Estimation of causal effects of a time-varying exposure at multiple time points through multivariable mendelian randomization.

Mendelian Randomisation (MR) is a powerful tool in epidemiology that can be used to estimate the causal effect of an exposure on an outcome in the presence of unobserved confounding, by utilising genetic variants as instrumental variables (IVs) for the exposure. The effect estimates obtained from MR studies are often interpreted as the lifetime effect of the exposure in question. However, the causal effects of some exposures are thought to vary throughout an individual's lifetime with periods during which an exposure has a greater effect on a particular outcome. Multivariable MR (MVMR) is an extension of MR that allows for multiple, potentially highly related, exposures to be included in an MR estimation. MVMR estimates the direct effect of each exposure on the outcome conditional on all the other exposures included in the estimation. We explore the use of MVMR to estimate the direct effect of a single exposure at different time points in an individual's lifetime on an outcome. We use simulations to illustrate the interpretation of the results from such analyses and the key assumptions required. We show that causal effects at different time periods can be estimated through MVMR when the association between the genetic variants used as instruments and the exposure measured at those time periods varies. However, this estimation will not necessarily identify exact time periods over which an exposure has the most effect on the outcome. Prior knowledge regarding the biological basis of exposure trajectories can help interpretation. We illustrate the method through estimation of the causal effects of childhood and adult BMI on C-Reactive protein and smoking behaviour. Author summary: Mendelian Randomisation (MR) can be used to estimate whether a potential exposure has a causal effect on an outcome in the presence of a third (unobserved) variable that affects both of them and so biases the observed association between them. The effect estimates obtained from MR studies can be interpreted as the effect of the exposure on the outcome over the lifetime. However, for some exposures there may be periods during which the causal effect on an outcome is greater or lesser than other periods. Multivariable MR (MVMR) is an extension of MR that allows for estimation of the causal effect of multiple, potentially highly related, exposures. In this paper we investigate how MVMR can be used to estimate the causal effect of the same exposure at different points across the lifecourse. We show that these effects can be estimated through MVMR when the association between the genetic variants used as instruments and the exposure varies between measurements of the exposures. However, we find that this estimation will not necessarily identify exact time periods over which an exposure has the most effect on the outcome as different periods in the lifecourse can only be separated when they are differently associated with genetic variants. [ABSTRACT FROM AUTHOR]