Weak convergence for the conditional distribution function in a Koziol–Green model under dependent censoring

In this paper we consider the conditional Koziol–Green model of Braekers and Veraverbeke [2008. A conditional Koziol–Green model under dependent censoring. Statist. Probab. Lett., accepted for publication] in which they generalized the Koziol–Green model of Veraverbeke and Cadarso Suárez [2000. Estimation of the conditional distribution in a conditional Koziol–Green model. Test 9, 97–122] by assuming that the association between a censoring time and a time until an event is described by a known Archimedean copula function. They got in this way, an informative censoring model with two different types of informative censoring. Braekers and Veraverbeke [2008. A conditional Koziol–Green model under dependent censoring. Statist. Probab. Lett., accepted for publication] derived in this model a non-parametric Koziol–Green estimator for the conditional distribution function of the time until an event, for which they showed the uniform consistency and the asymptotic normality. In this paper we extend their results and prove the weak convergence of the process associated to this estimator. Furthermore we show that the conditional Koziol–Green estimator is asymptotically more efficient in this model than the general copula-graphic estimator of Braekers and Veraverbeke [2005. A copula-graphic estimator for the conditional survival function under dependent censoring. Canad. J. Statist. 33, 429–447]. As last result, we construct an asymptotic confidence band for the conditional Koziol–Green estimator. Through a simulation study, we investigate the small sample properties of this asymptotic confidence band. Afterwards we apply this estimator and its confidence band on a practical data set.     

On estimation of frequency data with censored observations

The problem of the estimation of mean frequency of events in the presence of censoring is important in assessing the efficacy, safety and cost of therapies. The mean frequency is typically estimated by dividing the total number of events by the total number of patients under study. This method, referred to in this paper as the ‘naïve estimator’, ignores the censoring. Other approaches available for this problem require many assumptions that are rarely acceptable. These include the assumption of independence, constant hazard rate over time and other similar distributional assumptions. In this paper a simple non‐parametric estimator based on the sum of the products of Kaplan–Meier estimators is proposed as an estimator of mean frequency, and its approximate variance and standard error are derived. An illustration is provided to show the derivation of the proposed estimator. Although the clinical trial setting is used in this paper, the problem has applications in other areas where survival analysis is used and recurrent events are studied. Copyright © 2003 John Wiley & Sons, Ltd.     

Non parametric hazard estimation with dependent censoring using penalized likelihood and an assumed copula

This article introduces a novel non parametric penalized likelihood hazard estimation when the censoring time is dependent on the failure time for each subject under observation. More specifically, we model this dependence using a copula, and the method of maximum penalized likelihood (MPL) is adopted to estimate the hazard function. We do not consider covariates in this article. The non negatively constrained MPL hazard estimation is obtained using a multiplicative iterative algorithm. The consistency results and the asymptotic properties of the proposed hazard estimator are derived. The simulation studies show that our MPL estimator under dependent censoring with an assumed copula model provides a better accuracy than the MPL estimator under independent censoring if the sign of dependence is correctly specified in the copula function. The proposed method is applied to a real dataset, with a sensitivity analysis performed over various values of correlation between failure and censoring times.     

Estimating stage occupation probabilities in non-Markov models

We study non-Markov multistage models under dependent censoring regarding estimation of stage occupation probabilities. The individual transition and censoring mechanisms are linked together through covariate processes that affect both the transition intensities and the censoring hazard for the corresponding subjects. In order to adjust for the dependent censoring, an additive hazard regression model is applied to the censoring times, and all observed counting and “at risk” processes are subsequently given an inverse probability of censoring weighted form. We examine the bias of the Datta–Satten and Aalen–Johansen estimators of stage occupation probability, and also consider the variability of these estimators by studying their estimated standard errors and mean squared errors. Results from different simulation studies of frailty models indicate that the Datta–Satten estimator is approximately unbiased, whereas the Aalen–Johansen estimator either under- or overestimates the stage occupation probability due to the dependent nature of the censoring process. However, in our simulations, the mean squared error of the latter estimator tends to be slightly smaller than that of the former estimator. Studies on development of nephropathy among diabetics and on blood platelet recovery among bone marrow transplant patients are used as demonstrations on how the two estimation methods work in practice. Our analyses show that the Datta–Satten estimator performs well in estimating stage occupation probability, but that the censoring mechanism has to be quite selective before a deviation from the Aalen-Johansen estimator is of practical importance. N. Gunnes—Supported by a grant from the Norwegian Cancer Society.     

Parametric Estimation of Menarcheal Age Distribution Based on Recall Data

Menarche, the onset of menstruation, is an important maturational event of female childhood. Most of the studies of age at menarche make use of dichotomous (status quo) data. More information can be harnessed from recall data, but such data are often censored in a informative way. We show that the usual maximum likelihood estimator based on interval censored data, which ignores the informative nature of censoring, can be biased and inconsistent. We propose a parametric estimator of the menarcheal age distribution on the basis of a realistic model of the recall phenomenon. We identify the additional information contained in the recall data and demonstrate theoretically as well as through simulations the advantage of the maximum likelihood estimator based on recall data over that based on status quo data.     

