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.     

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.     

Comparing crossing hazard rate functions by joint modelling of survival and longitudinal data

Abstract

It is one of the important issues in survival analysis to compare two hazard rate functions to evaluate treatment effect. It is quite common that the two hazard rate functions cross each other at one or more unknown time points, representing temporal changes of the treatment effect. In certain applications, besides survival data, we also have related longitudinal data available regarding some time-dependent covariates. In such cases, a joint model that accommodates both types of data can allow us to infer the association between the survival and longitudinal data and to assess the treatment effect better. In this paper, we propose a modelling approach for comparing two crossing hazard rate functions by joint modelling survival and longitudinal data. Maximum likelihood estimation is used in estimating the parameters of the proposed joint model using the EM algorithm. Asymptotic properties of the maximum likelihood estimators are studied. To illustrate the virtues of the proposed method, we compare the performance of the proposed method with several existing methods in a simulation study. Our proposed method is also demonstrated using a real dataset obtained from an HIV clinical trial.     

AN APPROACH FOR JOINTLY MODELING MULTIVARIATE LONGITUDINAL MEASUREMENTS AND DISCRETE TIME-TO-EVENT DATA

In many medical studies, patients are followed longitudinally and interest is on assessing the relationship between longitudinal measurements and time to an event. Recently, various authors have proposed joint modeling approaches for longitudinal and time-to-event data for a single longitudinal variable. These joint modeling approaches become intractable with even a few longitudinal variables. In this paper we propose a regression calibration approach for jointly modeling multiple longitudinal measurements and discrete time-to-event data. Ideally, a two-stage modeling approach could be applied in which the multiple longitudinal measurements are modeled in the first stage and the longitudinal model is related to the time-to-event data in the second stage. Biased parameter estimation due to informative dropout makes this direct two-stage modeling approach problematic. We propose a regression calibration approach which appropriately accounts for informative dropout. We approximate the conditional distribution of the multiple longitudinal measurements given the event time by modeling all pairwise combinations of the longitudinal measurements using a bivariate linear mixed model which conditions on the event time. Complete data are then simulated based on estimates from these pairwise conditional models, and regression calibration is used to estimate the relationship between longitudinal data and time-to-event data using the complete data. We show that this approach performs well in estimating the relationship between multivariate longitudinal measurements and the time-to-event data and in estimating the parameters of the multiple longitudinal process subject to informative dropout. We illustrate this methodology with simulations and with an analysis of primary biliary cirrhosis (PBC) data.     

Penalized spline joint models for longitudinal and time-to-event data

The joint models for longitudinal data and time-to-event data have recently received numerous attention in clinical and epidemiologic studies. Our interest is in modeling the relationship between event time outcomes and internal time-dependent covariates. In practice, the longitudinal responses often show non linear and fluctuated curves. Therefore, the main aim of this paper is to use penalized splines with a truncated polynomial basis to parameterize the non linear longitudinal process. Then, the linear mixed-effects model is applied to subject-specific curves and to control the smoothing. The association between the dropout process and longitudinal outcomes is modeled through a proportional hazard model. Two types of baseline risk functions are considered, namely a Gompertz distribution and a piecewise constant model. The resulting models are referred to as penalized spline joint models; an extension of the standard joint models. The expectation conditional maximization (ECM) algorithm is applied to estimate the parameters in the proposed models. To validate the proposed algorithm, extensive simulation studies were implemented followed by a case study. In summary, the penalized spline joint models provide a new approach for joint models that have improved the existing standard joint models.     

Joint modelling of longitudinal and repeated time-to-event data using nonlinear mixed-effects models and the stochastic approximation expectation–maximization algorithm

We propose a nonlinear mixed-effects framework to jointly model longitudinal and repeated time-to-event data. A parametric nonlinear mixed-effects model is used for the longitudinal observations and a parametric mixed-effects hazard model for repeated event times. We show the importance for parameter estimation of properly calculating the conditional density of the observations (given the individual parameters) in the presence of interval and/or right censoring. Parameters are estimated by maximizing the exact joint likelihood with the stochastic approximation expectation–maximization algorithm. This workflow for joint models is now implemented in the Monolix software, and illustrated here on five simulated and two real datasets.     

