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107. Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): Explanation and elaboration

Author

Skrivankova, Veronika W, Richmond, Rebecca C, Woolf, Benjamin A R, Davies, Neil M, Swanson, Sonja A, VanderWeele, Tyler J, Timpson, Nicholas J, Higgins, Julian P T, Dimou, Niki, Langenberg, Claudia, Loder, Elizabeth W, Golub, Robert M, Egger, Matthias, Davey Smith, George, Richards, J Brent, Epidemiology, Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
Observational Studies as Topic, 360 Social problems & social services, Epidemiologic Research Design, Research Methods & Reporting, Humans, 610 Medicine & health, Guidelines as Topic, Mendelian Randomization Analysis
Abstract

Mendelian randomisation (MR) studies allow a better understanding of the causal effects of modifiable exposures on health outcomes, but the published evidence is often hampered by inadequate reporting. Reporting guidelines help authors effectively communicate all critical information about what was done and what was found. STROBE-MR (strengthening the reporting of observational studies in epidemiology using mendelian randomisation) assists authors in reporting their MR research clearly and transparently. Adopting STROBE-MR should help readers, reviewers, and journal editors evaluate the quality of published MR studies. This article explains the 20 items of the STROBE-MR checklist, along with their meaning and rationale, using terms defined in a glossary. Examples of transparent reporting are used for each item to illustrate best practices.

Published
2021

109. Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses

Author

Heilbron, Karl, Howe, Laura D., Hughes, Amanda, Boomsma, Dorret I., Hopper, John, Pedersen, Nancy L., Reynolds, Chandra A., Tucker-Drob, Elliot M., Howe, Laurence, Li, Shuai, Auton, Adam, Windmeijer, Frank, Chen, Wei-Min, Bjørngaard, Johan Håkon, Hveem, Kristian, Davey Smith, George, Åsvold, Bjørn Olav, Brumpton, Ben, Sanderson, Eleanor, Hartwig, Fernando Pires, Harrison, Sean, Vie, Gunnhild Åberge, Cho, Yoonsu, Havdahl, Alexandra, Neale, Michael, Nivard, Michel G., Grotzinger, Andrew, Morris, Tim, Willer, Cristen, Evans, David M., Kaprio, Jaakko, Smith, George Davey, Hemani, Gibran, Davies, Neil M., Brumpton, Ben [0000-0002-3058-1059], Sanderson, Eleanor [0000-0001-5188-5775], Hartwig, Fernando Pires [0000-0003-3729-0710], Harrison, Sean [0000-0002-7966-0700], Vie, Gunnhild Åberge [0000-0003-1552-5291], Cho, Yoonsu [0000-0001-6118-6652], Havdahl, Alexandra [0000-0002-9268-0423], Neale, Michael [0000-0003-4887-659X], Nivard, Michel G. [0000-0003-2015-1888], Grotzinger, Andrew [0000-0001-7852-9244], Morris, Tim [0000-0001-8178-6815], Willer, Cristen [0000-0001-5645-4966], Evans, David M. [0000-0003-0663-4621], Kaprio, Jaakko [0000-0002-3716-2455], Davey Smith, George [0000-0002-1407-8314], Hemani, Gibran [0000-0003-0920-1055], Davies, Neil M. [0000-0002-2460-0508], and Apollo - University of Cambridge Repository

Subjects
631/208, 692/308, 692/308/2056, 45/43, article, 692/308/174, 692/499
Abstract

Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.

