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.     

Two-step and likelihood methods for joint models of longitudinal and survival data

We compare the commonly used two-step methods and joint likelihood method for joint models of longitudinal and survival data via extensive simulations. The longitudinal models include LME, GLMM, and NLME models, and the survival models include Cox models and AFT models. We find that the full likelihood method outperforms the two-step methods for various joint models, but it can be computationally challenging when the dimension of the random effects in the longitudinal model is not small. We thus propose an approximate joint likelihood method which is computationally efficient. We find that the proposed approximation method performs well in the joint model context, and it performs better for more “continuous” longitudinal data. Finally, a real AIDS data example shows that patients with higher initial viral load or lower initial CD4 are more likely to drop out earlier during an anti-HIV treatment.     

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.     

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.     

Marginalized transition random effect models for multivariate longitudinal binary data

Generalized linear models with random effects and/or serial dependence are commonly used to analyze longitudinal data. However, the computation and interpretation of marginal covariate effects can be difficult. This led Heagerty (1999, 2002) to propose models for longitudinal binary data in which a logistic regression is first used to explain the average marginal response. The model is then completed by introducing a conditional regression that allows for the longitudinal, within‐subject, dependence, either via random effects or regressing on previous responses. In this paper, the authors extend the work of Heagerty to handle multivariate longitudinal binary response data using a triple of regression models that directly model the marginal mean response while taking into account dependence across time and across responses. Markov Chain Monte Carlo methods are used for inference. Data from the Iowa Youth and Families Project are used to illustrate the methods.     

A generalized linear mixed model for longitudinal binary data with a marginal logit link function

Longitudinal studies of a binary outcome are common in the health, social, and behavioral sciences. In general, a feature of random effects logistic regression models for longitudinal binary data is that the marginal functional form, when integrated over the distribution of the random effects, is no longer of logistic form. Recently, Wang and Louis (2003) proposed a random intercept model in the clustered binary data setting where the marginal model has a logistic form. An acknowledged limitation of their model is that it allows only a single random effect that varies from cluster to cluster. In this paper, we propose a modification of their model to handle longitudinal data, allowing separate, but correlated, random intercepts at each measurement occasion. The proposed model allows for a flexible correlation structure among the random intercepts, where the correlations can be interpreted in terms of Kendall's τ. For example, the marginal correlations among the repeated binary outcomes can decline with increasing time separation, while the model retains the property of having matching conditional and marginal logit link functions. Finally, the proposed method is used to analyze data from a longitudinal study designed to monitor cardiac abnormalities in children born to HIV-infected women.     

A general joint model for longitudinal measurements and competing risks survival data with heterogeneous random effects

This article studies a general joint model for longitudinal measurements and competing risks survival data. The model consists of a linear mixed effects sub-model for the longitudinal outcome, a proportional cause-specific hazards frailty sub-model for the competing risks survival data, and a regression sub-model for the variance–covariance matrix of the multivariate latent random effects based on a modified Cholesky decomposition. The model provides a useful approach to adjust for non-ignorable missing data due to dropout for the longitudinal outcome, enables analysis of the survival outcome with informative censoring and intermittently measured time-dependent covariates, as well as joint analysis of the longitudinal and survival outcomes. Unlike previously studied joint models, our model allows for heterogeneous random covariance matrices. It also offers a framework to assess the homogeneous covariance assumption of existing joint models. A Bayesian MCMC procedure is developed for parameter estimation and inference. Its performances and frequentist properties are investigated using simulations. A real data example is used to illustrate the usefulness of the approach.     

A joint marginalized multilevel model for longitudinal outcomes

The shared-parameter model and its so-called hierarchical or random-effects extension are widely used joint modeling approaches for a combination of longitudinal continuous, binary, count, missing, and survival outcomes that naturally occurs in many clinical and other studies. A random effect is introduced and shared or allowed to differ between two or more repeated measures or longitudinal outcomes, thereby acting as a vehicle to capture association between the outcomes in these joint models. It is generally known that parameter estimates in a linear mixed model (LMM) for continuous repeated measures or longitudinal outcomes allow for a marginal interpretation, even though a hierarchical formulation is employed. This is not the case for the generalized linear mixed model (GLMM), that is, for non-Gaussian outcomes. The aforementioned joint models formulated for continuous and binary or two longitudinal binomial outcomes, using the LMM and GLMM, will naturally have marginal interpretation for parameters associated with the continuous outcome but a subject-specific interpretation for the fixed effects parameters relating covariates to binary outcomes. To derive marginally meaningful parameters for the binary models in a joint model, we adopt the marginal multilevel model (MMM) due to Heagerty [13] and Heagerty and Zeger [14] and formulate a joint MMM for two longitudinal responses. This enables to (1) capture association between the two responses and (2) obtain parameter estimates that have a population-averaged interpretation for both outcomes. The model is applied to two sets of data. The results are compared with those obtained from the existing approaches such as generalized estimating equations, GLMM, and the model of Heagerty [13]. Estimates were found to be very close to those from single analysis per outcome but the joint model yields higher precision and allows for quantifying the association between outcomes. Parameters were estimated using maximum likelihood. The model is easy to fit using available tools such as the SAS NLMIXED procedure.     

