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.     

Joint modeling of hierarchically clustered and overdispersed non‐gaussian continuous outcomes for comet assay data

Multivariate longitudinal or clustered data are commonly encountered in clinical trials and toxicological studies. Typically, there is no single standard endpoint to assess the toxicity or efficacy of the compound of interest, but co‐primary endpoints are available to assess the toxic effects or the working of the compound. Modeling the responses jointly is thus appealing to draw overall inferences using all responses and to capture the association among the responses. Non‐Gaussian outcomes are often modeled univariately using exponential family models. To accommodate both the overdispersion and hierarchical structure in the data, Molenberghs et al. A family of generalized linear models for repeated measures with normal and conjugate random effects. Statistical Science 2010; 25:325–347 proposed using two separate sets of random effects. This papers considers a model for multivariate data with hierarchically clustered and overdispersed non‐Gaussian data. Gamma random effect for the over‐dispersion and normal random effects for the clustering in the data are being used. The two outcomes are jointly analyzed by assuming that the normal random effects for both endpoints are correlated. The association structure between the response is analytically derived. The fit of the joint model to data from a so‐called comet assay are compared with the univariate analysis of the two outcomes. Copyright © 2012 John Wiley & Sons, Ltd.     

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.     

Empirical Bayes estimates for correlated hierarchical data with overdispersion

An extension of the generalized linear mixed model was constructed to simultaneously accommodate overdispersion and hierarchies present in longitudinal or clustered data. This so‐called combined model includes conjugate random effects at observation level for overdispersion and normal random effects at subject level to handle correlation, respectively. A variety of data types can be handled in this way, using different members of the exponential family. Both maximum likelihood and Bayesian estimation for covariate effects and variance components were proposed. The focus of this paper is the development of an estimation procedure for the two sets of random effects. These are necessary when making predictions for future responses or their associated probabilities. Such (empirical) Bayes estimates will also be helpful in model diagnosis, both when checking the fit of the model as well as when investigating outlying observations. The proposed procedure is applied to three datasets of different outcome types. Copyright © 2014 John Wiley & Sons, Ltd.     

Functional approach of flexibly modelling generalized longitudinal data and survival time

We propose a flexible functional approach for modelling generalized longitudinal data and survival time using principal components. In the proposed model the longitudinal observations can be continuous or categorical data, such as Gaussian, binomial or Poisson outcomes. We generalize the traditional joint models that treat categorical data as continuous data by using some transformations, such as CD4 counts. The proposed model is data-adaptive, which does not require pre-specified functional forms for longitudinal trajectories and automatically detects characteristic patterns. The longitudinal trajectories observed with measurement error or random error are represented by flexible basis functions through a possibly nonlinear link function, combining dimension reduction techniques resulting from functional principal component (FPC) analysis. The relationship between the longitudinal process and event history is assessed using a Cox regression model. Although the proposed model inherits the flexibility of non-parametric methods, the estimation procedure based on the EM algorithm is still parametric in computation, and thus simple and easy to implement. The computation is simplified by dimension reduction for random coefficients or FPC scores. An iterative selection procedure based on Akaike information criterion (AIC) is proposed to choose the tuning parameters, such as the knots of spline basis and the number of FPCs, so that appropriate degree of smoothness and fluctuation can be addressed. The effectiveness of the proposed approach is illustrated through a simulation study, followed by an application to longitudinal CD4 counts and survival data which were collected in a recent clinical trial to compare the efficiency and safety of two antiretroviral drugs.     

MODELLING TRUNCATED AND CLUSTERED COUNT DATA

Count response data often exhibit departures from the assumptions of standard Poisson generalized linear models. In particular, cluster level correlation of the data and truncation at zero are two common characteristics of such data. This paper describes a random components truncated Poisson model that can be applied to clustered and zero‐truncated count data. Residual maximum likelihood method estimators for the parameters of this model are developed and their use is illustrated using a dataset of non‐zero counts of sheets with edge‐strain defects in iron sheets produced by the Mobarekeh Steel Complex, Iran. The paper also reports on a small‐scale simulation study that supports the estimation procedure.     

