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.     

Bayesian epidemic models for spatially aggregated count data

Epidemic data often possess certain characteristics, such as the presence of many zeros, the spatial nature of the disease spread mechanism, environmental noise, serial correlation and dependence on time‐varying factors. This paper addresses these issues via suitable Bayesian modelling. In doing so, we utilize a general class of stochastic regression models appropriate for spatio‐temporal count data with an excess number of zeros. The developed regression framework does incorporate serial correlation and time‐varying covariates through an Ornstein–Uhlenbeck process formulation. In addition, we explore the effect of different priors, including default options and variations of mixtures of g‐priors. The effect of different distance kernels for the epidemic model component is investigated. We proceed by developing branching process‐based methods for testing scenarios for disease control, thus linking traditional epidemiological models with stochastic epidemic processes, useful in policy‐focused decision making. The approach is illustrated with an application to a sheep pox dataset from the Evros region, Greece. Copyright © 2017 John Wiley & Sons, Ltd.     

Variational methods for fitting complex Bayesian mixed effects models to health data

We consider approximate inference methods for Bayesian inference to longitudinal and multilevel data within the context of health science studies. The complexity of these grouped data often necessitates the use of sophisticated statistical models. However, the large size of these data can pose significant challenges for model fitting in terms of computational speed and memory storage. Our methodology is motivated by a study that examines trends in cesarean section rates in the largest state of Australia, New South Wales, between 1994 and 2010. We propose a group‐specific curve model that encapsulates the complex nonlinear features of the overall and hospital‐specific trends in cesarean section rates while taking into account hospital variability over time. We use penalized spline‐based smooth functions that represent trends and implement a fully mean field variational Bayes approach to model fitting. Our mean field variational Bayes algorithms allow a fast (up to the order of thousands) and streamlined analytical approximate inference for complex mixed effects models, with minor degradation in accuracy compared with the standard Markov chain Monte Carlo methods. Copyright © 2015 John Wiley & Sons, Ltd.     

BAREB: A Bayesian repulsive biclustering model for periodontal data

Preventing periodontal diseases (PD) and maintaining the structure and function of teeth are important goals for personal oral care. To understand the heterogeneity in patients with diverse PD patterns, we develop a Bayesian repulsive biclustering method that can simultaneously cluster the PD patients and their tooth sites after taking the patient- and site-level covariates into consideration. BAREB uses the determinantal point process prior to induce diversity among different biclusters to facilitate parsimony and interpretability. Since PD progression is hypothesized to be spatially referenced, BAREB factors in the spatial dependence among tooth sites. In addition, since PD is the leading cause for tooth loss, the missing data mechanism is nonignorable. Such nonrandom missingness is incorporated into BAREB. For the posterior inference, we design an efficient reversible jump Markov chain Monte Carlo sampler. Simulation studies show that BAREB is able to accurately estimate the biclusters, and compares favorably to alternatives. For real world application, we apply BAREB to a dataset from a clinical PD study, and obtain desirable and interpretable results. A major contribution of this article is the Rcpp implementation of our methodology, available in the R package BAREB .     

Copula-based regression models for a bivariate mixed discrete and continuous outcome

This paper is concerned with regression models for correlated mixed discrete and continuous outcomes constructed using copulas. Our approach entails specifying marginal regression models for the outcomes, and combining them via a copula to form a joint model. Specifically, we propose marginal regression models (e.g. generalized linear models) to link the outcomes' marginal means to covariates. To account for associations between outcomes, we adopt the Gaussian copula to indirectly specify their joint distributions. Our approach has two advantages over current methods: one, regression parameters in models for both outcomes are marginally meaningful, and two, the association is 'margin-free', in the sense that it is characterized by the copula alone. By assuming a latent variable framework to describe discrete outcomes, the copula used still uniquely determines the joint distribution. In addition, association measures between outcomes can be interpreted in the usual way. We report results of simulations concerning the bias and efficiency of two likelihood-based estimation methods for the model. Finally, we illustrate the model using data on burn injuries.     

