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Intrauterine Wellcome Open Research 2017, 2:11 Last updated: 13 JUN 2018 RESEARCH ARTICLE Using Mendelian randomization to determine causal effects of maternal pregnancy (intrauterine) exposures on offspring outcomes: Sources of bias and methods for assessing them [version 1; referees: 4 approved] Deborah Lawlor 1,2, Rebecca Richmond1,2, Nicole Warrington3,4, George McMahon2, George Davey Smith 1,2, Jack Bowden1,2, David M Evans1,3 1Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK 2School of Social and Community Medicine, University of Bristol, Bristol, UK 3University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia 4School of Women’s and Infants’ Health, The University of Western Australia, Perth, Australia v1 First published: 14 Feb 2017, 2:11 (doi: 10.12688/wellcomeopenres.10567.1) Open Peer Review Latest published: 14 Feb 2017, 2:11 (doi: 10.12688/wellcomeopenres.10567.1) Referee Status: Abstract Mendelian randomization (MR), the use of genetic variants as instrumental variables (IVs) to test causal effects, is increasingly used in aetiological Invited Referees epidemiology. Few of the methodological developments in MR have 1 2 3 4 considered the specific situation of using genetic IVs to test the causal effect of exposures in pregnant women on postnatal offspring outcomes. In this paper, version 1 we describe specific ways in which the IV assumptions might be violated when published report report report report MR is used to test such intrauterine effects. We highlight the importance of 14 Feb 2017 considering the extent to which there is overlap between genetic variants in offspring that influence their outcome with genetic variants used as IVs in their Brandon L. Pierce, University of Chicago, mothers. Where there is overlap, and particularly if it generates a strong 1 association of maternal genetic IVs with offspring outcome via the offspring USA genotype, the exclusion restriction assumption of IV analyses will be violated. 2 C. Mary Schooling, The University of We recommend a set of analyses that ought to be considered when MR is used Hong Kong, Hong Kong to address research questions concerned with intrauterine effects on post-natal offspring outcomes, and provide details of how these can be undertaken and 3 Lorenzo Richiardi, University of Turin, interpreted. These additional analyses include the use of genetic data from Italy offspring and fathers, examining associations using maternal non-transmitted alleles, and using simulated data in sensitivity analyses (for which we provide Maja Popovic , University of Turin, code). We explore the extent to which new methods that have been developed Italy for exploring violation of the exclusion restriction assumption in the two-sample Sridharan Raghavan, Eastern Colorado setting (MR-Egger and median based methods) might be used when exploring 4 intrauterine effects in one-sample MR. We provide a list of recommendations Healthcare System, USA that researchers should use when applying MR to test the effects of intrauterine exposures on postnatal offspring outcomes and use an illustrative example with Discuss this article real data to demonstrate how our recommendations can be applied and subsequent results appropriately interpreted. Comments (0) Keywords Causality, developmental origins, intrauterine effects, Mendelian randomization, ALSPAC Page 1 of 23 Wellcome Open Research 2017, 2:11 Last updated: 13 JUN 2018 This article is included in the Avon Longitudinal Study of Parents and Children (ALSPAC) gateway. Corresponding author: Deborah Lawlor ([email protected]) Competing interests: No competing interests were disclosed. How to cite this article: Lawlor D, Richmond R, Warrington N et al. Using Mendelian randomization to determine causal effects of maternal pregnancy (intrauterine) exposures on offspring outcomes: Sources of bias and methods for assessing them [version 1; referees: 4 approved] Wellcome Open Research 2017, 2:11 (doi: 10.12688/wellcomeopenres.10567.1) Copyright: © 2017 Lawlor D et al. