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Title: MR genius: A principled approach to robust Mendelian randomization inference Authors:  Eric Tchetgen Tchetgen - The Wharton School, University of Pennsylvania (United States) [presenting]
Abstract: Mendelian randomization (MR) is a popular instrumental variable (IV) approach, in which one or several genetic markers serve as IVs that can sometimes be leveraged to recover valid inferences about a given exposure-outcome causal association subject to unmeasured confounding. A key IV identification condition known as the exclusion restriction states that the IV cannot have a direct effect on the outcome which is not mediated by the exposure in view. In MR studies, such an assumption requires an unrealistic level of prior knowledge about the mechanism by which genetic markers causally affect the outcome. As a result, possible violation of the exclusion restriction due to pleiotropic genetic effects can seldom be ruled out in practice. To address this concern, we introduce a new class of IV estimators which are robust to violation of the exclusion restriction under data generating mechanisms commonly assumed in MR literature. The proposed approach named "MR G-Estimation under No Interaction with Unmeasured Selection" (MR GENIUS) improves on Robins' G-estimation by making it robust to both additive unmeasured confounding and violation of the exclusion restriction assumption. Time permitting we will also discuss a many weak invalid IV MR GENIUS approach which appropriately accounts for the fact that in addition to violations due to pleiotropic effects, genetic IVs typically only exhibit a weak effect on phenotypes defining the exposure of interest.