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. 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-transplantation PTCy GVHD prophylaxis for lymphoma patients.

翻译：在临床研究中，主要（终末）事件的风险可能受到中间事件的影响，从而形成半竞争风险。为研究治疗通过中间事件对终末事件产生的效应，研究者希望将总效应分解为直接效应与间接效应。本文将随机干预方法拓展至生存时间结局，其中中间事件与终末事件均存在右删失。我们设想从某个参考分布中随机抽取中间事件过程，该参考分布可基于时变混杂变量的边际分布构建，也可基于观测历史的条件分布构建。我们给出了干预效应的识别公式，并讨论了识别假设的若干变体。我们采用非参数最大似然估计方法估计处理效应，并提出了敏感性分析方案。在一项以移植物抗宿主病（GVHD）作为时变混杂因素的造血细胞移植研究中，我们分析了匹配无关供者与单倍体相合供者对死亡风险的影响（以复发为中介变量）。研究发现，对于接受移植后PTCy GVHD预防治疗的淋巴瘤患者，匹配无关供者移植在生存率方面更具优势。