Public Library of Science", number = "6", } . PLoS ONE.

Instrumental Variable Estimation of the Causal Effect of Plasma 25-Hydroxy-Vitamin D on Colorectal Cancer Risk: A Mendelian Randomization Analysis @article{a8c4bd7a73674ab69bdde6f8b1074218, title = "Instrumental Variable Estimation of the Causal Effect of Plasma 25-Hydroxy-Vitamin D on Colorectal Cancer Risk: A Mendelian Randomization Analysis", abstract = "Vitamin D deficiency has been associated with several common diseases, including cancer and is being investigated as a possible risk factor for these conditions. We reported the striking prevalence of vitamin D deficiency in Scotland. Previous epidemiological studies have reported an association between low dietary vitamin D and colorectal cancer (CRC). Using a case-control study design, we tested the association between plasma 25-hydroxy-vitamin D (25-OHD) and CRC (2,001 cases, 2,237 controls). To determine whether plasma 25-OHD levels are causally linked to CRC risk, we applied the control function instrumental variable (IV) method of the Mendelian randomization (MR) approach using four single nucleotide polymorphisms (rs2282679, rs12785878, rs10741657, rs6013897) previously shown to be associated with plasma 25-OHD. Low plasma 25-OHD levels were associated with CRC risk in the crude model (odds ratio (OR): 0.76, 95% Confidence Interval (CI): 0.71, 0.81, p: 1.4x10(-14)) and after adjusting for age, sex and other confounding factors. Using an allele score that combined all four SNPs as the IV, the estimated causal effect was OR 1.16 (95% CI 0.60, 2.23), whilst it was 0.94 (95% CI 0.46, 1.91) and 0.93 (0.53, 1.63) when using an upstream (rs12785878, rs10741657) and a downstream allele score (rs2282679, rs6013897), respectively. 25-OHD levels were inversely associated with CRC risk, in agreement with recent meta-analyses. The fact that this finding was not replicated when the MR approach was employed might be due to weak instruments, giving low power to demonstrate an effect (", keywords = "VITAMIN-D DEFICIENCY, 25-HYDROXYVITAMIN D, D SUPPLEMENTATION, ASSOCIATION, CALCIUM, HEALTH, TRIAL, METAANALYSIS, PREVENTION, ASPIRIN", author = "Evropi Theodoratou and Tom Palmer and Lina Zgaga and Farrington, {Susan M.} and Paul McKeigue and Din, {Farhat V. N.} and Albert Tenesa and {Davey Smith}, George and Dunlop, {Malcolm G.} and Harry Campbell", year = "2012", month = jun, day = "6", doi = "10.1371/journal.pone.0037662", language = "English", volume = "7", journal = "PLoS ONE", issn = "1932-6203", publisher = "Public Library of Science", number = "6", } . PLoS ONE.

Using multiple genetic variants as instrumental variables for modifiable risk factors @article{9d879cad4081461d8551fd9e8523ef62, title = "Using multiple genetic variants as instrumental variables for modifiable risk factors", abstract = "Mendelian randomisation analyses use genetic variants as instrumental variables (IVs) to estimate causal effects of modifiable risk factors on disease outcomes. Genetic variants typically explain a small proportion of the variability in risk factors; hence Mendelian randomisation analyses can require large sample sizes. However, an increasing number of genetic variants have been found to be robustly associated with disease-related outcomes in genome-wide association studies. Use of multiple instruments can improve the precision of IV estimates, and also permit examination of underlying IV assumptions. We discuss the use of multiple genetic variants in Mendelian randomisation analyses with continuous outcome variables where all relationships are assumed to be linear. We describe possible violations of IV assumptions, and how multiple instrument analyses can be used to identify them. We present an example using four adiposity-associated genetic variants as IVs for the causal effect of fat mass on bone density, using data on 5509 children enrolled in the ALSPAC birth cohort study. We also use simulation studies to examine the effect of different sets of IVs on precision and bias. When each instrument independently explains variability in the risk factor, use of multiple instruments increases the precision of IV estimates. However, inclusion of weak instruments could increase finite sample bias. Missing data on multiple genetic variants can diminish the available sample size, compared with single instrument analyses. In simulations with additive genotype-risk factor effects, IV estimates using a weighted allele score had similar properties to estimates using multiple instruments. Under the correct conditions, multiple instrument analyses are a promising approach for Mendelian randomisation studies. Further research is required into multiple imputation methods to address missing data issues in IV estimation.", keywords = "Female, Genetic Variation, Genotype, Humans, Male, Mendelian Randomization Analysis, Risk Factors", author = "Palmer, {Tom M.} and Lawlor, {Debbie A.} and Harbord, {Roger M.} and Sheehan, {Nuala A.} and Tobias, {Jon H.} and Timpson, {Nicholas J.} and {Davey Smith}, George and Sterne, {Jonathan A. C.}", year = "2012", month = jun, doi = "10.1177/0962280210394459", language = "English", volume = "21", pages = "223--242", journal = "Statistical Methods in Medical Research", issn = "0962-2802", publisher = "SAGE Publications Ltd", number = "3", } . Statistical Methods in Medical Research.

Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure @article{be8df5c0b6b0405fb88dafb42170d4ad, title = "Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure", abstract = "BACKGROUND: Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure.METHODS: We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730-rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730-rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided.RESULTS: Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730-rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10(-6)) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10(-11)). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730-rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42).CONCLUSIONS: Our data show a stronger association of rs1051730-rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.", keywords = "Biological Markers, Chromosomes, Human, Pair 15, Cotinine, Gene Frequency, Humans, Linear Models, Linkage Disequilibrium, Lung Neoplasms, Odds Ratio, Polymorphism, Single Nucleotide, Receptors, Nicotinic, Risk Factors, Smoking", author = "Munaf{\`o}, {Marcus R.} and Timofeeva, {Maria N.} and Morris, {Richard W.} and David Prieto-Merino and Naveed Sattar and Paul Brennan and Johnstone, {Elaine C.} and Caroline Relton and Johnson, {Paul C. D.} and Donna Walther and Whincup, {Peter H.} and Casas, {Juan P.} and Uhl, {George R.} and Paolo Vineis and Sandosh Padmanabhan and Jefferis, {Barbara J.} and Antoinette Amuzu and Elio Riboli and Upton, {Mark N.} and Paul Aveyard and Shah Ebrahim and Hingorani, {Aroon D.} and Graham Watt and Palmer, {Tom M.} and Timpson, {Nicholas J.} and {Davey Smith}, George and {EPIC Study Group}", year = "2012", month = may, day = "16", doi = "10.1093/jnci/djs191", language = "English", volume = "104", pages = "740--748", journal = "JNCI: Journal of the National Cancer Institute", issn = "0027-8874", publisher = "Oxford University Press", number = "10", } . JNCI: Journal of the National Cancer Institute.

The effect of elevated body mass index on ischemic heart disease risk @article{29f538dddd4c4210961fa30751a68dde, title = "The effect of elevated body mass index on ischemic heart disease risk: causal estimates from a Mendelian randomisation approach", abstract = "BACKGROUND: Adiposity, assessed as elevated body mass index (BMI), is associated with increased risk of ischemic heart disease (IHD); however, whether this is causal is unknown. We tested the hypothesis that positive observational associations between BMI and IHD are causal.METHODS AND FINDINGS: In 75,627 individuals taken from two population-based and one case-control study in Copenhagen, we measured BMI, ascertained 11,056 IHD events, and genotyped FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238). Using genotypes as a combined allele score in instrumental variable analyses, the causal odds ratio (OR) between BMI and IHD was estimated and compared with observational estimates. The allele score-BMI and the allele score-IHD associations used to estimate the causal OR were also calculated individually. In observational analyses the OR for IHD was 1.26 (95% CI 1.19-1.34) for every 4 kg/m(2) increase in BMI. A one-unit allele score increase associated with a 0.28 kg/m(2) (95 CI% 0.20-0.36) increase in BMI and an OR for IHD of 1.03 (95% CI 1.01-1.05) (corresponding to an average 1.68 kg/m(2) BMI increase and 18% increase in the odds of IHD for those carrying all six BMI increasing alleles). In instrumental variable analysis using the same allele score the causal IHD OR for a 4 kg/m(2) increase in BMI was 1.52 (95% CI 1.12-2.05).CONCLUSIONS: For every 4 kg/m(2) increase in BMI, observational estimates suggested a 26% increase in odds for IHD while causal estimates suggested a 52% increase. These data add evidence to support a causal link between increased BMI and IHD risk, though the mechanism may ultimately be through intermediate factors like hypertension, dyslipidemia, and type 2 diabetes. This work has important policy implications for public health, given the continuous nature of the BMI-IHD association and the modifiable nature of BMI. This analysis demonstrates the value of observational studies and their ability to provide unbiased results through inclusion of genetic data avoiding confounding, reverse causation, and bias.", keywords = "Adiposity, Adult, Aged, Alleles, Body Mass Index, Female, Genotype, Humans, Incidence, Male, Membrane Proteins, Mendelian Randomization Analysis, Middle Aged, Myocardial Ischemia, Obesity, Odds Ratio, Proteins, Receptor, Melanocortin, Type 4, Risk Factors", author = "Nordestgaard, {B{\o}rge G.} and Palmer, {Tom M.} and Marianne Benn and Jeppe Zacho and Anne Tybjaerg-Hansen and {Davey Smith}, George and Timpson, {Nicholas J.}", year = "2012", month = may, day = "1", doi = "10.1371/journal.pmed.1001212", language = "English", volume = "9", journal = "PLoS Medicine", issn = "1549-1277", publisher = "Public Library of Science", number = "5", } . PLoS Medicine.

Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure @article{2f8a7f7cdd2a4408a71deede7f476eca, title = "Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure", abstract = "Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure.", author = "Munaf{\`o}, {Marcus R} and Timofeeva, {Maria N} and Morris, {Richard W} and David Prieto-Merino and Naveed Sattar and Paul Brennan and Johnstone, {Elaine C} and Caroline Relton and Johnson, {Paul C D} and Donna Walther and Whincup, {Peter H} and Casas, {Juan P} and Uhl, {George R} and Paolo Vineis and Sandosh Padmanabhan and Jefferis, {Barbara J} and Antoinette Amuzu and Elio Riboli and Upton, {Mark N} and Paul Aveyard and Shah Ebrahim and Hingorani, {Aroon D} and Graham Watt and Palmer, {Tom M} and Timpson, {Nicholas J} and {Davey Smith}, George and {EPIC Study Group}", year = "2012", month = may, doi = "10.1093/jnci/djs191", language = "English", volume = "104", pages = "740 -- 748", journal = "Journal of the National Cancer Institute", issn = "0027-8874", publisher = "Oxford University Press", number = "10", } . Journal of the National Cancer Institute.

