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.     

Bayesian age-stratified joinpoint regression model: an application to lung and brain cancer mortality

Joinpoint regression model identifies significant changes in the trends of the incidence, mortality, and survival of a specific disease in a given population. The purpose of the present study is to develop an age-stratified Bayesian joinpoint regression model to describe mortality trend assuming that the observed counts are probabilistically characterized by the Poisson distribution. The proposed model is based on Bayesian model selection criteria with the smallest number of joinpoints that are sufficient to explain the Annual Percentage Change. The prior probability distributions are chosen in such a way that they are automatically derived from the model index contained in the model space. The proposed model and methodology estimates the age-adjusted mortality rates in different epidemiological studies to compare the trends by accounting the confounding effects of age. In developing the subject methods, we use the cancer mortality counts of adult lung and bronchus cancer, and brain and other Central Nervous System cancer patients obtained from the Surveillance Epidemiology and End Results data base of the National Cancer Institute.     

A joint model for incomplete data in crossover trials

Crossover designs are popular in early phases of clinical trials and in bioavailability and bioequivalence studies. Assessment of carryover effects, in addition to the treatment effects, is a critical issue in crossover trails. The observed data from a crossover trial can be incomplete because of potential dropouts. A joint model for analyzing incomplete data from crossover trials is proposed in this article; the model includes a measurement model and an outcome dependent informative model for the dropout process. The informative-dropout model is compared with the ignorable-dropout model as specific cases of the latter are nested subcases of the proposed joint model. Markov chain sampling methods are used for Bayesian analysis of this model. The joint model is used to analyze depression score data from a clinical trial in women with late luteal phase dysphoric disorder. Interestingly, carryover effect is found to have a strong effect in the informative dropout model, but it is less significant when dropout is considered ignorable.     

A joint model for hierarchical continuous and zero-inflated overdispersed count data

Many applications in public health, medical and biomedical or other studies demand modelling of two or more longitudinal outcomes jointly to get better insight into their joint evolution. In this regard, a joint model for a longitudinal continuous and a count sequence, the latter possibly overdispersed and zero-inflated (ZI), will be specified that assembles aspects coming from each one of them into one single model. Further, a subject-specific random effect is included to account for the correlation in the continuous outcome. For the count outcome, clustering and overdispersion are accommodated through two distinct sets of random effects in a generalized linear model as proposed by Molenberghs et al. [A family of generalized linear models for repeated measures with normal and conjugate random effects. Stat Sci. 2010;25:325–347]; one is normally distributed, the other conjugate to the outcome distribution. The association among the two sequences is captured by correlating the normal random effects describing the continuous and count outcome sequences, respectively. An excessive number of zero counts is often accounted for by using a so-called ZI or hurdle model. ZI models combine either a Poisson or negative-binomial model with an atom at zero as a mixture, while the hurdle model separately handles the zero observations and the positive counts. This paper proposes a general joint modelling framework in which all these features can appear together. We illustrate the proposed method with a case study and examine it further with simulations.     

A joint test for arch and bilinearity in the regression model

In this paper we argue that a simultaneous test for ARCH and bilinearity should be used to test for the possible nonlinearity of the error process in the regression model. We suggest such a joint test statistic. An empirical example shows that the individual tests of ARCH and bilinearity may not be conclusive while a joint test clearly rejects the linearity hypothesis. Our results are also applicable to pure time series models.     

A shared component model for detecting joint and selective clustering of two diseases

The study of spatial variations in disease rates is a common epidemiological approach used to describe the geographical clustering of diseases and to generate hypotheses about the possible 'causes' which could explain apparent differences in risk. Recent statistical and computational developments have led to the use of realistically complex models to account for overdispersion and spatial correlation. However, these developments have focused almost exclusively on spatial modelling of a single disease. Many diseases share common risk factors (smoking being an obvious example) and, if similar patterns of geographical variation of related diseases can be identified, this may provide more convincing evidence of real clustering in the underlying risk surface. We propose a shared component model for the joint spatial analysis of two diseases. The key idea is to separate the underlying risk surface for each disease into a shared and a disease-specific component. The various components of this formulation are modelled simultaneously by using spatial cluster models implemented via reversible jump Markov chain Monte Carlo methods. We illustrate the methodology through an analysis of oral and oesophageal cancer mortality in the 544 districts of Germany, 1986–1990.     

Frequentist and Bayesian approaches for a joint model for prostate cancer risk and longitudinal prostate-specific antigen data

The paper describes the use of frequentist and Bayesian shared-parameter joint models of longitudinal measurements of prostate-specific antigen (PSA) and the risk of prostate cancer (PCa). The motivating dataset corresponds to the screening arm of the Spanish branch of the European Randomized Screening for Prostate Cancer study. The results show that PSA is highly associated with the risk of being diagnosed with PCa and that there is an age-varying effect of PSA on PCa risk. Both the frequentist and Bayesian paradigms produced very close parameter estimates and subsequent 95% confidence and credibility intervals. Dynamic estimations of disease-free probabilities obtained using Bayesian inference highlight the potential of joint models to guide personalized risk-based screening strategies.     

