A semi-markov model for clinical trials

Abstract

This paper applies the theory of semi-Markov processes to the construction of a stochastic model for interpreting data obtained from clinical trials. The model characterizes the patient as being in one of a finite number of states at any given time with an arbitrary probability distribution to describe the length of stay in a state. Transitions between states are assumed to be chosen according to a stationary finite Markov chain.Other attempts have been made to develop stochastic models of clinical trials. However, these have all been essentially Markovian with constant transition probabilities which implies that the distribution of time spent during a visit to a state is exponential (or geometric for discrete Markov chains). Markov models need also to assume that the transitions in the state of a patient depend only on absolute time whereas the semi-Markov model assumes that transitions depend on time relative to a patient. Thus the models are applicable to degenerative diseases (cancer, acute leukemia), while Markov models with time dependent transition probabilities are applicable to colds and epidemic diseases. In this paper the Laplace transforms are obtained for (i) probability of being in a state at timet, (ii) probability distribution to reach absorption state and (iii) the probability distribution of the first passage times to go from initial states to transient or absorbing states, transient to transient, and transient to absorbing. The model is applied to a clinical study of acute leukemia in which patients have been treated with methotrexate and 6-mercaptopurine. The agreement between the data and the model is very good.