Theodoratou, E., Palmer, T., Zgaga, L., Farrington, S.M., McKeigue, P., Din, F.V.N., Tenesa, A., Davey-Smith, G., Dunlop, M.G., Campbell, H., et al.(2012). Instrumental variable estimation of the causal effect of plasma 25-hydroxy-vitamin D on colorectal cancer risk: A Mendelian randomization analysis . PLoS ONE. 7. (6).

Palmer, T.M., Ramsahai, R.R., Lawlor, D.A., Sheehan, N.A., Didelez, V., Palmer, T.M., Ramsahai, R.R., Lawlor, D.A., Sheehan, N.A., Didelez, V.(2012). Re: "credible mendelian randomization studies: Approaches for evaluating the instrumental variable assumptions" . American Journal of Epidemiology. 176. (5). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 457-458.

TM Palmer, D Lawlor, RM Harbord, NA Sheehan, Jonathan H Tobias, NJ Timpson, G Davey Smith, J Sterne(2012). Using multiple genetic variants as instrumental variables for modifiable risk factors . Statistical Methods in Medical Research. 21. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 223 -- 242. SAGE Publications Ltd

Evropi Theodoratou, Tom M Palmer, Lina Zgaga, Susan M Farrington, Paul McKeigue, Farhat V. N. Din, Albert Tenesa, George Davey Smith, Malcolm G. Dunlop, Harry Campbell(2012). The Effect of Elevated Body Mass Index on Ischemic Heart Disease Risk: Causal Estimates from a Mendelian Randomisation Approach . PLoS ONE. 7. (6). Public Library of Science

Palmer, T.M., Lawlor, D.A., Harbord, R.M., Sheehan, N.A., Tobias, J.H., Timpson, N.J., Smith, G.D., Sterne, J.A.C., Palmer, T.M., Lawlor, D.A., et al.(2012). Using multiple genetic variants as instrumental variables for modifiable risk factors . Statistical Methods in Medical Research. 21. (3). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 223-242.

Tom M Palmer, RR Ramsahai, Debbie A Lawlor, NA Sheehan, Vanessa Didelez(2012). RE: “Credible Mendelian randomization studies: approaches for evaluating the instrumental variable assumptions” . American Journal of Epidemiology. 176. (5). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 457. Oxford University Press

Nordestgaard, B.G., Palmer, T.M., Benn, M., Zacho, J., Tybj&#230;rg-Hansen, A., Smith, G.D., Timpson, N.J., Nordestgaard, B.G., Palmer, T.M., Benn, M., et al.(2012). The effect of elevated body mass index on ischemic heart disease risk: Causal estimates from a mendelian randomisation approach . PLoS Medicine. 9. (5).

Munaf&#242;, M.R., Timofeeva, M.N., Morris, R.W., Prieto-Merino, D., Sattar, N., Brennan, P., Johnstone, E.C., Relton, C., Johnson, P.C.D., Walther, D., et al.(2012). Association between genetic variants on chromosome 15q25 locus and objective measures of Tobacco exposure . Journal of the National Cancer Institute. 104. (10). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 740-748.

BG Nordestgaard, TM Palmer, M Benn, J Zacho, A Tybaerg-Hansen, G Davey Smith, NJ Timpson(2012). The Effect of Elevated Body Mass Index on Ischemic Heart Disease Risk: Causal Estimates from a Mendelian Randomisation Approach . PLoS Medicine. 9. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString e1001212. Public Library of Science

Macdonald-Wallis, C., Lawlor, D.A., Palmer, T., Tilling, K., Macdonald-Wallis, C., Lawlor, D.A., Palmer, T., Tilling, K.(2012). Multivariate multilevel spline models for parallel growth processes: Application to weight and mean arterial pressure in pregnancy . Statistics in Medicine. 31. (26). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 3147-3164.

The causal roles of vitamin B 12 and transcobalamin in prostate cancer @article{37a79b9aff654f6d983516087fee819d, title = "The causal roles of vitamin B 12 and transcobalamin in prostate cancer: Can Mendelian randomization analysis provide definitive answers?", abstract = "Circulating vitamin B 12 (cobalamin/B 12) and total transcobalamin (tTC) have been associated with increased and reduced risk, respectively, of prostate cancer. Mendelian randomization has the potential to determine whether these are causal associations. We estimated associations of single nucleotide polymorphisms in B 12-related genes (MTR, MTRR, FUT2, TCN2, TCN1, CUBN, and MUT) with plasma concentrations of B 12, tTC, holo-transcobalamin, holohaptocorrin, folate, and homocysteine and with prostate cancer risk in a case-control study (913 cases, 895 controls) nested within the UK-wide population-based ProtecT study of prostate cancer in men age 45-69 years. Instrumental variable (IV) analysis was used to estimate odds ratios for effects of B 12 and tTC on prostate cancer. We observed that B 12 was lower in men with FUT2 204G>A (rs492602), CUBN 758C>T (rs1801222) and MUT 1595G>A (rs1141321) alleles (P trend<0.001); tTC was lower in men with the TCN2 776C>G (rs1801198) allele (P trend<0.001). FUT2 204G>A and CUBN 758C>T were selected as instruments for B 12; TCN2 776C>G for tTC. Conventional and IV estimates for the association of log e (B 12) with prostate cancer were: OR=1.17 (95% CI 0.90-1.51), P=0.2 and OR=0.60 (0.16-2.15), P=0.4, respectively. Conventional and IV estimates for the association of log e (tTC) with prostate cancer were: OR=0.81 (0.54-1.20), P=0.3 and OR=0.41 (0.13-1.32), P=0.1, respectively. Confidence intervals around the IV estimates in our study were too wide to allow robust inference. Sample size estimates based on our data indicated that Mendelian randomization in this context requires much larger studies or multiple genetic variants that explain all of the variance in the intermediate phenotype.", keywords = "Mendelian randomization, Prostate cancer, Transcobalamin, Vitamin B /cobalamin", author = "Collin, {Simon M.} and Chris Metcalfe and Palmer, {Tom M.} and Helga Refsum and Lewis, {Sarah J.} and Smith, {George Davey} and Angela Cox and Michael Davis and Gemma Marsden and Carole Johnston and {Athene Lane}, J. and Donovan, {Jenny L.} and Neal, {David E.} and Hamdy, {Freddie C.} and Smith, {A. David} and Martin, {Richard M.}", year = "2011", month = dec, day = "21", language = "English", volume = "2", pages = "316--327", journal = "International journal of molecular epidemiology and genetics", issn = "1948-1756", publisher = "e-Century Publishing Corporation", number = "4", } . International journal of molecular epidemiology and genetics.

Smoking is associated with, but does not cause, depressed mood in pregnancy--a mendelian randomization study @article{72eb84420cb04f8a804eb1731f08ce0b, title = "Smoking is associated with, but does not cause, depressed mood in pregnancy--a mendelian randomization study", abstract = "Smokers have a higher prevalence of major depressive episodes and depressive symptoms than the general population, but whether this association is causal, or is due to confounding or reverse causation is uncertain because of the problems inherent in some epidemiological studies. Mendelian randomization, in which a genetic variant is used as a surrogate for measuring exposure, is an approach which may be used to better understand this association. We investigated the rs1051730 single nucleotide polymorphism in the nicotine acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4), associated with smoking phenotypes, to determine whether women who continued to smoke were also more likely to report a low mood during pregnancy. We found among women who smoked pre-pregnancy, those with the 1051730 T allele smoked more and were less likely to quit smoking during pregnancy, but were also less likely to report high levels of depressed mood at 18 weeks of pregnancy (per allele OR = 0.84, 95%CI 0.72 to 0.99, p = 0.034). The association between genotype and depressed mood was limited to women who were smokers prior to pregnancy, with weak evidence of an interaction between smoking status and genotype (p = 0.07). Our results do not support a causal role of smoking on depressed mood, but are consistent with a self-medication hypothesis, whereby smoking is used to alleviate symptoms of depression. A replication study using multiple genetic variants which influence smoking via different pathways is required to confirm these findings and provide evidence that the genetic variant is reflecting the effect of quitting smoking on depressed mood, and is not directly affecting mood.", keywords = "Affect, Depression, Female, Genetic Predisposition to Disease, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Pregnancy, Risk Factors, Smoking", author = "Lewis, {Sarah J.} and Ricardo Araya and Smith, {George Davey} and Rachel Freathy and David Gunnell and Tom Palmer and Marcus Munaf{\`o}", year = "2011", month = jul, doi = "10.1371/journal.pone.0021689", language = "English", volume = "6", journal = "PLoS ONE", issn = "1932-6203", publisher = "Public Library of Science", number = "7", } . PLoS ONE.

Maternal and offspring adiposity-related genetic variants and gestational weight gain @article{a296f330650d41948be5184077d0c6ef, title = "Maternal and offspring adiposity-related genetic variants and gestational weight gain", abstract = "BACKGROUND: Gestational weight gain (GWG) is associated with a range of health outcomes, but little is known about the factors that influence it.OBJECTIVE: The objective was to test the hypothesis that maternal and fetal genetic variants that are reliably associated with adiposity are associated with GWG.DESIGN: We examined the association of a risk allele score by using 4 adiposity-related single nucleotide polymorphisms (SNPs; rs9939609 in FTO, rs17782313 near MC4R, rs6548238 near TMEM18, and rs10938397 near GNPDA2) with GWG in a pregnancy cohort in which women had detailed repeated assessment of GWG (median number of weight measurements: 10; interquartile range: 8, 11). The numbers included in our analyses varied between 2324 and 7563 for different variant-outcome analyses. A linear spline random-effects model was used to model weight change with gestational age and to relate genetic variants to this. This modeling confirmed 3 distinct periods of GWG: 0-18, 19-28, and ≥29 wk of gestation.RESULTS: Maternal risk allele score and SNPs in FTO, MC4R, and TMEM18 were positively associated with prepregnancy weight. Maternal allele score was inversely associated with GWG in the first 18 wk of pregnancy (-14.46 g/wk per allele; 95% CI: -24.75, -4.17 g/wk per allele) but was not associated with other periods of GWG. Offspring allele score and maternal and offspring individual SNPs were not associated with GWG in any period or with birth weight or postnatal weight retention.CONCLUSIONS: Our findings suggest that neither maternal nor fetal adiposity-related genetic variants are associated with greater GWG. The inverse association of maternal allele score with GWG in the first 18 wk requires replication.", keywords = "Adiposity, Adult, Birth Weight, Body Mass Index, Female, Genotype, Humans, Infant, Newborn, Longitudinal Studies, Polymorphism, Single Nucleotide, Pregnancy, Weight Gain", author = "Lawlor, {Debbie A.} and Abigail Fraser and Corrie Macdonald-Wallis and Nelson, {Scott M.} and Palmer, {Tom M.} and {Davey Smith}, George and Kate Tilling", year = "2011", month = jul, doi = "10.3945/ajcn.110.010751", language = "English", volume = "94", pages = "149--155", journal = "American Journal of Clinical Nutrition", issn = "0002-9165", publisher = "Elsevier BV", number = "1", } . American Journal of Clinical Nutrition.

