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.     

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.     

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.     

Bayesian composite quantile regression for linear mixed-effects models

Longitudinal data are commonly modeled with the normal mixed-effects models. Most modeling methods are based on traditional mean regression, which results in non robust estimation when suffering extreme values or outliers. Median regression is also not a best choice to estimation especially for non normal errors. Compared to conventional modeling methods, composite quantile regression can provide robust estimation results even for non normal errors. In this paper, based on a so-called pseudo composite asymmetric Laplace distribution (PCALD), we develop a Bayesian treatment to composite quantile regression for mixed-effects models. Furthermore, with the location-scale mixture representation of the PCALD, we establish a Bayesian hierarchical model and achieve the posterior inference of all unknown parameters and latent variables using Markov Chain Monte Carlo (MCMC) method. Finally, this newly developed procedure is illustrated by some Monte Carlo simulations and a case analysis of HIV/AIDS clinical data set.     

A Bayesian approach to estimating linear mixtures with unknown covariance structure

In this paper, we study a new Bayesian approach for the analysis of linearly mixed structures. In particular, we consider the case of hyperspectral images, which have to be decomposed into a collection of distinct spectra, called endmembers, and a set of associated proportions for every pixel in the scene. This problem, often referred to as spectral unmixing, is usually considered on the basis of the linear mixing model (LMM). In unsupervised approaches, the endmember signatures have to be calculated by an endmember extraction algorithm, which generally relies on the supposition that there are pure (unmixed) pixels contained in the image. In practice, this assumption may not hold for highly mixed data and consequently the extracted endmember spectra differ from the true ones. A way out of this dilemma is to consider the problem under the normal compositional model (NCM). Contrary to the LMM, the NCM treats the endmembers as random Gaussian vectors and not as deterministic quantities. Existing Bayesian approaches for estimating the proportions under the NCM are restricted to the case that the covariance matrix of the Gaussian endmembers is a multiple of the identity matrix. The self-evident conclusion is that this model is not suitable when the variance differs from one spectral channel to the other, which is a common phenomenon in practice. In this paper, we first propose a Bayesian strategy for the estimation of the mixing proportions under the assumption of varying variances in the spectral bands. Then we generalize this model to handle the case of a completely unknown covariance structure. For both algorithms, we present Gibbs sampling strategies and compare their performance with other, state of the art, unmixing routines on synthetic as well as on real hyperspectral fluorescence spectroscopy data.     

A Bayesian approach for parameter estimation in multi-stage models

Multi-stage time evolving models are common statistical models for biological systems, especially insect populations. In stage-duration distribution models, parameter estimation for the models use the Laplace transform method. This method involves assumptions such as known constant shapes, known constant rates or the same overall hazard rate for all stages. These assumptions are strong and restrictive. The main aim of this paper is to weaken these assumptions by using a Bayesian approach. In particular, a Metropolis-Hastings algorithm based on deterministic transformations is used to estimate parameters. We will use two models, one which has no hazard rates, and the other has stage-wise constant hazard rates. These methods are validated in simulation studies followed by a case study of cattle parasites. The results show that the proposed methods are able to estimate the parameters comparably well, as opposed to using the Laplace transform methods.     

Granger-causal analysis of GARCH models: A Bayesian approach

A multivariate GARCH model is used to investigate Granger causality in the conditional variance of time series. Parametric restrictions for the hypothesis of noncausality in conditional variances between two groups of variables, when there are other variables in the system as well, are derived. These novel conditions are convenient for the analysis of potentially large systems of economic variables. To evaluate hypotheses of noncausality, a Bayesian testing procedure is proposed. It avoids the singularity problem that may appear in the Wald test, and it relaxes the assumption of the existence of higher-order moments of the residuals required in classical tests.     

Bayesian quantile regression for skew-normal linear mixed models

Linear mixed models have been widely used to analyze repeated measures data which arise in many studies. In most applications, it is assumed that both the random effects and the within-subjects errors are normally distributed. This can be extremely restrictive, obscuring important features of within-and among-subject variations. Here, quantile regression in the Bayesian framework for the linear mixed models is described to carry out the robust inferences. We also relax the normality assumption for the random effects by using a multivariate skew-normal distribution, which includes the normal ones as a special case and provides robust estimation in the linear mixed models. For posterior inference, we propose a Gibbs sampling algorithm based on a mixture representation of the asymmetric Laplace distribution and multivariate skew-normal distribution. The procedures are demonstrated by both simulated and real data examples.     

Bayesian emulation of complex multi-output and dynamic computer models

Computer models are widely used in scientific research to study and predict the behaviour of complex systems. The run times of computer-intensive simulators are often such that it is impractical to make the thousands of model runs that are conventionally required for sensitivity analysis, uncertainty analysis or calibration. In response to this problem, highly efficient techniques have recently been developed based on a statistical meta-model (the emulator) that is built to approximate the computer model. The approach, however, is less straightforward for dynamic simulators, designed to represent time-evolving systems. Generalisations of the established methodology to allow for dynamic emulation are here proposed and contrasted. Advantages and difficulties are discussed and illustrated with an application to the Sheffield Dynamic Global Vegetation Model, developed within the UK Centre for Terrestrial Carbon Dynamics.     

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.     

