A multistate approach for mediation analysis in the presence of semi-competing risks with application in cancer survival disparities

Abstract: We propose a novel methodology to quantify the effect of stochastic interventions on non-terminal time-to-events that lie on the pathway between an exposure and a terminal time-to-event outcome. Investigating these effects is particularly important in health disparities research when we seek to quantify inequities in timely delivery of treatment and its impact on patients survival time. Current approaches fail to account for semi-competing risks arising in this setting. Under the potential outcome framework, we define and provide identifiability conditions for causal estimands for stochastic direct and indirect effects. Causal contrasts are estimated in continuous time within a multistate modeling framework and analytic formulae for the estimators of the causal contrasts are developed. We show via simulations that ignoring censoring in mediator and or outcome time-to-event processes, or ignoring competing risks may give misleading results. This work demonstrates that rigorous definition of the direct and indirect effects and joint estimation of the outcome and mediator time-to-event distributions in the presence of semi-competing risks are crucial for valid investigation of mechanisms in continuous time. We employ this novel methodology to investigate the role of delaying treatment uptake in explaining racial disparities in cancer survival in a cohort study of colon cancer patients.