Maternal and offspring adiposity-related genetic variants and gestational weight gain @article{3f27493ee36a41beb283cbf26b23f098, title = "Maternal and offspring adiposity-related genetic variants and gestational weight gain", abstract = "Gestational weight gain (GWG) is associated with a range of health outcomes, but little is known about the factors that influence it.", keywords = "Adiposity, Adult, Birth Weight, Body Mass Index, Female, Genotype, Humans, Infant, Newborn, Longitudinal Studies, Polymorphism, Single Nucleotide, Pregnancy, Weight Gain", author = "Lawlor, {Debbie A} and Abigail Fraser and Corrie Macdonald-Wallis and Nelson, {Scott M} and Palmer, {Tom M} and {Davey Smith}, George and Kate Tilling", year = "2011", month = jul, doi = "10.3945/ajcn.110.010751", language = "English", volume = "94", pages = "149 -- 155", journal = "American Journal of Clinical Nutrition", issn = "1938-3207", publisher = "American Society for Nutrition", number = "1", } . American Journal of Clinical Nutrition.

Instrumental variable estimation of causal risk ratios and causal odds ratios in Mendelian randomization analyses @article{b5692b3f5e734d9eb1910cc3ac76254d, title = "Instrumental variable estimation of causal risk ratios and causal odds ratios in Mendelian randomization analyses", abstract = "In this paper, the authors describe different instrumental variable (IV) estimators of causal risk ratios and odds ratios with particular attention to methods that can handle continuously measured exposures. The authors present this discussion in the context of a Mendelian randomization analysis of the effect of body mass index (BMI; weight (kg)/height (m)(2)) on the risk of asthma at age 7 years (Avon Longitudinal Study of Parents and Children, 1991-1992). The authors show that the multiplicative structural mean model (MSMM) and the multiplicative generalized method of moments (MGMM) estimator produce identical estimates of the causal risk ratio. In the example, MSMM and MGMM estimates suggested an inverse relation between BMI and asthma but other IV estimates suggested a positive relation, although all estimates had wide confidence intervals. An interaction between the associations of BMI and fat mass and obesity-associated (FTO) genotype with asthma explained the different directions of the different estimates, and a simulation study supported the observation that MSMM/MGMM estimators are negatively correlated with the other estimators when such an interaction is present. The authors conclude that point estimates from various IV methods can differ in practical applications. Based on the theoretical properties of the estimators, structural mean models make weaker assumptions than other IV estimators and can therefore be expected to be consistent in a wider range of situations.", keywords = "Asthma, Body Mass Index, Causality, Child, Confounding Factors (Epidemiology), Female, Humans, Longitudinal Studies, Male, Mendelian Randomization Analysis, Odds Ratio", author = "Palmer, {Tom M.} and Sterne, {Jonathan A. C.} and Harbord, {Roger M.} and Lawlor, {Debbie A.} and Sheehan, {Nuala A.} and Sha Meng and Raquel Granell and Smith, {George Davey} and Vanessa Didelez", year = "2011", month = jun, day = "15", doi = "10.1093/aje/kwr026", language = "English", volume = "173", pages = "1392--1403", journal = "American Journal of Epidemiology", issn = "0002-9262", publisher = "Oxford University Press", number = "12", } . American Journal of Epidemiology.

Using genetic loci to understand the relationship between adiposity and psychological distress @article{377ff556d99c42f1869ca7477e8f50c3, title = "Using genetic loci to understand the relationship between adiposity and psychological distress: a Mendelian Randomization study in the Copenhagen General Population Study of 53,221 adults", abstract = "OBJECTIVE: We used genetic variants that are robustly associated with adiposity to examine the causal association of adiposity with psychological distress.METHODS: We examined the association of adiposity with psychological distress in a large (N = 53,221) general population cohort of 20- to 99-year-old adults from Copenhagen, Denmark. Psychological distress was assessed using four questions that asked about: feeling stressed; not accomplishing very much; wanting to give up; and regular use of antidepressants/sedatives. We used the genetic loci FTO rs9939609 and MC4R rs17782313 as instrumental variables for adiposity quantified by body mass index (BMI) and waist to hip ratio (WHR).RESULTS: In conventional multivariable analyses, BMI and WHR were positively associated with distress. For example, the odds ratio of reporting not accomplishing for each additional standard deviation increase for BMI was 1.11 (95% CI: 1.09, 1.13) and for WHR was 1.10 (95% CI: 1.08, 1.13) in the fully adjusted analyses. In contrast, instrumental variable analyses showed an inverse association of adiposity on distress; corresponding odds ratio in instrumental variable analyses was 0.64 (95% CI: 0.46, 0.89) for BMI and 0.49 (95% CI: 0.25, 0.94) for WHR (P-values for difference between the two approaches both = 0.001).CONCLUSION: The inverse associations of adiposity and psychological distress when genetic variants are used as instrumental variables could be explained by biological pathways linking adiposity and distress. The positive associations of adiposity with distress in multivariable analyses might be explained by residual confounding or reverse causality.", keywords = "Adiposity, Adult, Aged, Aged, 80 and over, Anxiety Disorders, Body Mass Index, Cohort Studies, Cross-Sectional Studies, Denmark, Female, Genetic Loci, Genotype, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Proteins, Receptor, Melanocortin, Type 4, Risk Factors, Stress, Psychological, Waist-Hip Ratio, Young Adult", author = "Lawlor, {Debbie A.} and Harbord, {Roger M.} and Anne Tybjaerg-Hansen and Palmer, {Tom M.} and Jeppe Zacho and Marianne Benn and Timpson, {Nicholas J.} and Smith, {George Davey} and Nordestgaard, {B{\o}rge G.}", note = "{\textcopyright} 2011 The Association for the Publication of the Journal of Internal Medicine.", year = "2011", month = may, doi = "10.1111/j.1365-2796.2011.02343.x", language = "English", volume = "269", pages = "525--537", journal = "Journal of Internal Medicine", issn = "1365-2796", publisher = "Wiley-Blackwell", number = "5", } . Journal of Internal Medicine.

Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance @article{465023c403a14798bd77411165bdd594, title = "Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance", abstract = "OBJECTIVE: The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance.RESEARCH DESIGN AND METHODS: We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies.RESULTS: Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log(10) triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002).CONCLUSIONS: Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal.", keywords = "Aged, Alleles, Blood Glucose, Case-Control Studies, Diabetes Mellitus, Type 2, Female, Genetic Variation, Genotype, Humans, Insulin, Insulin Resistance, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Triglycerides", author = "{De Silva}, {N. Maneka G.} and Freathy, {Rachel M.} and Palmer, {Tom M.} and Donnelly, {Louise A.} and Jian'an Luan and Tom Gaunt and Claudia Langenberg and Weedon, {Michael N.} and Beverley Shields and Knight, {Beatrice A.} and Ward, {Kirsten J.} and Sandhu, {Manjinder S.} and Harbord, {Roger M.} and McCarthy, {Mark I.} and Smith, {George Davey} and Shah Ebrahim and Hattersley, {Andrew T.} and Nicholas Wareham and Lawlor, {Debbie A.} and Morris, {Andrew D.} and Palmer, {Colin N. A.} and Frayling, {Timothy M.}", year = "2011", month = mar, doi = "10.2337/db10-1317", language = "English", volume = "60", pages = "1008--1018", journal = "Diabetes Care", issn = "0149-5992", publisher = "American Diabetes Association Inc.", number = "3", } . Diabetes Care.

Simon M. Collin, Chris Metcalfe, Tom M. Palmer, Helga Refsum, Sarah J. Lewis, George Davey Smith, Angela Cox, Michael Davis, Gemma Marsden, Carole Johnston, et al.(2011). The causal roles of vitamin B(12) and transcobalamin in prostate cancer . International Journal of Molecular Epidemiology and Genetics. 2. (4). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 316--327. e-Century Publishing Corporation

Lawlor, D.A., Harbord, R.M., Tybjaerg-Hansen, A., Palmer, T.M., Zacho, J., Benn, M., Timpson, N.J., Davey Smith, G., Nordestgaard, B.G., Lawlor, D.A., et al.(2011). Using genetic loci to understand the relationship between adiposity and psychological distress: A Mendelian Randomization study in the Copenhagen General Population Study of 53221 adults . Journal of Internal Medicine. 269. (5). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 525-537.

