Selection bias in Mendelian randomization studies with adjustment for medication use

Background. Mendelian randomization (MR) studies often evaluate exposures such as LDL cholesterol (LDL-C). The widespread use of lipid lowering medications complicates the interpretation and the validity of MR estimates. Methods. We describe two causal estimands in populations with medication use: a lifetime effect, and a lifetime effect under no medication use. In simulations, we compared the common approach of excluding medication users with estimation based on inverse probability (IP) weighting to adjust for medication use. We applied both approaches to a MR analysis of LDL-C and coronary artery disease in the Million Veteran Program (MVP), a large prospective cohort of U.S. veterans with linked electronic health record and genetic data. Results. In simulations, MR analyses that did not adjust for medication use estimated a lifetime effect that reflected a valid estimate of a total effect that included both the harms of higher LDL-C and the benefits of statins. To estimate the effect under no medication use, excluding statin users introduced selection bias. Alternatively, IP weighting could address bias from incident statin users, but could not address bias related to prevalent medication use. Estimates from MVP data varied considerably, reflecting the importance of these analytic choices. Conclusions. Different medication adjustment strategies in MR studies implicitly target different causal estimands and are subject to distinct biases. Transparent analytical choices and careful interpretation are essential for informative MR results in the context of widespread medication use.