Bayesian Modeling of Recurrent Event Data with Dependent Censoring

The recurrent-event setting, where the subjects experience multiple occurrences of the event of interest, are encountered in many biomedical applications. In analyzing recurrent event data, non informative censoring is often assumed for the implementation of statistical methods. However, when a terminating event such as death serves as part of the censoring mechanism, validity of the censoring assumption may be violated because recurrence can be a powerful risk factor for death. We consider joint modeling of recurrent event process and terminating event under a Bayesian framework in which a shared frailty is used to model the association between the intensity of the recurrent event process and the hazard of the terminating event. Our proposed model is implemented on data from a well-known cancer study.     

An analytic method for randomized trials with informative censoring: Part II

Consider a randomized trial in which time to the occurrence of a particular disease, say pneumocystic pneumonia in an AIDS trial or breast cancer in a mammographic screening trial, is the failure time of primary interest. Suppose that time to disease is subject to informative censoring by the minimum of time to death, loss to and end of follow-up. In such a trial, the potential censoring time is observed for all study subjects, including failures. In the presence of informative censoring, it is not possible to consistently estimate the effect of treatment on time to disease without imposing additional non-identifiable assumptions. Robins (1995) specified two non-identifiable assumptions that allow one to test for and estimate an effect of treatment on time to disease in the presence of informative censoring. The goal of this paper is to provide a class of consistent and reasonably efficient semiparametric tests and estimators for the treatment effect under these assumptions. The tests in our class, like standard weighted-log-rank tests, are asymptotically distribution-free -level tests under the null hypothesis of no causal effect of treatment on time to disease whenever the censoring and failure distributions are conditionally independent given treatment arm. However, our tests remain asymptotically distribution-free -level tests in the presence of informative censoring provided either of our assumptions are true. In contrast, a weighted log-rank test will be an -level test in the presence of informative censoring only if (1) one of our two non-identifiable assumptions hold, and (2) the distribution of time to censoring is the same in the two treatment arms. We also study the estimation, in the presence of informative censoring, of the effect of treatment on the evolution over time of the mean of repeated measures outcome such as CD4 count.     

An Estimator of the Survival Function Basedon the Semi-Markov Model Under Dependent Censorship

Lee and Wolfe (Biometrics vol. 54 pp. 1176–1178, 1998) proposed the two-stage sampling design for testing the assumption of independent censoring, which involves further follow-up of a subset of lost-to-follow-up censored subjects. They also proposed an adjusted estimator for the survivor function for a proportional hazards model under the dependent censoring model. In this paper, a new estimator for the survivor function is proposed for the semi-Markov model under the dependent censorship on the basis of the two-stage sampling data. The consistency and the asymptotic distribution of the proposed estimator are derived. The estimation procedure is illustrated with an example of lung cancer clinical trial and simulation results are reported of the mean squared errors of estimators under a proportional hazards and two different nonproportional hazards models.     

An analytic method for randomized trials with informative censoring: Part 1

Consider a randomized trial in which time to the occurrence of a particular disease, say pneumocystis pneumonia in an AIDS trial or breast cancer in a mammographic screening trial, is the failure time of primary interest. Suppose that time to disease is subject to informative censoring by the minimum of time to death, loss to and end of follow-up. In such a trial, the censoring time is observed for all study subjects, including failures. In the presence of informative censoring, it is not possible to consistently estimate the effect of treatment on time to disease without imposing additional non-identifiable assumptions. The goals of this paper are to specify two non-identifiable assumptions that allow one to test for and estimate an effect of treatment on time to disease in the presence of informative censoring. In a companion paper (Robins, 1995), we provide consistent and reasonably efficient semiparametric estimators for the treatment effect under these assumptions. In this paper we largely restrict attention to testing. We propose tests that, like standard weighted-log-rank tests, are asymptotically distribution-free -level tests under the null hypothesis of no causal effect of treatment on time to disease whenever the censoring and failure distributions are conditionally independent given treatment arm. However, our tests remain asymptotically distribution-free -level tests in the presence of informative censoring provided either of our assumptions are true. In contrast, a weighted log-rank test will be an -level test in the presence of informative censoring only if (1) one of our two non-identifiable assumptions hold, and (2) the distribution of time to censoring is the same in the two treatment arms. We also extend our methods to studies of the effect of a treatment on the evolution over time of the mean of a repeated measures outcome, such as CD-4 count.     

