Extending multivariate Student's- t $$ t $$ semiparametric mixed models for longitudinal data with censored responses and heavy tails.

This article extends the semiparametric mixed model for longitudinal censored data with Gaussian errors by considering the Student's t $$ t $$ -distribution. This model allows us to consider a flexible, functional dependence of an outcome variable over the covariates using nonparametric regression. Moreover, the proposed model takes into account the correlation between observations by using random effects. Penalized likelihood equations are applied to derive the maximum likelihood estimates that appear to be robust against outlying observations with respect to the Mahalanobis distance. We estimate nonparametric functions using smoothing splines under an EM-type algorithm framework. Finally, the proposed approach's performance is evaluated through extensive simulation studies and an application to two datasets from acquired immunodeficiency syndrome clinical trials.

A semiparametric mixed-effects model for censored longitudinal data.

In longitudinal studies involving laboratory-based outcomes, repeated measurements can be censored due to assay detection limits. Linear mixed-effects (LMEs) models are a powerful tool to model the relationship between a response variable and covariates in longitudinal studies. However, the linear parametric form of linear mixed-effect models is often too restrictive to characterize the complex relationship between a response variable and covariates. More general and robust modeling tools, such as nonparametric and semiparametric regression models, have become increasingly popular in the last decade. In this article, we use semiparametric mixed models to analyze censored longitudinal data with irregularly observed repeated measures. The proposed model extends the censored linear mixed-effect model and provides more flexible modeling schemes by allowing the time effect to vary nonparametrically over time. We develop an Expectation-Maximization (EM) algorithm for maximum penalized likelihood estimation of model parameters and the nonparametric component. Further, as a byproduct of the EM algorithm, the smoothing parameter is estimated using a modified linear mixed-effects model, which is faster than alternative methods such as the restricted maximum likelihood approach. Finally, the performance of the proposed approaches is evaluated through extensive simulation studies as well as applications to data sets from acquired immune deficiency syndrome studies.

Spatial skew-normal/independent models for nonrandomly missing clustered data.

Clinical studies on periodontal disease (PD) often lead to data collected which are clustered in nature (viz. clinical attachment level, or CAL, measured at tooth-sites and clustered within subjects) that are routinely analyzed under a linear mixed model framework, with underlying normality assumptions of the random effects and random errors. However, a careful look reveals that these data might exhibit skewness and tail behavior, and hence the usual normality assumptions might be questionable. Besides, PD progression is often hypothesized to be spatially associated, that is, a diseased tooth-site may influence the disease status of a set of neighboring sites. Also, the presence/absence of a tooth is informative, as the number and location of missing teeth informs about the periodontal health in that region. In this paper, we develop a (shared) random effects model for site-level CAL and binary presence/absence status of a tooth under a Bayesian paradigm. The random effects are modeled using a spatial skew-normal/independent (S-SNI) distribution, whose dependence structure is conditionally autoregressive (CAR). Our S-SNI density presents an attractive parametric tool to model spatially referenced asymmetric thick-tailed structures. Both simulation studies and application to a clinical dataset recording PD status reveal the advantages of our proposition in providing a significantly improved fit, over models that do not consider these features in a unified way.

Scale mixture of skew-normal linear mixed models with within-subject serial dependence.

In longitudinal studies, repeated measures are collected over time and hence they tend to be serially correlated. These studies are commonly analyzed using linear mixed models (LMMs), and in this article we consider an extension of the skew-normal/independent LMM, where the error term has a dependence structure, such as damped exponential correlation or autoregressive correlation of order p. The proposed model provides flexibility in capturing the effects of skewness and heavy tails simultaneously when continuous repeated measures are serially correlated. For this robust model, we present an efficient EM-type algorithm for parameters estimation via maximum likelihood and the observed information matrix is derived analytically to account for standard errors. The methodology is illustrated through an application to schizophrenia data and some simulation studies. The proposed algorithm and methods are implemented in the new R package skewlmm.

Comparisons of zero-augmented continuous regression models from a Bayesian perspective.

The two-part model and the Tweedie model are two essential methods to analyze the positive continuous and zero-augmented responses. Compared with other continuous zero-augmented models, the zero-augmented gamma model (ZAG) demonstrates its performance on the mass zeros data. In this article, we compare the Bayesian model for continuous data of excess zeros by considering the ZAG and Tweedie model. We model the mean of both models in a logarithmic scale and the probability of zero within the zero-augmented model in a logit scale. As previous researchers employed different priors in Bayesian settings for the Tweedie model, by conducting a sensitivity analysis, we select the optimal priors for Tweedie model. Furthermore, we present a simulation study to evaluate the performance of two models in the comparison and apply them to a dataset about the daily fish intake and blood mercury levels from National Health and Nutrition Examination Survey. According to the Watanabe-Akaike information criterion and leave-one-out cross-validation criterion, the Tweedie model provides higher predictive accuracy for the positive continuous and zero-augmented data.