On the Correlation Structure of Gaussian Copula Models for Geostatistical Count Data

We describe a class of random field models for geostatistical count data based on Gaussian copulas. Unlike hierarchical Poisson models often used to describe this type of data, Gaussian copula models allow a more direct modelling of the marginal distributions and association structure of the count data. We study in detail the correlation structure of these random fields when the family of marginal distributions is either negative binomial or zero‐inflated Poisson; these represent two types of overdispersion often encountered in geostatistical count data. We also contrast the correlation structure of one of these Gaussian copula models with that of a hierarchical Poisson model having the same family of marginal distributions, and show that the former is more flexible than the latter in terms of range of feasible correlation, sensitivity to the mean function and modelling of isotropy. An exploratory analysis of a dataset of Japanese beetle larvae counts illustrate some of the findings. All of these investigations show that Gaussian copula models are useful alternatives to hierarchical Poisson models, specially for geostatistical count data that display substantial correlation and small overdispersion.     

Estimated estimating equations: semiparametric inference for clustered and longitudinal data

Summary.  We introduce a flexible marginal modelling approach for statistical inference for clustered and longitudinal data under minimal assumptions. This estimated estimating equations approach is semiparametric and the proposed models are fitted by quasi-likelihood regression, where the unknown marginal means are a function of the fixed effects linear predictor with unknown smooth link, and variance–covariance is an unknown smooth function of the marginal means. We propose to estimate the nonparametric link and variance–covariance functions via smoothing methods, whereas the regression parameters are obtained via the estimated estimating equations. These are score equations that contain nonparametric function estimates. The proposed estimated estimating equations approach is motivated by its flexibility and easy implementation. Moreover, if data follow a generalized linear mixed model, with either a specified or an unspecified distribution of random effects and link function, the model proposed emerges as the corresponding marginal (population-average) version and can be used to obtain inference for the fixed effects in the underlying generalized linear mixed model, without the need to specify any other components of this generalized linear mixed model. Among marginal models, the estimated estimating equations approach provides a flexible alternative to modelling with generalized estimating equations. Applications of estimated estimating equations include diagnostics and link selection. The asymptotic distribution of the proposed estimators for the model parameters is derived, enabling statistical inference. Practical illustrations include Poisson modelling of repeated epileptic seizure counts and simulations for clustered binomial responses.     

Hierarchical Bayes estimation in small area estimation using cross-sectional and time-series data

Bayesian methods have been extensively used in small area estimation. A linear model incorporating autocorrelated random effects and sampling errors was previously proposed in small area estimation using both cross-sectional and time-series data in the Bayesian paradigm. There are, however, many situations that we have time-related counts or proportions in small area estimation; for example, monthly dataset on the number of incidence in small areas. This article considers hierarchical Bayes generalized linear models for a unified analysis of both discrete and continuous data with incorporating cross-sectional and time-series data. The performance of the proposed approach is evaluated through several simulation studies and also by a real dataset.     

A latent variable model for analyzing mixed longitudinal (k,l)-inflated count and ordinal responses

A random effects model for analyzing mixed longitudinal count and ordinal data is presented where the count response is inflated in two points (k and l) and an (k,l)-Inflated Power series distribution is used as its distribution. A full likelihood-based approach is used to obtain maximum likelihood estimates of parameters of the model. For data with non-ignorable missing values models with probit model for missing mechanism are used.The dependence between longitudinal sequences of responses and inflation parameters are investigated using a random effects approach. Also, to investigate the correlation between mixed ordinal and count responses of each individuals at each time, a shared random effect is used. In order to assess the performance of the model, a simulation study is performed for a case that the count response has (k,l)-Inflated Binomial distribution. Performance comparisons of count-ordinal random effect model, Zero-Inflated ordinal random effects model and (k,l)-Inflated ordinal random effects model are also given. The model is applied to a real social data set from the first two waves of the national longitudinal study of adolescent to adult health (Add Health study). In this data set, the joint responses are the number of days in a month that each individual smoked as the count response and the general health condition of each individual as the ordinal response. For the count response there is incidence of excess values of 0 and 30.     