SM Collin, C Metcalfe, TM Palmer, H Refsum, SJ Lewis, G Davey Smith, A Cox, MJ Davis, G Marsden, C Johnston, et al.(2011). The causal roles of vitamin B12 and transcobalamin in prostate cancer: can Mendelian randomization analysis provide definitive answers? . International journal of molecular epidemiology and genetics. 2(4). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 316 -- 327. e-Century Publishing Corporation

Smoking is associated with, but does not cause, depressed mood in pregnancy – a Mendelian randomization study @article{74f1f308f77e462d8a174c3f322a6eb1, title = "Smoking is associated with, but does not cause, depressed mood in pregnancy – a Mendelian randomization study", abstract = "Smokers have a higher prevalence of major depressive episodes and depressive symptoms than the general population, but whether this association is causal, or is due to confounding or reverse causation is uncertain because of the problems inherent in some epidemiological studies. Mendelian randomization, in which a genetic variant is used as a surrogate for measuring exposure, is an approach which may be used to better understand this association. We investigated the rs1051730 single nucleotide polymorphism in the nicotine acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4), associated with smoking phenotypes, to determine whether women who continued to smoke were also more likely to report a low mood during pregnancy. We found among women who smoked pre-pregnancy, those with the 1051730 T allele smoked more and were less likely to quit smoking during pregnancy, but were also less likely to report high levels of depressed mood at 18 weeks of pregnancy (per allele OR = 0.84, 95%CI 0.72 to 0.99, p = 0.034). The association between genotype and depressed mood was limited to women who were smokers prior to pregnancy, with weak evidence of an interaction between smoking status and genotype (p = 0.07). Our results do not support a causal role of smoking on depressed mood, but are consistent with a self-medication hypothesis, whereby smoking is used to alleviate symptoms of depression. A replication study using multiple genetic variants which influence smoking via different pathways is required to confirm these findings and provide evidence that the genetic variant is reflecting the effect of quitting smoking on depressed mood, and is not directly affecting mood.", author = "Lewis, {Sarah J} and Ricardo Araya and Smith, {George Davey} and Rachel Freathy and David Gunnell and Tom Palmer and Marcus Munaf{\`o}", year = "2011", doi = "10.1371/journal.pone.0021689", language = "English", volume = "6", pages = "e21689", journal = "PLoS ONE", issn = "1932-6203", publisher = "Public Library of Science", number = "7", } . PLoS ONE.

Palmer, T.M., Sterne, J.A.C., Harbord, R.M., Lawlor, D.A., Sheehan, N.A., Meng, S., Granell, R., Smith, G.D., Didelez, V., Palmer, T.M., et al.(2011). Instrumental variable estimation of causal risk ratios and causal odds ratios in mendelian randomization analyses . American Journal of Epidemiology. 173. (12). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1392-1403.

D Lawlor, RM Harbord, A Tybjaerg-Hansen, TM Palmer, J Zacho, M Benn, NJ Timpson, G Davey Smith, BG Nordestgaard(2011). Using genetic loci to understand the relationship between adiposity and psychological distress: a Mendelian Randomization study in the Copenhagen General Population Study of 53,221 adults . Journal of Internal Medicine. 269. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 525 -- 537. Wiley-Blackwell

Collin, S.M., Metcalfe, C., Palmer, T.M., Refsum, H., Lewis, S.J., Smith, G.D., Cox, A., Davis, M., Marsden, G., Johnston, C., et al.(2011). The causal roles of vitamin B<inf>12</inf>and transcobalamin in prostate cancer: Can Mendelian randomization analysis provide definitive answers? . International Journal of Molecular Epidemiology and Genetics. 2. (4). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 316-327.

De Silva, N.M.G., Freathy, R.M., Palmer, T.M., Donnelly, L.A., Luan, J., Gaunt, T., Langenberg, C., Weedon, M.N., Shields, B., Knight, B.A., et al.(2011). Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance . Diabetes. 60. (3). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1008-1018.

Lawlor, D.A., Fraser, A., Macdonald-Wallis, C., Nelson, S.M., Palmer, T.M., Smith, G.D., Tilling, K., Lawlor, D.A., Fraser, A., Macdonald-Wallis, C., et al.(2011). Maternal and offspring adiposity-related genetic variants and gestational weight gain . American Journal of Clinical Nutrition. 94. (1). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 149-155.

TM Palmer, J Sterne, RM Harbord, D Lawlor, NA Sheehan, S Meng, R Granell, G Davey Smith, V Didelez(2011). Instrumental variable estimation of causal risk ratios and causal odds ratios in Mendelian randomization analyses . American Journal of Epidemiology. 173. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1392 -- 1403. Oxford University Press

N M G De Silva, Rachel M Freathy, TM Palmer, LA Donnelly, J Luan, TR Gaunt, C Langenberg, MN Weedon, B Shields, BA Knight, et al.(2011). Mendelian Randomization Studies Do Not Support a Role for Raised Circulating Triglyceride Levels Influencing Type 2 Diabetes, Glucose Levels, or Insulin Resistance . Diabetes. 60. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1008 -- 1018. American Diabetes Association Inc.

Palmer, T.M., Ramsahai, R.R., Didelez, V., Sheehan, N.A., Palmer, T.M., Ramsahai, R.R., Didelez, V., Sheehan, N.A.(2011). Nonparametric bounds for the causal effect in a binary instrumental-variable model . Stata Journal. 11. (3). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 345-367.

TM Palmer, RR Ramsahai, V Didelez, NA Sheehan(2011). Nonparametric bounds for the causal effect in a binary instrumental-variable model . Stata Journal. 11. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 345 -- 367. DPC Nederland

Nonparametric bounds for the causal effect in a binary instrumental variable model @article{18e793121a7f431c849c7893c8a2f55d, title = "Nonparametric bounds for the causal effect in a binary instrumental variable model", abstract = "Instrumental variables can be used to make inferences about causal effects in the presence of unmeasured confounding. For a model in which the instrument, intermediate/treatment, and outcome variables are all binary, Balke and Pearl (1997, Journal of the American Statistical Association 92: 1172–1176) derived nonparametric bounds for the intervention probabilities and the average causal effect. We have implemented these bounds in two commands: bpbounds and bpboundsi. We have also implemented several extensions to these bounds. One of these extensions applies when the instrument and outcome are measured in one sample and the instrument and intermediate are measured in another sample. We have also implemented the bounds for an instrument with three categories, as is common in Mendelian randomization analyses in epidemiology and for the case where a monotonic effect of the instrument on the intermediate can be assumed. In each case, we calculate the instrumental-variable inequality constraints as a check for gross violations of the instrumental-variable conditions. The use of the commands is illustrated with a re-creation of the original Balke and Pearl analysis and with a Mendelian randomization analysis. We also give a simulated example to demonstrate that the instrumental-variable inequality constraints can both detect and fail to detect violations of the instrumental-variable conditions. ", keywords = "bpbounds, bpboundsi, average causal effect, causal inference, instrumental variables, nonparametric bounds", author = "Palmer, {Thomas Michael} and Roland Ramsahai and Vanessa Didelez and Sheehan, {Nuala A.}", year = "2011", language = "English", volume = "11", pages = "345--367", journal = "Stata Journal", issn = "1536-867X", publisher = "SAGE Publications Inc.", number = "3", } . Stata Journal.

Lewis, S.J., Araya, R., Smith, G.D., Freathy, R., Gunnell, D., Palmer, T., Munaf&#242;, M., Lewis, S.J., Araya, R., Smith, G.D., et al.(2011). Smoking is associated with, but does not cause, depressed mood in pregnancy - a mendelian randomization study . PLoS ONE. 6. (7).

Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk @article{1a25f77747c64ccea1cb2eff3dee4e08, title = "Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk", abstract = "UNLABELLED: Observational studies suggest that obese men have a lower risk of incident prostate cancer, but an increased risk of advanced and fatal cancers. These observations could be due to confounding, detection bias, or a biological effect of obesity. Genetic studies are less susceptible to confounding than observational epidemiology and can suggest how associations between phenotypes (such as obesity) and diseases arise. To determine whether the associations between obesity and prostate cancer are causal, we conducted a genetic association study of the relationship between a single nucleotide polymorphism known to be associated with obesity (FTO rs9939609) and prostate cancer. Data are from a population-based sample of 1550 screen-detected prostate cancers, 1815 age- and general practice matched controls with unrestricted prostate specific antigen (PSA) values and 1175 low-PSA controls (PSA <0.5 ng/ml). The rs9939609 A allele, which was associated with higher BMI in the sample, was inversely associated with overall (odds ratio (OR) versus all controls  = 0.93; 95% confidence interval (CI): 0.85-1.02 p = 0.12 per allele) and low-grade (OR = 0.90; 0.81-0.99 p = 0.03 per allele) prostate cancer risk, but positively associated with high-grade cancer among cases (OR high- versus low-grade cancer  = 1.16; 0.99-1.37 p = 0.07 per allele). Although evidence for these effects was weak, they are consistent with observational data based on BMI phenotypes and suggest that the observed association between obesity and prostate cancer is not due to confounding. Further research should confirm these findings, extend them to other BMI-related genetic variants and determine whether they are due to detection bias or obesity-related hormonal changes.TRIAL REGISTRATION: Controlled-Trials.com ISRCTN20141297.", keywords = "Aged, Body Mass Index, Case-Control Studies, Genetic Variation, Genotype, Humans, Male, Middle Aged, Obesity, Prostate-Specific Antigen, Prostatic Neoplasms, Risk Factors", author = "Lewis, {Sarah J.} and Ali Murad and Lina Chen and {Davey Smith}, George and Jenny Donovan and Tom Palmer and Freddie Hamdy and David Neal and Lane, {J. Athene} and Michael Davis and Angela Cox and Martin, {Richard M.}", year = "2010", month = oct, day = "19", doi = "10.1371/journal.pone.0013485", language = "English", volume = "5", journal = "PLoS ONE", issn = "1932-6203", publisher = "Public Library of Science", number = "10", } . PLoS ONE.

Lewis, S.J., Murad, A., Chen, L., Smith, G.D., Lewis, S.J., Donovan, J., Palmer, T., Murad, A., Hamdy, F., Neal, D., et al.(2010). Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk . PLoS ONE. 5. (10).

SJ Lewis, AS Murad, L Chen, G Davey Smith, JL Donovan, TM Palmer, F Hamdy, D Neal, JA Lane, MJ Davis, et al.(2010). Associations between an Obesity Related Genetic Variant (FTO rs9939609) and Prostate Cancer Risk . PLoS ONE. 5(10). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString e13485. Public Library of Science

Novel methods to deal with publication biases: secondary analysis of antidepressant trials in the FDA trial registry database and related journal publications @article{80fcafb4afe2410087747ccd8a61558b, title = "Novel methods to deal with publication biases: secondary analysis of antidepressant trials in the FDA trial registry database and related journal publications", author = "SG Moreno and AJ Sutton and EH Turner and KR Abrams and NJ Cooper and TM Palmer and AE Ades", year = "2009", month = aug, day = "29", doi = "10.1136/bmj.b2981", language = "English", volume = "339", journal = "BMJ", issn = "0959-8138", publisher = "BMJ Publishing Group", number = "7719", } . BMJ.

