Almost exact Mendelian randomization

Mendelian randomization (MR) is an observational design based on the random transmission of genes from parents to offspring. However, this inferential basis is typically only implicit or used as an informal justification. As parent-offspring data becomes more widely available, we advocate a different approach to MR that is exactly based on this randomization, making explicit the common analogy between MR and a randomized controlled trial. We begin by developing a causal graphical framework for MR which formalizes several biological processes and phenomena, including population structure, gamete formation, fertilization, genetic linkage, and pleiotropy. This causal graph is then used to detect biases in the MR design and identify sufficient confounder adjustment sets to correct them. We then propose a randomization test for causal hypotheses in the MR design by using precisely the exogenous randomness in meiosis and fertilization. We term this "almost exact MR", because exactness of the inference depends on precisely knowing the distribution of offspring haplotypes resulting from meioses in one or both parents, which is widely studied in genetics. We demonstrate via simulation that propensity scores obtained from the underlying meiosis model can form powerful test statistics. Besides transparency and conceptual appeals, our approach also offers some practical advantages, including lack of commitment to a particular phenotype model, robustness to weak instruments, and eliminating bias that may arise from population structure, assortative mating, dynastic effects and linkage disequilibrium with pleiotropic variants. We conclude with a negative and positive control analysis in the Avon Longitudinal Study of Parents and Children using our R package almostexactmr (https://github.com/matt-tudball/almostexactmr).