Published
2020

112. Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration

Author

Skrivankova, Veronika W, primary, Richmond, Rebecca C, additional, Woolf, Benjamin A R, additional, Davies, Neil M, additional, Swanson, Sonja A, additional, VanderWeele, Tyler J, additional, Timpson, Nicholas J, additional, Higgins, Julian P T, additional, Dimou, Niki, additional, Langenberg, Claudia, additional, Loder, Elizabeth W, additional, Golub, Robert M, additional, Egger, Matthias, additional, Davey Smith, George, additional, and Richards, J Brent, additional

Published
2021
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113. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization

Author

Skrivankova, Veronika W., primary, Richmond, Rebecca C., additional, Woolf, Benjamin A. R., additional, Yarmolinsky, James, additional, Davies, Neil M., additional, Swanson, Sonja A., additional, VanderWeele, Tyler J., additional, Higgins, Julian P. T., additional, Timpson, Nicholas J., additional, Dimou, Niki, additional, Langenberg, Claudia, additional, Golub, Robert M., additional, Loder, Elizabeth W., additional, Gallo, Valentina, additional, Tybjaerg-Hansen, Anne, additional, Davey Smith, George, additional, Egger, Matthias, additional, and Richards, J. Brent, additional

Published
2021
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118. Body mass index and childhood symptoms of depression, anxiety, and attention-deficit hyperactivity disorder: a within-family Mendelian randomization study

Author

Hughes, Amanda M, primary, Sanderson, Eleanor, additional, Morris, Tim, additional, Ayorech, Ziada, additional, Tesli, Martin, additional, Ask, Helga, additional, Reichborn-Kjennerud, Ted, additional, Andreassen, Ole A., additional, Magnus, Per, additional, Helgeland, Øyvind, additional, Johansson, Stefan, additional, Njølstad, Pål, additional, Davey Smith, George, additional, Havdahl, Alexandra, additional, Howe, Laura D, additional, and Davies, Neil M, additional

Published
2021
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123. Navigating sample overlap, winner’s curse and weak instrument bias in Mendelian randomization studies using the UK Biobank

Author

Sadreev, Ildar I, primary, Elsworth, Benjamin L, additional, Mitchell, Ruth E, additional, Paternoster, Lavinia, additional, Sanderson, Eleanor, additional, Davies, Neil M, additional, Millard, Louise AC, additional, Smith, George Davey, additional, Haycock, Philip C, additional, Bowden, Jack, additional, Gaunt, Tom R, additional, and Hemani, Gibran, additional

Published
2021
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124. Is genetic liability to ADHD and ASD causally linked to educational attainment?

Author

Dardani, Christina, primary, Riglin, Lucy, additional, Leppert, Beate, additional, Sanderson, Eleanor, additional, Rai, Dheeraj, additional, Howe, Laura D, additional, Davey Smith, George, additional, Tilling, Kate, additional, Thapar, Anita, additional, Davies, Neil M, additional, Anderson, Emma, additional, and Stergiakouli, Evie, additional

Published
2021
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125. Mendelian randomization for studying the effects of perturbing drug targets [version 2; peer review: 3 approved, 1 approved with reservations]

Author

Gill, Dipender, Georgakis, Marios K., Swerdlow, Daniel I., Davey Smith, George, Holmes, Michael V., Dichgans, Martin, Zheng, Jie, Psaty, Bruce M., Davies, Neil M., Walker, Venexia M., Schmidt, A. Floriaan, Gkatzionis, Apostolos, Freitag, Daniel F., Finan, Chris, Hingorani, Aroon D., Howson, Joanna M. M., and Burgess, Stephen

Subjects
ddc:500
Abstract

Drugs whose targets have genetic evidence to support efficacy and safety are more likely to be approved after clinical development. In this paper, we provide an overview of how natural sequence variation in the genes that encode drug targets can be used in Mendelian randomization analyses to offer insight into mechanism-based efficacy and adverse effects. Large databases of summary level genetic association data are increasingly available and can be leveraged to identify and validate variants that serve as proxies for drug target perturbation. As with all empirical research, Mendelian randomization has limitations including genetic confounding, its consideration of lifelong effects, and issues related to heterogeneity across different tissues and populations. When appropriately applied, Mendelian randomization provides a useful empirical framework for using population level data to improve the success rates of the drug development pipeline.

