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Mediation analysis in epidemiology: methods, interpretation and bias

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TLDR
The impact of the three main sources of potential bias in the traditional approach to mediation analyses are reviewed and discussed: (i) mediator-outcome confounding; (ii) exposure-mediator interaction and (iii) mediATOR- outcome confounding affected by the exposure.
Abstract
In epidemiological studies it is often necessary to disentangle the pathways that link an exposure to an outcome. Typically the aim is to identify the total effect of the exposure on the outcome, the effect of the exposure that acts through a given set of mediators of interest (indirect effect) and the effect of the exposure unexplained by those same mediators (direct effect). The traditional approach to mediation analysis is based on adjusting for the mediator in standard regression models to estimate the direct effect. However, several methodological papers have shown that under a number of circumstances this traditional approach may produce flawed conclusions. Through a better understanding of the causal structure of the variables involved in the analysis, with a formal definition of direct and indirect effects in a counterfactual framework, alternative analytical methods have been introduced to improve the validity and interpretation of mediation analysis. In this paper, we review and discuss the impact of the three main sources of potential bias in the traditional approach to mediation analyses: (i) mediator-outcome confounding;(ii) exposure-mediator interaction and (iii) mediator-outcome confounding affected by the exposure. We provide examples and discuss the impact these sources have in terms of bias.

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References
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The moderator–mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations.

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Journal ArticleDOI

A new approach to causal inference in mortality studies with a sustained exposure period—application to control of the healthy worker survivor effect

TL;DR: A graphical approach to the identification and computation of causal parameters in mortality studies with sustained exposure periods is offered and an adverse effect of arsenic exposure on all-cause and lung cancer mortality which standard methods fail to detect is found.
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