Using Mendelian randomization to determine causal effects of maternal pregnancy (intrauterine) exposures on offspring outcomes: Sources of bias and methods for assessing them

Lawlor, Deborah, Richmond, Rebecca, Warrington, Nicole , McMahon, George, Davery Smith, George, Bowden, Jack and Evans, David M. (2017) Using Mendelian randomization to determine causal effects of maternal pregnancy (intrauterine) exposures on offspring outcomes: Sources of bias and methods for assessing them. Wellcome Open Research, 2 11: . doi:10.12688/wellcomeopenres.10567.1


Author Lawlor, Deborah
Richmond, Rebecca
Warrington, Nicole
McMahon, George
Davery Smith, George
Bowden, Jack
Evans, David M.
Title Using Mendelian randomization to determine causal effects of maternal pregnancy (intrauterine) exposures on offspring outcomes: Sources of bias and methods for assessing them
Journal name Wellcome Open Research   Check publisher's open access policy
ISSN 2398-502X
Publication date 2017-02-14
Sub-type Article (original research)
DOI 10.12688/wellcomeopenres.10567.1
Open Access Status DOI
Volume 2
Issue 11
Total pages 23
Place of publication London, United Kingdom
Publisher F1000 Research
Collection year 2018
Language eng
Abstract Mendelian randomization (MR), the use of genetic variants as instrumental variables (IVs) to test causal effects, is increasingly used in aetiological epidemiology. Few of the methodological developments in MR have 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, we describe specific ways in which the IV assumptions might be violated when MR is used to test such intrauterine effects. We highlight the importance of 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 mothers. Where there is overlap, and particularly if it generates a strong association of maternal genetic IVs with offspring outcome via the offspring genotype, the exclusion restriction assumption of IV analyses will be violated. We recommend a set of analyses that ought to be considered when MR is used to address research questions concerned with intrauterine effects on post-natal offspring outcomes, and provide details of how these can be undertaken and interpreted. These additional analyses include the use of genetic data from offspring and fathers, examining associations using maternal non-transmitted alleles, and using simulated data in sensitivity analyses (for which we provide code). We explore the extent to which new methods that have been developed for exploring violation of the exclusion restriction assumption in the two-sample setting (MR-Egger and median based methods) might be used when exploring intrauterine effects in one-sample MR. We provide a list of recommendations that researchers should use when applying MR to test the effects of intrauterine exposures on postnatal offspring outcomes and use an illustrative example with real data to demonstrate how our recommendations can be applied and subsequent results appropriately interpreted.
Keyword ALSPAC
Causality
Mendelian randomization
Developmental Origins
intrauterine effects
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute - Open Access Collection
UQ Diamantina Institute Publications
 
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Created: Fri, 21 Apr 2017, 11:24:00 EST by Kylie Hengst on behalf of Research Strategy and Support (Medicine)