Santiago G. Moreno, Alex J. Sutton, Erick H. Turner, Keith R. Abrams, Nicola J. Cooper, Tom M. Palmer, A. E. Ades(2009). Novel methods to deal with publication biases . BMJ. 339. British Medical Association

Moreno, S.G., Sutton, A.J., Turner, E.H., Abrams, K.R., Cooper, N.J., Palmer, T.M., Ades, A.E., Moreno, S.G., Sutton, A.J., Turner, E.H., et al.(2009). Novel methods to deal with publication biases: Secondary analysis of antidepressant trials in the FDA trial registry database and related journal publications . BMJ (Online). 339. (7719). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 494-497.

Meta-analysis of Mendelian randomization studies incorporating all three genotypes @article{8296a59b5e6242f199f18404243bcca7, title = "Meta-analysis of Mendelian randomization studies incorporating all three genotypes", abstract = "In Mendelian randomization a carefully selected gene is used as an instrumental variable in the estimation of the association between a biological phenotype and a disease. A study using Mendelian randomization will have information on an individual's disease status, the genotype and the phenotype. The phenotype must be on the causal pathway between gene and disease for the instrumental-variable analysis to be valid. For a biallelic polymorphism there are three possible genotypes with which to compare disease risk. Existing methods select two of the three possible genotypes for use in a Mendelian randomization analysis. Multivariate meta-analysis models for Mendelian randomization case-control studies are proposed, which extend previous methods by estimating the pooled phenotype-disease association across both genotype comparisons by using the gene-disease log odds ratios and differences in mean phenotypes. The methods are illustrated using a meta-analysis of the effect of a gene related to collagen production on bone mineral density and osteoporotic fracture.", keywords = "Bone Density, Case-Control Studies, Collagen Type I, Genotype, Humans, Meta-Analysis as Topic, Models, Genetic, Models, Statistical, Osteoporosis, Phenotype, Polymorphism, Genetic, Random Allocation, Risk", author = "Palmer, {Tom M.} and Thompson, {John R.} and Tobin, {Martin D.}", note = " Copyright 2008 John Wiley & Sons, Ltd.", year = "2008", month = dec, day = "30", doi = "10.1002/sim.3423", language = "English", volume = "27", pages = "6570--6582", journal = "Statistics in Medicine", issn = "0277-6715", publisher = "John Wiley and Sons Ltd", number = "30", } . Statistics in Medicine.

Common variation in the WNK1 gene and blood pressure in childhood @article{4da25bb5e60d4bbc8a9075357e6bd783, title = "Common variation in the WNK1 gene and blood pressure in childhood: the Avon Longitudinal Study of Parents and Children", abstract = "WNK1 gene variants have been associated with adult blood pressure. We aimed to investigate relationships between WNK1 variants and blood pressure, as well as blood pressure change with age, in a longitudinal childhood study. Associations between single nucleotide polymorphisms in WNK1 and blood pressure and the rate of blood pressure change between 7 and 11 years were examined in the Avon Longitudinal Study of Parent and Children Study (n=5326 for systolic blood pressure at 11 years). We observed associations (P<0.05) with diastolic blood pressure gradient with age for 33 of 82 typed and imputed polymorphisms, including polymorphisms in exons 4, 10, and 11 (rs10774466, rs1012729, and rs9804992). The minor allele (G) of rs1012729 (frequency: 25.6%) was associated with a gender-adjusted change in a diastolic blood pressure gradient of -0.11 mm Hg/y (95% CI: -0.20 to -0.03 mm Hg/y; P=0.0054). No associations were shown with the systolic blood pressure gradient. At age 11 years, 30 polymorphisms showed association (P<0.05) with systolic blood pressure, including variants in exons 4 and 10 (rs10774466 and rs1012729). Only 3 polymorphisms were associated with diastolic blood pressure at 11 years. In exploration of polymorphism-dietary cation interactions on systolic blood pressure at 11 years, 59 reached significance (P<0.05; 12.3 expected by chance), mostly (n=33) related to dietary calcium. The findings show that common intronic and exonic WNK1 variants are associated with diastolic blood pressure gradient from 7 to 11 years and with systolic blood pressure at 11 years. Our study suggests that previously reported effects of WNK1 variants on blood pressure are mediated via effects on the gradient of blood pressure change with age.", keywords = "Aging, Alleles, Blood Pressure, Child, Cohort Studies, Cross-Sectional Studies, England, Exons, Female, Gene Frequency, Genotype, Humans, Intracellular Signaling Peptides and Proteins, Longitudinal Studies, Male, Polymorphism, Single Nucleotide, Prospective Studies, Protein-Serine-Threonine Kinases", author = "Tobin, {Martin D.} and Timpson, {Nicholas J.} and Wain, {Louise V.} and Susan Ring and Jones, {Louise R.} and Emmett, {Pauline M.} and Palmer, {Thomas M.} and Ness, {Andrew R.} and Samani, {Nilesh J.} and Smith, {George Davey} and Burton, {Paul R.}", year = "2008", month = nov, doi = "10.1161/HYPERTENSIONAHA.108.118414", language = "English", volume = "52", pages = "974--979", journal = "Hypertension", issn = "1524-4563", publisher = "Lippincott Williams and Wilkins", number = "5", } . Hypertension.

Adjusting for bias and unmeasured confounding in Mendelian randomization studies with binary responses @article{d0e34db2c5a74fc298479834b26dbbbc, title = "Adjusting for bias and unmeasured confounding in Mendelian randomization studies with binary responses", abstract = "BACKGROUND: Mendelian randomization uses a carefully selected gene as an instrumental-variable (IV) to test or estimate an association between a phenotype and a disease. Classical IV analysis assumes linear relationships between the variables, but disease status is often binary and modelled by a logistic regression. When the linearity assumption between the variables does not hold the IV estimates will be biased. The extent of this bias in the phenotype-disease log odds ratio of a Mendelian randomization study is investigated.METHODS: Three estimators termed direct, standard IV and adjusted IV, of the phenotype-disease log odds ratio are compared through a simulation study which incorporates unmeasured confounding. The simulations are verified using formulae relating marginal and conditional estimates given in the Appendix.RESULTS: The simulations show that the direct estimator is biased by unmeasured confounding factors and the standard IV estimator is attenuated towards the null. Under most circumstances the adjusted IV estimator has the smallest bias, although it has inflated type I error when the unmeasured confounders have a large effect.CONCLUSIONS: In a Mendelian randomization study with a binary disease outcome the bias associated with estimating the phenotype-disease log odds ratio may be of practical importance and so estimates should be subject to a sensitivity analysis against different amounts of hypothesized confounding.", keywords = "Bias (Epidemiology), Computer Simulation, Confounding Factors (Epidemiology), Data Interpretation, Statistical, Humans, Phenotype, Random Allocation, Treatment Outcome", author = "Palmer, {Tom M.} and Thompson, {John R.} and Tobin, {Martin D.} and Sheehan, {Nuala A.} and Burton, {Paul R.}", year = "2008", month = oct, doi = "10.1093/ije/dyn080", language = "English", volume = "37", pages = "1161--1168", journal = "International Journal of Epidemiology", issn = "0300-5771", publisher = "Oxford University Press", number = "5", } . International Journal of Epidemiology.

Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population @article{f83b750080b54f34965f5ae8a10fcff5, title = "Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population", abstract = "The genes responsible for several monogenic hypertensive and hypotensive disorders have been identified. Our aim was to evaluate whether common variants in these genes affect blood pressure in the general population. We studied 2037 adults from 520 nuclear families characterized for 24-hour ambulatory blood pressure and related cardiovascular traits. We genotyped 298 tagging and putative functional single nucleotide polymorphisms, achieving a median coverage of 82.4% across 11 candidate loci. Five polymorphisms in the KCNJ1 gene coding for the potassium channel, ROMK, showed associations with mean 24-hour systolic or diastolic blood pressure. The strongest association was with an intronic polymorphism, rs2846679, where the minor allele (frequency 16%) was associated with a -1.58 (95% CI -2.47 to -0.69) mm Hg change in mean 24-hour systolic blood pressure, after accounting for age, sex, and familial correlations (P=0.00048). Polymorphisms in the gene were also associated with clinic blood pressure and left ventricular mass as assessed by ECG Sokolow-Lyon voltage (P=0.0081 for rs675759). Associations with mean 24-hour systolic or diastolic blood pressure were also observed for variants in CASR, NR3C2, SCNN1B, and SCNN1G. The findings show that common variants in genes responsible for some Mendelian disorders of hypertension and hypotension affect blood pressure in the general population. Notably, variants in KCNJ1, which causes Bartter syndrome type 2, were strongly associated, potentially providing a novel target for intervention.", keywords = "Adolescent, Adult, Blood Pressure, Epithelial Sodium Channels, Family Health, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Hypertension, Hypotension, Male, Middle Aged, Polymorphism, Single Nucleotide, Potassium Channels, Inwardly Rectifying, Receptors, Calcium-Sensing, Receptors, Mineralocorticoid, Risk Factors", author = "Tobin, {Martin D.} and Maciej Tomaszewski and Braund, {Peter S.} and Cother Hajat and Raleigh, {Stuart M.} and Palmer, {Thomas M.} and Mark Caulfield and Burton, {Paul R.} and Samani, {Nilesh J.}", year = "2008", month = jun, doi = "10.1161/HYPERTENSIONAHA.108.112664", language = "English", volume = "51", pages = "1658--1664", journal = "Hypertension", issn = "1524-4563", publisher = "Lippincott Williams and Wilkins", number = "6", } . Hypertension.

Palmer, T.M., Peters, J.L., Sutton, A.J., Moreno, S.G., Palmer, T.M., Peters, J.L., Sutton, A.J., Moreno, S.G.(2008). Contour-enhanced funnel plots for meta-analysis . Stata Journal. 8. (2). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 242-254.

Palmer, T.M., Thompson, J.R., Tobin, M.D., Palmer, T.M., Thompson, J.R., Tobin, M.D.(2008). Meta-analysis of mendelian randomization studies incorporating all three genotypes . Statistics in Medicine. 27. (30). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 6570-6582.

TM Palmer, JL Peters, AJ Sutton, SG Moreno(2008). Contour enhanced funnel plots for meta-analysis . Stata Journal. 8. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 242 -- 254. DPC Nederland

TM Palmer, JR Thompson, MD Tobin(2008). Meta-analysis of Mendelian randomization studies using all three genotypes . Statistics in Medicine. 27. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 6570 -- 6582. John Wiley & Sons, Ltd.

Palmer, T.M., Thompson, J.R., Tobin, M.D., Sheehan, N.A., Burton, P.R., Palmer, T.M., Thompson, J.R., Tobin, M.D., Sheehan, N.A., Burton, P.R.(2008). Adjusting for bias and unmeasured confounding in Mendelian randomization studies with binary responses . International Journal of Epidemiology. 37. (5). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1161-1168.

