A Bayesian approach in differential equation dynamic models incorporating clinical factors and covariates

A virologic marker, the number of HIV RNA copies or viral load, is currently used to evaluate antiretroviral (ARV) therapies in AIDS clinical trials. This marker can be used to assess the antiviral potency of therapies, but may be easily affected by clinical factors such as drug exposures and drug resistance as well as baseline characteristics during the long-term treatment evaluation process. HIV dynamic studies have significantly contributed to the understanding of HIV pathogenesis and ARV treatment strategies. Viral dynamic models can be formulated through differential equations, but there has been only limited development of statistical methodologies for estimating such models or assessing their agreement with observed data. This paper develops mechanism-based nonlinear differential equation models for characterizing long-term viral dynamics with ARV therapy. In this model we not only incorporate clinical factors (drug exposures, and susceptibility), but also baseline covariate (baseline viral load, CD4 count, weight, or age) into a function of treatment efficacy. A Bayesian nonlinear mixed-effects modeling approach is investigated with application to an AIDS clinical trial study. The effects of confounding interaction of clinical factors with covariate-based models are compared using the deviance information criteria (DIC), a Bayesian version of the classical deviance for model assessment, designed from complex hierarchical model settings. Relationships between baseline covariate combined with confounding clinical factors and drug efficacy are explored. In addition, we compared models incorporating each of four baseline covariates through DIC and some interesting findings are presented. Our results suggest that modeling HIV dynamics and virologic responses with consideration of time-varying clinical factors as well as baseline characteristics may play an important role in understanding HIV pathogenesis, designing new treatment strategies for long-term care of AIDS patients.     

Bayesian Experimental Design for Long-Term Longitudinal HIV Dynamic Studies

The study of HIV dynamics is one of the most important developments in recent AIDS research for understanding the pathogenesis of HIV-1 infection and antiviral treatment strategies. Currently a large number of AIDS clinical trials on HIV dynamics are in development worldwide. However, many design issues that arise from AIDS clinical trials have not been addressed. In this paper, we use a simulation-based approach to deal with design problems in Bayesian hierarchical nonlinear (mixed-effects) models. The underlying model characterizes the long-term viral dynamics with antiretroviral treatment where we directly incorporate drug susceptibility and exposure into a function of treatment efficacy. The Bayesian design method is investigated under the framework of hierarchical Bayesian (mixed-effects) models. We compare a finite number of feasible candidate designs numerically, which are currently used in AIDS clinical trials from different perspectives, and provide guidance on how a design might be chosen in practice.     

Hybrid Bayesian inference on HIV viral dynamic models

Modelling of HIV dynamics in AIDS research has greatly improved our understanding of the pathogenesis of HIV-1 infection and guided for the treatment of AIDS patients and evaluation of antiretroviral therapies. Some of the model parameters may have practical meanings with prior knowledge available, but others might not have prior knowledge. Incorporating priors can improve the statistical inference. Although there have been extensive Bayesian and frequentist estimation methods for the viral dynamic models, little work has been done on making simultaneous inference about the Bayesian and frequentist parameters. In this article, we propose a hybrid Bayesian inference approach for viral dynamic nonlinear mixed-effects models using the Bayesian frequentist hybrid theory developed in Yuan [Bayesian frequentist hybrid inference, Ann. Statist. 37 (2009), pp. 2458–2501]. Compared with frequentist inference in a real example and two simulation examples, the hybrid Bayesian approach is able to improve the inference accuracy without compromising the computational load.     

Comparison of Mixed-Effects Models for Skew-Normal Responses with an Application to AIDS Data: A Bayesian Approach

The potency of antiretroviral agents in AIDS clinical trials can be assessed on the basis of a viral response such as viral decay rate or change in viral load (number of HIV RNA copies in plasma). Linear, nonlinear, and nonparametric mixed-effects models have been proposed to estimate such parameters in viral dynamic models. However, there are two critical questions that stand out: whether these models achieve consistent estimates for viral decay rates, and which model is more appropriate for use in practice. Moreover, one often assumes that a model random error is normally distributed, but this assumption may be unrealistic, obscuring important features of within- and among-subject variations. In this article, we develop a skew-normal (SN) Bayesian linear mixed-effects (SN-BLME) model, an SN Bayesian nonlinear mixed-effects (SN-BNLME) model, and an SN Bayesian semiparametric nonlinear mixed-effects (SN-BSNLME) model that relax the normality assumption by considering model random error to have an SN distribution. We compare the performance of these SN models, and also compare their performance with the corresponding normal models. An AIDS dataset is used to test the proposed models and methods. It was found that there is a significant incongruity in the estimated viral decay rates. The results indicate that SN-BSNLME model is preferred to the other models, implying that an arbitrary data truncation is not necessary. The findings also suggest that it is important to assume a model with an SN distribution in order to achieve reasonable results when the data exhibit skewness.     

