Predictive comparison of joint longitudinal-survival modeling: a case study illustrating competing approaches

The joint modeling of longitudinal and survival data has received extraordinary attention in the statistics literature recently, with models and methods becoming increasingly more complex. Most of these approaches pair a proportional hazards survival with longitudinal trajectory modeling through parametric or nonparametric specifications. In this paper we closely examine one data set previously analyzed using a two parameter parametric model for Mediterranean fruit fly (medfly) egg-laying trajectories paired with accelerated failure time and proportional hazards survival models. We consider parametric and nonparametric versions of these two models, as well as a proportional odds rate model paired with a wide variety of longitudinal trajectory assumptions reflecting the types of analyses seen in the literature. In addition to developing novel nonparametric Bayesian methods for joint models, we emphasize the importance of model selection from among joint and non joint models. The default in the literature is to omit at the outset non joint models from consideration. For the medfly data, a predictive diagnostic criterion suggests that both the choice of survival model and longitudinal assumptions can grossly affect model adequacy and prediction. Specifically for these data, the simple joint model used in by Tseng et al. (Biometrika 92:587–603, 2005) and models with much more flexibility in their longitudinal components are predictively outperformed by simpler analyses. This case study underscores the need for data analysts to compare on the basis of predictive performance different joint models and to include non joint models in the pool of candidates under consideration.     

Some asymptotic results for semiparametric nonlinear mixed-effects models with incomplete data

In modeling complex longitudinal data, semiparametric nonlinear mixed-effects (SNLME) models are very flexible and useful. Covariates are often introduced in the models to partially explain the inter-individual variations. In practice, data are often incomplete in the sense that there are often measurement errors and missing data in longitudinal studies. The likelihood method is a standard approach for inference for these models but it can be computationally very challenging, so computationally efficient approximate methods are quite valuable. However, the performance of these approximate methods is often based on limited simulation studies, and theoretical results are unavailable for many approximate methods. In this article, we consider a computationally efficient approximate method for a class of SNLME models with incomplete data and investigate its theoretical properties. We show that the estimates based on the approximate method are consistent and asymptotically normally distributed.     

Joint models with multiple longitudinal outcomes and a time-to-event outcome: a corrected two-stage approach

Joint models for longitudinal and survival data have gained a lot of attention in recent years, with the development of myriad extensions to the basic model, including those which allow for multivariate longitudinal data, competing risks and recurrent events. Several software packages are now also available for their implementation. Although mathematically straightforward, the inclusion of multiple longitudinal outcomes in the joint model remains computationally difficult due to the large number of random effects required, which hampers the practical application of this extension. We present a novel approach that enables the fitting of such models with more realistic computational times. The idea behind the approach is to split the estimation of the joint model in two steps: estimating a multivariate mixed model for the longitudinal outcomes and then using the output from this model to fit the survival submodel. So-called two-stage approaches have previously been proposed and shown to be biased. Our approach differs from the standard version, in that we additionally propose the application of a correction factor, adjusting the estimates obtained such that they more closely resemble those we would expect to find with the multivariate joint model. This correction is based on importance sampling ideas. Simulation studies show that this corrected two-stage approach works satisfactorily, eliminating the bias while maintaining substantial improvement in computational time, even in more difficult settings.

     

Regression analysis of longitudinal data with outcome‐dependent sampling and informative censoring

We consider a regression analysis of longitudinal data in the presence of outcome‐dependent observation times and informative censoring. Existing approaches commonly require a correct specification of the joint distribution of longitudinal measurements, the observation time process, and informative censoring time under the joint modeling framework and can be computationally cumbersome due to the complex form of the likelihood function. In view of these issues, we propose a semiparametric joint regression model and construct a composite likelihood function based on a conditional order statistics argument. As a major feature of our proposed methods, the aforementioned joint distribution is not required to be specified, and the random effect in the proposed joint model is treated as a nuisance parameter. Consequently, the derived composite likelihood bypasses the need to integrate over the random effect and offers the advantage of easy computation. We show that the resulting estimators are consistent and asymptotically normal. We use simulation studies to evaluate the finite‐sample performance of the proposed method and apply it to a study of weight loss data that motivated our investigation.     

Approximate bounded influence estimation for longitudinal data with outliers and measurement errors

Mixed effects models or random effects models are popular for the analysis of longitudinal data. In practice, longitudinal data are often complex since there may be outliers in both the response and the covariates and there may be measurement errors. The likelihood method is a common approach for these problems but it can be computationally very intensive and sometimes may even be computationally infeasible. In this article, we consider approximate robust methods for nonlinear mixed effects models to simultaneously address outliers and measurement errors. The approximate methods are computationally very efficient. We show the consistency and asymptotic normality of the approximate estimates. The methods can also be extended to missing data problems. An example is used to illustrate the methods and a simulation is conducted to evaluate the methods.     

