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.     

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.     

Recurrent events analysis in the presence of time-dependent covariates and dependent censoring

Summary.  Recurrent events models have had considerable attention recently. The majority of approaches show the consistency of parameter estimates under the assumption that censoring is independent of the recurrent events process of interest conditional on the covariates that are included in the model. We provide an overview of available recurrent events analysis methods and present an inverse probability of censoring weighted estimator for the regression parameters in the Andersen–Gill model that is commonly used for recurrent event analysis. This estimator remains consistent under informative censoring if the censoring mechanism is estimated consistently, and it generally improves on the naïve estimator for the Andersen–Gill model in the case of independent censoring. We illustrate the bias of ad hoc estimators in the presence of informative censoring with a simulation study and provide a data analysis of recurrent lung exacerbations in cystic fibrosis patients when some patients are lost to follow-up.     

A semiparametric regression cure model for interval-censored and left-truncated data

Medical advancements have made it possible for patients to be cured of certain types of diseases. In follow-up studies, the disease event time can be subject to left truncation and interval censoring. In this article, we propose a semiparametric nonmixture cure model for the regression analysis of left-truncated and interval-censored (LTIC) data. We develop semiparametric maximum likelihood estimation for the nonmixture cure model with LTIC data. A simulation study is conducted to investigate the performance of the proposed estimators.     

Inverse censoring weighted median regression

We implement semiparametric random censorship model aided inference for censored median regression models. This is based on the idea that, when the censoring is specified by a common distribution, a semiparametric survival function estimator acts as an improved weight in the so-called inverse censoring weighted estimating function. We show that the proposed method will always produce estimates of the model parameters that are as good as or better than an existing estimator based on the traditional Kaplan–Meier weights. We also provide an illustration of the method through an analysis of a lung cancer data set.     

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.     

For censored and truncated data

In this paper we develop nonparametric methods for regression analysis when the response variable is subject to censoring and/or truncation. The development is based on a data completion princple that enables us to apply, via an iterative scheme, nonparametric regression techniques to iteratively com¬pleted data from a given sample with censored and/or truncated observations. In particular, locally weighted regression smoothers and additive regression models are extended to left-truncated and right-censored data Nonparamet¬ric regression analysis is applied to the Stanford heart transplant data, which have been analyzed by previous authors using semiparametric regression meth¬ods. and provides new insights into the relationship between expected survival time after a heart transplant and explanatory variables.     

Tobit regression for modeling mean survival time using data subject to multiple sources of censoring

Mean survival time is often of inherent interest in medical and epidemiologic studies. In the presence of censoring and when covariate effects are of interest, Cox regression is the strong default, but mostly due to convenience and familiarity. When survival times are uncensored, covariate effects can be estimated as differences in mean survival through linear regression. Tobit regression can validly be performed through maximum likelihood when the censoring times are fixed (ie, known for each subject, even in cases where the outcome is observed). However, Tobit regression is generally inapplicable when the response is subject to random right censoring. We propose Tobit regression methods based on weighted maximum likelihood which are applicable to survival times subject to both fixed and random censoring times. Under the proposed approach, known right censoring is handled naturally through the Tobit model, with inverse probability of censoring weighting used to overcome random censoring. Essentially, the re‐weighting data are intended to represent those that would have been observed in the absence of random censoring. We develop methods for estimating the Tobit regression parameter, then the population mean survival time. A closed form large‐sample variance estimator is proposed for the regression parameter estimator, with a semiparametric bootstrap standard error estimator derived for the population mean. The proposed methods are easily implementable using standard software. Finite‐sample properties are assessed through simulation. The methods are applied to a large cohort of patients wait‐listed for kidney transplantation.     

Semiparametric regression of clustered current status data

This paper discusses regression analysis of clustered current status data under semiparametric additive hazards models. In particular, we consider the situation when cluster sizes can be informative about correlated failure times from the same cluster. To address the problem, we present estimating equation-based estimation procedures and establish asymptotic properties of the resulting estimates. Finite sample performance of the proposed method is assessed through an extensive simulation study, which indicates the procedure works well. The method is applied to a motivating data set from a lung tumorigenicity study.     

Semiparametric simultaneous confidence bands for the difference of survival functions

In the analysis of censored survival data, simultaneous confidence bands are useful devices to help determine the efficacy of a treatment over a control. Semiparametric confidence bands are developed for the difference of two survival curves using empirical likelihood and compared with the nonparametric counterpart. Simulation studies are presented to show that the proposed semiparametric approach is superior, with the new confidence bands giving empirical coverage closer to the nominal level. Further comparisons reveal that the semiparametric confidence bands are tighter and, hence, more informative. For censoring rates between 10 and 40 %, the semiparametric confidence bands provide a relative reduction in enclosed area amounting to between 2 and 10 % over their nonparametric bands, with increased reduction attained for higher censoring rates. The methods are illustrated using an University of Massachusetts AIDS data set.     

Analyzing Length-biased Data with Semiparametric Transformation and Accelerated Failure Time Models

Right-censored time-to-event data are often observed from a cohort of prevalent cases that are subject to length-biased sampling. Informative right censoring of data from the prevalent cohort within the population often makes it difficult to model risk factors on the unbiased failure times for the general population, because the observed failure times are length biased. In this paper, we consider two classes of flexible semiparametric models: the transformation models and the accelerated failure time models, to assess covariate effects on the population failure times by modeling the length-biased times. We develop unbiased estimating equation approaches to obtain the consistent estimators of the regression coefficients. Large sample properties for the estimators are derived. The methods are confirmed through simulations and illustrated by application to data from a study of a prevalent cohort of dementia patients.     

