Longitudinal data arise frequently in medical studies and it is a common practice to analyze such complex data with nonlinear mixed-effects (NLME) models, which enable us to account for between-subject and within-subject variations. To partially explain the variations, time-dependent covariates are usually introduced to these models. Some covariates, however, may be often measured with substantial errors and missing observations. It is often the case that model random error is assumed to be distributed normally, but the normality assumption may not always give robust and reliable results, particularly if the data exhibit skewness. In the literature, there has been considerable interest in accommodating either skewed response or covariate measured with error and missing data in such models, but there has been relatively little study concerning all these features simultaneously. This article is to address simultaneous impact of skewness in response and measurement error and missing data in covariate by jointly modeling the response and covariate processes under a framework of Bayesian semiparametric nonlinear mixed-effects models. In particular, we aim at exploring how mixed-effects joint models based on one-compartment model with one phase time-varying decay rate and two-compartment model with two phase time-varying decay rates contribute to modeling results and inference. The method is illustrated by an AIDS data example to compare potential models with different distributional specifications and various scenarios. The findings from this study suggest that the one-compartment model with a skewnormal distribution may provide more reasonable results if the data exhibit skewness in response and/or have measurement error and missing observations in covariates.
In longitudinal studies it is often of interest to investigate how a repeatedly measured marker in time is associated with a time to an event of interest. This type of research question has given rise to a rapidly developing field of biostatistics research that deals with the joint modeling of longitudinal and time-to-event data. Normality of model errors in longitudinal model is a routine assumption, but it may be unrealistically obscuring important features of subject variations. Covariates are usually introduced in the models to partially explain between- and within-subject variations, but some covariates such as CD4 cell count may be often measured with substantial errors. Moreover, the responses may encounter nonignorable missing. Statistical analysis may be complicated dramatically based on longitudinal-survival joint models where longitudinal data with skewness, missing values, and measurement errors are observed. In this article, we relax the distributional assumptions for the longitudinal models using skewed (parametric) distribution and unspecified (nonparametric) distribution placed by a Dirichlet process prior, and address the simultaneous influence of skewness, missingness, covariate measurement error, and time-to-event process by jointly modeling three components (response process with missing values, covariate process with measurement errors, and time-to-event process) linked through the random-effects that characterize the underlying individual-specific longitudinal processes in Bayesian analysis. The method is illustrated with an AIDS study by jointly modeling HIV/CD4 dynamics and time to viral rebound in comparison with potential models with various scenarios and different distributional specifications.
After initiation of treatment, HIV viral load has multiphasic changes, which indicates that the viral decay rate is a time-varying process. Mixed-effects models with different time-varying decay rate functions have been proposed in literature. However, there are two unresolved critical issues: (i) it is not clear which model is more appropriate for practical use, and (ii) the model random errors are commonly assumed to follow a normal distribution, which may be unrealistic and can obscure important features of within- and among-subject variations. Because asymmetry of HIV viral load data is still noticeable even after transformation, it is important to use a more general distribution family that enables the unrealistic normal assumption to be relaxed. We developed skew-elliptical (SE) Bayesian mixed-effects models by considering the model random errors to have an SE distribution. We compared the performance among five SE models that have different time-varying decay rate functions. For each model, we also contrasted the performance under different model random error assumption such as normal, Student-t, skew-normal or skew-t distribution. Two AIDS clinical trial data sets were used to illustrate the proposed models and methods. The results indicate that the model with a time-varying viral decay rate that has two exponential components is preferred. Among the four distribution assumptions, the skew-t and skew-normal models provided better fitting to the data than normal or Student-t model, suggesting that it is important to assume a model with a skewed distribution in order to achieve reasonable results when the data exhibit skewness.
Longitudinal data arise frequently in medical studies and it is a common practice to analyze such complex data with nonlinear mixed-effects (NLME) models. However, the following four issues may be critical in longitudinal data analysis. (i) A homogeneous population assumption for models may be unrealistically obscuring important features of between-subject and within-subject variations; (ii) normality assumption for model errors may not always give robust and reliable results, in particular, if the data exhibit skewness; (iii) the responses may be missing and the missingness may be nonignorable; and (iv) some covariates of interest may often be measured with substantial errors. When carrying out statistical inference in such settings, it is important to account for the effects of these data features; otherwise, erroneous or even misleading results may be produced. Inferential procedures can be complicated dramatically when these four data features arise. In this article, the Bayesian joint modeling approach based on a finite mixture of NLME joint models with skew distributions is developed to study simultaneous impact of these four data features, allowing estimates of both model parameters and class membership probabilities at population and individual levels. A real data example is analyzed to demonstrate the proposed methodologies, and to compare various scenarios-based potential models with different specifications of distributions.
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