Published
2021

126. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization:The STROBE-MR Statement

Author

Skrivankova, Veronika W., Richmond, Rebecca C., Woolf, Benjamin A.R., Yarmolinsky, James, Davies, Neil M., Swanson, Sonja A., Vanderweele, Tyler J., Higgins, Julian P.T., Timpson, Nicholas J., Dimou, Niki, Langenberg, Claudia, Golub, Robert M., Loder, Elizabeth W., Gallo, Valentina, Tybjaerg-Hansen, Anne, Davey Smith, George, Egger, Matthias, Richards, J. Brent, Skrivankova, Veronika W., Richmond, Rebecca C., Woolf, Benjamin A.R., Yarmolinsky, James, Davies, Neil M., Swanson, Sonja A., Vanderweele, Tyler J., Higgins, Julian P.T., Timpson, Nicholas J., Dimou, Niki, Langenberg, Claudia, Golub, Robert M., Loder, Elizabeth W., Gallo, Valentina, Tybjaerg-Hansen, Anne, Davey Smith, George, Egger, Matthias, and Richards, J. Brent

Abstract

Importance: Mendelian randomization (MR) studies use genetic variation associated with modifiable exposures to assess their possible causal relationship with outcomes and aim to reduce potential bias from confounding and reverse causation. Objective: To develop the STROBE-MR Statement as a stand-alone extension to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the reporting of MR studies. Design, Setting, and Participants: The development of the STROBE-MR Statement followed the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework guidance and used the STROBE Statement as a starting point to draft a checklist tailored to MR studies. The project was initiated in 2018 by reviewing the literature on the reporting of instrumental variable and MR studies. A group of 17 experts, including MR methodologists, MR study design users, developers of previous reporting guidelines, and journal editors, participated in a workshop in May 2019 to define the scope of the Statement and draft the checklist. The draft checklist was published as a preprint in July 2019 and discussed on the preprint platform, in social media, and at the 4th Mendelian Randomization Conference. The checklist was then revised based on comments, further refined through 2020, and finalized in July 2021. Findings: The STROBE-MR checklist is organized into 6 sections (Title and Abstract, Introduction, Methods, Results, Discussion, and Other Information) and includes 20 main items and 30 subitems. It covers both 1-sample and 2-sample MR studies that assess 1 or multiple exposures and outcomes, and addresses MR studies that follow a genome-wide association study and are reported in the same article. The checklist asks authors to justify why MR is a helpful method to address the study question and state prespecified causal hypotheses. The measurement, quality, and selection of genetic variants must be described and attempts to assess validi

Published
2021

127. Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR):Explanation and elaboration

Author

Skrivankova, Veronika W., Richmond, Rebecca C., Woolf, Benjamin A.R., Davies, Neil M., Swanson, Sonja A., Vanderweele, Tyler J., Timpson, Nicholas J., Higgins, Julian P.T., Dimou, Niki, Langenberg, Claudia, Loder, Elizabeth W., Golub, Robert M., Egger, Matthias, Smith, George Davey, Richards, J. Brent, Skrivankova, Veronika W., Richmond, Rebecca C., Woolf, Benjamin A.R., Davies, Neil M., Swanson, Sonja A., Vanderweele, Tyler J., Timpson, Nicholas J., Higgins, Julian P.T., Dimou, Niki, Langenberg, Claudia, Loder, Elizabeth W., Golub, Robert M., Egger, Matthias, Smith, George Davey, and Richards, J. Brent

Abstract

Mendelian randomisation (MR) studies allow a better understanding of the causal effects of modifiable exposures on health outcomes, but the published evidence is often hampered by inadequate reporting. Reporting guidelines help authors effectively communicate all critical information about what was done and what was found. STROBE-MR (strengthening the reporting of observational studies in epidemiology using mendelian randomisation) assists authors in reporting their MR research clearly and transparently. Adopting STROBE-MR should help readers, reviewers, and journal editors evaluate the quality of published MR studies. This article explains the 20 items of the STROBE-MR checklist, along with their meaning and rationale, using terms defined in a glossary. Examples of transparent reporting are used for each item to illustrate best practices.