Inferences in dynamic logit models in semi-parametric setup for repeated binary data

Binary dynamic fixed and mixed logit models are extensively studied in the literature. These models are developed to examine the effects of certain fixed covariates through a parametric regression function as a part of the models. However, there are situations where one may like to consider more covariates in the model but their direct effect is not of interest. In this paper we propose a generalization of the existing binary dynamic logit (BDL) models to the semi-parametric longitudinal setup to address this issue of additional covariates. The regression function involved in such a semi-parametric BDL model contains (i) a parametric linear regression function in some primary covariates, and (ii) a non-parametric function in certain secondary covariates. We use a simple semi-parametric conditional quasi-likelihood approach for consistent estimation of the non-parametric function, and a semi-parametric likelihood approach for the joint estimation of the main regression and dynamic dependence parameters of the model. The finite sample performance of the estimation approaches is examined through a simulation study. The asymptotic properties of the estimators are also discussed. The proposed model and the estimation approaches are illustrated by reanalysing a longitudinal infectious disease data.     

Semiparametric log-linear regression for longitudinal measurements subject to outcome-dependent follow-up

A common problem for longitudinal data analyses is that subjects follow-up is irregular, often related to the past outcome or other factors associated with the outcome measure that are not included in the regression model. Analyses unadjusted for outcome-dependent follow-up yield biased estimates. We propose a longitudinal data analysis that can provide consistent estimates in regression models that are subject to outcome-dependent follow-up. We focus on semiparametric marginal log-link regression with arbitrary unspecified baseline function. Based on estimating equations, the proposed class of estimators are root n consistent and asymptotically normal. We present simulation studies that assess the performance of the estimators under finite samples. We illustrate our approach using data from a health services research study.     

Identification of longitudinal biomarkers for survival by a score test derived from a joint model of longitudinal and competing risks data

In this paper, we consider joint modelling of repeated measurements and competing risks failure time data. For competing risks time data, a semiparametric mixture model in which proportional hazards model are specified for failure time models conditional on cause and a multinomial model for the marginal distribution of cause conditional on covariates. We also derive a score test based on joint modelling of repeated measurements and competing risks failure time data to identify longitudinal biomarkers or surrogates for a time to event outcome in competing risks data.     

Bayesian quantile regression for ordinal longitudinal data

Since the pioneering work by Koenker and Bassett [27], quantile regression models and its applications have become increasingly popular and important for research in many areas. In this paper, a random effects ordinal quantile regression model is proposed for analysis of longitudinal data with ordinal outcome of interest. An efficient Gibbs sampling algorithm was derived for fitting the model to the data based on a location-scale mixture representation of the skewed double-exponential distribution. The proposed approach is illustrated using simulated data and a real data example. This is the first work to discuss quantile regression for analysis of longitudinal data with ordinal outcome.     

Different methods for handling incomplete longitudinal binary outcome due to missing at random dropout

This paper compares the performance of weighted generalized estimating equations (WGEEs), multiple imputation based on generalized estimating equations (MI-GEEs) and generalized linear mixed models (GLMMs) for analyzing incomplete longitudinal binary data when the underlying study is subject to dropout. The paper aims to explore the performance of the above methods in terms of handling dropouts that are missing at random (MAR). The methods are compared on simulated data. The longitudinal binary data are generated from a logistic regression model, under different sample sizes. The incomplete data are created for three different dropout rates. The methods are evaluated in terms of bias, precision and mean square error in case where data are subject to MAR dropout. In conclusion, across the simulations performed, the MI-GEE method performed better in both small and large sample sizes. Evidently, this should not be seen as formal and definitive proof, but adds to the body of knowledge about the methods’ relative performance. In addition, the methods are compared using data from a randomized clinical trial.     

A class of finite mixture of quantile regressions with its applications

Mixture of linear regression models provide a popular treatment for modeling nonlinear regression relationship. The traditional estimation of mixture of regression models is based on Gaussian error assumption. It is well known that such assumption is sensitive to outliers and extreme values. To overcome this issue, a new class of finite mixture of quantile regressions (FMQR) is proposed in this article. Compared with the existing Gaussian mixture regression models, the proposed FMQR model can provide a complete specification on the conditional distribution of response variable for each component. From the likelihood point of view, the FMQR model is equivalent to the finite mixture of regression models based on errors following asymmetric Laplace distribution (ALD), which can be regarded as an extension to the traditional mixture of regression models with normal error terms. An EM algorithm is proposed to obtain the parameter estimates of the FMQR model by combining a hierarchical representation of the ALD. Finally, the iterated weighted least square estimation for each mixture component of the FMQR model is derived. Simulation studies are conducted to illustrate the finite sample performance of the estimation procedure. Analysis of an aphid data set is used to illustrate our methodologies.     

