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Eur J Epidemiol. 2015 Oct;30(10):1115-8. doi: 10.1007/s10654-015-0087-5. Epub 2015 Oct 5.

A proposed clinical and biological interpretation of mediated interaction.

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Departments of Epidemiology, Neurology, and Radiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
Departments of Epidemiology and Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA.


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.


Causal inference; Clinical medicine; Direct effect; Four-way decomposition; Indirect effect; Mediated interaction; Mediation; Total effect

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