Published
2021

128. Mendelian randomization for studying the effects of perturbing drug targets [version 1; peer review: awaiting peer review]

Author

Verpleegafdeling Cardiologie, Onderzoek Precision medicine, Gill, Dipender, Georgakis, Marios K., Walker, Venexia M., Schmidt, A. Floriaan, Gkatzionis, Apostolos, Freitag, Daniel F., Finan, Chris, Hingorani, Aroon D., Howson, Joanna M.M., Burgess, Stephen, Swerdlow, Daniel I., Smith, George Davey, Holmes, Michael V., Dichgans, Martin, Zheng, Jie, Psaty, Bruce M., Davies, Neil M., Verpleegafdeling Cardiologie, Onderzoek Precision medicine, Gill, Dipender, Georgakis, Marios K., Walker, Venexia M., Schmidt, A. Floriaan, Gkatzionis, Apostolos, Freitag, Daniel F., Finan, Chris, Hingorani, Aroon D., Howson, Joanna M.M., Burgess, Stephen, Swerdlow, Daniel I., Smith, George Davey, Holmes, Michael V., Dichgans, Martin, Zheng, Jie, Psaty, Bruce M., and Davies, Neil M.

Published
2021

129. Mendelian randomization for studying the effects of perturbing drug targets [version 2; peer review: 3 approved, 1 approved with reservations]

Author

Onderzoek Vrouw Hart & Vaatziekten, Onderzoek Precision medicine, Gill, Dipender, Georgakis, Marios K., Walker, Venexia M., Schmidt, A. Floriaan, Gkatzionis, Apostolos, Freitag, Daniel F., Finan, Chris, Hingorani, Aroon D., Howson, Joanna M.M., Burgess, Stephen, Swerdlow, Daniel I., Davey Smith, George, Holmes, Michael V., Dichgans, Martin, Scott, Robert A., Zheng, Jie, Psaty, Bruce M., Davies, Neil M., Onderzoek Vrouw Hart & Vaatziekten, Onderzoek Precision medicine, Gill, Dipender, Georgakis, Marios K., Walker, Venexia M., Schmidt, A. Floriaan, Gkatzionis, Apostolos, Freitag, Daniel F., Finan, Chris, Hingorani, Aroon D., Howson, Joanna M.M., Burgess, Stephen, Swerdlow, Daniel I., Davey Smith, George, Holmes, Michael V., Dichgans, Martin, Scott, Robert A., Zheng, Jie, Psaty, Bruce M., and Davies, Neil M.

Published
2021

130. The bidirectional causal effects of brain morphology across the life course and risk of Alzheimer’s disease: A cross-cohort comparison and Mendelian randomization meta-analysis

Author

Korologou-Linden, Roxanna, primary, Xu, Bing, additional, Coulthard, Elizabeth, additional, Walton, Esther, additional, Wearn, Alfie, additional, Hemani, Gibran, additional, White, Tonya, additional, Cecil, Charlotte, additional, Sharp, Tamsin, additional, Tiemeier, Henning, additional, Banaschewski, Tobias, additional, Bokde, Arun L.W., additional, Quinlan, Erin Burke, additional, Desrivières, Sylvane, additional, Flor, Herta, additional, Grigis, Antoine, additional, Garavan, Hugh, additional, Gowland, Penny, additional, Heinz, Andreas, additional, Brühl, Rüdiger, additional, Martinot, Jean-Luc, additional, Martinot, Marie-Laure Paillère, additional, Artiges, Eric, additional, Nees, Frauke, additional, Orfanos, Dimitri Papadopoulos, additional, Paus, Tomáš, additional, Poustka, Luise, additional, Millenet, Sabina, additional, Fröhner, Juliane H., additional, Smolka, M, additional, Walter, Henrik, additional, Whelan, Robert, additional, Schumann, Gunter, additional, Howe, Laura D, additional, Ben-Shlomo, Yoav, additional, Davies, Neil M, additional, and Anderson, Emma L, additional

Published
2021
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132. Interpreting Mendelian-randomization estimates of the effects of categorical exposures such as disease status and educational attainment.