Prediction of transplant-free survival in idiopathic pulmonary fibrosis patients using joint models for event times and mixed multivariate longitudinal data

We implement a joint model for mixed multivariate longitudinal measurements, applied to the prediction of time until lung transplant or death in idiopathic pulmonary fibrosis. Specifically, we formulate a unified Bayesian joint model for the mixed longitudinal responses and time-to-event outcomes. For the longitudinal model of continuous and binary responses, we investigate multivariate generalized linear mixed models using shared random effects. Longitudinal and time-to-event data are assumed to be independent conditional on available covariates and shared parameters. A Markov chain Monte Carlo algorithm, implemented in OpenBUGS, is used for parameter estimation. To illustrate practical considerations in choosing a final model, we fit 37 different candidate models using all possible combinations of random effects and employ a deviance information criterion to select a best-fitting model. We demonstrate the prediction of future event probabilities within a fixed time interval for patients utilizing baseline data, post-baseline longitudinal responses, and the time-to-event outcome. The performance of our joint model is also evaluated in simulation studies.     

Survival analysis with long‐term survivors and partially observed covariates

The authors describe a method for fitting failure time mixture models that postulate the existence of both susceptibles and long‐term survivors when covariate data are only partially observed. Their method is based on a joint model that combines a Weibull regression model for the susceptibles, a logistic regression model for the probability of being a susceptible, and a general location model for the distribution of the covariates. A Bayesian approach is taken, and Gibbs sampling is used to fit the model to the incomplete data. An application to clinical data on tonsil cancer and a small Monte Carlo study indicate potential large gains in efficiency over standard complete‐case analysis as well as reasonable performance in a variety of situations.     

Jointly modeling longitudinal proportional data and survival times with an application to the quality of life data in a breast cancer trial

Motivated by the joint analysis of longitudinal quality of life data and recurrence free survival times from a cancer clinical trial, we present in this paper two approaches to jointly model the longitudinal proportional measurements, which are confined in a finite interval, and survival data. Both approaches assume a proportional hazards model for the survival times. For the longitudinal component, the first approach applies the classical linear mixed model to logit transformed responses, while the second approach directly models the responses using a simplex distribution. A semiparametric method based on a penalized joint likelihood generated by the Laplace approximation is derived to fit the joint model defined by the second approach. The proposed procedures are evaluated in a simulation study and applied to the analysis of breast cancer data motivated this research.     

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.     

Simulation-based Inference in a Zero-inflated Bernoulli Regression Model

The logistic regression model has become a standard tool to investigate the relationship between a binary outcome and a set of potential predictors. When analyzing binary data, it often arises that the observed proportion of zeros is greater than expected under the postulated logistic model. Zero-inflated binomial (ZIB) models have been developed to fit binary data that contain too many zeros. Maximum likelihood estimators in these models have been proposed and their asymptotic properties established. Several aspects of ZIB models still deserve attention however, such as the estimation of odds-ratios and event probabilities. In this article, we propose estimators of these quantities and we investigate their properties both theoretically and via simulations. Based on these results, we provide recommendations about the range of conditions (minimum sample size, maximum proportion of zeros in excess) under which a reliable statistical inference on the odds-ratios and event probabilities can be obtained in a ZIB regression model. A real-data example illustrates the proposed estimators.     

Joint analysis of longitudinal measurements and survival times with a cure fraction based on partly linear mixed and semiparametric cure models

In a joint analysis of longitudinal quality of life (QoL) scores and relapse-free survival (RFS) times from a clinical trial on early breast cancer conducted by the Canadian Cancer Trials Group, we observed a complicated trajectory of QoL scores and existence of long-term survivors. Motivated by this observation, we proposed in this paper a flexible joint model for the longitudinal measurements and survival times. A partly linear mixed effect model is used to capture the complicated but smooth trajectory of longitudinal measurements and approximated by B-splines and a semiparametric mixture cure model with the B-spline baseline hazard to model survival times with a cure fraction. These two models are linked by shared random effects to explore the dependence between longitudinal measurements and survival times. A semiparametric inference procedure with an EM algorithm is proposed to estimate the parameters in the joint model. The performance of proposed procedures are evaluated by simulation studies and through the application to the analysis of data from the clinical trial which motivated this research.