Mediation model with a categorical exposure and a censored mediator with application to a genetic study

Mediation analysis is a statistical method for evaluating the direct and indirect effects of an exposure on an outcome in the presence of a mediator. Mediation models have been widely used to determine direct and indirect contributions of genetic variants in clinical phenotypes. In genetic studies, the additive genetic model is the most commonly used model because it can detect effects from either recessive or dominant models (or any model in between). However, the existing approaches for mediation model cannot be directly applied when the genetic model is additive (e.g. the most commonly used model for SNPs) or categorical (e.g. polymorphic loci), and thus modification to measures of indirect and direct effects is warranted. In this study, we proposed overall measures of indirect, direct, and total effects for a mediation model with a categorical exposure and a censored mediator, which accounts for the frequency of different values of the categorical exposure. The proposed approach provides the overall contribution of the categorical exposure to the outcome variable. We assessed the empirical performance of the proposed overall measures via simulation studies and applied the measures to evaluate the mediating effect of a women’s age at menopause on the association between genetic variants and type 2 diabetes.