Testing homogeneity in clustered (longitudinal) count data regression model with over-dispersion

Clustered (longitudinal) count data arise in many bio-statistical practices in which a number of repeated count responses are observed on a number of individuals. The repeated observations may also represent counts over time from a number of individuals. One important problem that arises in practice is to test homogeneity within clusters (individuals) and between clusters (individuals). As data within clusters are observations of repeated responses, the count data may be correlated and/or over-dispersed. For over-dispersed count data with unknown over-dispersion parameter we derive two score tests by assuming a random intercept model within the framework of (i) the negative binomial mixed effects model and (ii) the double extended quasi-likelihood mixed effects model (Lee and Nelder, 2001). These two statistics are much simpler than a statistic derived by Jacqmin-Gadda and Commenges (1995) under the framework of the over-dispersed generalized linear model. The first statistic takes the over-dispersion more directly into the model and therefore is expected to do well when the model assumptions are satisfied and the other statistic is expected to be robust. Simulations show superior level property of the statistics derived under the negative binomial and double extended quasi-likelihood model assumptions. A data set is analyzed and a discussion is given.     

Posterior consistency of random effects models for binary data

In longitudinal studies or clustered designs, observations for each subject or cluster are dependent and exhibit intra-correlation. To account for this dependency, we consider Bayesian analysis for conditionally specified models, so-called generalized linear mixed model. In nonlinear mixed models, the maximum likelihood estimator of the regression coefficients is typically a function of the distribution of random effects, and so the misspecified choice of the distribution of random effects can cause bias in the estimator. To avoid the problem of the misspecification of the distribution of random effects, one can resort in nonparametric approaches. We give sufficient conditions for posterior consistency of the distribution of random effects as well as regression coefficients.     

Fully exponential Laplace approximations for the joint modelling of survival and longitudinal data

Summary.  A common objective in longitudinal studies is the joint modelling of a longitudinal response with a time-to-event outcome. Random effects are typically used in the joint modelling framework to explain the interrelationships between these two processes. However, estimation in the presence of random effects involves intractable integrals requiring numerical integration. We propose a new computational approach for fitting such models that is based on the Laplace method for integrals that makes the consideration of high dimensional random-effects structures feasible. Contrary to the standard Laplace approximation, our method requires much fewer repeated measurements per individual to produce reliable results.     

Analysis of mixed correlated bivariate zero-inflated count and (k,l)-inflated beta responses with application to social network datasets

This paper presents a new model that monitors the basic network formation mechanisms via the attributes through time. It considers the issue of joint modeling of longitudinal inflated (0, 1)-support continuous and inflated count response variables. For joint model of mentioned response variables, a correlated generalized linear mixed model is studied. The fraction response is inflated in two points k and l (k < l) and a k and l inflated beta distribution is introduced to use as its distribution. Also, the count response is inflated in zero and we use some members of zero-inflated power series distributions, hurdle-at-zero, members of zero-inflated double power series distributions and zero-inflated generalized Poisson distribution as our count response distribution. A full likelihood-based approach is used to yield maximum likelihood estimates of the model parameters and the model is applied to a real social network obtained from an observational study where the rate of the ith node’s responsiveness to the jth node and the number of arrows or edges with some specific characteristics from the ith node to the jth node are the correlated inflated (0, 1)-support continuous and inflated count response variables, respectively. The effect of the sender and receiver positions in an office environment on the responses are investigated simultaneously.     

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.     

Joint (k,l)-hurdle random effects models for mixed longitudinal power series and normal outcomes

A random effects model for analyzing mixed longitudinal normal and count outcomes with and without the possibility of non ignorable missing outcomes is presented. The count response is inflated in two points (k and l) and the (k, l)-Hurdle power series is used as its distribution. The new distribution contains, as special submodels, several important distributions which are discussed, such as (k, l)-Hurdle Poisson and (k, l)-Hurdle negative binomial and (k, l)-Hurdle binomial distributions among others. Random effects are used to take into account the correlation between longitudinal outcomes and inflation parameters. A full likelihood-based approach is used to yield maximum likelihood estimates of the model parameters. A simulation study is performed in which for count outcome (k, l)-Hurdle Poisson, (k, l)-Hurdle negative binomial and (k, l)-Hurdle binomial distributions are considered. To illustrate the application of such modelling the longitudinal data of body mass index and the number of joint damage are analyzed.     

