Guide to Decomposition of Causal Effects Into Mediation, Interaction, and Direct Effects

Mediation analysis can be applied in medical research with the aim of understanding the pathways that operate between an exposure and its effects on an outcome. This method can help to improve our understanding of pathophysiologic mechanisms and may guide the choice of potential treatment strategies. Traditional mediation analysis decomposes the total effect of an intervention on the outcome into 2 effects: (1) an indirect effect, from exposure using a mediator to the outcome, and (2) a direct effect, directly from exposure to outcome. A limitation of this method is that it assumes no interaction between the exposure and the mediator, which can either lead to an over- or underestimation of clinically relevant effects. The "4-way decomposition" method has the advantage of overcoming this limitation. Specifically, the total effect of an exposure on the outcome is decomposed into 4 elements: (1) reference interaction (interaction only), (2) mediated interaction (mediation and interaction), (3) the pure indirect effect (mediation but not interaction), and (4) the direct effect (no mediation and no interaction). We provide a guide to select the most appropriate method to investigate and decompose any causal effect given the research question at hand. We explain the application of the 4-way decomposition and illustrate this with a real-world example of how aerobic exercise may influence motor function in persons with Parkinson disease.