Mixed-effects models for censored data with autoregressive errors.

Mixed-effects models, with modifications to accommodate censored observations (LMEC/NLMEC), are routinely used to analyze measurements, collected irregularly over time, which are often subject to some upper and lower detection limits. This paper presents a likelihood-based approach for fitting LMEC/NLMEC models with autoregressive of order p dependence of the error term. An EM-type algorithm is developed for computing the maximum likelihood estimates, obtaining as a byproduct the standard errors of the fixed effects and the likelihood value. Moreover, the constraints on the parameter space that arise from the stationarity conditions for the autoregressive parameters in the EM algorithm are handled by a reparameterization scheme, as discussed in Lin and Lee (2007). To examine the performance of the proposed method, we present some simulation studies and analyze a real AIDS case study. The proposed algorithm and methods are implemented in the new R package ARpLMEC.

An extended poisson family of life distribution: a unified approach in competitive and complementary risks.

In this paper, we introduce a new approach to generate flexible parametric families of distributions. These models arise on competitive and complementary risks scenario, in which the lifetime associated with a particular risk is not observable; rather, we observe only the minimum/maximum lifetime value among all risks. The latent variables have a zero-truncated Poisson distribution. For the proposed family of distribution, the extra shape parameter has an important physical interpretation in the competing and complementary risks scenario. The mathematical properties and inferential procedures are discussed. The proposed approach is applied in some existing distributions in which it is fully illustrated by an important data set.

Inference and diagnostics for heteroscedastic nonlinear regression models under skew scale mixtures of normal distributions.

The heteroscedastic nonlinear regression model (HNLM) is an important tool in data modeling. In this paper we propose a HNLM considering skew scale mixtures of normal (SSMN) distributions, which allows fitting asymmetric and heavy-tailed data simultaneously. Maximum likelihood (ML) estimation is performed via the expectation-maximization (EM) algorithm. The observed information matrix is derived analytically to account for standard errors. In addition, diagnostic analysis is developed using case-deletion measures and the local influence approach. A simulation study is developed to verify the empirical distribution of the likelihood ratio statistic, the power of the homogeneity of variances test and a study for misspecification of the structure function. The method proposed is also illustrated by analyzing a real dataset.

Bayesian semiparametric modeling for HIV longitudinal data with censoring and skewness.

In biomedical studies, the analysis of longitudinal data based on Gaussian assumptions is common practice. Nevertheless, more often than not, the observed responses are naturally skewed, rendering the use of symmetric mixed effects models inadequate. In addition, it is also common in clinical assays that the patient's responses are subject to some upper and/or lower quantification limit, depending on the diagnostic assays used for their detection. Furthermore, responses may also often present a nonlinear relation with some covariates, such as time. To address the aforementioned three issues, we consider a Bayesian semiparametric longitudinal censored model based on a combination of splines, wavelets, and the skew-normal distribution. Specifically, we focus on the use of splines to approximate the general mean, wavelets for modeling the individual subject trajectories, and on the skew-normal distribution for modeling the random effects. The newly developed method is illustrated through simulated data and real data concerning AIDS/HIV viral loads.

Flexible longitudinal linear mixed models for multiple censored responses data.

In biomedical studies and clinical trials, repeated measures are often subject to some upper and/or lower limits of detection. Hence, the responses are either left or right censored. A complication arises when more than one series of responses is repeatedly collected on each subject at irregular intervals over a period of time and the data exhibit tails heavier than the normal distribution. The multivariate censored linear mixed effect (MLMEC) model is a frequently used tool for a joint analysis of more than one series of longitudinal data. In this context, we develop a robust generalization of the MLMEC based on the scale mixtures of normal distributions. To take into account the autocorrelation existing among irregularly observed measures, a damped exponential correlation structure is considered. For this complex longitudinal structure, we propose an exact estimation procedure to obtain the maximum-likelihood estimates of the fixed effects and variance components using a stochastic approximation of the EM algorithm. This approach allows us to estimate the parameters of interest easily and quickly as well as to obtain the standard errors of the fixed effects, the predictions of unobservable values of the responses, and the log-likelihood function as a byproduct. The proposed method is applied to analyze a set of AIDS data and is examined via a simulation study.

Multivariate longitudinal data analysis with censored and intermittent missing responses.

