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.     

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.     

Semiparametric Hierarchical Composite Quantile Regression

In biological, medical, and social sciences, multilevel structures are very common. Hierarchical models that take the dependencies among subjects within the same level are necessary. In this article, we introduce a semiparametric hierarchical composite quantile regression model for hierarchical data. This model (i) keeps the easy interpretability of the simple parametric model; (ii) retains some of the flexibility of the complex non parametric model; (iii) relaxes the assumptions that the noise variances and higher-order moments exist and are finite; and (iv) takes the dependencies among subjects within the same hierarchy into consideration. We establish the asymptotic properties of the proposed estimators. Our simulation results show that the proposed method is more efficient than the least-squares-based method for many non normally distributed errors. We illustrate our methodology with a real biometric data set.     

Semiparametric models of longitudinal and time-to-event data with applications to HIV viral dynamics and CD4 counts

We propose a semiparametric approach based on proportional hazards and copula method to jointly model longitudinal outcomes and the time-to-event. The dependence between the longitudinal outcomes on the covariates is modeled by a copula-based times series, which allows non-Gaussian random effects and overcomes the limitation of the parametric assumptions in existing linear and nonlinear random effects models. A modified partial likelihood method using estimated covariates at failure times is employed to draw statistical inference. The proposed model and method are applied to analyze a set of progression to AIDS data in a study of the association between the human immunodeficiency virus viral dynamics and the time trend in the CD4/CD8 ratio with measurement errors. Simulations are also reported to evaluate the proposed model and method.     

Bayesian estimation of varying-coefficient models with missing data,with application to the Singapore Longitudinal Aging Study

Motivated by the Singapore Longitudinal Aging Study (SLAS), we propose a Bayesian approach for the estimation of semiparametric varying-coefficient models for longitudinal continuous and cross-sectional binary responses. These models have proved to be more flexible than simple parametric regression models. Our development is a new contribution towards their Bayesian solution, which eases computational complexity. We also consider adapting all kinds of familiar statistical strategies to address the missing data issue in the SLAS. Our simulation results indicate that a Bayesian imputation (BI) approach performs better than complete-case (CC) and available-case (AC) approaches, especially under small sample designs, and may provide more useful results in practice. In the real data analysis for the SLAS, the results for longitudinal outcomes from BI are similar to AC analysis, differing from those with CC analysis.     

Bayesian Semiparametric Modelling in Quantile Regression

Abstract. We propose a Bayesian semiparametric methodology for quantile regression modelling. In particular, working with parametric quantile regression functions, we develop Dirichlet process mixture models for the error distribution in an additive quantile regression formulation. The proposed non‐parametric prior probability models allow the shape of the error density to adapt to the data and thus provide more reliable predictive inference than models based on parametric error distributions. We consider extensions to quantile regression for data sets that include censored observations. Moreover, we employ dependent Dirichlet processes to develop quantile regression models that allow the error distribution to change non‐parametrically with the covariates. Posterior inference is implemented using Markov chain Monte Carlo methods. We assess and compare the performance of our models using both simulated and real data sets.     

A semiparametric approach for modelling multivariate nonlinear time series

In this article, a semiparametric time‐varying nonlinear vector autoregressive (NVAR) model is proposed to model nonlinear vector time series data. We consider a combination of parametric and nonparametric estimation approaches to estimate the NVAR function for both independent and dependent errors. We use the multivariate Taylor series expansion of the link function up to the second order which has a parametric framework as a representation of the nonlinear vector regression function. After the unknown parameters are estimated by the maximum likelihood estimation procedure, the obtained NVAR function is adjusted by a nonparametric diagonal matrix, where the proposed adjusted matrix is estimated by the nonparametric kernel estimator. The asymptotic consistency properties of the proposed estimators are established. Simulation studies are conducted to evaluate the performance of the proposed semiparametric method. A real data example on short‐run interest rates and long‐run interest rates of United States Treasury securities is analyzed to demonstrate the application of the proposed approach. The Canadian Journal of Statistics 47: 668–687; 2019 © 2019 Statistical Society of Canada     

Joint model-based clustering of nonlinear longitudinal trajectories and associated time-to-event data analysis,linked by latent class membership: with application to AIDS clinical studies

Longitudinal and time-to-event data are often observed together. Finite mixture models are currently used to analyze nonlinear heterogeneous longitudinal data, which, by releasing the homogeneity restriction of nonlinear mixed-effects (NLME) models, can cluster individuals into one of the pre-specified classes with class membership probabilities. This clustering may have clinical significance, and be associated with clinically important time-to-event data. This article develops a joint modeling approach to a finite mixture of NLME models for longitudinal data and proportional hazard Cox model for time-to-event data, linked by individual latent class indicators, under a Bayesian framework. The proposed joint models and method are applied to a real AIDS clinical trial data set, followed by simulation studies to assess the performance of the proposed joint model and a naive two-step model, in which finite mixture model and Cox model are fitted separately.     