Tobin, M.D., Timpson, N.J., Wain, L.V., Ring, S., Jones, L.R., Emmett, P.M., Palmer, T.M., Ness, A.R., Samani, N.J., Smith, G.D., et al.(2008). Common variation in the WNK1 gene and blood pressure in childhood the avon longitudinal study of parents and children . Hypertension. 52. (5). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 974-979.

Tobin, M.D., Tomaszewski, M., Braund, P.S., Hajat, C., Raleigh, S.M., Palmer, T.M., Caulfield, M., Burton, P.R., Samani, N.J., Tobin, M.D., et al.(2008). Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population . Hypertension. 51. (6). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 1658-1664.

Maznyczka, A., Mangino, M., Whittaker, A., Braund, P., Palmer, T., Tobin, M., Goodall, A.H., Bradding, P., Samani, N.J., Maznyczka, A., et al.(2007). Leukotriene B <inf>4</inf> production in healthy subjects carrying variants of the arachidonate 5-lipoxygenase-activating protein gene associated with a risk of myocardial infarction . Clinical Science. 112. (7-8). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 411-416.

JR Thompson, TM Palmer, SG Moreno(2007). Bayesian analysis in Stata using WinBUGS . Stata Journal. 6. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 530 -- 549. DPC Nederland

A Maznyczka, M Mangino, A Whittaker, PS Braund, TM Palmer, MD Tobin, AH Goodall, P Bradding, NJ Samani(2007). Leukotriene B4 production in healthy subjects carrying variants of the Arachidonate 5-Lipoxygenase-Activating protein gene associated with a risk of myocardial infarction . Clinical Science. 112. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 411 -- 416. Portland Press

Bayesian analysis in Stata with WinBUGS @article{47b508f8f512424baf72c91c15b1f36b, title = "Bayesian analysis in Stata with WinBUGS", abstract = "WinBUGS is a program for Baycsian model fitting by Gibbs sampling. WinBUGS has limited facilities for data handling, whereas Stata has no routines for Baycsian analysis; therefore, much can be gained by running Stata and WinBUGS together. We present a set of ado-files that enable data to be processed in Stata and then passed to WinBUGS for model fitting; finally, the results are read back into Stata for further processing.", keywords = "Bayesian methods, Gibbs sampling, MCMC, St0115, Wbac, Wbarray, Wbbgr, Wbbull, Wbcoda, Wbdata, Wbdecode, Wbdensity, Wbdic, Wbgeweke, Wbintervals, Wbrun, Wbscalar, Wbscript, Wbsection, Wbstats, Wbstructure, Wbtrace, Wbvector, WinBUGS", author = "John Thompson and Tom Palmer and Santiago Moreno", year = "2006", month = dec, day = "1", language = "English", volume = "6", pages = "530--549", journal = "Stata Journal", issn = "1536-867X", publisher = "DPC Nederland", number = "4", } . Stata Journal.

Thompson, J., Palmer, T., Moreno, S., Thompson, J., Palmer, T., Moreno, S.(2006). Bayesian analysis in Stata with WinBUGS . Stata Journal. 6. (4). Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 530-549.

WORKING PAPER

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: Findings from a Mendelian randomisation study @techreport{41e2d720aa344457aefdfab72138cd33, title = "Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: Findings from a Mendelian randomisation study", abstract = "Introduction Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin-6 (IL-6). Genetic variants in IL6R known to downregulate IL-6 signalling are associated with improved COVID-19 outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RA). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. Methods We performed a Mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis, sepsis severity, other infections, and COVID-19. We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP in a similar analysis. Results In the UK Biobank cohort (N=485,825, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of sepsis (OR=0.80; 95% CI 0.66-0.96, per unit of natural log transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR=0.74; 95% CI 0.38-0.70); critical care admission with sepsis (OR=0.48, 95% CI 0.30-0.78) and critical care death with sepsis (OR=0.37, 95% CI 0.14 - 0.98) Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 - 0.97) and for sepsis survival in critical care (OR=0.22; 95% CI 0.04- 1.31) in the GainS and GenOSept consortium. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR=0.69, 95% 0.57 - 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. Conclusions IL6R blockade is causally associated with reduced incidence of sepsis, sepsis related critical care admission, and sepsis related mortality. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. This data suggests a randomised trial of IL-6 receptor antagonists in sepsis should be considered.Competing Interest StatementThe authors have declared no competing interest.Funding StatementFHs time was funded by the GW4 CAT Doctoral Fellowship scheme (Wellcome Trust, 222894/Z/21/Z). AHs time was funded by UCL British Heart Foundation Accelerator (AA/18/6/34223), the UCL NIHR Biomedical Research Centre, and the UKRI/NIHR funded Multimorbidity Mechanism and Therapeutics Research Collaborative (MR/V033867/1). AJM is a NIHR Academic Clinical Lecturer and supported by the Oxford Biomedical Research Centre (BRC). PGs time was funded by the Welsh Government and the EU-ERDF (Ser Cymru Scheme). CS is supported by funding from National Institute for Health and Care Research (NIHR133788) and UKRI (MR/X005070/1). Her research programme is also supported by the Cambridge NIHR Biomedical Research Centre (BRC-1215-20014), the Wellcome Trust, and GlaxoSmithKline plc. NJT is a Wellcome Trust Investigator (202802/Z/16/Z) and works within the University of Bristol National Institute for Health Research (NIHR) Biomedical Research Centre (BRC). NJT is supported by the Cancer Research UK (CRUK) Integrative Cancer Epidemiology Programme (C18281/A29019). The views expressed are those of the authors and not necessarily those of the NIHR, the NHS, or the Department of Health and Social Care. Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Most of the data in this study was publicly available and non-identifiable. Therefore, no ethical approval was required to access it. Access to UK Biobank was arranged by the UK Biobank IDAC. This study was performed under application number 56243. UK Biobank has ethical approval details here (https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/ethics)I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData availability Most data used in this study are publicly available. For ease curated data (harmonised SNPs and MR results) are available at the authors GitHub (https://github.com/gushamilton/il6-sepsis) so all findings can be replicated. Raw data from the FinnGen GWAS are available via the FinnGen website (https://www.finngen.fi/) COVID-HGI GWAS are available via the COVID-HGI website (https://www.covid19hg.org/) and the UK Biobank GWAS performed as part of this study are available at the MRC-IEU Open GWAS repository (https://gwas.mrcieu.ac.uk/). Access to the full summary statistics for the sepsis GWAS performed by the GaINS and GenOSept committee is by application to the relevant committee. This research was performed under UK Biobank application 56243. Individual access to UK Biobank can be arranged via the UK Biobank website.https://github.com/gushamilton/il6-sepsis", author = "Hamilton, {Fergus W} and Matt Thomas and Arnold, {David T} and Palmer, {Tom M} and Ed Moran and Mentzer, {Alexander J} and Maskell, {Nick A} and Baillie, {J Kenneth} and Charlotte Summers and Hingorani, {Aroon Dinesh} and MacGowan, {Alasdair P} and Khandaker, {Golam M} and Mitchell, {Ruth E} and {Davey Smith}, George and Peter Ghazal and Timpson, {Nicholas J}", year = "2022", month = jul, day = "15", doi = "10.1101/2022.07.14.22277638", language = "English", series = "medRxiv", publisher = "Cold Spring Harbor Laboratory Press", pages = "2022.07.14.22277638", type = "WorkingPaper", institution = "Cold Spring Harbor Laboratory Press", } . medRxiv.

Effectiveness of BNT162b2 booster doses in England: an observational study in OpenSAFELY-TPP @techreport{6d0a3a4966564a9fa140d15632066fae, title = "Effectiveness of BNT162b2 booster doses in England: an observational study in OpenSAFELY-TPP", abstract = "Background The UK COVID-19 vaccination programme delivered its first {"}booster{"} doses in September 2021, initially in groups at high risk of severe disease then across the adult population. The BNT162b2 Pfizer-BioNTech vaccine was used initially, with Moderna mRNA-1273 subsequently also used. Methods We used the OpenSAFELY-TPP database, covering 40% of English primary care practices and linked to national coronavirus surveillance, hospital episodes, and death registry data, to estimate the effectiveness of boosting with BNT162b2 compared with no boosting in eligible adults who had received two primary course vaccine doses between 16 September and 16 December 2021 when the Delta variant of SARS-CoV-2 was dominant. Follow up was for up to 10 weeks. Each booster recipient was matched with an unboosted control on factors relating to booster priority status and prior immunisation. Additional factors were adjusted for in Cox models estimating hazard ratios (HRs). Outcomes were positive SARS-CoV-2 test, COVID-19 hospitalisation, COVID-19 death and non-COVID-9 death. Booster vaccine effectiveness was defined as 1−HR. Results Among 4,352,417 BNT162b2 booster recipients matched with unboosted controls, estimated effectiveness of a booster dose compared with two doses only was 50.7% (95% CI 50.1-51.3) for positive SARS-CoV-2 test, 80.1% (78.3-81.8) for COVID-19 hospitalisation, 88.5% (85.0-91.1) for COVID-19 death, and 80.3% (79.0-81.5) for non-COVID-19 death. Estimated effectiveness was similar among those who had received a BNT162b2 or ChAdOx1-S two-dose primary vaccination course, but effectiveness against severe COVID-19 was slightly lower in those classified as clinically extremely vulnerable (76.3% (73.1-79.1) for COVID-19 hospitalisation, and 85.1% (79.6-89.1) for COVID-19 death). Estimated effectiveness against each outcome was lower in those aged 18-65 years than in those aged 65 and over. Conclusion Our findings are consistent with strong protection of BNT162b2 boosting against positive SARS-CoV-2 test, COVID-19 hospitalisation, and COVID-19 death.Competing Interest StatementBG's work on better use of data in healthcare more broadly is currently funded in part by: the Bennett Foundation, the Wellcome Trust, NIHR Oxford Biomedical Research Centre, NIHR Applied Research Collaboration Oxford and Thames Valley, the Mohn-Westlake Foundation; all Bennett Institute staff are supported by BG's grants on this work. AS is employed by LSHTM on a fellowship sponsored by GSK. KB holds a Wellcome Senior Research Fellowship (220283/Z/20/Z). HIM is funded by the National Institute for Health Research (NIHR) Health Protection Research Unit in Immunisation, a partnership between UK Health Security Agency and LSHTM. BMK is also employed by NHS England working on medicines policy and clinical lead for primary care medicines data. EW holds grants from MRC. ID holds grants from NIHR and GSK.Funding StatementThis work was jointly funded by UKRI [COV0076;MR/V015737/1], the Longitudinal Health and Wellbeing strand of the National Core Studies programme (MC_PC_20030; MC_PC_20059; COV-LT-0009), NIHR and Asthma UK-BLF. The OpenSAFELY data science platform is funded by the Wellcome Trust (222097/Z/20/Z).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study was approved by the Health Research Authority (REC reference 20/LO/0651) and by the London School of Hygeine and Tropical Medicine Ethics Board (reference 21863).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesDetailed pseudonymised patient data is potentially re-identifiable and therefore not shared.https://github.com/opensafely/booster-effectiveness/tree/713c93530701a1495b2cc742a1c6a1c24419880d", author = "Hulme, {William J} and Williamson, {Elizabeth J} and Elsie Horne and Green, {Amelia CA} and Linda Nab and Ruth Keogh and Parker, {Edward PK} and Walker, {Venexia M} and Palmer, {Tom M} and Curtis, {Helen J} and Milan Wiedemann and Christine Cunningham and Walker, {Alex J} and Louis Fisher and Brian MacKenna and Rentsch, {Christopher T} and Anna Schultze and Krishnan Bhaskaran and John Tazare and Tomlinson, {Laurie A} and McDonald, {Helen I} and Morton, {Caroline E} and Richard Croker and Andrews, {Colm D} and Hopcroft, {Lisa EM} and Park, {Robin Y} and Jon Massey and Amir Mehrkar and Jessica Morley and Bacon, {Sebastian CJ} and David Evans and Peter Inglesby and George Hickman and Simon Davy and Iaim Dillingham and Tom Ward and Viyaasan Mahalingasivam and Bang Zheng and Douglas, {Ian J} and Evans, {Stephen JW} and Christopher Bates and Sterne, {Jonathan AC} and Hernan, {Miguel A} and Ben Goldacre", year = "2022", month = jun, day = "6", doi = "10.1101/2022.06.06.22276026", language = "English", series = "medRxiv", publisher = "Cold Spring Harbor Laboratory Press", type = "WorkingPaper", institution = "Cold Spring Harbor Laboratory Press", } . medRxiv.

