Interpretation and potential biases of Mendelian randomization estimates with time-varying exposures

Abstract

Mendelian randomization (MR) is used to answer a variety of epidemiologic questions. One stated advantage of MR is that it estimates a "lifetime effect" of exposure though this term remains vaguely-defined. Instrumental variable analysis, on which MR is based, has focused on estimating the effects of point or time-fixed exposures rather than "lifetime effects". We use an empirical example with data from the Rotterdam Study to demonstrate how confusion can arise when estimating "lifetime effects". We provide one possible definition of a lifetime effect: the average change in outcome measured at time t when the entire exposure trajectory from conception to time t is shifted by one unit. We show that MR only estimates this type of lifetime effect under specific conditions, for example when the effect of the genetic variants used on exposure do not change over time (which many genetic variants commonly used in MR do). Lastly, we simulate the magnitude of bias that would result in realistic scenarios that use genetic variants with effects that change over time. We recommend future MR studies carefully consider the effect of interest and how genetic variants whose effects change with time may impact the interpretability and validity of their results.