Semiparametric analysis of longitudinal data with informative observation times and censoring times

We focus on regression analysis of irregularly observed longitudinal data which often occur in medical follow-up studies and observational investigations. The model for such data involves two processes: a longitudinal response process of interest and an observation process controlling observation times. Restrictive models and questionable assumptions, such as Poisson assumption and independent censoring time assumption, were posed in previous works for analysing longitudinal data. In this paper, we propose a more general model together with a robust estimation approach for longitudinal data with informative observation times and censoring times, and the asymptotic normalities of the proposed estimators are established. Both simulation studies and real data application indicate that the proposed method is promising.     

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.     

Regression analysis of longitudinal data with time-dependent covariates in the presence of informative observation and censoring times

In longitudinal observational studies, repeated measures are often correlated with observation times as well as censoring time. This article proposes joint modeling and analysis of longitudinal data with time-dependent covariates in the presence of informative observation and censoring times via a latent variable. Estimating equation approaches are developed for parameter estimation and asymptotic properties of the proposed estimators are established. In addition, a generalization of the semiparametric model with time-varying coefficients for the longitudinal response is considered. Furthermore, a lack-of-fit test is provided for assessing the adequacy of the model, and some tests are presented for investigating whether or not covariate effects vary with time. The finite-sample behavior of the proposed methods is examined in simulation studies, and an application to a bladder cancer study is illustrated.     

Joint analysis of longitudinal data and competing terminal events in the presence of dependent observation times with application to chronic kidney disease

In many prospective clinical and biomedical studies, longitudinal biomarkers are repeatedly measured as health indicators to evaluate disease progression when patients are followed up over a period of time. Patient visiting times can be referred to as informative observation times if they are assumed to carry information in addition to that of the longitudinal biomarker measures alone. Irregular visiting times may reflect compliance with physician instruction, disease progression and symptom severity. When the follow-up time may be stopped by competing terminal events, it is possible that patient observation times may correlate with the competing terminal events themselves, thus making the observation times difficult to assess. To explicitly account for the impact of competing terminal events and dependent observation times on the longitudinal data analysis in the context of such complex data, we propose a joint model using latent random effects to describe the association among them. A likelihood-based approach is derived for statistical inference. Extensive simulation studies reveal that the proposed approach performs well for practical situations, and an analysis of patients with chronic kidney disease in a cohort study is presented to illustrate the proposed method.     

Longitudinal data analysis for generalized linear models with follow‐up dependent on outcome‐related variables

In longitudinal studies, observation times are often irregular and subject‐specific. Frequently they are related to the outcome measure or other variables that are associated with the outcome measure but undesirable to condition upon in the model for outcome. Regression analyses that are unadjusted for outcome‐dependent follow‐up then yield biased estimates. The authors propose a class of inverse‐intensity rate‐ratio weighted estimators in generalized linear models that adjust for outcome‐dependent follow‐up. The estimators, based on estimating equations, are very simple and easily computed; they can be used under mixtures of continuous and discrete observation times. The predictors of observation times can be past observed outcomes, cumulative values of outcome‐model covariates and other factors associated with the outcome. The authors validate their approach through simulations and they illustrate it using data from a supported housing program from the US federal government.     

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.     

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 analysis of longitudinal measurements and survival times with a cure fraction based on partly linear mixed and semiparametric cure models

In a joint analysis of longitudinal quality of life (QoL) scores and relapse-free survival (RFS) times from a clinical trial on early breast cancer conducted by the Canadian Cancer Trials Group, we observed a complicated trajectory of QoL scores and existence of long-term survivors. Motivated by this observation, we proposed in this paper a flexible joint model for the longitudinal measurements and survival times. A partly linear mixed effect model is used to capture the complicated but smooth trajectory of longitudinal measurements and approximated by B-splines and a semiparametric mixture cure model with the B-spline baseline hazard to model survival times with a cure fraction. These two models are linked by shared random effects to explore the dependence between longitudinal measurements and survival times. A semiparametric inference procedure with an EM algorithm is proposed to estimate the parameters in the joint model. The performance of proposed procedures are evaluated by simulation studies and through the application to the analysis of data from the clinical trial which motivated this research.     