Author

Howe, Laurence J, Tudball, Matthew, Smith, George Davey, Davies, Neil M, and Davey Smith, George

Subjects
GENETICS, SEQUENCE analysis, TYPE 2 diabetes, RESEARCH funding, STATISTICAL sampling, EDUCATIONAL attainment
Abstract

Background: Mendelian randomization has been previously used to estimate the effects of binary and ordinal categorical exposures-e.g. Type 2 diabetes or educational attainment defined by qualification-on outcomes. Binary and categorical phenotypes can be modelled in terms of liability-an underlying latent continuous variable with liability thresholds separating individuals into categories. Genetic variants influence an individual's categorical exposure via their effects on liability, thus Mendelian-randomization analyses with categorical exposures will capture effects of liability that act independently of exposure category.Methods and Results: We discuss how groups in which the categorical exposure is invariant can be used to detect liability effects acting independently of exposure category. For example, associations between an adult educational-attainment polygenic score (PGS) and body mass index measured before the minimum school leaving age (e.g. age 10 years), cannot indicate the effects of years in full-time education on this outcome. Using UK Biobank data, we show that a higher educational-attainment PGS is strongly associated with lower smoking initiation and higher odds of glasses use at age 15 years. These associations were replicated in sibling models. An orthogonal approach using the raising of the school leaving age (ROSLA) policy change found that individuals who chose to remain in education to age 16 years before the reform likely had higher liability to educational attainment than those who were compelled to remain in education to age 16 years after the reform, and had higher income, lower pack-years of smoking, higher odds of glasses use and lower deprivation in adulthood. These results suggest that liability to educational attainment is associated with health and social outcomes independently of years in full-time education.Conclusions: Mendelian-randomization studies with non-continuous exposures should be interpreted in terms of liability, which may affect the outcome via changes in exposure category and/or independently. [ABSTRACT FROM AUTHOR]

Published
2022
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136. Early childhood general anesthesia and neurodevelopmental outcomes in the ALSPAC birth cohort

Author

Walkden, Graham, Gill, Hannah, Davies, Neil M, Peters, Alethea E, Wright, Ingram, and Pickering, Anthony E

Subjects
Anaesthesia Pain and Critical Care
Abstract

Background: Most common anesthetic agents have been implicated in causing neurodegeneration in the developing animal brain, leading to warnings regarding their use in children. We hypothesized that exposure to general anesthesia and surgery before 4y would associate with adverse neurodevelopmental outcomes at age 7-16y. Methods: This cohort study comprised 13,433 children enrolled in the Avon Longitudinal Study of Parents and Children – a prospective, population-based birth cohort born in 1991-1993 in South-West England. Children were grouped by none, single or multiple exposures to general anesthesia and surgery by 4y. Motor, cognitive, linguistic, educational, social and behavioral developmental outcomes were evaluated at 7-16y using school examination results, validated parent/teacher questionnaires or clinic assessments. Continuous outcomes were z-scored. P-value thresholds were corrected using false discovery rate procedures.Results: 46 neurodevelopmental outcomes were compared in 13,433 children: 8.3% (1,110)exposed singly and 1.6% (212) exposed multiply to general anesthesia and surgery. Of these,the following reached predefined levels of statistical significance (corrected P0.00652).Conclusions: Early childhood general anesthesia and surgery were not associated with a global picture of clinically and statistically significant neurodegenerative effects, providing reassurance about the neurotoxic potential of general anesthesia. Exposure to anesthesia and surgery was associated with significantly lower motor and social linguistic performance.