Linear mixed models for skew‐normal/independent bivariate responses with an application to periodontal disease

Bivariate clustered (correlated) data often encountered in epidemiological and clinical research are routinely analyzed under a linear mixed model (LMM) framework with underlying normality assumptions of the random effects and within‐subject errors. However, such normality assumptions might be questionable if the data set particularly exhibits skewness and heavy tails. Using a Bayesian paradigm, we use the skew‐normal/independent (SNI) distribution as a tool for modeling clustered data with bivariate non‐normal responses in an LMM framework. The SNI distribution is an attractive class of asymmetric thick‐tailed parametric structure which includes the skew‐normal distribution as a special case. We assume that the random effects follow multivariate SNI distributions and the random errors follow SNI distributions which provides substantial robustness over the symmetric normal process in an LMM framework. Specific distributions obtained as special cases, viz. the skew‐t, the skew‐slash and the skew‐contaminated normal distributions are compared, along with the default skew‐normal density. The methodology is illustrated through an application to a real data which records the periodontal health status of an interesting population using periodontal pocket depth (PPD) and clinical attachment level (CAL). Copyright © 2010 John Wiley & Sons, Ltd.     

Flexible regression models for ROC and risk analysis,with or without a gold standard

A novel semiparametric regression model is developed for evaluating the covariate‐specific accuracy of a continuous medical test or biomarker. Ideally, studies designed to estimate or compare medical test accuracy will use a separate, flawless gold‐standard procedure to determine the true disease status of sampled individuals. We treat this as a special case of the more complicated and increasingly common scenario in which disease status is unknown because a gold‐standard procedure does not exist or is too costly or invasive for widespread use. To compensate for missing data on disease status, covariate information is used to discriminate between diseased and healthy units. We thus model the probability of disease as a function of ‘disease covariates’. In addition, we model test/biomarker outcome data to depend on ‘test covariates’, which provides researchers the opportunity to quantify the impact of covariates on the accuracy of a medical test. We further model the distributions of test outcomes using flexible semiparametric classes. An important new theoretical result demonstrating model identifiability under mild conditions is presented. The modeling framework can be used to obtain inferences about covariate‐specific test accuracy and the probability of disease based on subject‐specific disease and test covariate information. The value of the model is illustrated using multiple simulation studies and data on the age‐adjusted ability of soluble epidermal growth factor receptor – a ubiquitous serum protein – to serve as a biomarker of lung cancer in men. SAS code for fitting the model is provided. Copyright © 2015 John Wiley & Sons, Ltd.     

A power series beta Weibull regression model for predicting breast carcinoma

The postmastectomy survival rates are often based on previous outcomes of large numbers of women who had a disease, but they do not accurately predict what will happen in any particular patient's case. Pathologic explanatory variables such as disease multifocality, tumor size, tumor grade, lymphovascular invasion, and enhanced lymph node staining are prognostically significant to predict these survival rates. We propose a new cure rate survival regression model for predicting breast carcinoma survival in women who underwent mastectomy. We assume that the unknown number of competing causes that can influence the survival time is given by a power series distribution and that the time of the tumor cells left active after the mastectomy for metastasizing follows the beta Weibull distribution. The new compounding regression model includes as special cases several well‐known cure rate models discussed in the literature. The model parameters are estimated by maximum likelihood. Further, for different parameter settings, sample sizes, and censoring percentages, some simulations are performed. We derive the appropriate matrices for assessing local influences on the parameter estimates under different perturbation schemes and present some ways to assess local influences. The potentiality of the new regression model to predict accurately breast carcinoma mortality is illustrated by means of real data. Copyright © 2015 John Wiley & Sons, Ltd.     