A flexible semiparametric regression model for bimodal,asymmetric and censored data

In this paper, we propose a new semiparametric heteroscedastic regression model allowing for positive and negative skewness and bimodal shapes using the B-spline basis for nonlinear effects. The proposed distribution is based on the generalized additive models for location, scale and shape framework in order to model any or all parameters of the distribution using parametric linear and/or nonparametric smooth functions of explanatory variables. We motivate the new model by means of Monte Carlo simulations, thus ignoring the skewness and bimodality of the random errors in semiparametric regression models, which may introduce biases on the parameter estimates and/or on the estimation of the associated variability measures. An iterative estimation process and some diagnostic methods are investigated. Applications to two real data sets are presented and the method is compared to the usual regression methods.     

A generalized Bayesian nonlinear mixed‐effects regression model for zero‐inflated longitudinal count data in tuberculosis trials

In this paper, we investigate Bayesian generalized nonlinear mixed‐effects (NLME) regression models for zero‐inflated longitudinal count data. The methodology is motivated by and applied to colony forming unit (CFU) counts in extended bactericidal activity tuberculosis (TB) trials. Furthermore, for model comparisons, we present a generalized method for calculating the marginal likelihoods required to determine Bayes factors. A simulation study shows that the proposed zero‐inflated negative binomial regression model has good accuracy, precision, and credibility interval coverage. In contrast, conventional normal NLME regression models applied to log‐transformed count data, which handle zero counts as left censored values, may yield credibility intervals that undercover the true bactericidal activity of anti‐TB drugs. We therefore recommend that zero‐inflated NLME regression models should be fitted to CFU count on the original scale, as an alternative to conventional normal NLME regression models on the logarithmic scale.     

A Partially Linear Model Using a Gaussian Process Prior

A partially linear model is a semiparametric regression model that consists of parametric and nonparametric regression components in an additive form. In this article, we propose a partially linear model using a Gaussian process regression approach and consider statistical inference of the proposed model. Based on the proposed model, the estimation procedure is described by posterior distributions of the unknown parameters and model comparisons between parametric representation and semi- and nonparametric representation are explored. Empirical analysis of the proposed model is performed with synthetic data and real data applications.     

Semiparametric ROC surface estimation for continuous diagnostic tests via polytomous logistic regression procedures

In this paper, we propose a semiparametric method of estimating receiver operating characteristic (ROC) surfaces for continuous diagnostic tests under density ratio models. Implementation of our method is easy since the usual polytomous logistic regression procedures in many statistical software packages can be employed. A simulated example is provided to facilitate the implementation of our method. Simulation results show that the proposed semiparametric ROC surface estimator is more efficient than the nonparametric counterpart and the parametric counterpart whether the normality assumption of data holds or not. Moreover, some simulation results on the underlying semiparametric distribution function estimators are also reported. In addition, some discussions on the proposed method as well as analysis of a real data set are provided.     

Parametric and semiparametric hypotheses in the linear model

The independent additive errors linear model consists of a structure for the mean and a separate structure for the error distribution. The error structure may be parametric or it may be semiparametric. Under alternative values of the mean structure, the best fitting additive errors model has an error distribution which can be represented as the convolution of the actual error distribution and the marginal distribution of a misspecification term. The model misspecification term results from the covariates' distribution. Conditions are developed to distinguish when the semiparametric model yields sharper inference than the parametric model and vice versa. The main conditions concern the actual error distribution and the covariates' distribution. The theoretical results explain a paradoxical finding in semiparametric Bayesian modelling, where the posterior distribution under a semiparametric model is found to be more concentrated than is the posterior distribution under a corresponding parametric model. The paradox is illustrated on a set of allometric data. The Canadian Journal of Statistics 39: 165–180; 2011 ©2011 Statistical Society of Canada     

Bayesian quantile regression for parametric nonlinear mixed effects models

We propose quantile regression (QR) in the Bayesian framework for a class of nonlinear mixed effects models with a known, parametric model form for longitudinal data. Estimation of the regression quantiles is based on a likelihood-based approach using the asymmetric Laplace density. Posterior computations are carried out via Gibbs sampling and the adaptive rejection Metropolis algorithm. To assess the performance of the Bayesian QR estimator, we compare it with the mean regression estimator using real and simulated data. Results show that the Bayesian QR estimator provides a fuller examination of the shape of the conditional distribution of the response variable. Our approach is proposed for parametric nonlinear mixed effects models, and therefore may not be generalized to models without a given model form.     

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

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.     

