Segmental modeling of changing immunologic response for CD4 data with skewness, missingness and dropout

Abstract

In clinical practice, the profile of each subject's CD4 response from a longitudinal study may follow a ‘broken stick’ like trajectory, indicating multiple phases of increase and/or decline in response. Such multiple phases (changepoints) may be important indicators to help quantify treatment effect and improve management of patient care. Although it is a common practice to analyze complex AIDS longitudinal data using nonlinear mixed-effects (NLME) or nonparametric mixed-effects (NPME) models in the literature, NLME or NPME models become a challenge to estimate changepoint due to complicated structures of model formulations. In this paper, we propose a changepoint mixed-effects model with random subject-specific parameters, including the changepoint for the analysis of longitudinal CD4 cell counts for HIV infected subjects following highly active antiretroviral treatment. The longitudinal CD4 data in this study may exhibit departures from symmetry, may encounter missing observations due to various reasons, which are likely to be non-ignorable in the sense that missingness may be related to the missing values, and may be censored at the time of the subject going off study-treatment, which is a potentially informative dropout mechanism. Inferential procedures can be complicated dramatically when longitudinal CD4 data with asymmetry (skewness), incompleteness and informative dropout are observed in conjunction with an unknown changepoint. Our objective is to address the simultaneous impact of skewness, missingness and informative censoring by jointly modeling the CD4 response and dropout time processes under a Bayesian framework. The method is illustrated using a real AIDS data set to compare potential models with various scenarios, and some interested results are presented.

Keywords:

• Bayesian inference
• changepoint mixed-effects model
• dropout time model
• missing data
• skew normal distribution

Acknowledgements

The author is extremely grateful to the editor and two anonymous reviewers for their insightful comments and suggestions that led to a marked improvement of the article. This research was partially supported by NIAID/NIH grant AI080338 and USF Proposal Enhancement grant to Huang, NIMH/NIH grant R01MH040859-22 to Dagne and NIAID/NIH grant AI068634 to Park.