Two-step and likelihood methods for HIV viral dynamic models with covariate measurement errors and missing data

HIV viral dynamic models have received much attention in the literature. Long-term viral dynamics may be modelled by semiparametric nonlinear mixed-effect models, which incorporate large variation between subjects and autocorrelation within subjects and are flexible in modelling complex viral load trajectories. Time-dependent covariates may be introduced in the dynamic models to partially explain the between-individual variations. In the presence of measurement errors and missing data in time-dependent covariates, we show that the commonly used two-step method may give approximately unbiased estimates but may under-estimate standard errors. We propose a two-stage bootstrap method to adjust the standard errors in the two-step method and a likelihood method.     

A refined parameter estimating approach for HIV dynamic model

HIV dynamic models, a set of ordinary differential equations (ODEs), have provided new understanding of the pathogenesis of HIV infection and the treatment effects of antiviral therapies. However, to estimate parameters for ODEs is very challenging due to the complexity of this nonlinear system. In this article, we propose a comprehensive procedure to deal with this issue. In the proposed procedure, a series of cutting-edge statistical methods and techniques are employed, including nonparametric mixed-effects smoothing-based methods for ODE models and stochastic approximation expectation–maximization (EM) approach for mixed-effects ODE models. A simulation study is performed to validate the proposed approach. An application example from a real HIV clinical trial study is used to illustrate the usefulness of the proposed method.     

Evidence for hedge fund predictability from a multivariate Student's t full-factor GARCH model

Extending previous work on hedge fund return predictability, this paper introduces the idea of modelling the conditional distribution of hedge fund returns using Student's t full-factor multivariate GARCH models. This class of models takes into account the stylized facts of hedge fund return series, that is, heteroskedasticity, fat tails and deviations from normality. For the proposed class of multivariate predictive regression models, we derive analytic expressions for the score and the Hessian matrix, which can be used within classical and Bayesian inferential procedures to estimate the model parameters, as well as to compare different predictive regression models. We propose a Bayesian approach to model comparison which provides posterior probabilities for various predictive models that can be used for model averaging. Our empirical application indicates that accounting for fat tails and time-varying covariances/correlations provides a more appropriate modelling approach of the underlying dynamics of financial series and improves our ability to predict hedge fund returns.     

Missing time-dependent covariates in human immunodeficiency virus dynamic models

Summary. The study of human immunodeficiency virus dynamics is one of the most important areas in research into acquired immune deficiency syndrome in recent years. Non-linear mixed effects models have been proposed for modelling viral dynamic processes. A challenging problem in the modelling is to identify repeatedly measured (time-dependent), but possibly missing, immunologic or virologic markers (covariates) for viral dynamic parameters. For missing time-dependent covariates in non-linear mixed effects models, the commonly used complete-case, mean imputation and last value carried forward methods may give misleading results. We propose a three-step hierarchical multiple-imputation method, implemented by Gibbs sampling, which imputes the missing data at the individual level but can pool information across individuals. We compare various methods by Monte Carlo simulations and find that the multiple-imputation method proposed performs the best in terms of bias and mean-squared errors in the estimates of covariate coefficients. By applying the favoured multiple-imputation method to clinical data, we conclude that there is a negative correlation between the viral decay rate (a virological response parameter) and CD4 or CD8 cell counts during the treatment; this is counter-intuitive, but biologically interpretable on the basis of findings from other clinical studies. These results may have an important influence on decisions about treatment for acquired immune deficiency syndrome patients.     

Jointly modeling time-to-event and longitudinal data: a Bayesian approach

This article explores Bayesian joint models of event times and longitudinal measures with an attempt to overcome departures from normality of the longitudinal response, measurement errors, and shortages of confidence in specifying a parametric time-to-event model. We allow the longitudinal response to have a skew distribution in the presence of measurement errors, and assume the time-to-event variable to have a nonparametric prior distribution. Posterior distributions of the parameters are attained simultaneously for inference based on Bayesian approach. An example from a recent AIDS clinical trial illustrates the methodology by jointly modeling the viral dynamics and the time to decrease in CD4/CD8 ratio in the presence of CD4 counts with measurement errors to compare potential models with various scenarios and different distribution specifications. The analysis outcome indicates that the time-varying CD4 covariate is closely related to the first-phase viral decay rate, but the time to CD4/CD8 decrease is not highly associated with either the two viral decay rates or the CD4 changing rate over time. These findings may provide some quantitative guidance to better understand the relationship of the virological and immunological responses to antiretroviral treatments.     