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.     

Estimation and Inference in Two-Step Econometric Models

A commonly used procedure in a wide class of empirical applications is to impute unobserved regressors, such as expectations, from an auxiliary econometric model. This two-step (T-S) procedure fails to account for the fact that imputed regressors are measured with sampling error, so hypothesis tests based on the estimated covariance matrix of the second-step estimator are biased, even in large samples. We present a simple yet general method of calculating asymptotically correct standard errors in T-S models. The procedure may be applied even when joint estimation methods, such as full information maximum likelihood, are inappropriate or computationally infeasible. We present two examples from recent empirical literature in which these corrections have a major impact on hypothesis testing.     

Inference about regression parameters using highly stratified survey count data with over-dispersion and repeated measurements

We study methods to estimate regression and variance parameters for over-dispersed and correlated count data from highly stratified surveys. Our application involves counts of fish catches from stratified research surveys and we propose a novel model in fisheries science to address changes in survey protocols. A challenge with this model is the large number of nuisance parameters which leads to computational issues and biased statistical inferences. We use a computationally efficient profile generalized estimating equation method and compare it to marginal maximum likelihood (MLE) and restricted MLE (REML) methods. We use REML to address bias and inaccurate confidence intervals because of many nuisance parameters. The marginal MLE and REML approaches involve intractable integrals and we used a new R package that is designed for estimating complex nonlinear models that may include random effects. We conclude from simulation analyses that the REML method provides more reliable statistical inferences among the three methods we investigated.     

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.     

Simulated maximum likelihood estimation in joint models for multiple longitudinal markers and recurrent events of multiple types,in the presence of a terminal event

In medical studies we are often confronted with complex longitudinal data. During the follow-up period, which can be ended prematurely by a terminal event (e.g. death), a subject can experience recurrent events of multiple types. In addition, we collect repeated measurements from multiple markers. An adverse health status, represented by ‘bad’ marker values and an abnormal number of recurrent events, is often associated with the risk of experiencing the terminal event. In this situation, the missingness of the data is not at random and, to avoid bias, it is necessary to model all data simultaneously using a joint model. The correlations between the repeated observations of a marker or an event type within an individual are captured by normally distributed random effects. Because the joint likelihood contains an analytically intractable integral, Bayesian approaches or quadrature approximation techniques are necessary to evaluate the likelihood. However, when the number of recurrent event types and markers is large, the dimensionality of the integral is high and these methods are too computationally expensive. As an alternative, we propose a simulated maximum-likelihood approach based on quasi-Monte Carlo integration to evaluate the likelihood of joint models with multiple recurrent event types and markers.     

Jointly modeling skew longitudinal survival data with missingness and mismeasured covariates

Jointly modeling longitudinal and survival data has been an active research area. Most researches focus on improving the estimating efficiency but ignore many data features frequently encountered in practice. In the current study, we develop the joint models that concurrently accounting for longitudinal and survival data with multiple features. Specifically, the proposed model handles skewness, missingness and measurement errors in covariates which are typically observed in the collection of longitudinal survival data from many studies. We employ a Bayesian inferential method to make inference on the proposed model. We applied the proposed model to an real data study. A few alternative models under different conditions are compared. We conduct extensive simulations in order to evaluate how the method works.     

Modelling Survival Events with Longitudinal Covariates Measured with Error

In survival analysis, time-dependent covariates are usually present as longitudinal data collected periodically and measured with error. The longitudinal data can be assumed to follow a linear mixed effect model and Cox regression models may be used for modelling of survival events. The hazard rate of survival times depends on the underlying time-dependent covariate measured with error, which may be described by random effects. Most existing methods proposed for such models assume a parametric distribution assumption on the random effects and specify a normally distributed error term for the linear mixed effect model. These assumptions may not be always valid in practice. In this article, we propose a new likelihood method for Cox regression models with error-contaminated time-dependent covariates. The proposed method does not require any parametric distribution assumption on random effects and random errors. Asymptotic properties for parameter estimators are provided. Simulation results show that under certain situations the proposed methods are more efficient than the existing methods.     

Starting Values for EM Estimation of Latent Class Joint Model

Latent class model is one of the important latent variable methods for joint modeling longitudinal and survival data. Latent class joint model can handle underlying heterogeneous population, discover subpopulation structure, and incorporate correlated non normally distributed outcomes. The maximum likelihood estimates of parameters in latent class joint model are generally obtained by the EM algorithm. Finding the starting values is one of the major issues to implement the EM algorithm successfully. In this article, initial value formulas are provided, a simulation study is conducted to show that the proposed starting values perform very well, and two illustrative examples are presented.     

