Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Public Health

Major Professor

Yiliang Zhu

Co-Major Professor

Kathleen O'Rourke

Abstract

Statistical analyses and modeling have contributed greatly to our understanding of the pathogenesis of HIV-1 infection; they also provide guidance for the treatment of AIDS patients and evaluation of antiretroviral (ARV) therapies. Various statistical methods, nonlinear mixed-effects models in particular, have been applied to model the CD4 and viral load trajectories. A common assumption in these methods is all patients come from a homogeneous population following one mean trajectories. This assumption unfortunately obscures important characteristic difference between subgroups of patients whose response to treatment and whose disease trajectories are biologically different. It also may lack the robustness against population heterogeneity resulting misleading or biased inference.

Finite mixture models, also known as latent class models, are commonly used to model nonpredetermined heterogeneity in a population; they provide an empirical representation of heterogeneity by grouping the population into a finite number of latent classes and modeling the population through a mixture distribution. For each latent class, a finite mixture model allows individuals in each class to vary around their own mean trajectory, instead of a common one shared by all classes. Furthermore, a mixture model has ability to cluster and estimate class membership probabilities at both population and individual levels. This important feature may help physicians to better understand a particular patient disease progression and refine the therapeutical strategy in advance.

In this research, we developed mixture dynamic model and related Bayesian inferences via Markov chain Monte Carlo (MCMC). One real data set from HIV/AIDS clinical management and another from clinical trial were used to illustrate the proposed models and methods.

This dissertation explored three topics. First, we modeled the CD4 trajectories using a finite mixture model with four distinct components of which the mean functions are designed based on Michaelis-Menten function. Relevant covariates both baseline and time-varying were considered and model comparison and selection were based on such-criteria as Deviance Information Criteria (DIC). Class membership model was allowed to depend on covariates for prediction. Second, we explored disease status prediction HIV/AIDS using the latent class membership model. Third, we modeled viral load trajectories using a finite mixture model with three components of which the mean functions are designed based on published HIV dynamic systems. Although this research is motivated by HIV/AIDS studies, the basic concepts and methods developed here have much broader applications in management of other chronic diseases; they can also be applied to dynamic systems in other fields. Implementation of our methods using the publicly- vailable WinBUGS package suggest that our approach can be made quite accessible to practicing statisticians and data analysts.

Included in

Biostatistics Commons

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