A model of toxoplasmosis incidence in the UK: evidence synthesis and consistency of evidence

Summary.  We present a Bayesian evidence synthesis model combining data on seroprevalence, seroconversion and tests of recent infection, to produce estimates of current incidence of toxoplasmosis in the UK. The motivation for the study was the need for an estimate of current average incidence in the UK, with a realistic assessment of its uncertainty, to inform a decision model for a national screening programme to prevent congenital toxoplasmosis. The model has a hierarchical structure over geographic region, a random-walk model for temporal effects and a fixed age effect, with one or more types of data informing the regional estimates of incidence. Inference is obtained by using Markov chain Monte Carlo simulations. A key issue in the synthesis of evidence from multiple sources is model selection and the consistency of different types of evidence. Alternative models of incidence are compared by using the deviance information criterion, and we find that temporal effects are region specific. We assess the consistency of the various forms of evidence by using cross-validation where practical, and posterior and mixed prediction otherwise, and we discuss how these measures can be used to assess different aspects of consistency in a complex evidence structure. We discuss the contribution of the various forms of evidence to estimated current average incidence.     

A Bayesian shared parameter model for joint modeling of longitudinal continuous and binary outcomes

Joint modeling of associated mixed biomarkers in longitudinal studies leads to a better clinical decision by improving the efficiency of parameter estimates. In many clinical studies, the observed time for two biomarkers may not be equivalent and one of the longitudinal responses may have recorded in a longer time than the other one. In addition, the response variables may have different missing patterns. In this paper, we propose a new joint model of associated continuous and binary responses by accounting different missing patterns for two longitudinal outcomes. A conditional model for joint modeling of the two responses is used and two shared random effects models are considered for intermittent missingness of two responses. A Bayesian approach using Markov Chain Monte Carlo (MCMC) is adopted for parameter estimation and model implementation. The validation and performance of the proposed model are investigated using some simulation studies. The proposed model is also applied for analyzing a real data set of bariatric surgery.     

A Potts‐mixture spatiotemporal joint model for combined magnetoencephalography and electroencephalography data

We develop a new methodology for determining the location and dynamics of brain activity from combined magnetoencephalography (MEG) and electroencephalography (EEG) data. The resulting inverse problem is ill‐posed and is one of the most difficult problems in neuroimaging data analysis. In our development we propose a solution that combines the data from three different modalities, magnetic resonance imaging (MRI), MEG and EEG, together. We propose a new Bayesian spatial finite mixture model that builds on the mesostate‐space model developed by Daunizeau & Friston [Daunizeau and Friston, NeuroImage 2007; 38, 67–81]. Our new model incorporates two major extensions: (i) We combine EEG and MEG data together and formulate a joint model for dealing with the two modalities simultaneously; (ii) we incorporate the Potts model to represent the spatial dependence in an allocation process that partitions the cortical surface into a small number of latent states termed mesostates. The cortical surface is obtained from MRI. We formulate the new spatiotemporal model and derive an efficient procedure for simultaneous point estimation and model selection based on the iterated conditional modes algorithm combined with local polynomial smoothing. The proposed method results in a novel estimator for the number of mixture components and is able to select active brain regions, which correspond to active variables in a high‐dimensional dynamic linear model. The methodology is investigated using synthetic data and simulation studies and then demonstrated on an application examining the neural response to the perception of scrambled faces. R software implementing the methodology along with several sample datasets are available at the following GitHub repository https://github.com/v2south/PottsMix . The Canadian Journal of Statistics 47: 688–711; 2019 © 2019 Statistical Society of Canada     

A hierarchical model for space–time surveillance data on meningococcal disease incidence

Summary. We describe a model-based approach to analyse space–time surveillance data on meningococcal disease. Such data typically comprise a number of time series of disease counts, each representing a specific geographical area. We propose a hierarchical formulation, where latent parameters capture temporal, seasonal and spatial trends in disease incidence. We then add—for each area—a hidden Markov model to describe potential additional (autoregressive) effects of the number of cases at the previous time point. Different specifications for the functional form of this autoregressive term are compared which involve the number of cases in the same or in neighbouring areas. The two states of the Markov chain can be interpreted as representing an 'endemic' and a 'hyperendemic' state. The methodology is applied to a data set of monthly counts of the incidence of meningococcal disease in the 94 départements of France from 1985 to 1997. Inference is carried out by using Markov chain Monte Carlo simulation techniques in a fully Bayesian framework. We emphasize that a central feature of our model is the possibility of calculating—for each region and each time point—the posterior probability of being in a hyperendemic state, adjusted for global spatial and temporal trends, which we believe is of particular public health interest.     