Using logistic regression for semiparametric comparison of population means and variances

Abstract

We propose to compare population means and variances under a semiparametric density ratio model. The proposed method is easy to implement by employing logistic regression procedures in many statistical software, and it often works very well when data are not normal. In this paper, we construct semiparametric estimators of the differences of two population means and variances, and derive their asymptotic distributions. We prove that the proposed semiparametric estimators are asymptotically more efficient than the corresponding non parametric ones. In addition, a simulation study and the analysis of two real data sets are presented. Finally, a short discussion is provided.     

Efficient Estimation in Marginal Partially Linear Models for Longitudinal/Clustered Data Using Splines

Abstract.  We consider marginal semiparametric partially linear models for longitudinal/clustered data and propose an estimation procedure based on a spline approximation of the non-parametric part of the model and an extension of the parametric marginal generalized estimating equations (GEE). Our estimates of both parametric part and non-parametric part of the model have properties parallel to those of parametric GEE, that is, the estimates are efficient if the covariance structure is correctly specified and they are still consistent and asymptotically normal even if the covariance structure is misspecified. By showing that our estimate achieves the semiparametric information bound, we actually establish the efficiency of estimating the parametric part of the model in a stronger sense than what is typically considered for GEE. The semiparametric efficiency of our estimate is obtained by assuming only conditional moment restrictions instead of the strict multivariate Gaussian error assumption.     

Semiparametric multinomial logit models for analysing consumer choice behaviour

The multinomial logit model (MNL) is one of the most frequently used statistical models in marketing applications. It allows one to relate an unordered categorical response variable, for example representing the choice of a brand, to a vector of covariates such as the price of the brand or variables characterising the consumer. In its classical form, all covariates enter in strictly parametric, linear form into the utility function of the MNL model. In this paper, we introduce semiparametric extensions, where smooth effects of continuous covariates are modelled by penalised splines. A mixed model representation of these penalised splines is employed to obtain estimates of the corresponding smoothing parameters, leading to a fully automated estimation procedure. To validate semiparametric models against parametric models, we utilise different scoring rules as well as predicted market share and compare parametric and semiparametric approaches for a number of brand choice data sets.     

NEW EFFICIENT ESTIMATION AND VARIABLE SELECTION METHODS FOR SEMIPARAMETRIC VARYING-COEFFICIENT PARTIALLY LINEAR MODELS

The complexity of semiparametric models poses new challenges to statistical inference and model selection that frequently arise from real applications. In this work, we propose new estimation and variable selection procedures for the semiparametric varying-coefficient partially linear model. We first study quantile regression estimates for the nonparametric varying-coefficient functions and the parametric regression coefficients. To achieve nice efficiency properties, we further develop a semiparametric composite quantile regression procedure. We establish the asymptotic normality of proposed estimators for both the parametric and nonparametric parts and show that the estimators achieve the best convergence rate. Moreover, we show that the proposed method is much more efficient than the least-squares-based method for many non-normal errors and that it only loses a small amount of efficiency for normal errors. In addition, it is shown that the loss in efficiency is at most 11.1% for estimating varying coefficient functions and is no greater than 13.6% for estimating parametric components. To achieve sparsity with high-dimensional covariates, we propose adaptive penalization methods for variable selection in the semiparametric varying-coefficient partially linear model and prove that the methods possess the oracle property. Extensive Monte Carlo simulation studies are conducted to examine the finite-sample performance of the proposed procedures. Finally, we apply the new methods to analyze the plasma beta-carotene level data.     

A Bayesian approach of joint models for clustered zero-inflated count data with skewness and measurement errors

Count data with excess zeros are widely encountered in the fields of biomedical, medical, public health and social survey, etc. Zero-inflated Poisson (ZIP) regression models with mixed effects are useful tools for analyzing such data, in which covariates are usually incorporated in the model to explain inter-subject variation and normal distribution is assumed for both random effects and random errors. However, in many practical applications, such assumptions may be violated as the data often exhibit skewness and some covariates may be measured with measurement errors. In this paper, we deal with these issues simultaneously by developing a Bayesian joint hierarchical modeling approach. Specifically, by treating intercepts and slopes in logistic and Poisson regression as random, a flexible two-level ZIP regression model is proposed, where a covariate process with measurement errors is established and a skew-t-distribution is considered for both random errors and random effects. Under the Bayesian framework, model selection is carried out using deviance information criterion (DIC) and a goodness-of-fit statistics is also developed for assessing the plausibility of the posited model. The main advantage of our method is that it allows for more robustness and correctness for investigating heterogeneity from different levels, while accommodating the skewness and measurement errors simultaneously. An application to Shanghai Youth Fitness Survey is used as an illustrate example. Through this real example, it is showed that our approach is of interest and usefulness for applications.