Mixed-effects Models with Skewed Distributions for Time-varying Decay Rate in HIV Dynamics

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 assumptions such as normal, Student-t, skew-normal, or skew-t distribution. Two AIDS clinical trial datasets 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.     

Joint analysis of nonlinear heterogeneous longitudinal data and binary outcome: an application to AIDS clinical studies

Finite mixture models are currently used to analyze heterogeneous longitudinal data. By releasing the homogeneity restriction of nonlinear mixed-effects (NLME) models, finite mixture models not only can estimate model parameters but also cluster individuals into one of the pre-specified classes with class membership probabilities. This clustering may have clinical significance, which might be associated with a clinically important binary outcome. This article develops a joint modeling of a finite mixture of NLME models for longitudinal data in the presence of covariate measurement errors and a logistic regression for a binary outcome, linked by individual latent class indicators, under a Bayesian framework. Simulation studies are conducted to assess the performance of the proposed joint model and a naive two-step model, in which finite mixture model and logistic regression are fitted separately, followed by an application to a real data set from an AIDS clinical trial, in which the viral dynamics and dichotomized time to the first decline of CD4/CD8 ratio are analyzed jointly.     

Bayesian penalized B-spline estimation approach for epidemic models

Ordinary differential equations (ODEs) are normally used to model dynamic processes in applied sciences such as biology, engineering, physics, and many other areas. In these models, the parameters are usually unknown, and thus they are often specified artificially or empirically. Alternatively, a feasible method is to estimate the parameters based on observed data. In this study, we propose a Bayesian penalized B-spline approach to estimate the parameters and initial values for ODEs used in epidemiology. We evaluated the efficiency of the proposed method based on simulations using the Markov chain Monte Carlo algorithm for the Kermack–McKendrick model. The proposed approach is also illustrated based on a real application to the transmission dynamics of hepatitis C virus in mainland China.     

基于贝叶斯推断的HIV非线性混合效应联合模型研究

 在纵向数据研究中,混合效应模型的随机误差通常采用正态性假设。而诸如病毒载量和CD4细胞数目等病毒性数据通常呈现偏斜性,因此正态性假设可能影响模型结果甚至导致错误的结论。在HIV动力学研究中,病毒响应值往往与协变量相关,且协变量的测量值通常存在误差,为此论文中联立协变量过程建立具有偏正态分布的非线性混合效应联合模型,并用贝叶斯推断方法估计模型的参数。由于协变量能够解释个体内的部分变化,因此协变量过程的模型选择对病毒载量的拟合效果有重要的影响。该文提出了一次移动平均模型作为协变量过程的改进模型,比较后发现当协变量采用移动平均模型时,病毒载量模型的拟合效果更好。该结果对协变量模型的研究具有重要的指导意义。     

Non-linear state space modelling of fisheries biomass dynamics by using Metropolis-Hastings within-Gibbs sampling

State space modelling and Bayesian analysis are both active areas of applied research in fisheries stock assessment. Combining these two methodologies facilitates the fitting of state space models that may be non-linear and have non-normal errors, and hence it is particularly useful for modelling fisheries dynamics. Here, this approach is demonstrated by fitting a non-linear surplus production model to data on South Atlantic albacore tuna ( Thunnus alalunga ). The state space approach allows for random variability in both the data (the measurement of relative biomass) and in annual biomass dynamics of the tuna stock. Sampling from the joint posterior distribution of the unobservables was achieved by using Metropolis-Hastings within-Gibbs sampling.     

Comparing crossing hazard rate functions by joint modelling of survival and longitudinal data

Abstract

It is one of the important issues in survival analysis to compare two hazard rate functions to evaluate treatment effect. It is quite common that the two hazard rate functions cross each other at one or more unknown time points, representing temporal changes of the treatment effect. In certain applications, besides survival data, we also have related longitudinal data available regarding some time-dependent covariates. In such cases, a joint model that accommodates both types of data can allow us to infer the association between the survival and longitudinal data and to assess the treatment effect better. In this paper, we propose a modelling approach for comparing two crossing hazard rate functions by joint modelling survival and longitudinal data. Maximum likelihood estimation is used in estimating the parameters of the proposed joint model using the EM algorithm. Asymptotic properties of the maximum likelihood estimators are studied. To illustrate the virtues of the proposed method, we compare the performance of the proposed method with several existing methods in a simulation study. Our proposed method is also demonstrated using a real dataset obtained from an HIV clinical trial.     