Joint models for multiple longitudinal processes and time-to-event outcome

ABSTRACT

Joint models are statistical tools for estimating the association between time-to-event and longitudinal outcomes. One challenge to the application of joint models is its computational complexity. Common estimation methods for joint models include a two-stage method, Bayesian and maximum-likelihood methods. In this work, we consider joint models of a time-to-event outcome and multiple longitudinal processes and develop a maximum-likelihood estimation method using the expectation–maximization algorithm. We assess the performance of the proposed method via simulations and apply the methodology to a data set to determine the association between longitudinal systolic and diastolic blood pressure measures and time to coronary artery disease.     

Profile likelihood approaches for semiparametric copula and frailty models for clustered survival data

ABSTRACT

In clustered survival data, the dependence among individual survival times within a cluster has usually been described using copula models and frailty models. In this paper we propose a profile likelihood approach for semiparametric copula models with different cluster sizes. We also propose a likelihood ratio method based on profile likelihood for testing the absence of association parameter (i.e. test of independence) under the copula models, leading to the boundary problem of the parameter space. For this purpose, we show via simulation study that the proposed likelihood ratio method using an asymptotic chi-square mixture distribution performs well as sample size increases. We compare the behaviors of the two models using the profile likelihood approach under a semiparametric setting. The proposed method is demonstrated using two well-known data sets.     

A Bezier curve method in interval-censored data

In this paper we propose a Bezier curve method to estimate the survival function and the median survival time in interval-censored data. We compare the proposed estimator with other existing methods such as the parametric method, the single point imputation method, and the nonparametric maximum likelihood estimator through extensive numerical studies, and it is shown that the proposed estimator performs better than others in the sense of mean squared error and mean integrated squared error. An illustrative example based on a real data set is given.     

Bayesian ROC curve estimation under binormality using a rank likelihood

There are various methods to estimate the parameters in the binormal model for the ROC curve. In this paper, we propose a conceptually simple and computationally feasible Bayesian estimation method using a rank-based likelihood. Posterior consistency is also established. We compare the new method with other estimation methods and conclude that our estimator generally performs better than its competitors.     

A Two-Stage Estimation Method for Random Coefficient Differential Equation Models with Application to Longitudinal HIV Dynamic Data

We propose a two-stage estimation method for random coefficient ordinary differential equation (ODE) models. A maximum pseudo-likelihood estimator (MPLE) is derived based on a mixed-effects modeling approach and its asymptotic properties for population parameters are established. The proposed method does not require repeatedly solving ODEs, and is computationally efficient although it does pay a price with the loss of some estimation efficiency. However, the method does offer an alternative approach when the exact likelihood approach fails due to model complexity and high-dimensional parameter space, and it can also serve as a method to obtain the starting estimates for more accurate estimation methods. In addition, the proposed method does not need to specify the initial values of state variables and preserves all the advantages of the mixed-effects modeling approach. The finite sample properties of the proposed estimator are studied via Monte Carlo simulations and the methodology is also illustrated with application to an AIDS clinical data set.     

Bayesian generalized varying coefficient models for longitudinal proportional data with errors-in-covariates

This paper is motivated from a neurophysiological study of muscle fatigue, in which biomedical researchers are interested in understanding the time-dependent relationships of handgrip force and electromyography measures. A varying coefficient model is appealing here to investigate the dynamic pattern in the longitudinal data. The response variable in the study is continuous but bounded on the standard unit interval (0, 1) over time, while the longitudinal covariates are contaminated with measurement errors. We propose a generalization of varying coefficient models for the longitudinal proportional data with errors-in-covariates. We describe two estimation methods with penalized splines, which are formalized under a Bayesian inferential perspective. The first method is an adaptation of the popular regression calibration approach. The second method is based on a joint likelihood under the hierarchical Bayesian model. A simulation study is conducted to evaluate the efficacy of the proposed methods under different scenarios. The analysis of the neurophysiological data is presented to demonstrate the use of the methods.     

Efficient calculation of the normalizing constant of the autologistic and related models on the cylinder and lattice

Summary. Motivated by the autologistic model for the analysis of spatial binary data on the two-dimensional lattice, we develop efficient computational methods for calculating the normalizing constant for models for discrete data defined on the cylinder and lattice. Because the normalizing constant is generally unknown analytically, statisticians have developed various ad hoc methods to overcome this difficulty. Our aim is to provide computationally and statistically efficient methods for calculating the normalizing constant so that efficient likelihood-based statistical methods are then available for inference. We extend the so-called transition method to find a feasible computational method of obtaining the normalizing constant for the cylinder boundary condition. To extend the result to the free-boundary condition on the lattice we use an efficient path sampling Markov chain Monte Carlo scheme. The methods are generally applicable to association patterns other than spatial, such as clustered binary data, and to variables taking three or more values described by, for example, Potts models.