Quantifying direct and indirect effect for longitudinal mediator and survival outcome using joint modeling approach

Longitudinal biomarkers are widely used in biomedical and translational researches to monitor the progressions of diseases. Methods have been proposed to jointly model longitudinal data and survival data, but its causal mechanism is yet to be investigated rigorously. Understanding how much of the total treatment effect is through the biomarker is important in understanding the treatment mechanism and evaluating the biomarker. In this work, we propose a causal mediation analysis method to compute the direct and indirect effects, when a joint modeling approach is used to take the longitudinal biomarker as the mediator and the survival endpoint as the outcome. Such a joint modeling approach allows us to relax the commonly used “sequential ignorability” assumption. We demonstrate how to evaluate longitudinally measured biomarkers using our method with two case studies, an AIDS study and a liver cirrhosis study.