Recent History Functional Linear Models for Sparse Longitudinal Data

We consider the recent history functional linear models, relating a longitudinal response to a longitudinal predictor where the predictor process only in a sliding window into the recent past has an effect on the response value at the current time. We propose an estimation procedure for recent history functional linear models that is geared towards sparse longitudinal data, where the observation times across subjects are irregular and total number of measurements per subject is small. The proposed estimation procedure builds upon recent developments in literature for estimation of functional linear models with sparse data and utilizes connections between the recent history functional linear models and varying coefficient models. We establish uniform consistency of the proposed estimators, propose prediction of the response trajectories and derive their asymptotic distribution leading to asymptotic point-wise confidence bands. We include a real data application and simulation studies to demonstrate the efficacy of the proposed methodology.     

Semiparametric analysis of panel count data with correlated observation and follow-up times

This paper discusses regression analysis of panel count data that often arise in longitudinal studies concerning occurrence rates of certain recurrent events. Panel count data mean that each study subject is observed only at discrete time points rather than under continuous observation. Furthermore, both observation and follow-up times can vary from subject to subject and may be correlated with the recurrent events. For inference, we propose some shared frailty models and estimating equations are developed for estimation of regression parameters. The proposed estimates are consistent and have asymptotically a normal distribution. The finite sample properties of the proposed estimates are investigated through simulation and an illustrative example from a cancer study is provided.     

Analysis of longitudinal health-related quality of life data with terminal events

Longitudinal health-related quality of life data arise naturally from studies of progressive and neurodegenerative diseases. In such studies, patients’ mental and physical conditions are measured over their follow-up periods and the resulting data are often complicated by subject-specific measurement times and possible terminal events associated with outcome variables. Motivated by the “Predictor’s Cohort” study on patients with advanced Alzheimer disease, we propose in this paper a semiparametric modeling approach to longitudinal health-related quality of life data. It builds upon and extends some recent developments for longitudinal data with irregular observation times. The new approach handles possibly dependent terminal events. It allows one to examine time-dependent covariate effects on the evolution of outcome variable and to assess nonparametrically change of outcome measurement that is due to factors not incorporated in the covariates. The usual large-sample properties for parameter estimation are established. In particular, it is shown that relevant parameter estimators are asymptotically normal and the asymptotic variances can be estimated consistently by the simple plug-in method. A general procedure for testing a specific parametric form in the nonparametric component is also developed. Simulation studies show that the proposed approach performs well for practical settings. The method is applied to the motivating example.     

Regression analysis of panel count data with covariate-dependent observation and censoring times

Panel count data often occur in a long-term study where the primary end point is the time to a specific event and each subject may experience multiple recurrences of this event. Furthermore, suppose that it is not feasible to keep subjects under observation continuously and the numbers of recurrences for each subject are only recorded at several distinct time points over the study period. Moreover, the set of observation times may vary from subject to subject. In this paper, regression methods, which are derived under simple semiparametric models, are proposed for the analysis of such longitudinal count data. Especially, we consider the situation when both observation and censoring times may depend on covariates. The new procedures are illustrated with data from a well-known cancer study.     

Joint Modelling of Survival and Longitudinal Data with Informative Observation Times

In this paper, we consider the joint modelling of survival and longitudinal data with informative observation time points. The survival model and the longitudinal model are linked via random effects, for which no distribution assumption is required under our estimation approach. The estimator is shown to be consistent and asymptotically normal. The proposed estimator and its estimated covariance matrix can be easily calculated. Simulation studies and an application to a primary biliary cirrhosis study are also provided.     

Hybrid pairwise‐likelihood estimation methods for incomplete longitudinal binary data

In longitudinal data, missing observations occur commonly with incomplete responses and covariates. Missing data can have a ‘missing not at random’ mechanism, a non‐monotone missing pattern, and moreover response and covariates can be missing not simultaneously. To avoid complexities in both modelling and computation, a two‐stage estimation method and a pairwise‐likelihood method are proposed. The two‐stage estimation method enjoys simplicities in computation, but incurs more severe efficiency loss. On the other hand, the pairwise approach leads to estimators with better efficiency, but can be cumbersome in computation. In this paper, we develop a compromise method using a hybrid pairwise‐likelihood framework. Our proposed approach has better efficiency than the two‐stage method, but its computational cost is still reasonable compared to the pairwise approach. The performance of the methods is evaluated empirically by means of simulation studies. Our methods are used to analyse longitudinal data obtained from the National Population Health Study.     

