The aims of this proposal are to develop flexible, semiparametric statistical models, methods, and inferences for longitudinal data, and to apply these models and methods to analyze AIDS data. The proposal consists of two aims. The first specific aim is to develop flexible models, methods, and inference for longitudinal data, which will involve (a) applying the penalized spline methods to longitudinal data analysis, comparing the methods with local kernel, regression spline methods to determine which is best in practice, developing statistical inference methods for penalized spline with longitudinal data; (b) developing flexible and efficient methods for time-varying coefficient mixed-effects models with longitudinal data, including investigation of local kernel regression and the penalized spline methods; and developing flexible methods for generalized varying-coefficient mixed-effects models with longitudinal data; (c) developing flexible methods for general two-stage semiparametric nonlinear mixed-effects models; (d) developing computer packages to implement the proposed methods.
The second aim i s to apply the proposed models and methods developed to study HIV dynamics by using data from AIDS clinical trials run by the AIDS Clinical Trial Group (ACTG) and data from AIDS clinical trials conducted at St. Jude Children's Research Hospital. We will focus on (a) characterizing long-term HIV/T-cell dynamics in HIV-l-infected patients treated with highly active antiretroviral therapy by using flexible, nonparametric or semiparametric methods for longitudinal data; and studying the relation between long-term HIV dynamics and T-lymphocyte kinetics during long-term antiretroviral drug exposure; (b) investigating which clinical and specific factors affect HIV dynamics; (c) investigating the relation between clinical endpoints and HIV dynamics; and (d) comparing the effects of different antiviral agents, and presenting statistical evidence to justify which of several treatments is the most effective. The proposed research is expected to benefit studies of the immune system in HIV-infected patients (one of the main focuses of future AIDS research).
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