A flexible approach for multivariate mixed-effects models with non-ignorable missing values

We propose a flexible model approach for the distribution of random effects when both response variables and covariates have non-ignorable missing values in a longitudinal study. A Bayesian approach is developed with a choice of nonparametric prior for the distribution of random effects. We apply the proposed method to a real data example from a national long-term survey by Statistics Canada. We also design simulation studies to further check the performance of the proposed approach. The result of simulation studies indicates that the proposed approach outperforms the conventional approach with normality assumption when the heterogeneity in random effects distribution is salient.     

A comparison of Bayesian model selection based on MCMC with an application to GARCH-type models

This paper presents a comprehensive review and comparison of five computational methods for Bayesian model selection, based on MCMC simulations from posterior model parameter distributions. We apply these methods to a well-known and important class of models in financial time series analysis, namely GARCH and GARCH-t models for conditional return distributions (assuming normal and t-distributions). We compare their performance with the more common maximum likelihood-based model selection for simulated and real market data. All five MCMC methods proved reliable in the simulation study, although differing in their computational demands. Results on simulated data also show that for large degrees of freedom (where the t-distribution becomes more similar to a normal one), Bayesian model selection results in better decisions in favor of the true model than maximum likelihood. Results on market data show the instability of the harmonic mean estimator and reliability of the advanced model selection methods.     

Bayesian analysis of censored linear regression models with scale mixtures of normal distributions

As is the case of many studies, the data collected are limited and an exact value is recorded only if it falls within an interval range. Hence, the responses can be either left, interval or right censored. Linear (and nonlinear) regression models are routinely used to analyze these types of data and are based on normality assumptions for the errors terms. However, those analyzes might not provide robust inference when the normality assumptions are questionable. In this article, we develop a Bayesian framework for censored linear regression models by replacing the Gaussian assumptions for the random errors with scale mixtures of normal (SMN) distributions. The SMN is an attractive class of symmetric heavy-tailed densities that includes the normal, Student-t, Pearson type VII, slash and the contaminated normal distributions, as special cases. Using a Bayesian paradigm, an efficient Markov chain Monte Carlo algorithm is introduced to carry out posterior inference. A new hierarchical prior distribution is suggested for the degrees of freedom parameter in the Student-t distribution. The likelihood function is utilized to compute not only some Bayesian model selection measures but also to develop Bayesian case-deletion influence diagnostics based on the q-divergence measure. The proposed Bayesian methods are implemented in the R package BayesCR. The newly developed procedures are illustrated with applications using real and simulated data.     

Bayesian analysis of skew-normal independent linear mixed models with heterogeneity in the random-effects population

We present a new class of models to fit longitudinal data, obtained with a suitable modification of the classical linear mixed-effects model. For each sample unit, the joint distribution of the random effect and the random error is a finite mixture of scale mixtures of multivariate skew-normal distributions. This extension allows us to model the data in a more flexible way, taking into account skewness, multimodality and discrepant observations at the same time. The scale mixtures of skew-normal form an attractive class of asymmetric heavy-tailed distributions that includes the skew-normal, skew-Student-t, skew-slash and the skew-contaminated normal distributions as special cases, being a flexible alternative to the use of the corresponding symmetric distributions in this type of models. A simple efficient MCMC Gibbs-type algorithm for posterior Bayesian inference is employed. In order to illustrate the usefulness of the proposed methodology, two artificial and two real data sets are analyzed.     

Bayesian analysis of generalized elliptical semi-parametric models

In this paper, we study the statistical inference based on the Bayesian approach for regression models with the assumption that independent additive errors follow normal, Student-t, slash, contaminated normal, Laplace or symmetric hyperbolic distribution, where both location and dispersion parameters of the response variable distribution include nonparametric additive components approximated by B-splines. This class of models provides a rich set of symmetric distributions for the model error. Some of these distributions have heavier or lighter tails than the normal as well as different levels of kurtosis. In order to draw samples of the posterior distribution of the interest parameters, we propose an efficient Markov Chain Monte Carlo (MCMC) algorithm, which combines Gibbs sampler and Metropolis–Hastings algorithms. The performance of the proposed MCMC algorithm is assessed through simulation experiments. We apply the proposed methodology to a real data set. The proposed methodology is implemented in the R package BayesGESM using the function gesm().     

Testing a linear ARMA model against threshold-ARMA models: A Bayesian approach

We introduce a Bayesian approach to test linear autoregressive moving-average (ARMA) models against threshold autoregressive moving-average (TARMA) models. First, the marginal posterior densities of all parameters, including the threshold and delay, of a TARMA model are obtained by using Gibbs sampler with Metropolis–Hastings algorithm. Second, reversible-jump Markov chain Monte Carlo (RJMCMC) method is adopted to calculate the posterior probabilities for ARMA and TARMA models: Posterior evidence in favor of TARMA models indicates threshold nonlinearity. Finally, based on RJMCMC scheme and Akaike information criterion (AIC) or Bayesian information criterion (BIC), the procedure for modeling TARMA models is exploited. Simulation experiments and a real data example show that our method works well for distinguishing an ARMA from a TARMA model and for building TARMA models.     

Mixture of Distributions in the Biparametric Exponential Family: A Bayesian Approach

In this article we propose mixture of distributions belonging to the biparametric exponential family, considering joint modeling of the mean and variance (or dispersion) parameters. As special cases we consider mixtures of normal and gamma distributions. A novel Bayesian methodology, using Markov Chain Monte Carlo (MCMC) methods, is proposed to obtain the posterior summaries of interest. We include simulations and real data examples to illustrate de performance of the proposal.     

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.