Joint regression analysis for survival data in the presence of two sets of semi-competing risks

In many clinical trials, multiple time-to-event endpoints including the primary endpoint (e.g., time to death) and secondary endpoints (e.g., progression-related endpoints) are commonly used to determine treatment efficacy. These endpoints are often biologically related. This work is motivated by a study of bone marrow transplant (BMT) for leukemia patients, who may experience the acute graft-versus-host disease (GVHD), relapse of leukemia, and death after an allogeneic BMT. The acute GVHD is associated with the relapse free survival, and both the acute GVHD and relapse of leukemia are intermediate nonterminal events subject to dependent censoring by the informative terminal event death, but not vice versa, giving rise to survival data that are subject to two sets of semi-competing risks. It is important to assess the impacts of prognostic factors on these three time-to-event endpoints. We propose a novel statistical approach that jointly models such data via a pair of copulas to account for multiple dependence structures, while the marginal distribution of each endpoint is formulated by a Cox proportional hazards model. We develop an estimation procedure based on pseudo-likelihood and carry out simulation studies to examine the performance of the proposed method in finite samples. The practical utility of the proposed method is further illustrated with data from the motivating example.