Marginal regression models with time-varying coefficients for recurrent event data

Recurrent event data arise frequently from medical research. Examples include repeated infections, recurrence of tumors, relapse of leukemia, repeated hospitalizations, recurrence of symptoms of a disease, and so on. In the analysis of recurrent event data, the proportional rates model assumes that the regression coefficients are time invariant. In reality, however, these parameters may vary over time, and the temporal covariate effects on the event process are of great interest. In this article, we formulate a class of semiparametric marginal rates models, which incorporate a mixture of time-varying and time-independent parameters, to analyze recurrent event data. For statistical inference on model parameters, an estimation procedure is developed and asymptotic properties of the proposed estimators are established. In addition, we develop tests for investigating whether or not covariate effects vary with time. The finite-sample behaviors of the proposed methods are examined in simulation studies. An example of application of the proposed methodology is illustrated on a set of data from a clinic study on chronic granulomatous disease.     

Model comparison of generalized linear mixed models

Generalized linear mixed models (GLMMs) have been widely appreciated in biological and medical research. Maximum likelihood estimation has received a great deal of attention. Comparatively, not much has been done on model comparison or hypotheses testing. In this article, we propose a path sampling procedure to compute the observed-data log-likelihood function, so that the Bayesian information criterion (BIC) can be applied to model comparison or hypothesis testing. Advantages of the proposed path sampling procedure are discussed. Two medical data sets are analysed for providing illustrative examples of the proposed methodology.     

Application of functional ANOVA models for hazard regression to the Hisayama data

A methodology for modeling covariate effects on the time-to-event data is developed. The covariates are allowed to be time dependent and their effects are modeled using polynomial splines in order to account for possibly non-linear effects. The methodology is applied to examine the effects on the incidence brain infarction based on a cohort study in Hisayama, Japan. The results indicate that at least two non-linear effects are significant (body mass index and systolic blood pressure) and there is a time-varying drug effect. The resulting significant risk factors are assessed by the proposed method that is more flexible and hence less biased than the traditional procedures where linear effects are imposed. These results are extremely important to the local medical investigation. In particular, more insight has been gained by examining the non-linear effects.     

Finite mixture varying coefficient models for analyzing longitudinal heterogenous data

This paper aims to develop a mixture model to study heterogeneous longitudinal data on the treatment effect of heroin use from a California Civil Addict Program. Each component of the mixture is characterized by a varying coefficient mixed effect model. We use the Bayesian P-splines approach to approximate the varying coefficient functions. We develop Markov chain Monte Carlo algorithms to estimate the smooth functions, unknown parameters, and latent variables in the model. We use modified deviance information criterion to determine the number of components in the mixture. A simulation study demonstrates that the modified deviance information criterion selects the correct number of components and the estimation of unknown quantities is accurate. We apply the proposed model to the heroin treatment study. Furthermore, we identify heterogeneous longitudinal patterns.     

Semi-parametric regression models for cost-effectiveness analysis: improving the efficiency of estimation from censored data

In a cost-effectiveness analysis using clinical trial data, estimates of the between-treatment difference in mean cost and mean effectiveness are needed. Several methods for handling censored data have been suggested. One of them is inverse-probability weighting, and has the advantage that it can also be applied to estimate the parameters from a linear regression of the mean. Such regression models can potentially estimate the treatment contrast more precisely, since some of the residual variance can be explained by baseline covariates. The drawback, however, is that inverse-probability weighting may not be efficient. Using existing results on semi-parametric efficiency, this paper derives the semi-parametric efficient parameter estimates for regression of mean cost, mean quality-adjusted survival time and mean survival time. The performance of these estimates is evaluated through a simulation study. Applying both the new estimators and the inverse-probability weighted estimators to the results of the EVALUATE trial showed that the new estimators achieved a halving of the variance of the estimated treatment contrast for cost. Some practical suggestions for choosing an estimator are offered.     