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.     

Power-transformed linear regression on quantile residual life for censored competing risks data

ABSTRACT

This paper proposes a power-transformed linear quantile regression model for the residual lifetime of competing risks data. The proposed model can describe the association between any quantile of a time-to-event distribution among survivors beyond a specific time point and the covariates. Under covariate-dependent censoring, we develop an estimation procedure with two steps, including an unbiased monotone estimating equation for regression parameters and cumulative sum processes for the Box–Cox transformation parameter. The asymptotic properties of the estimators are also derived. We employ an efficient bootstrap method for the estimation of the variance–covariance matrix. The finite-sample performance of the proposed approaches are evaluated through simulation studies and a real example.     

Joint modeling of longitudinal data with a dependent terminal event

ABSTRACT

Longitudinal data often arise in longitudinal follow-up studies, and there may exist a dependent terminal event such as death that stops the follow-up. In this article, we propose a new joint modeling for the analysis of longitudinal data with informative observation times via a dependent terminal event and two latent variables. Estimating equations are developed for parameter estimation, and asymptotic properties of the resulting estimators are established. In addition, a generalization of the joint model with time-varying coefficients for the longitudinal response variable is considered, and goodness-of-fit methods for assessing the adequacy of the model are also provided. The proposed method works well in our simulation studies, and is applied to a data set from a bladder cancer study.     

Joint modeling and estimation for longitudinal data with informative observation and terminal event times

ABSTRACT

In many longitudinal studies, there may exist informative observation times and a dependent terminal event that stops the follow-up. In this paper, we propose a joint model for analysis of longitudinal data with informative observation times and a dependent terminal event via two latent variables. Estimation procedures are developed for parameter estimation, and asymptotic properties of the proposed estimators are derived. Simulation studies demonstrate that the proposed method performs well for practical settings. An application to a bladder cancer study is illustrated.     

A transitional Markov switching autoregressive model

ABSTRACT

This paper is concerned with properties of a transitional Markov switching autoregressive (TMSAR) model, together with its maximum-likelihood estimation and inference. We extend existing MSAR models by allowing dependence of AR parameters on hidden states at time points prior to the current time t. A stationary solution is given and expressions for the theoretical autocovariance function are derived. Two time series are analyzed and the new model outperforms two existing MSAR models in terms of maximized log-likelihood, residual correlations, and one-step-ahead forecasting performance. The new model also gives more regime changes in agreement with real events.     

A new discrete probability distribution with integer support on (−∞, ∞)

ABSTRACT

A new discrete probability distribution with integer support on (?∞, ∞) is proposed as a discrete analog of the continuous logistic distribution. Some of its important distributional and reliability properties are established. Its relationship with some known distributions is discussed. Parameter estimation by maximum-likelihood method is presented. Simulation is done to investigate properties of maximum-likelihood estimators. Real life application of the proposed distribution as empirical model is considered by conducting a comparative data fitting with Skellam distribution, Kemp's discrete normal, Roy's discrete normal, and discrete Laplace distribution.     

Estimation and inference of the joint conditional distribution for multivariate longitudinal data using nonparametric copulas

In this paper we study estimating the joint conditional distributions of multivariate longitudinal outcomes using regression models and copulas. For the estimation of marginal models, we consider a class of time-varying transformation models and combine the two marginal models using nonparametric empirical copulas. Our models and estimation method can be applied in many situations where the conditional mean-based models are not good enough. Empirical copulas combined with time-varying transformation models may allow quite flexible modelling for the joint conditional distributions for multivariate longitudinal data. We derive the asymptotic properties for the copula-based estimators of the joint conditional distribution functions. For illustration we apply our estimation method to an epidemiological study of childhood growth and blood pressure.     

