Modeling two-state disease processes with random effects

Many chronic medical conditions are manifested by alternating sojourns in symptom-free and symptomatic states. In many cases, in addition to their relapsing and remitting nature, these conditions lead to worsening disease patterns over time and may exhibit seasonal trends. We develop a mixed-effect two-state model for such disease processes in which covariate effects are modeled multiplicatively on transition intensities. The transition intensities, in turn, are functions of three time scales: the semi-Markov scale involving the backward recurrence time for the cyclical component, the Markov scale for the time trend component, and a seasonal time scale. Multiplicative bivariate log-normal random effects are introduced to accommodate heterogeneity in disease activity between subjects and to admit a possible negative correlation between the transition intensities. Maximum likelihood estimation is carried out using Gauss-Hermite integration and a standard Newton-Raphson procedure. Tests of homogeneity are presented based on score statistics. An application of the methodology to data from a multi-center clinical trial of chronic bronchitis is provided for illustrative purposes.