A proposed clinical and biological interpretation of mediated interaction

Understanding of causal pathways in epidemiology involves the concepts of direct and indirect effects. Recently, causal mediation analysis has been formalized to quantify these direct and indirect effects in the presence of exposure–mediator interaction and even allows for four-way decomposition of the total effect: controlled direct effect, reference interaction, mediated interaction, pure indirect effect. Whereas the other three effects can be intuitively conceptualized, mediated interaction is often considered a nuisance in statistical analysis. In this paper, we focus on mediated interaction and contrast it against pure mediation. We also propose a clinical and biological interpretation of mediated interaction using three hypothetical examples. With these examples we aim to make researchers aware that mediated interaction can actually provide important clinical and biological information.