The multivariate linear mixed model (MLMM) has emerged as an important analytical tool for longitudinal data with multiple outcomes. However, the analysis of multivariate longitudinal data could be complicated by the presence of censored measurements because of a detection limit of the assay in combination with unavoidable missing values arising when subjects miss some of their scheduled visits intermittently. This paper presents a generalization of the MLMM approach, called the MLMM-CM, for a joint analysis of the multivariate longitudinal data with censored and intermittent missing responses. A computationally feasible expectation maximization-based procedure is developed to carry out maximum likelihood estimation within the MLMM-CM framework. Moreover, the asymptotic standard errors of fixed effects are explicitly obtained via the information-based method. We illustrate our methodology by using simulated data and a case study from an AIDS clinical trial. Experimental results reveal that the proposed method is able to provide more satisfactory performance as compared with the traditional MLMM approach.

Geostatistical estimation and prediction for censored responses.

Spatially-referenced geostatistical responses that are collected in environmental sciences research are often subject to detection limits, where the measures are not fully quantifiable. This leads to censoring (left, right, interval, etc), and various ad hoc statistical methods (such as choosing arbitrary detection limits, or data augmentation) are routinely employed during subsequent statistical analysis for inference and prediction. However, inference may be imprecise and sensitive to the assumptions and approximations involved in those arbitrary choices. To circumvent this, we propose an exact maximum likelihood estimation framework of the fixed effects and variance components and related prediction via a novel application of the Stochastic Approximation of the Expectation Maximization (SAEM) algorithm, allowing for easy and elegant estimation of model parameters under censoring. Both simulation studies and application to a real dataset on arsenic concentration collected by the Michigan Department of Environmental Quality demonstrate the advantages of our method over the available naïve techniques in terms of finite sample properties of the estimates, prediction, and robustness. The proposed methods can be implemented using the R package CensSpatial.

Extending multivariate- t linear mixed models for multiple longitudinal data with censored responses and heavy tails.

The analysis of complex longitudinal data is challenging due to several inherent features: (i) more than one series of responses are repeatedly collected on each subject at irregularly occasions over a period of time; (ii) censorship due to limits of quantification of responses arises left- and/or right- censoring effects; (iii) outliers or heavy-tailed noises are possibly embodied within multiple response variables. This article formulates the multivariate- t linear mixed model with censored responses (MtLMMC), which allows the analysts to model such data in the presence of the above described features simultaneously. An efficient expectation conditional maximization either (ECME) algorithm is developed to carry out maximum likelihood estimation of model parameters. The implementation of the E-step relies on the mean and covariance matrix of truncated multivariate- t distributions. To enhance the computational efficiency, two auxiliary permutation matrices are incorporated into the procedure to determine the observed and censored parts of each subject. The proposed methodology is demonstrated via a simulation study and a real application on HIV/AIDS data.

Quantile regression in linear mixed models: a stochastic approximation EM approach.

This paper develops a likelihood-based approach to analyze quantile regression (QR) models for continuous longitudinal data via the asymmetric Laplace distribution (ALD). Compared to the conventional mean regression approach, QR can characterize the entire conditional distribution of the outcome variable and is more robust to the presence of outliers and misspecification of the error distribution. Exploiting the nice hierarchical representation of the ALD, our classical approach follows a Stochastic Approximation of the EM (SAEM) algorithm in deriving exact maximum likelihood estimates of the fixed-effects and variance components. We evaluate the finite sample performance of the algorithm and the asymptotic properties of the ML estimates through empirical experiments and applications to two real life datasets. Our empirical results clearly indicate that the SAEM estimates outperforms the estimates obtained via the combination of Gaussian quadrature and non-smooth optimization routines of the Geraci and Bottai (2014) approach in terms of standard errors and mean square error. The proposed SAEM algorithm is implemented in the R package qrLMM().

Censored linear regression models for irregularly observed longitudinal data using the multivariate- t distribution.

In acquired immunodeficiency syndrome (AIDS) studies it is quite common to observe viral load measurements collected irregularly over time. Moreover, these measurements can be subjected to some upper and/or lower detection limits depending on the quantification assays. A complication arises when these continuous repeated measures have a heavy-tailed behavior. For such data structures, we propose a robust structure for a censored linear model based on the multivariate Student's t-distribution. To compensate for the autocorrelation existing among irregularly observed measures, a damped exponential correlation structure is employed. An efficient expectation maximization type algorithm is developed for computing the maximum likelihood estimates, obtaining as a by-product the standard errors of the fixed effects and the log-likelihood function. The proposed algorithm uses closed-form expressions at the E-step that rely on formulas for the mean and variance of a truncated multivariate Student's t-distribution. The methodology is illustrated through an application to an Human Immunodeficiency Virus-AIDS (HIV-AIDS) study and several simulation studies.

Augmented mixed models for clustered proportion data.