Identifying and interpreting subgroups in health care utilization data with count mixture regression models

Inpatient care is a large share of total health care spending, making analysis of inpatient utilization patterns an important part of understanding what drives health care spending growth. Common features of inpatient utilization measures such as length of stay and spending include zero inflation, overdispersion, and skewness, all of which complicate statistical modeling. Moreover, latent subgroups of patients may have distinct patterns of utilization and relationships between that utilization and observed covariates. In this work, we apply and compare likelihood-based and parametric Bayesian mixtures of negative binomial and zero-inflated negative binomial regression models. In a simulation, we find that the Bayesian approach finds the true number of mixture components more accurately than using information criteria to select among likelihood-based finite mixture models. When we apply the models to data on hospital lengths of stay for patients with lung cancer, we find distinct subgroups of patients with different means and variances of hospital days, health and treatment covariates, and relationships between covariates and length of stay.     

Partitioned GMM logistic regression models for longitudinal data

Correlation is inherent in longitudinal studies due to the repeated measurements on subjects, as well as due to time-dependent covariates in the study. In the National Longitudinal Study of Adolescent to Adult Health (Add Health), data were repeatedly collected on children in grades 7-12 across four waves. Thus, observations obtained on the same adolescent were correlated, while predictors were correlated with current and future outcomes such as obesity status, among other health issues. Previous methods, such as the generalized method of moments (GMM) approach have been proposed to estimate regression coefficients for time-dependent covariates. However, these approaches combined all valid moment conditions to produce an averaged parameter estimate for each covariate and thus assumed that the effect of each covariate on the response was constant across time. This assumption is not necessarily optimal in applications such as Add Health or health-related data. Thus, we depart from this assumption and instead use the Partitioned GMM approach to estimate multiple coefficients for the data based on different time periods. These extra regression coefficients are obtained using a partitioning of the moment conditions pertaining to each respective relationship. This approach offers a deeper understanding and appreciation into the effect of each covariate on the response. We conduct simulation studies, as well as analyses of obesity in Add Health, rehospitalization in Medicare data, and depression scores in a clinical study. The Partitioned GMM methods exhibit benefits over previously proposed models with improved insight into the nonconstant relationships realized when analyzing longitudinal data.     

Robust fit of Bayesian mixed effects regression models with application to colony forming unit count in tuberculosis research

Early bactericidal activity of tuberculosis drugs is conventionally assessed using statistical regression modeling of colony forming unit (CFU) counts over time. Typically, most CFU counts deviate little from the regression curve, but gross outliers due to erroneous sputum sampling are occasionally present and can markedly influence estimates of the rate of change in CFU count, which is the parameter of interest. A recently introduced Bayesian nonlinear mixed effects regression model was adapted to offer a robust approach that accommodates both outliers and potential skewness in the data. At its most general, the proposed regression model fits the skew Student t distribution to residuals and random coefficients. Deviance information criterion statistics and compound Laplace‐Metropolis marginal likelihoods were used to discriminate between alternative Bayesian nonlinear mixed effects regression models. We present a relatively easy method to calculate the marginal likelihoods required to determine compound Laplace‐Metropolis marginal likelihoods, by adapting methods available in currently available statistical software. The robust methodology proposed in this paper was applied to data from 6 clinical trials. The results provide strong evidence that the distribution of CFU count is often heavy tailed and negatively skewed (suggesting the presence of outliers). Therefore, we recommend that robust regression models, such as those proposed here, should be fitted to CFU count.     

Goodness-of-fit tests for ordinal response regression models

It is well documented that the commonly used Pearson chi-square and deviance statistics are not adequate for assessing goodness-of-fit in logistic regression models when continuous covariates are modelled. In recent years, several methods have been proposed which address this shortcoming in the binary logistic regression setting or assess model fit differently. However, these techniques have typically not been extended to the ordinal response setting and few techniques exist to assess model fit in that case. We present the modified Pearson chi-square and deviance tests that are appropriate for assessing goodness-of-fit in ordinal response models when both categorical and continuous covariates are present. The methods have good power to detect omitted interaction terms and reasonable power to detect failure of the proportional odds assumption or modelling the wrong functional form of a continuous covariate. These tests also provide immediate information as to where a model may not fit well. In addition, the methods are simple to understand and implement, and are non-specific. That is, they do not require prespecification of a type of lack-of-fit to detect.     