Quantile regression methods for censored gap time data

ABSTRACT

In longitudinal studies, subjects may potentially undergo a series of sequentially ordered events. The gap times, which are the times between two serial events, are often the outcome variables of interest. This study considers quantile regression models of gap times for censored serial-event data and adapts a weighted version of the estimating equation for regression coefficients. The resulting estimators are uniformly consistent and asymptotically normal. Extensive simulation studies are presented to evaluate the finite-sample performance of the proposed methods. An analysis of the tumor recurrence data for bladder cancer patients is also provided to illustrate our proposed methods.     

Unified Inference for Sparse and Dense Longitudinal Data in Time‐varying Coefficient Models

Time‐varying coefficient models are widely used in longitudinal data analysis. These models allow the effects of predictors on response to vary over time. In this article, we consider a mixed‐effects time‐varying coefficient model to account for the within subject correlation for longitudinal data. We show that when kernel smoothing is used to estimate the smooth functions in time‐varying coefficient models for sparse or dense longitudinal data, the asymptotic results of these two situations are essentially different. Therefore, a subjective choice between the sparse and dense cases might lead to erroneous conclusions for statistical inference. In order to solve this problem, we establish a unified self‐normalized central limit theorem, based on which a unified inference is proposed without deciding whether the data are sparse or dense. The effectiveness of the proposed unified inference is demonstrated through a simulation study and an analysis of Baltimore MACS data.     

Efficient estimation in partially linear single‐index models for longitudinal data

In this paper, we consider the estimation of both the parameters and the nonparametric link function in partially linear single‐index models for longitudinal data that may be unbalanced. In particular, a new three‐stage approach is proposed to estimate the nonparametric link function using marginal kernel regression and the parametric components with generalized estimating equations. The resulting estimators properly account for the within‐subject correlation. We show that the parameter estimators are asymptotically semiparametrically efficient. We also show that the asymptotic variance of the link function estimator is minimized when the working error covariance matrices are correctly specified. The new estimators are more efficient than estimators in the existing literature. These asymptotic results are obtained without assuming normality. The finite‐sample performance of the proposed method is demonstrated by simulation studies. In addition, two real‐data examples are analyzed to illustrate the methodology.     

Analysis of Panel Count Data with Dependent Observation Times

In this article, a semiparametric approach is proposed for the regression analysis of panel count data. Panel count data commonly arise in clinical trials and demographical studies where the response variable is the number of multiple recurrences of the event of interest and observation times are not fixed, varying from subject to subject. It is assumed that two processes exist in this data: the first is for a recurrent event and the second is for observation time. Many studies have been done to estimate mean function and regression parameters under the independency between recurrent event process and observation time process. In this article, the same statistical inference is studied, but the situation where these two processes may be related is also considered. The mixed Poisson process is applied for the recurrent event processes, and a frailty intensity function for the observation time is also used, respectively. Simulation studies are conducted to study the performance of the suggested methods. The bladder tumor data are applied to compare previous studie' results.     

A stochastic variant of the EM algorithm to fit mixed (discrete and continuous) longitudinal data with nonignorable missingness

Abstract

In longitudinal studies data are collected on the same set of units for more than one occasion. In medical studies it is very common to have mixed Poisson and continuous longitudinal data. In such studies, for different reasons, some intended measurements might not be available resulting in a missing data setting. When the probability of missingness is related to the missing values, the missingness mechanism is termed nonrandom. The stochastic expectation-maximization (SEM) algorithm and the parametric fractional imputation (PFI) method are developed to handle nonrandom missingness in mixed discrete and continuous longitudinal data assuming different covariance structures for the continuous outcome. The proposed techniques are evaluated using simulation studies. Also, the proposed techniques are applied to the interstitial cystitis data base (ICDB) data.     

Robust transformation mixed‐effects models for longitudinal continuous proportional data

The authors propose a robust transformation linear mixed‐effects model for longitudinal continuous proportional data when some of the subjects exhibit outlying trajectories over time. It becomes troublesome when including or excluding such subjects in the data analysis results in different statistical conclusions. To robustify the longitudinal analysis using the mixed‐effects model, they utilize the multivariate t distribution for random effects or/and error terms. Estimation and inference in the proposed model are established and illustrated by a real data example from an ophthalmology study. Simulation studies show a substantial robustness gain by the proposed model in comparison to the mixed‐effects model based on Aitchison's logit‐normal approach. As a result, the data analysis benefits from the robustness of making consistent conclusions in the presence of influential outliers. The Canadian Journal of Statistics © 2009 Statistical Society of Canada