Multiple Longitudinal Responses Research Articles

A copula-based approach to joint modelling of multiple longitudinal responses with multimodal structures

This article introduces a flexible modelling strategy to extend the familiar mixed-effects models for analysing longitudinal responses in the multivariate setting. By initiating a flexible multivariate multimodal distribution, this strategy relaxes the imposed normality assumption of related random-effects. We use copulas to construct a multimodal form of elliptical distributions. It can deal with the multimodality of responses and the non-linearity of dependence structure. Moreover, the proposed model can flexibly accommodate clustered subject-effects for multiple longitudinal measurements. It is much useful when several subpopulations exist but cannot be directly identifiable. Since the implied marginal distribution is not in the closed form, to approximate the associated likelihood functions, we suggest a computational methodology based on the Gauss–Hermite quadrature that consequently enables us to implement standard optimization techniques. We conduct a simulation study to highlight the main properties of the theoretical part and make a comparison with regular mixture distributions. Results confirm that the new strategy deserves to receive attention in practice. We illustrate the usefulness of our model by the analysis of a real-life dataset taken from a low back pain study.

An innovative strategy on the construction of multivariate multimodal linear mixed-effects models

This paper presents an attractive extension of multivariate mixed-effects models to allow the modeling of correlated responses. By initiating a new multivariate multimodal distribution, the proposed strategy takes multimodality and the asymmetric structure into account in a flexible way. It can also accommodate clustered random effects on multiple longitudinal responses when data comprise various hidden sub-populations that are not directly identifiable. We introduce an explicit stochastic hierarchical representation of the proposed model to render its theoretical properties straightforward and to carry out estimation processes easily. A fully Bayesian approach is proposed to compute posterior distributions using MCMC techniques in modeling multivariate longitudinal data. Moreover, we present an EM-based maximum likelihood estimation procedure. To facilitate Bayesian computation, the estimation process of mixed models utilizes a data augmentation scheme. We analyze two real-life data on the low-back pain study and the height of school-girls to illustrate the usefulness of our proposed model in practical applications.

Modelling cancer outcomes of bone metastatic patients: combining survival data with N-Telopeptide of type I collagen (NTX) dynamics through joint models

BackgroundJoint models (JM) have emerged as a promising statistical framework to concurrently analyse survival data and multiple longitudinal responses. This is particularly relevant in clinical studies where the goal is to estimate the association between time-to-event data and the biomarkers evolution. In the context of oncological data, JM can indeed provide interesting prognostic markers for the event under study and thus support clinical decisions and treatment choices. However, several problems arise when dealing with this type of data, such as the high-dimensionality of the covariates space, the lack of knowledge about the function structure of the time series and the presence of missing data, facts that may hamper the accurate estimation of the JM.MethodsWe propose to apply JM for the analysis of bone metastatic patients and infer the association of their survival with several covariates, in particular the N-Telopeptide of Type I Collagen (NTX) dynamics. This biomarker has been identified as a relevant prognostic factor in patients with metastatic cancer, but only using static information in some specific time points.ResultsWe extended this analysis using the full NTX time series for a larger cohort of patients with bone metastasis, and compared the results obtained by the JM and the extended Cox regression model. Imputation based on fuzzy clustering was used to deal with missing values and several functions for NTX evolution were compared, such as rational, exponential and cubic splines.ConclusionsThe JM obtained confirm the association between NTX values and patients’ response, attesting the importance of this time series, and additionally provide a deep understanding of the key survival covariates.

Joint Modeling of Multivariate Longitudinal Data and Competing Risks Using Multiphase Sub-models

In many clinical studies that involve follow-up, it is common to observe one or more sequences of longitudinal measurements, as well as one or more time to event outcomes. A competing risks situation arises when the probability of occurrence of one event is altered/hindered by another time to event. Recently, there has been much attention paid to the joint analysis of a single longitudinal response and a single time to event outcome, when the missing data mechanism in the longitudinal process is non-ignorable. We, in this paper, propose an extension where multiple longitudinal responses are jointly modeled with competing risks (multiple time to events). Our shared parameter joint model consists of a system of multiphase non-linear mixed effects sub-models for the multiple longitudinal responses, and a system of cause-specific non-proportional hazards frailty sub-models for competing risks, with associations among multiple longitudinal responses and competing risks modeled using latent parameters. The joint model is applied to a data set of patients who are on mechanical circulatory support and are awaiting heart transplant, using readily available software. While on the mechanical circulatory support, patient liver and renal functions may worsen and these in turn may influence one of the two possible competing outcomes: (i) death before transplant; (ii) transplant. In one application, we propose a system of multiphase cause-specific non-proportional hazard sub-model where frailty can be time varying. Performance under different scenarios was assessed using simulation studies. By using the proposed joint modeling of the multiphase sub-models, one can identify: (i) non-linear trends in multiple longitudinal outcomes; (ii) time-varying hazards and cumulative incidence functions of the competing risks; (iii) identify risk factors for the both types of outcomes, where the effect may or may not change with time; and (iv) assess the association between multiple longitudinal and competing risks outcomes, where the association may or may not change with time.

A joint quantile regression model for multiple longitudinal outcomes

Complexity of longitudinal data lies in the inherent dependence among measurements from same subject over different time points. For multiple longitudinal responses, the problem is challenging due to inter-trait and intra-trait dependence. While linear mixed models are popularly used for analysing such data, appropriate inference on the shape of the population cannot be drawn for non-normal data sets. We propose a linear mixed model for joint quantile regression of multiple longitudinal responses. We consider an asymmetric Laplace distribution for quantile regression and estimate model parameters by Monte Carlo EM algorithm. Nonparametric bootstrap resampling method is used for estimating confidence intervals of parameter estimates. Through extensive simulation studies, we investigate the operating characteristics of our proposed model and compare the performance to other traditional quantile regression models. We apply proposed model for analysing data from nutrition education programme on hypercholesterolemic children of the USA.

Multivariate longitudinal data analysis with mixed effects hidden Markov models.

Multiple longitudinal responses are often collected as a means to capture relevant features of the true outcome of interest, which is often hidden and not directly measurable. We outline an approach which models these multivariate longitudinal responses as generated from a hidden disease process. We propose a class of models which uses a hidden Markov model with separate but correlated random effects between multiple longitudinal responses. This approach was motivated by a smoking cessation clinical trial, where a bivariate longitudinal response involving both a continuous and a binomial response was collected for each participant to monitor smoking behavior. A Bayesian method using Markov chain Monte Carlo is used. Comparison of separate univariate response models to the bivariate response models was undertaken. Our methods are demonstrated on the smoking cessation clinical trial dataset, and properties of our approach are examined through extensive simulation studies.