A joint model of binary and longitudinal data with non-ignorable missingness,with application to marital stress and late-life major depression in women

Understanding how long-term marital stress affects major depressive disorder (MDD) in older women has clinical implications for the treatment of women at risk. In this paper, we consider the problem of predicting MDD in older women (mean age 60) from a marital stress scale administered four times during the preceding 20-year period, with a greater dropout by women experiencing marital stress or MDD. To analyze these data, we propose a Bayesian joint model consisting of: (1) a linear mixed effects model for the longitudinal measurements, (2) a generalized linear model for the binary primary endpoint, and (3) a shared parameter model for the missing data mechanism. Our analysis indicates that MDD in older women is significantly associated with higher levels of prior marital stress and increasing marital stress over time, although there is a generally decreasing trend in marital stress. This is the first study to propose a joint model for incompletely observed longitudinal measurements, a binary primary endpoint, and non-ignorable missing data; a comparison shows that the joint model yields better predictive accuracy than a two-stage model. These findings suggest that women who experience marital stress in mid-life need treatment to help prevent late-life MDD, which has serious consequences for older persons.     

Past and recent attempts to model mortality at all ages

"Most laws of mortality are partial in the sense that they apply only to a broad age group and not to all ages. This paper focuses on three laws of mortality that apply to all ages. Two of them were developed by the actuaries Thiele and Wittstein in the late 19th century. The third, developed by Heligman and Pollard, is of recent origin. The three laws are discussed with references to Scandinavian mortality data. The results suggest that the most recently proposed law can be used for generation of model life tables, for making population projections, simulations, and other statistical work where there is a need for a realistic model of human mortality."     

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.     

Generalized linear mixed joint model for longitudinal and survival outcomes

Longitudinal studies often entail categorical outcomes as primary responses. When dropout occurs, non-ignorability is frequently accounted for through shared parameter models (SPMs). In this context, several extensions from Gaussian to non-Gaussian longitudinal processes have been proposed. In this paper, we formulate an approach for non-Gaussian longitudinal outcomes in the framework of joint models. As an extension of SPMs, based on shared latent effects, we assume that the history of the response up to current time may have an influence on the risk of dropout. This history is represented by the current, expected, value of the response. Since the time a subject spends in the study is continuous, we parametrize the dropout process through a proportional hazard model. The resulting model is referred to as Generalized Linear Mixed Joint Model (GLMJM). To estimate model parameters, we adopt a maximum likelihood approach via the EM algorithm. In this context, the maximization of the observed data log-likelihood requires numerical integration over the random effect posterior distribution, which is usually not straightforward; under the assumption of Gaussian random effects, we compare Gauss-Hermite and Pseudo-Adaptive Gaussian quadrature rules. We investigate in a simulation study the behaviour of parameter estimates in the case of Poisson and Binomial longitudinal responses, and apply the GLMJM to a benchmark dataset.     

A joint latent class changepoint model to improve the prediction of time to graft failure

Summary.  The reciprocal of serum creatinine concentration, RC, is often used as a biomarker to monitor renal function. It has been observed that RC trajectories remain relatively stable after transplantation until a certain moment, when an irreversible decrease in the RC levels occurs. This decreasing trend commonly precedes failure of a graft. Two subsets of individuals can be distinguished according to their RC trajectories: a subset of individuals having stable RC levels and a subset of individuals who present an irrevocable decrease in their RC levels. To describe such data, the paper proposes a joint latent class model for longitudinal and survival data with two latent classes. RC trajectories within latent class one are modelled by an intercept-only random-effects model and RC trajectories within latent class two are modelled by a segmented random changepoint model. A Bayesian approach is used to fit this joint model to data from patients who had their first kidney transplantation in the Leiden University Medical Center between 1983 and 2002. The resulting model describes the kidney transplantation data very well and provides better predictions of the time to failure than other joint and survival models.     

A factor model approach for the joint segmentation with between‐series correlation

We consider the detection of changes in the mean of a set of time series. The breakpoints are allowed to be series specific, and the series are assumed to be correlated. The correlation between the series is supposed to be constant along time but is allowed to take an arbitrary form. We show that such a dependence structure can be encoded in a factor model. Thanks to this representation, the inference of the breakpoints can be achieved via dynamic programming, which remains one the most efficient algorithms. We propose a model selection procedure to determine both the number of breakpoints and the number of factors. This proposed method is implemented in the FASeg R package, which is available on the CRAN. We demonstrate the performances of our procedure through simulation experiments and present an application to geodesic data.     

A new parametric family for modelling cumulative incidence functions: application to breast cancer data

Summary.  Competing risks situations can be encountered in many research areas such as medicine, social science and engineering. The main stream of analyses of those competing risks data has been nonparametric or semiparametric in the statistical literature. We propose a new parametric family to parameterize the cumulative incidence function completely. The new distribution is sufficiently flexible to fit various shapes of hazard patterns in survival data and increases the efficiency of the cumulative incidence estimates over the distribution-free approaches. A simple two-sample parametric test statistic is also proposed to compare the cumulative incidence functions between two groups at a given time point. The new parametric approach is illustrated by using breast cancer data sets from the National Surgical Adjuvant Breast and Bowel Project.