In this dissertation, we are interested in studying processes which generate events repeatedly over the follow-up time of a given subject. Such processes are called recurrent event processes and the data they provide are referred to as recurrent event data. Examples include the cancer recurrences, recurrent infections or disease episodes, hospital readmissions, the filing of warranty claims, and insurance claims for policy holders. In particular, we focus on the multi-type recurrent event times which usually arise when two or more different kinds of events may occur repeatedly over a period of observation. Our main objectives are to describe features of each marginal process simultaneously and study the dependence among different types of events. We present applications to a real dataset collected from the Nutritional Prevention of Cancer Trial. The objective of the clinical trial was to evaluate the efficacy of Selenium in preventing the recurrence of several types of skin cancer among 1312 residents of the Eastern United States. Four chapters are involved in this dissertation. Chapter 1 introduces a brief background to the statistical techniques used to develop the proposed methodology. We cover some concepts and useful functions related to survival data analysis and present a short introduction to frailty distributions. The Monte Carlo expectation maximization (MCEM) algorithm and copula functions for the multivariate variables are also presented in this chapter. Chapter 2 develops a multi-type recurrent events model with multivariate Gaussian random effects (frailties) for the intensity functions. In this chapter, we present nonparametric baseline intensity functions and a multivariate Gaussian distribution for the multivariate correlated random effects. An MCEM algorithm with MCMC routines in the E-step is adopted for the partial likelihood to estimate model parameters. Equations for the variances of the estimates are derived and variances of estimates are computed by Louis' formula. Predictions of the individual random effects are obtained because in some applications the magnitude of the random effects is of interest for a better understanding and interpretation of the variability in the data. The performance of the proposed methodology is evaluated by simulation studies, and the developed model is applied to the skin cancer dataset. Chapter 3 presents copula-based semiparametric multivariate frailty models for multi-type recurrent event data with applications to the skin cancer data. In this chapter, we generalize the multivariate Gaussian assumption of the frailty terms and allow the frailty distributions to have more features than the symmetric, unimodal properties of the Gaussian density. More flexible approaches to modeling the correlated frailty, referred to as copula functions, are introduced. Copula functions provide tremendous flexibility especially in allowing taking the advantages of a variety of choices for the marginal distributions and correlation structures. Semiparametric intensity models for multi-type recurrent events based on a combination of the MCEM with MCMC sampling methods and copula functions are introduced. The combination of the MCEM approach and copula function is flexible and is a generally applicable approach for obtaining inferences of the unknown parameters for high dimension frailty models. Estimation procedures for fixed effects, nonparametric baseline intensity functions, copula parameters, and predictions for the subject-specific multivariate frailties and random effects are obtained. Louis' formula for variance estimates are derived and calculated. We investigate the impact of the specification of the frailty and random effect models on the inference of covariate effects, cumulative baseline intensity functions, prediction of random effects and frailties, and the estimation of the variance-covariance components. Performances of proposed models are evaluated by simulation studies. Applications are illustrated through the dataset collected from the clinical trial of patients with skin cancer. Conclusions and some remarks for future work are presented in Chapter 4. / Ph. D.

I have developed time-varying coefficient models for recurrent event data to evaluate the temporal profiles for recurrence rate and covariate effects. There are three major parts in this dissertation. The first two parts propose a mixed Poisson process model with gamma frailties for single type recurrent events. The third part proposes a Bayesian joint model based on multivariate log-normal frailties for multi-type recurrent events. In the first part, I propose an approach based on penalized B-splines to obtain smooth estimation for both time-varying coefficients and the log baseline intensity. An EM algorithm is developed for parameter estimation. One issue with this approach is that the estimating procedure is conditional on smoothing parameters, which have to be selected by cross-validation or optimizing certain performance criterion. The procedure can be computationally demanding with a large number of time-varying coefficients. To achieve objective estimation of smoothing parameters, I propose a mixed-model representation approach for penalized splines. Spline coefficients are treated as random effects and smoothing parameters are to be estimated as variance components. An EM algorithm embedded with penalized quasi-likelihood approximation is developed to estimate the model parameters. The third part proposes a Bayesian joint model with time-varying coefficients for multi-type recurrent events. Bayesian penalized splines are used to estimate time-varying coefficients and the log baseline intensity. One challenge in Bayesian penalized splines is that the smoothness of a spline fit is considerably sensitive to the subjective choice of hyperparameters. I establish a procedure to objectively determine the hyperparameters through a robust prior specification. A Markov chain Monte Carlo procedure based on Metropolis-adjusted Langevin algorithms is developed to sample from the high-dimensional distribution of spline coefficients. The procedure includes a joint sampling scheme to achieve better convergence and mixing properties. Simulation studies in the second and third part have confirmed satisfactory model performance in estimating time-varying coefficients under different curvature and event rate conditions. The models in the second and third part were applied to data from a commercial truck driver naturalistic driving study. The application results reveal that drivers with 7-hours-or-less sleep prior to a shift have a significantly higher intensity after 8 hours of on-duty driving and that their intensity remains higher after taking a break. In addition, the results also show drivers' self-selection on sleep time, total driving hours in a shift, and breaks. These applications provide crucial insight into the impact of sleep time on driving performance for commercial truck drivers and highlights the on-road safety implications of insufficient sleep and breaks while driving. This dissertation provides flexible and robust tools to evaluate the temporal profile of intensity for recurrent events. / PHD / The overall objective of this dissertation is to develop models to evaluate the time-varying profiles for event occurrences and the time-varying effects of risk factors upon event occurrences. There are three major parts in this dissertation. The first two parts are designed for single event type. They are based on approaches such that the whole model is conditional on a certain kind of tuning parameter. The value of this tuning parameter has to be pre-specified by users and is influential to the model results. Instead of pre-specifying the value, I develop an approach to achieve an objective estimate for the optimal value of tuning parameter and obtain model results simultaneously. The third part proposes a model for multi-type events. One challenge is that the model results are considerably sensitive to the subjective choice of hyperparameters. I establish a procedure to objectively determine the hyperparameters. Simulation studies have confirmed satisfactory model performance in estimating the temporal profiles for both event occurrences and effects of risk factors. The models were applied to data from a commercial truck driver naturalistic driving study. The results reveal that drivers with 7-hours-or-less sleep prior to a shift have a significantly higher intensity after 8 hours of on-duty driving and that their driving risk remains higher after taking a break. In addition, the results also show drivers’ self-selection on sleep time, total driving hours in a shift, and breaks. These applications provide crucial insight into the impact of sleep time on driving performance for commercial truck drivers and highlights the on-road safety implications of insufficient sleep and breaks while driving. This dissertation provides flexible and robust tools to evaluate the temporal profile of both event occurrences and effects of risk factors.