Diagnostics for repeated measurements in linear mixed effects models

Most currently available methods for detecting discordant subjects and observations in linear mixed effects model fits adapt existing methods for single‐level regression data. The most common methods are generalizations of deletion‐based approaches, primarily Cook's distance. This article describes the limitations of modifications to Cook's distance and local influence, and suggests a new nondeletion subject‐level method, studentized residual sum of squares (TRSS) plots. We also suggest a new observation‐level deletion method that detects discordant observations as an application of TRSS plots. The proposed method provides greater information on repeated measurements by utilizing revised residuals and efficiently evaluating the effect of discordant subjects and observations on the estimation of parameters including variance components. We compare the performance of the proposed methods with current methods by using the orthodontic growth data: a longitudinal dataset with 27 subjects each observed four times. TRSS plots successfully identified discordant subjects that were missed by modified Cook's distance methods and the local influence approach. Extensions of TRSS plots are also described. Copyright © 2012 John Wiley & Sons, Ltd.     

An assessment of estimation methods for generalized linear mixed models with binary outcomes

Two main classes of methodology have been developed for addressing the analytical intractability of generalized linear mixed models: likelihood‐based methods and Bayesian methods. Likelihood‐based methods such as the penalized quasi‐likelihood approach have been shown to produce biased estimates especially for binary clustered data with small clusters sizes. More recent methods using adaptive Gaussian quadrature perform well but can be overwhelmed by problems with large numbers of random effects, and efficient algorithms to better handle these situations have not yet been integrated in standard statistical packages. Bayesian methods, although they have good frequentist properties when the model is correct, are known to be computationally intensive and also require specialized code, limiting their use in practice. In this article, we introduce a modification of the hybrid approach of Capanu and Begg, 2011, Biometrics 67 , 371–380, as a bridge between the likelihood‐based and Bayesian approaches by employing Bayesian estimation for the variance components followed by Laplacian estimation for the regression coefficients. We investigate its performance as well as that of several likelihood‐based methods in the setting of generalized linear mixed models with binary outcomes. We apply the methods to three datasets and conduct simulations to illustrate their properties. Simulation results indicate that for moderate to large numbers of observations per random effect, adaptive Gaussian quadrature and the Laplacian approximation are very accurate, with adaptive Gaussian quadrature preferable as the number of observations per random effect increases. The hybrid approach is overall similar to the Laplace method, and it can be superior for data with very sparse random effects. Copyright © 2013 John Wiley & Sons, Ltd.     

Spatial small area smoothing models for handling survey data with nonresponse

Spatial smoothing models play an important role in the field of small area estimation. In the context of complex survey designs, the use of design weights is indispensable in the estimation process. Recently, efforts have been made in these spatial smoothing models, in order to obtain reliable estimates of the spatial trend. However, the concept of missing data remains a prevalent problem in the context of spatial trend estimation as estimates are potentially subject to bias. In this paper, we focus on spatial health surveys where the available information consists of a binary response and its associated design weight. Furthermore, we investigate the impact of nonresponse as missing data on a range of spatial models for different missingness mechanisms and different degrees of missingness by means of an extensive simulation study. The computations were performed in R, using INLA and other existing packages. The results show that weight adjustment to correct for missingness has a beneficial effect on the bias in the missing at random setting for all models. Furthermore, we estimate the geographical distribution of perceived health at the district level based on the Belgian Health Interview Survey (2001). Copyright © 2017 John Wiley & Sons, Ltd.