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Grant information: The work was supported by the Wellcome Trust [WT088806]; the European Research Council under the European Union’s Seventh Framework Programme [FP7/2007-2013/ERC grant agreement no 669545]; the US National Institute of Health [R01 DK10324]. The UK Medical Research Council and Wellcome Trust [102215/2/13/2] and the University of Bristol provide core support for ALSPAC. DAL, RCR, JB, GDS and DME work in a unit that receives funds from the University of Bristol and the UK Medical Research Council [MC_UU_12013/1; MC_UU_12013/4; MC_UU_12013/5]. DAL is a National Institute of Health Research Senior Investigator [NF-SI-0611-10196]. NMW is supported by a National Health and Medical Research Council Early Career Fellowship [APP1104818]. JB is a Medical Research Council Methodology Research Fellow [MR/N501906/1]. DME is supported by an Australian Research Council Future Fellowship [FT130101709]. RCR is funded by a CRUK programme grant [C18281/A19169]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. First published: 14 Feb 2017, 2:11 (doi: 10.12688/wellcomeopenres.10567.1) Page 2 of 23 Wellcome Open Research 2017, 2:11 Last updated: 13 JUN 2018 Introduction causal understanding has been achieved through proof-of-concept The possibility that a wide-range of maternal pregnancy exposures, studies, such as those confirming the causal effects of greater such as her gestational adiposity, smoking, diet and mental health, body mass index (BMI)11, systolic blood pressure12, and low have long-term effects on an equally wide-range of post-natal off- density lipoprotein cholesterol (LDLc) on coronary heart dis- spring outcomes has gained such traction that it is influencing ante- ease (CHD)13,14, and of smoking intensity and duration on lung natal care. For example, the Independent Association of Diabetes cancer15–17, as well as concerted efforts by researchers using and Pregnancy Study Groups (IADPSG) criteria for diagnosing MR to acknowledge its underlying assumptions and how these gestational diabetes, which have been adopted by the World Health might be violated, together with the development of methods to test Organisation and many other national and international policy assumption violations and/or be able to relax these3–5,18–24. and guideline groups, aim to identify women whose children are at risk of future obesity, in order to ultimately prevent childhood Methods to improve causal understanding of intrauterine expo- obesity though antenatal care1. However, evidence that the proxy sures on offspring outcomes are important, given the likelihood measures used by IADPSG developers to indicate offspring obes- for residual confounding in conventional multivariable analyses, ity (high birthweight, birth skinfolds and cord-blood c-peptide) and the infeasibility, or marked difficulty, of using RCTs to test are accurate predictors of future risk of childhood obesity, or that effects of maternal pregnancy exposures on long-term offspring treating women with the IADPSG criteria will effectively reduce outcomes2. The first paper to describe the MR method, highlighted childhood obesity, is lacking. In other areas women’s lifestyle in the value of having genetic (MTHFR) data on trios (both parents pregnancy is potentially being blamed for all future health risks in and offspring) when using MR to test the intrauterine effects of her offspring. It is essential, therefore, that methods are developed folic acid on offspring neural tube defects3. However, the majority that can provide valid causal answers to questions about the long- of methodological developments in MR have not considered the term effects of intrauterine exposures. However, conventional case, where maternal genetic variants are used as IVs to test methods are unlikely to be suitable; conventional approaches the effect of a pregnancy (intrauterine) exposure on offspring applied to cohort study data are likely to be influenced by outcomes. The aim of this paper is to describe specific ways residual confounding, and it is infeasible or extremely difficult in which the MR assumptions might be violated in studies con- to undertake randomised controlled trials (RCTs) of the effects cerning the effect of maternal pregnancy exposures on offspring of maternal pregnancy exposures on long-term offspring outcomes, and to provide recommendations for how to test and outcomes2. potentially reduce the biases that might result from these assumption violations. Mendelian randomization (MR), the use of genetic vari- ants as instrumental variables (IVs) to test causal effects3–5, is Mendelian randomization assumptions and increasingly used in aetiological epidemiology, including to assessing causal intrauterine effects test the effects of intrauterine exposures on long-term offspring Figure 1 shows the key IV assumptions as they apply to MR stud- outcomes6–10. Increased confidence in the use of MR to improve ies of maternal pregnancy exposures on offspring outcomes. We Figure 1. Directed Acyclic Graph of use of Mendelian randomization to assess developmental origins (intrauterine) causal effects on offspring outcomes. Page 3 of 23 Wellcome Open Research 2017,
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