Bayesian Semiparametric Regression for Median Residual Life

Abstract.  With survival data there is often interest not only in the survival time distribution but also in the residual survival time distribution. In fact, regression models to explain residual survival time might be desired. Building upon recent work of Kottas & Gelfand [ J. Amer. Statist. Assoc. 96 (2001) 1458], we formulate a semiparametric median residual life regression model induced by a semiparametric accelerated failure time regression model. We utilize a Bayesian approach which allows full and exact inference. Classical work essentially ignores covariates and is either based upon parametric assumptions or is limited to asymptotic inference in non-parametric settings. No regression modelling of median residual life appears to exist. The Bayesian modelling is developed through Dirichlet process mixing. The models are fitted using Gibbs sampling. Residual life inference is implemented extending the approach of Gelfand & Kottas [ J. Comput. Graph. Statist. 11 (2002) 289]. Finally, we present a fairly detailed analysis of a set of survival times with moderate censoring for patients with small cell lung cancer.     

Locally Efficient Semiparametric Estimators for Proportional Hazards Models with Measurement Error

We propose a new class of semiparametric estimators for proportional hazards models in the presence of measurement error in the covariates, where the baseline hazard function, the hazard function for the censoring time, and the distribution of the true covariates are considered as unknown infinite dimensional parameters. We estimate the model components by solving estimating equations based on the semiparametric efficient scores under a sequence of restricted models where the logarithm of the hazard functions are approximated by reduced rank regression splines. The proposed estimators are locally efficient in the sense that the estimators are semiparametrically efficient if the distribution of the error‐prone covariates is specified correctly and are still consistent and asymptotically normal if the distribution is misspecified. Our simulation studies show that the proposed estimators have smaller biases and variances than competing methods. We further illustrate the new method with a real application in an HIV clinical trial.     

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.     

Semiparametric estimation of treatment effect with time-lagged response in the presence of informative censoring

In many randomized clinical trials, the primary response variable, for example, the survival time, is not observed directly after the patients enroll in the study but rather observed after some period of time (lag time). It is often the case that such a response variable is missing for some patients due to censoring that occurs when the study ends before the patient’s response is observed or when the patients drop out of the study. It is often assumed that censoring occurs at random which is referred to as noninformative censoring; however, in many cases such an assumption may not be reasonable. If the missing data are not analyzed properly, the estimator or test for the treatment effect may be biased. In this paper, we use semiparametric theory to derive a class of consistent and asymptotically normal estimators for the treatment effect parameter which are applicable when the response variable is right censored. The baseline auxiliary covariates and post-treatment auxiliary covariates, which may be time-dependent, are also considered in our semiparametric model. These auxiliary covariates are used to derive estimators that both account for informative censoring and are more efficient then the estimators which do not consider the auxiliary covariates.     

The effect of omitted covariates in marginal and partially conditional recurrent event analyses

There have been many advances in statistical methodology for the analysis of recurrent event data in recent years. Multiplicative semiparametric rate-based models are widely used in clinical trials, as are more general partially conditional rate-based models involving event-based stratification. The partially conditional model provides protection against extra-Poisson variation as well as event-dependent censoring, but conditioning on outcomes post-randomization can induce confounding and compromise causal inference. The purpose of this article is to examine the consequences of model misspecification in semiparametric marginal and partially conditional rate-based analysis through omission of prognostic variables. We do so using estimating function theory and empirical studies.

     

Efficient estimation for the proportional hazards model with bivariate current status data

We consider efficient estimation of regression and association parameters jointly for bivariate current status data with the marginal proportional hazards model. Current status data occur in many fields including demographical studies and tumorigenicity experiments and several approaches have been proposed for regression analysis of univariate current status data. We discuss bivariate current status data and propose an efficient score estimation approach for the problem. In the approach, the copula model is used for joint survival function with the survival times assumed to follow the proportional hazards model marginally. Simulation studies are performed to evaluate the proposed estimates and suggest that the approach works well in practical situations. A real life data application is provided for illustration.     

Semiparametric estimation method for accelerated failure time model with dependent censoring

Independent censoring is commonly assumed in survival analysis. However, it may be questionable when censoring is related to event time. We model the event and censoring time marginally through accelerated failure time models, and model their association by a known copula. An iteration algorithm is proposed to estimate the regression parameters. Simulation results show the improvement of the proposed method compared to the naive method under independent censoring. Sensitivity analysis gives the evidences that the proposed method can obtain reasonable estimates even when the forms of copula are misspecified. We illustrate its application by analyzing prostate cancer data.     

Regression analysis of current-status data: an application to breast-feeding

"Although techniques for calculating mean survival time from current-status data are well known, their use in multiple regression models is somewhat troublesome. Using data on current breast-feeding behavior, this article considers a number of techniques that have been suggested in the literature, including parametric, nonparametric, and semiparametric models as well as the application of standard schedules. Models are tested in both proportional-odds and proportional-hazards frameworks....I fit [the] models to current status data on breast-feeding from the Demographic and Health Survey (DHS) in six countries: two African (Mali and Ondo State, Nigeria), two Asian (Indonesia and Sri Lanka), and two Latin American (Colombia and Peru)."     

Semiparametric Additive Accelerated Life Models

In this paper we investigate the asymptotic properties of estimators obtained for the semiparametric additive accelerated life model proposed by Bagdonavicius & Nikulin (1995). This model generalizes the well known additive hazards model of survival analysis and is close to the general transformation model (see Dabrowska & Doksum, 1988). Asymptotic properties of the estimator of the regression parameter and the estimator of the reliability function are given in the case of right censoring for discretized data and a numerical example illustrates these results.