An extended random-effects approach to modeling repeated, overdispersed count data

Non-Gaussian outcomes are often modeled using members of the so-called exponential family. The Poisson model for count data falls within this tradition. The family in general, and the Poisson model in particular, are at the same time convenient since mathematically elegant, but in need of extension since often somewhat restrictive. Two of the main rationales for existing extensions are (1) the occurrence of overdispersion, in the sense that the variability in the data is not adequately captured by the model's prescribed mean-variance link, and (2) the accommodation of data hierarchies owing to, for example, repeatedly measuring the outcome on the same subject, recording information from various members of the same family, etc. There is a variety of overdispersion models for count data, such as, for example, the negative-binomial model. Hierarchies are often accommodated through the inclusion of subject-specific, random effects. Though not always, one conventionally assumes such random effects to be normally distributed. While both of these issues may occur simultaneously, models accommodating them at once are less than common. This paper proposes a generalized linear model, accommodating overdispersion and clustering through two separate sets of random effects, of gamma and normal type, respectively. This is in line with the proposal by Booth et al. (Stat Model 3:179-181, 2003). The model extends both classical overdispersion models for count data (Breslow, Appl Stat 33:38-44, 1984), in particular the negative binomial model, as well as the generalized linear mixed model (Breslow and Clayton, J Am Stat Assoc 88:9-25, 1993). Apart from model formulation, we briefly discuss several estimation options, and then settle for maximum likelihood estimation with both fully analytic integration as well as hybrid between analytic and numerical integration. The latter is implemented in the SAS procedure NLMIXED. The methodology is applied to data from a study in epileptic seizures.     

A Simulation-based Goodness-of-fit Test for Random Effects in Generalized Linear Mixed Models

Abstract.  The goodness-of-fit of the distribution of random effects in a generalized linear mixed model is assessed using a conditional simulation of the random effects conditional on the observations. Provided that the specified joint model for random effects and observations is correct, the marginal distribution of the simulated random effects coincides with the assumed random effects distribution. In practice, the specified model depends on some unknown parameter which is replaced by an estimate. We obtain a correction for this by deriving the asymptotic distribution of the empirical distribution function obtained from the conditional sample of the random effects. The approach is illustrated by simulation studies and data examples.     

Fast two-stage estimator for clustered count data with overdispersion

Clustered count data are commonly analysed by the generalized linear mixed model (GLMM). Here, the correlation due to clustering and some overdispersion is captured by the inclusion of cluster-specific normally distributed random effects. Often, the model does not capture the variability completely. Therefore, the GLMM can be extended by including a set of gamma random effects. Routinely, the GLMM is fitted by maximizing the marginal likelihood. However, this process is computationally intensive. Although feasible with medium to large data, it can be too time-consuming or computationally intractable with very large data. Therefore, a fast two-stage estimator for correlated, overdispersed count data is proposed. It is rooted in the split-sample methodology. Based on a simulation study, it shows good statistical properties. Furthermore, it is computationally much faster than the full maximum likelihood estimator. The approach is illustrated using a large dataset belonging to a network of Belgian general practices.     

On efficient inferences in familial-longitudinal binary models with two variance components

When a generalized linear mixed model (GLMM) with multiple (two or more) sources of random effects is considered, the inferences may vary depending on the nature of the random effects. For example, the inference in GLMMs with two independent random effects with two distinct components of dispersion will be different from the inference in GLMMs with two random effects in a two factor factorial design set-up. In this paper, we consider a familial-longitudinal model for repeated binary data where the binary response of an individual member of a family at a given time point is assumed to be influenced by the past responses of the member as well as two but independent sources of random family effects. For the estimation of the parameters of the proposed model, we discuss the well-known maximum-likelihood (ML) method as well as a generalized quasi-likelihood (GQL) approach. The main objective of the paper is to examine the relative asymptotic efficiency performance of the ML and GQL estimators for the regression effects, dynamic (longitudinal) dependence and variance parameters of the random family effects from two sources.