Using multistate models with clinical trial data for a deeper understanding of complex disease processes

Abstract

A clinical trial represents a large commitment from all individuals involved and a huge financial obligation given its high cost; therefore, it is wise to make the most of all collected data by learning as much as possible. A multistate model is a generalized framework to describe longitudinal events; multistate hazards models can treat multiple intermediate/final clinical endpoints as outcomes and estimate the impact of covariates simultaneously. Proportional hazards models are fitted (one per transition), which can be used to calculate the absolute risks, that is, the probability of being in a state at a given time, the expected number of visits to a state, and the expected amount of time spent in a state. Three publicly available clinical trial datasets, colon, myeloid, and rhDNase, in the survival package in R were used to showcase the utility of multistate hazards models. In the colon dataset, a very well-known and well-used dataset, we found that the levamisole+fluorouracil treatment extended time in the recurrence-free state more than it extended overall survival, which resulted in less time in the recurrence state, an example of the classic “compression of morbidity.” In the myeloid dataset, we found that complete response (CR) is durable, patients who received treatment B have longer sojourn time in CR than patients who received treatment A, while the mutation status does not impact the transition rate to CR but is highly influential on the sojourn time in CR. We also found that more patients in treatment A received transplants without CR, and more patients in treatment B received transplants after CR. In addition, the mutation status is highly influential on the CR to transplant transition rate. The observations that we made on these three datasets would not be possible without multistate models. We want to encourage readers to spend more time to look deeper into clinical trial data. It has a lot more to offer than a simple yes/no answer if only we, the statisticians, are willing to look for it.