Treatment group outcome variance difference after dropout as an indicator of missing-not-at-random bias in randomized clinical trials @techreport{1c80846f2f6c4444a5d28f3febd003fd, title = "Treatment group outcome variance difference after dropout as an indicator of missing-not-at-random bias in randomized clinical trials", abstract = "Randomized controlled trials (RCTs) are considered the gold standard for assessing the causal effect of an exposure on an outcome, but are vulnerable to bias from missing data. When outcomes are missing not at random (MNAR), estimates from complete case analysis (CCA) will be biased. There is no statistical test for distinguishing between outcomes missing at random (MAR) and MNAR, and current strategies rely on comparing dropout proportions and covariate distributions, and using auxiliary information to assess the likelihood of dropout being associated with the outcome. We propose using the observed variance difference across treatment groups as a tool for assessing the risk of dropout being MNAR. In an RCT, at randomization, the distributions of all covariates should be equal in the populations randomized to the intervention and control arms. Under the assumption of homogeneous treatment effects, the variance of the outcome will also be equal in the two populations over the course of followup. We show that under MAR dropout, the observed outcome variances, conditional on the variables included in the model, are equal across groups, while MNAR dropout may result in unequal variances. Consequently, unequal observed conditional group variances are an indicator of MNAR dropout and possible bias of the estimated treatment effect. Heterogeneity of treatment effect affects the intervention group variance, and is another potential cause of observing different outcome variances. We show that, for longitudinal data, we can isolate the effect of MNAR outcome-dependent dropout by considering the variance difference at baseline in the same set of patients that are observed at final follow-up. We illustrate our method in simulation and in applications using individual-level patient data and summary data.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialISRCTN96537534Funding StatementAH, TP and KT were supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC\_UU\_00011/3). KHW is affiliated to the Integrative Cancer Epidemiology Programme (ICEP), and works within the Medical Research Council Integrative Epidemiology UnitAuthor DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study used individual-level patient data from a randomized controlled trial investigating the benefit of an acupuncture treatment policy for patients with chronic headaches (ISRCTN96537534), available from https://www.causeweb.org/tshs/acupuncture/.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe individual-level patient data used in this study are available from https://www.causeweb.org/tshs/acupuncture/. https://www.causeweb.org/tshs/acupuncture/", author = "Audinga-Dea Hazewinkel and Kate Tilling and Wade, {Kaitlin H.} and Tom Palmer", year = "2022", month = apr, day = "18", doi = "10.1101/2022.04.15.22273918", language = "English", series = "medRxiv", publisher = "Cold Spring Harbor Laboratory Press", pages = "2022.04.15.22273918", type = "WorkingPaper", institution = "Cold Spring Harbor Laboratory Press", } . medRxiv.

Waning effectiveness of BNT162b2 and ChAdOx1 COVID-19 vaccines over six months since second dose: a cohort study using linked electronic health records @techreport{94dc1e65258e4e03938a44ed5f381eca, title = "Waning effectiveness of BNT162b2 and ChAdOx1 COVID-19 vaccines over six months since second dose: a cohort study using linked electronic health records", abstract = "Background The rate at which COVID-19 vaccine effectiveness wanes over time is crucial for vaccination policies, but is incompletely understood with conflicting results from different studies. Methods This cohort study, using the OpenSAFELY-TPP database and approved by NHS England, included individuals without prior SARS-CoV-2 infection assigned to vaccines priority groups 2-12 defined by the UK Joint Committee on Vaccination and Immunisation. We compared individuals who had received two doses of BNT162b2 or ChAdOx1 with unvaccinated individuals during six 4-week comparison periods, separately for subgroups aged 65+ years; 16-64 years and clinically vulnerable; 40-64 years and 18-39 years. We used Cox regression, stratified by first dose eligibility and geographical region and controlled for calendar time, to estimate adjusted hazard ratios (aHRs) comparing vaccinated with unvaccinated individuals, and quantified waning vaccine effectiveness as ratios of aHRs per-4-week period. The outcomes were COVID-19 hospitalisation, COVID-19 death, positive SARS-CoV-2 test, and non-COVID-19 death. Findings The BNT162b2, ChAdOx1 and unvaccinated groups comprised 1,773,970, 2,961,011 and 2,433,988 individuals, respectively. Waning of vaccine effectiveness was similar across outcomes and vaccine brands: e.g. in the 65+ years subgroup ratios of aHRs versus unvaccinated for COVID-19 hospitalisation, COVID-19 death and positive SARS-CoV-2 test ranged from 1.23 (95% CI 1.15-1.32) to 1.27 (1.20-1.34) for BNT162b2 and 1.16 (0.98-1.37) to 1.20 (1.14-1.27) for ChAdOx1. Despite waning, rates of COVID-19 hospitalisation and COVID-19 death were substantially lower among vaccinated individuals compared to unvaccinated individuals up to 26 weeks after second dose, with estimated aHRs <0.20 (>80% vaccine effectiveness) for BNT162b2, and <0.26 (>74%) for ChAdOx1. By weeks 23-26, rates of SARS-CoV-2 infection in fully vaccinated individuals were similar to or higher than those in unvaccinated individuals: aHRs ranged from 0.85 (0.78-0.92) to 1.53 (1.07-2.18) for BNT162b2, and 1.21 (1.13-1.30) to 1.99 (1.94-2.05) for ChAdOx1. Interpretation The rate at which estimated vaccine effectiveness waned was strikingly consistent for COVID-19 hospitalisation, COVID-19 death and positive SARS-CoV-2 test, and similar across subgroups defined by age and clinical vulnerability. If sustained to outcomes of infection with the Omicron variant and to booster vaccination, these findings will facilitate scheduling of booster vaccination doses.Competing Interest StatementBen Goldacre has received research funding from the Laura and John Arnold Foundation, the NHS National Institute for Health Research (NIHR), the NIHR School of Primary Care Research, the NIHR Oxford Biomedical Research Centre, the Mohn-Westlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, the Wellcome Trust, the Good Thinking Foundation, Health Data Research UK, the Health Foundation, the World Health Organisation, UKRI, Asthma UK, the British Lung Foundation, and the Longitudinal Health and Wellbeing strand of the National Core Studies programme; he receives personal income from speaking and writing for lay audiences on the misuse of science; he is also a Non-executive Director of NHS Digital.Funding StatementThis work was supported by the This work was supported by the Longitudinal Health and Wellbeing COVID-19 National Core Study (UKRI Medical Research Council MC_PC_20030 and MC_PC_20059), Asthma UK, and NIHR grant MR/V015737/1. The OpenSAFELY software platform is funded by Wellcome and by the Data and Connectivity COVID-19 National Core Study which is led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20058). TPP provided technical expertise and infrastructure within their data centre pro bono in the context of a national emergency. BG's work on better use of data in healthcare more broadly is currently funded in part by: NIHR Oxford Biomedical Research Centre, NIHR Applied Research Collaboration Oxford and Thames Valley, the Mohn-Westlake Foundation, NHS England, and the Health Foundation, all DataLab staff are supported by BG's grants on this work. RHK was funded by UK Research and Innovation (Future Leaders Fellowship MR/S017968/1). VW and TMP were supported by the MRC Integrative Epidemiology Unit which receives funding from the UKRI Medical Research Council and the University of Bristol (MC_UU_00011/1 and MC_UU_00011/3). EPKP was funded by UK Research and Innovation (COVID-19 data analysis secondment MR/W021420/1). EW holds grants from MRC. JACS is supported by the NIHR Bristol Biomedical Research Centre and by Health Data Research UK. The views expressed are those of the authors and not necessarily those of the NIHR, NHS England, Public Health England or the Department of Health and Social Care. Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study was approved by the Health Research Authority (REC reference 20/LO/0651) and by the London School of Hygiene and Tropical Medicine Ethics Board (reference 21863).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data were linked, stored and analysed securely within the OpenSAFELY platform: https://opensafely.org/. Data include pseudonymised data such as coded diagnoses, medications and physiological parameters. No free text data are included. All code is shared openly for review and re-use under MIT open license https://github.com/opensafely/covid-ve-change-over-time. Detailed pseudonymised patient data is potentially re-identifiable and therefore not shared. Codelists are available at https://www.opencodelists.org/.https://github.com/opensafely/covid-ve-change-over-time", author = "Horne, {Elsie MF} and Hulme, {William J} and Keogh, {Ruth H} and Palmer, {Tom M} and Williamson, {Elizabeth J} and Parker, {Edward PK} and Amelia Green and Venexia Walker and Walker, {Alex J} and Helen Curtis and Louis Fisher and Brian MacKenna and Richard Croker and Lisa Hopcroft and Park, {Robin Y} and Jon Massey and Jessica Morely and Amir Mehrkar and Sebastian Bacon and David Evans and Peter Inglesby and Morton, {Caroline E} and George Hickman and Simon Davy and Tom Ward and Iain Dillingham and Ben Goldacre and Hernan, {Miguel A} and Sterne, {Jonathan AC}", year = "2022", month = jan, day = "1", doi = "10.1101/2022.03.23.22272804", language = "English", series = "medRxiv", publisher = "Cold Spring Harbor Laboratory Press", pages = "2022.03.23.22272804", type = "WorkingPaper", institution = "Cold Spring Harbor Laboratory Press", } . medRxiv.

