Mediation analysis when a continuous mediator is measured with error and the outcome follows a generalized linear model

Mediation analysis is a popular approach to examine the extent to which the effect of an exposure on an outcome is through an intermediate variable (mediator) and the extent to which the effect is direct. When the mediator is mis-measured, the validity of mediation analysis can be severely undermined. In this paper, we first study the bias of classical, non-differential measurement error on a continuous mediator in the estimation of direct and indirect causal effects in generalized linear models when the outcome is either continuous or discrete and exposure-mediator interaction may be present. Our theoretical results as well as a numerical study demonstrate that in the presence of non-linearities, the bias of naive estimators for direct and indirect effects that ignore measurement error can take unintuitive directions. We then develop methods to correct for measurement error. Three correction approaches using method of moments, regression calibration, and SIMEX are compared. We apply the proposed method to the Massachusetts General Hospital lung cancer study to evaluate the effect of genetic variants mediated through smoking on lung cancer risk. Copyright (C) 2014 John Wiley & Sons, Ltd.