A modified two-stage approach for joint modelling of longitudinal and time-to-event data

Joint models for longitudinal and time-to-event data have been applied in many different fields of statistics and clinical studies. However, the main difficulty these models have to face with is the computational problem. The requirement for numerical integration becomes severe when the dimension of random effects increases. In this paper, a modified two-stage approach has been proposed to estimate the parameters in joint models. In particular, in the first stage, the linear mixed-effects models and best linear unbiased predictorsare applied to estimate parameters in the longitudinal submodel. In the second stage, an approximation of the fully joint log-likelihood is proposed using the estimated the values of these parameters from the longitudinal submodel. Survival parameters are estimated bymaximizing the approximation of the fully joint log-likelihood. Simulation studies show that the approach performs well, especially when the dimension of random effects increases. Finally, we implement this approach on AIDS data.     

Semiparametric models of longitudinal and time-to-event data with applications to HIV viral dynamics and CD4 counts

We propose a semiparametric approach based on proportional hazards and copula method to jointly model longitudinal outcomes and the time-to-event. The dependence between the longitudinal outcomes on the covariates is modeled by a copula-based times series, which allows non-Gaussian random effects and overcomes the limitation of the parametric assumptions in existing linear and nonlinear random effects models. A modified partial likelihood method using estimated covariates at failure times is employed to draw statistical inference. The proposed model and method are applied to analyze a set of progression to AIDS data in a study of the association between the human immunodeficiency virus viral dynamics and the time trend in the CD4/CD8 ratio with measurement errors. Simulations are also reported to evaluate the proposed model and method.     

Simultaneous Bayesian modeling of longitudinal and survival data in breast cancer patients

Abstract

Using simultaneous Bayesian modeling, an attempt is made to analyze data on the size of lymphedema occurring in the arms of breast cancer patients after breast cancer surgery (as the longitudinal data) and the time interval for disease progression (as the time-to-event occurrence). A model based on a multivariate skew t distribution is shown to provide the best fit. This outcome was confirmed by simulation studies too.     

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.     

Penalized variable selection in competing risks regression

Penalized variable selection methods have been extensively studied for standard time-to-event data. Such methods cannot be directly applied when subjects are at risk of multiple mutually exclusive events, known as competing risks. The proportional subdistribution hazard (PSH) model proposed by Fine and Gray (J Am Stat Assoc 94:496–509, 1999) has become a popular semi-parametric model for time-to-event data with competing risks. It allows for direct assessment of covariate effects on the cumulative incidence function. In this paper, we propose a general penalized variable selection strategy that simultaneously handles variable selection and parameter estimation in the PSH model. We rigorously establish the asymptotic properties of the proposed penalized estimators and modify the coordinate descent algorithm for implementation. Simulation studies are conducted to demonstrate the good performance of the proposed method. Data from deceased donor kidney transplants from the United Network of Organ Sharing illustrate the utility of the proposed method.     

The Identification of Multiple Outliers in ARIMA Models

Abstract

There are three main problems in the existing procedures for detecting outliers in ARIMA models. The first one is the biased estimation of the initial parameter values that may strongly affect the power to detect outliers. The second problem is the confusion between level shifts and innovative outliers when the series has a level shift. The third problem is masking. We propose a procedure that keeps the powerful features of previous methods but improves the initial parameter estimate, avoids the confusion between innovative outliers and level shifts and includes joint tests for sequences of additive outliers in order to solve the masking problem. A Monte Carlo study and one example of the performance of the proposed procedure are presented.     

Progressive multi-state models for informatively incomplete longitudinal data

Progressive multi-state models provide a convenient framework for characterizing chronic disease processes where the states represent the degree of damage resulting from the disease. Incomplete data often arise in studies of such processes, and standard methods of analysis can lead to biased parameter estimates when observation of data is response-dependent. This paper describes a joint analysis useful for fitting progressive multi-state models to data arising in longitudinal studies in such settings. Likelihood based methods are described and parameters are shown to be identifiable. An EM algorithm is described for parameter estimation, and variance estimation is carried out using the Louis’ method. Simulation studies demonstrate that the proposed method works well in practice under a variety of settings. An application to data from a smoking prevention study illustrates the utility of the method.