Randomized interventional effects in semicompeting risks, with application to a hematopoietic cell transplantation study

TL;DR

This paper extends the randomized interventional approach to semicompeting risks in clinical studies, enabling decomposition of treatment effects on terminal events mediated by intermediate events, with application to hematopoietic cell transplantation.

Contribution

It introduces a new methodology for analyzing treatment effects in semicompeting risks with censored time-to-event data, including identification formulas and estimation techniques.

Findings

Matched unrelated donor transplantation improves survival rates.

The proposed method effectively decomposes direct and indirect treatment effects.

Sensitivity analysis accounts for latent frailty in the model.

Abstract

In clinical studies, the risk of the primary (terminal) event may be modified by intermediate events, resulting in semicompeting risks. To study the treatment effect on the terminal event mediated by the intermediate event, researchers wish to decompose the total effect into direct and indirect effects. In this article, we extend the randomized interventional approach to time-to-event outcomes, where both intermediate and terminal events are subject to right censoring. We envision a random draw for the intermediate event process from a reference distribution, either marginally over time-varying confounders or conditionally given the observed history. We present the identification formula for interventional effects. We also discuss some variants of the identification assumptions. We estimate the treatment effects using nonparametric maximum likelihood estimation and propose a sensitivity analysis that incorporates a latent frailty. As an illustration, we study the effect of matched unrelated donor versus haploidentical donor on death mediated by relapse in a hematopoietic cell transplantation study with graft-versus-host disease (GVHD) as the time-varying confounder. We find that matched unrelated donor transplantation is preferable in terms of survival rates under the use of post-transplant PTCy GVHD prophylaxis for lymphoma patients.