Conditioning on a mediator @techreport{7b16d6cea9804f6bb1dd0dcb5a594f37, title = "Conditioning on a mediator", author = "Rolf Groenwold and Tom Palmer and Tilling, {Kate M}", year = "2019", month = dec, day = "23", language = "English", publisher = "OSF Preprints", type = "WorkingPaper", institution = "OSF Preprints", } .

Conditioning on a mediator @techreport{d5cc52863df846a1a1f13e962bc2ca14, title = "Conditioning on a mediator", author = "Rolf Groenwold and Tom Palmer and Kate Tilling", year = "2019", month = dec, day = "23", language = "English", publisher = "OSF Preprints", type = "WorkingPaper", institution = "OSF Preprints", } .

Bayesian estimation of IVW and MR-Egger models for two-sample Mendelian randomization studies @techreport{63cd04e78b6b4260b1f27e2dbb8732bc, title = "Bayesian estimation of IVW and MR-Egger models for two-sample Mendelian randomization studies", author = "Okezie Uche-Ikonne and Frank Dondelinger and Tom Palmer", year = "2019", month = sep, day = "21", doi = "10.1101/19005868", language = "English", publisher = "medRxiv", type = "WorkingPaper", institution = "medRxiv", } .

A Mendelian Randomization dictionary @techreport{e1a1b4690e914fef95511a9c7b1abf48, title = "A Mendelian Randomization dictionary: Useful definitions and descriptions for undertaking, understanding and interpreting Mendelian Randomization studies", abstract = "Mendelian randomization (MR) has been increasingly used to interrogate the causal effects of modifiable risk factors on human health and disease over the last 15 years. As MR becomes more commonplace in clinical guidelines and drug development, there is a need for researchers and practitioners from multiple disciplines to understand the existing and rapidly evolving {\textquoteleft}language{\textquoteright} of MR. The MR Dictionary provides useful definitions and descriptions for undertaking, understanding and interpreting MR studies to a wide, inter-disciplinary audience – both those new to MR and those who are experienced in its use but who want to remain up to date. The full searchable (with terms cross-referenced throughout) version of the MR Dictionary is provided on the journal website. In the first instance, we aim to update the MR Dictionary annually and encourage users of the Dictionary to help us in this endeavour. By the first update (August 2020), we aim to have moved to an open, collaborative and interactive online tool on the journal website that will support more rapid and extensive linked searches and more immediate updates and online discussion.", author = "Lawlor, {Debbie A} and Wade, {K H} and Borges, {Maria Carolina} and Tom Palmer and Hartwig, {Fernando Pires} and Gibran Hemani and Jack Bowden", year = "2019", month = feb, day = "5", doi = "10.31219/osf.io/6yzs7", language = "English", publisher = "OSF Preprints", type = "WorkingPaper", institution = "OSF Preprints", } .

A Mendelian Randomization dictionary @techreport{be0e4e877ee94beda0b0b4f109be1892, title = "A Mendelian Randomization dictionary: Useful definitions and descriptions for undertaking, understanding and interpreting Mendelian Randomization studies", abstract = "Mendelian randomization (MR) has been increasingly used to interrogate the causal effects of modifiable risk factors on human health and disease over the last 15 years. As MR becomes more commonplace in clinical guidelines and drug development, there is a need for researchers and practitioners from multiple disciplines to understand the existing and rapidly evolving {\textquoteleft}language{\textquoteright} of MR. The MR Dictionary provides useful definitions and descriptions for undertaking, understanding and interpreting MR studies to a wide, inter-disciplinary audience – both those new to MR and those who are experienced in its use but who want to remain up to date. The full searchable (with terms cross-referenced throughout) version of the MR Dictionary is provided on the journal website. In the first instance, we aim to update the MR Dictionary annually and encourage users of the Dictionary to help us in this endeavour. By the first update (August 2020), we aim to have moved to an open, collaborative and interactive online tool on the journal website that will support more rapid and extensive linked searches and more immediate updates and online discussion.", author = "Lawlor, {Debbie A} and Wade, {K H} and Borges, {Maria Carolina} and Palmer, {Thomas Michael} and Hartwig, {Fernando Pires} and Gibran Hemani and Jack Bowden", year = "2019", month = feb, day = "5", doi = "10.31219/osf.io/6yzs7", language = "English", publisher = "OSF Preprints", type = "WorkingPaper", institution = "OSF Preprints", } .

OTHER

Older people with long term conditions using technologies supporting home based care @article{d016eb40a0744b5685fe90ecf7bb0df6, title = "Older people with long term conditions using technologies supporting home based care: patterns of resource use, costs and health related quality of life", author = "C. Mateus and A. Hernandez and T. Palmer and S. Varey and C. Milligan", year = "2018", month = oct, doi = "10.1016/j.jval.2018.09.1309", language = "English", volume = "21", pages = "S220--S220", journal = "Value in Health", issn = "1098-3015", publisher = "ELSEVIER SCIENCE INC", number = "Suppl. 3", } . Value in Health.

Erratum @article{5c6fc567cec140319017abc1bee6520f, title = "Erratum: Genetic evidence for causal relationships between maternal obesity-related traits and birth weight (JAMA (2016) 315:11 (1129-1140) 10.1001/JAMA.2016.1975))", author = "J. Tyrrell and Richmond, {R. C.} and Palmer, {T. M.}", year = "2016", month = apr, day = "19", doi = "10.1001/jama.2016.3680", language = "English", volume = "315", journal = "JAMA - Journal of the American Medical Association", issn = "0098-7484", publisher = "American Medical Association", number = "15", } . JAMA - Journal of the American Medical Association.

Erratum @article{9194708e451442ad8d5053a9417b0f74, title = "Erratum: Causal effects of body mass index on cardiometabolic traits and events: A mendelian randomization analysis (American Journal of Human Genetics (2014) 94 (198-208))", author = "Holmes, {Michael V.} and Lange, {Leslie A.} and Tom Palmer and Lanktree, {Matthew B.} and North, {Kari E.} and Berta Almoguera and Sarah Buxbaum and Chandrupatla, {Hareesh R.} and Elbers, {Clara C.} and Yiran Guo and Hoogeveen, {Ron C.} and Jin Li and Li, {Yun R.} and Swerdlow, {Daniel I.} and Mary Cushman and Price, {Tom S.} and Curtis, {Sean P.} and Myriam Fornage and Hakon Hakonarson and Patel, {Sanjay R.} and Susan Redline and Siscovick, {David S.} and Tsai, {Michael Y.} and Wilson, {James G.} and {Van Der Schouw}, {Yvonne T.} and Fitzgerald, {Garret A.} and Hingorani, {Aroon D.} and Casas, {Juan P.} and {De Bakker}, {Paul I.W.} and Rich, {Stephen S.} and Schadt, {Eric E.} and Asselbergs, {Folkert W.} and Reiner, {Alex P.} and Keating, {Brendan J.}", year = "2014", month = feb, day = "6", doi = "10.1016/j.ajhg.2014.01.012", language = "English", volume = "94", journal = "American Journal of Human Genetics", issn = "0002-9297", publisher = "Cell Press", number = "2", } . American Journal of Human Genetics.

REPORT

Lancashire and Cumbria Innovation Alliance Test Bed @book{4d31d9dc0cfe43fc9bc6b8efe894b4a4, title = "Lancashire and Cumbria Innovation Alliance Test Bed: Final Evaluation Report for a Targeted Supported Self-Care Programme ", author = "Christine Milligan and Ceu Mateus and Tom Palmer and Sandra Varey and {Hernandez Huerta}, Alejandra and Mandy Dixon", year = "2018", month = jun, day = "30", language = "English", publisher = "Lancaster University", } .

BOOK

Lancashire and Cumbria Innovation Alliance Test Bed @book{16bcbc22ebe74233857ba184fddb0171, title = "Lancashire and Cumbria Innovation Alliance Test Bed: Final Evaluation Report for a Targeted Supported Self-Care Programme", author = "Christine Milligan and Ceu Mateus and Tom Palmer and Sandra Varey and {Hernandez Huerta}, Alejandra and Mandy Dixon", year = "2018", month = jun, day = "30", language = "English", publisher = "Lancaster University", } .

Martin, R.M., Patel, R., Kramer, M.S., Vilchuck, K., Bogdanovich, N., Sergeichick, N., Gusina, N., Foo, Y., Palmer, T., Thompson, J., et al.(2016). Effects of promoting longer-term and exclusive breastfeeding on cardiometabolic risk factors at age 11.5 years: A cluster-randomized, controlled trial . World Review of Nutrition and Dietetics. 114. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 25-26.

Tom Palmer, Jonathan A. C. Sterne(2016). Meta-analysis in Stata . Stata Press

CONFERENCE PAPER

RM Harbord, S Meng, V Didelez, J Sterne, TM Palmer, N Sheehan(2010). Mendelian randomization: How biased is a simple odds ratio estimator? . 31st Annual Conference of the International Society for Clinical Biostatistics, Montpellier, France.

BOOK CHAPTER

TM Palmer, JL Peters, AJ Sutton, SG Moreno(2009). Contour-enhanced funnel plots for meta-analysis . Meta-Analysis in Stata: An Updated Collection from the Stata Journal. Microsoft.AspNetCore.Mvc.Localization.LocalizedHtmlString 124 -- 137. Stata Press