A path-specific effect approach to mediation analysis with time-varying mediators and time-to-event outcomes accounting for competing risks

TL;DR

This paper introduces a novel path-specific effects framework for mediation analysis in survival data with competing risks, enabling more accurate causal inference by modeling competing events as mediators.

Contribution

It presents the first formal approach to mediation analysis with competing risks, using the mediational g-formula and a detailed algorithm implementation.

Findings

Applied to the Strong Heart Study data on arsenic and cadmium exposure.

Quantified the mediating role of blood pressure in cardiovascular risk.

Demonstrated the importance of accounting for competing risks in causal mediation analysis.

Abstract

Not accounting for competing events in survival analysis can lead to biased estimates, as individuals who die from other causes do not have the opportunity to develop the event of interest. Formal definitions and considerations for causal effects in the presence of competing risks have been published, but not for the mediation analysis setting. We propose, for the first time, an approach based on the path-specific effects framework to account for competing risks in longitudinal mediation analysis with time-to-event outcomes. We do so by considering the pathway through the competing event as another mediator, which is nested within our longitudinal mediator of interest. We provide a theoretical formulation and related definitions of the effects of interest based on the mediational g-formula, as well as a detailed description of the algorithm. We also present an application of our algorithm to data from the Strong Heart Study, a prospective cohort of American Indian adults. In this application, we evaluated the mediating role of the blood pressure trajectory (measured during three visits) on the association between arsenic and cadmium, in separate models, with time to cardiovascular disease, accounting for competing risks by death. Identifying the effects through different paths enables us to evaluate the impact of metals on the outcome of interest, as well as through competing risks, more transparently.