Often in biomedical research, we deal with continuous (clustered) proportion responses ranging between zero and one quantifying the disease status of the cluster units. Interestingly, the study population might also consist of relatively disease-free as well as highly diseased subjects, contributing to proportion values in the interval [0, 1]. Regression on a variety of parametric densities with support lying in (0, 1), such as beta regression, can assess important covariate effects. However, they are deemed inappropriate due to the presence of zeros and/or ones. To evade this, we introduce a class of general proportion density, and further augment the probabilities of zero and one to this general proportion density, controlling for the clustering. Our approach is Bayesian and presents a computationally convenient framework amenable to available freeware. Bayesian case-deletion influence diagnostics based on q-divergence measures are automatic from the Markov chain Monte Carlo output. The methodology is illustrated using both simulation studies and application to a real dataset from a clinical periodontology study.

Influence assessment in censored mixed-effects models using the multivariate Student's-t distribution.

In biomedical studies on HIV RNA dynamics, viral loads generate repeated measures that are often subjected to upper and lower detection limits, and hence these responses are either left- or right-censored. Linear and non-linear mixed-effects censored (LMEC/NLMEC) models are routinely used to analyse these longitudinal data, with normality assumptions for the random effects and residual errors. However, the derived inference may not be robust when these underlying normality assumptions are questionable, especially the presence of outliers and thick-tails. Motivated by this, Matos et al. (2013b) recently proposed an exact EM-type algorithm for LMEC/NLMEC models using a multivariate Student's-t distribution, with closed-form expressions at the E-step. In this paper, we develop influence diagnostics for LMEC/NLMEC models using the multivariate Student's-t density, based on the conditional expectation of the complete data log-likelihood. This partially eliminates the complexity associated with the approach of Cook (1977, 1986) for censored mixed-effects models. The new methodology is illustrated via an application to a longitudinal HIV dataset. In addition, a simulation study explores the accuracy of the proposed measures in detecting possible influential observations for heavy-tailed censored data under different perturbation and censoring schemes.

A mixed-effect model for positive responses augmented by zeros.

In this research article, we propose a class of models for positive and zero responses by means of a zero-augmented mixed regression model. Under this class, we are particularly interested in studying positive responses whose distribution accommodates skewness. At the same time, responses can be zero, and therefore, we justify the use of a zero-augmented mixture model. We model the mean of the positive response in a logarithmic scale and the mixture probability in a logit scale, both as a function of fixed and random effects. Moreover, the random effects link the two random components through their joint distribution and incorporate within-subject correlation because of the repeated measurements and between-subject heterogeneity. A Markov chain Monte Carlo algorithm is tailored to obtain Bayesian posterior distributions of the unknown quantities of interest, and Bayesian case-deletion influence diagnostics based on the q-divergence measure is performed. We apply the proposed method to a dataset from a 24 hour dietary recall study conducted in the city of São Paulo and present a simulation study to evaluate the performance of the proposed methods.

Quantile regression for censored mixed-effects models with applications to HIV studies.

HIV RNA viral load measures are often subjected to some upper and lower detection limits depending on the quantification assays. Hence, the responses are either left or right censored. Linear/nonlinear mixed-effects models, with slight modifications to accommodate censoring, are routinely used to analyze this type of data. Usually, the inference procedures are based on normality (or elliptical distribution) assumptions for the random terms. However, those analyses might not provide robust inference when the distribution assumptions are questionable. In this paper, we discuss a fully Bayesian quantile regression inference using Markov Chain Monte Carlo (MCMC) methods for longitudinal data models with random effects and censored responses. Compared to the conventional mean regression approach, quantile regression can characterize the entire conditional distribution of the outcome variable, and is more robust to outliers and misspecification of the error distribution. Under the assumption that the error term follows an asymmetric Laplace distribution, we develop a hierarchical Bayesian model and obtain the posterior distribution of unknown parameters at the pth level, with the median regression (p = 0.5) as a special case. The proposed procedures are illustrated with two HIV AIDS studies on viral loads that were initially analyzed using the typical normal (censored) mean regression mixed-effects models, as well as a simulation study.

Augmented mixed beta regression models for periodontal proportion data.

Continuous (clustered) proportion data often arise in various domains of medicine and public health where the response variable of interest is a proportion (or percentage) quantifying disease status for the cluster units, ranging between zero and one. However, because of the presence of relatively disease-free as well as heavily diseased subjects in any study, the proportion values can lie in the interval [0,1]. While beta regression can be adapted to assess covariate effects in these situations, its versatility is often challenged because of the presence/excess of zeros and ones because the beta support lies in the interval (0,1). To circumvent this, we augment the probabilities of zero and one with the beta density, controlling for the clustering effect. Our approach is Bayesian with the ability to borrow information across various stages of the complex model hierarchy and produces a computationally convenient framework amenable to available freeware. The marginal likelihood is tractable and can be used to develop Bayesian case-deletion influence diagnostics based on q-divergence measures. Both simulation studies and application to a real dataset from a clinical periodontology study quantify the gain in model fit and parameter estimation over other ad hoc alternatives and provide quantitative insight into assessing the true covariate effects on the proportion responses.