Exact Bayesian modeling for bivariate Poisson data and extensions

Bivariate count data arise in several different disciplines (epidemiology, marketing, sports statistics just to name a few) and the bivariate Poisson distribution being a generalization of the Poisson distribution plays an important role in modelling such data. In the present paper we present a Bayesian estimation approach for the parameters of the bivariate Poisson model and provide the posterior distributions in closed forms. It is shown that the joint posterior distributions are finite mixtures of conditionally independent gamma distributions for which their full form can be easily deduced by a recursively updating scheme. Thus, the need of applying computationally demanding MCMC schemes for Bayesian inference in such models will be removed, since direct sampling from the posterior will become available, even in cases where the posterior distribution of functions of the parameters is not available in closed form. In addition, we define a class of prior distributions that possess an interesting conjugacy property which extends the typical notion of conjugacy, in the sense that both prior and posteriors belong to the same family of finite mixture models but with different number of components. Extension to certain other models including multivariate models or models with other marginal distributions are discussed.     

Bayesian fractional polynomials

This paper sets out to implement the Bayesian paradigm for fractional polynomial models under the assumption of normally distributed error terms. Fractional polynomials widen the class of ordinary polynomials and offer an additive and transportable modelling approach. The methodology is based on a Bayesian linear model with a quasi-default hyper-g prior and combines variable selection with parametric modelling of additive effects. A Markov chain Monte Carlo algorithm for the exploration of the model space is presented. This theoretically well-founded stochastic search constitutes a substantial improvement to ad hoc stepwise procedures for the fitting of fractional polynomial models. The method is applied to a data set on the relationship between ozone levels and meteorological parameters, previously analysed in the literature.     

A weakly informative prior for Bayesian dynamic model selection with applications in fMRI

In recent years, Bayesian statistics methods in neuroscience have been showing important advances. In particular, detection of brain signals for studying the complexity of the brain is an active area of research. Functional magnetic resonance imagining (fMRI) is an important tool to determine which parts of the brain are activated by different types of physical behavior. According to recent results, there is evidence that the values of the connectivity brain signal parameters are close to zero and due to the nature of time series fMRI data with high-frequency behavior, Bayesian dynamic models for identifying sparsity are indeed far-reaching. We propose a multivariate Bayesian dynamic approach for model selection and shrinkage estimation of the connectivity parameters. We describe the coupling or lead-lag between any pair of regions by using mixture priors for the connectivity parameters and propose a new weakly informative default prior for the state variances. This framework produces one-step-ahead proper posterior predictive results and induces shrinkage and robustness suitable for fMRI data in the presence of sparsity. To explore the performance of the proposed methodology, we present simulation studies and an application to functional magnetic resonance imaging data.     

Bayesian analysis of multivariate mortality data with large families

This paper presents a Bayesian method for the analysis of toxicological multivariate mortality data when the discrete mortality rate for each family of subjects at a given time depends on familial random effects and the toxicity level experienced by the family. Our aim is to model and analyse one set of such multivariate mortality data with large family sizes: the potassium thiocyanate (KSCN) tainted fish tank data of O'Hara Hines. The model used is based on a discretized hazard with additional time-varying familial random effects. A similar previous study (using sodium thiocyanate (NaSCN)) is used to construct a prior for the parameters in the current study. A simulation-based approach is used to compute posterior estimates of the model parameters and mortality rates and several other quantities of interest. Recent tools in Bayesian model diagnostics and variable subset selection have been incorporated to verify important modelling assumptions regarding the effects of time and heterogeneity among the families on the mortality rate. Further, Bayesian methods using predictive distributions are used for comparing several plausible models.     

Some state space models of hiv epidemic and its applications for the estimation of hiv infection and incubation

In this paper we have developed some state space models for the HIV epidemic for populations at risk for AIDS. By using these state space models, we have developed a general Bayesian procedure for estimating simultaneously the unknown parameters and the state variables. The unknown parameters include the immigration and recruitment rates, the death and retirement rates, the incidence of HIV infection ( and hence the HIV infection distribution ) and the incidence of HIV incubation ( and hence the HIV incubation distribution). The state variables are the numbers of susceptible people (S people), HIV-infected people (I people) and AIDS incidence over time. The basic approach is through multi-level Gibbs sampler combined with the weighted bootstrap method. We have applied the methods to the Swiss AIDS homosexual and IV drug data to estimate simultaneously the unknown parameters and the state variables. Our results show that in both populations, both the HIV infection and HIV incubation have multi-peaks indicating the mixture nature of these distributions. Our results have also shown that the estimates of the death and retirement rates for I people are greater than those of S people, suggesting that the infection by HIV may have increased the death and retirement rates of the individuals.