Published
2020

137. Mendelian randomization for studying the effects of perturbing drug targets

Author

Gill, Dipender, primary, Georgakis, Marios K., additional, Walker, Venexia M., additional, Schmidt, A. Floriaan, additional, Gkatzionis, Apostolos, additional, Freitag, Daniel F., additional, Finan, Chris, additional, Hingorani, Aroon D., additional, Howson, Joanna M.M., additional, Burgess, Stephen, additional, Swerdlow, Daniel I., additional, Davey Smith, George, additional, Holmes, Michael V., additional, Dichgans, Martin, additional, Scott, Robert A, additional, Zheng, Jie, additional, Psaty, Bruce M., additional, and Davies, Neil M., additional

Published
2021
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143. Cross-sectional analysis of educational inequalities in primary prevention statin use in UK Biobank.

Author

Carter, Alice Rose, Gill, Dipender, Smith, George Davey, Taylor, Amy E., Davies, Neil M., Howe, Laura D., and Davey Smith, George

Subjects
STATINS (Cardiovascular agents), CARDIOVASCULAR diseases, DYSLIPIDEMIA, EDUCATIONAL equalization, CROSS-sectional method
Abstract

Objective: Identify whether participants with lower education are less likely to report taking statins for primary cardiovascular prevention than those with higher education, but an equivalent increase in underlying cardiovascular risk.Methods: Using data from a large prospective cohort study, UK Biobank, we calculated a QRISK3 cardiovascular risk score for 472 097 eligible participants with complete data on self-reported educational attainment and statin use (55% female participants; mean age 56 years). We used logistic regression to explore the association between (i) QRISK3 score and (ii) educational attainment on self-reported statin use. We then stratified the association between QRISK3 score and statin use, by educational attainment to test for interactions.Results: There was evidence of an interaction between QRISK3 score and educational attainment. Per unit increase in QRISK3 score, more educated individuals were more likely to report taking statins. In women with ≤7 years of schooling, a one unit increase in QRISK3 score was associated with a 7% higher odds of statin use (OR 1.07, 95% CI 1.07 to 1.07). In women with ≥20 years of schooling, a one unit increase in QRISK3 score was associated with an 14% higher odds of statin use (OR 1.14, 95% CI 1.14 to 1.15). Comparable ORs in men were 1.04 (95% CI 1.04 to 1.05) for ≤7 years of schooling and 1.08 (95% CI 1.08, 1.08) for ≥20 years of schooling.Conclusion: Per unit increase in QRISK3 score, individuals with lower educational attainment were less likely to report using statins, likely contributing to health inequalities. [ABSTRACT FROM AUTHOR]

Published
2022
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146. Genetic Variation in Blood Pressure and Lifetime Risk of Peripheral Artery Disease: A Mendelian Randomization Study

Author

Levin, Michael G., primary, Klarin, Derek, additional, Walker, Venexia M., additional, Gill, Dipender, additional, Lynch, Julie, additional, Lee, Kyung M., additional, Assimes, Themistocles L., additional, Natarajan, Pradeep, additional, Hung, Adriana M., additional, Edwards, Todd, additional, Rader, Daniel J., additional, Gaziano, J. Michael, additional, Davies, Neil M., additional, Tsao, Philip S., additional, Chang, Kyong-Mi, additional, Voight, Benjamin F., additional, and Damrauer, Scott M., additional

Published
2020
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147. The causal effects of health conditions and risk factors on social and socioeconomic outcomes: Mendelian randomization in UK Biobank

Author

Harrison, Sean, primary, Davies, Alisha R, additional, Dickson, Matt, additional, Tyrrell, Jessica, additional, Green, Michael J, additional, Katikireddi, Srinivasa Vittal, additional, Campbell, Desmond, additional, Munafò, Marcus, additional, Dixon, Padraig, additional, Jones, Hayley E, additional, Rice, Frances, additional, Davies, Neil M, additional, and Howe, Laura D, additional

Published
2020
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