Random Weighted Bootstrap Method for Recurrent Events with Informative Censoring

Using the data from the AIDS Link to Intravenous Experiences cohort study as an example, an informative censoring model was used to characterize the repeated hospitalization process of a group of patients. Under the informative censoring assumption, the estimators of the baseline rate function and the regression parameters were shown to be related to a latent variable. Hence, it becomes impractical to directly estimate the unknown quantities in the moments of the estimators for the bandwidth selection of a smoothing estimator and the construction of confidence intervals, which are respectively based on the asymptotic mean squared errors and the asymptotic distributions of the estimators. To overcome these difficulties, we develop a random weighted bootstrap procedure to select appropriate bandwidths and to construct approximated confidence intervals. One can see that our method is simple and faster to implement from a practical point of view, and is at least as accurate as other bootstrap methods. In this article, it is shown that the proposed method is useful through the performance of a Monte Carlo simulation. An application of our procedure is also illustrated by a recurrent event sample of intravenous drug users for inpatient cares over time.     

Large sample properties of nonparametric copula estimators under bivariate censoring

A new nonparametric estimator is proposed for the copula function of a bivariate survival function for data subject to random right-censoring. We consider two censoring models: univariate and copula censoring. We show strong consistency and we obtain an i.i.d. representation for the copula estimator. In a simulation study we compare the new estimator to the one of Gribkova and Lopez [Nonparametric copula estimation under bivariate censoring; doi:10.1111/sjos.12144].     

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.     

Using categorical markers as auxiliary variables in log‐rank tests and hazard ratio estimation

Markers, which are prognostic longitudinal variables, can be used to replace some of the information lost due to right censoring. They may also be used to remove or reduce bias due to informative censoring. In this paper, the authors propose novel methods for using markers to increase the efficiency of log‐rank tests and hazard ratio estimation, as well as parametric estimation. They propose a «plug‐in» methodology that consists of writing the test statistic or estimate of interest as a functional of Kaplan–Meier estimators. The latter are then replaced by an efficient estimator of the survival curve that incorporates information from markers. Using simulations, the authors show that the resulting estimators and tests can be up to 30% more efficient than the usual procedures, provided that the marker is highly prognostic and that the frequency of censoring is high.     

A Proportional Hazards Regression Model for the Subdistribution with Covariates‐adjusted Censoring Weight for Competing Risks Data

With competing risks data, one often needs to assess the treatment and covariate effects on the cumulative incidence function. Fine and Gray proposed a proportional hazards regression model for the subdistribution of a competing risk with the assumption that the censoring distribution and the covariates are independent. Covariate‐dependent censoring sometimes occurs in medical studies. In this paper, we study the proportional hazards regression model for the subdistribution of a competing risk with proper adjustments for covariate‐dependent censoring. We consider a covariate‐adjusted weight function by fitting the Cox model for the censoring distribution and using the predictive probability for each individual. Our simulation study shows that the covariate‐adjusted weight estimator is basically unbiased when the censoring time depends on the covariates, and the covariate‐adjusted weight approach works well for the variance estimator as well. We illustrate our methods with bone marrow transplant data from the Center for International Blood and Marrow Transplant Research. Here, cancer relapse and death in complete remission are two competing risks.     

Bayesian analysis of categorical data informatively censored

This article presents a general Bayesian analysis of incomplete categorical data considered as generated by a statistical model involving the categorical sampling process and the observable censoring process. The novelty is that we allow dependence of the censoring process paramenters on the sampling categories; i.e., an informative censoring process. In this way, we relax the assumptions under which both classical and Bayesian solutions have been de-veloped. The proposed solution is outlined for the relevant case of the censoring pattern based on partitions. It is completely developed for a simple but typical examples. Several possible extensions of our procedure are discussed in the final remarks.     

Estimation of the cumulative incidence function under multiple dependent and independent censoring mechanisms

Competing risks occur in a time-to-event analysis in which a patient can experience one of several types of events. Traditional methods for handling competing risks data presuppose one censoring process, which is assumed to be independent. In a controlled clinical trial, censoring can occur for several reasons: some independent, others dependent. We propose an estimator of the cumulative incidence function in the presence of both independent and dependent censoring mechanisms. We rely on semi-parametric theory to derive an augmented inverse probability of censoring weighted (AIPCW) estimator. We demonstrate the efficiency gained when using the AIPCW estimator compared to a non-augmented estimator via simulations. We then apply our method to evaluate the safety and efficacy of three anti-HIV regimens in a randomized trial conducted by the AIDS Clinical Trial Group, ACTG A5095.     

Approximate MLE for the scale parameter of the generalized exponential distribution under random censoring

In this paper, we consider the maximum likelihood estimator (MLE) of the scale parameter of the generalized exponential (GE) distribution based on a random censoring model. We assume the censoring distribution also follows a GE distribution. Since the estimator does not provide an explicit solution, we propose a simple method of deriving an explicit estimator by approximating the likelihood function. In order to compare the performance of the estimators, Monte Carlo simulation is conducted. The results show that the MLE and the approximate MLE are almost identical in terms of bias and variance.     

Survival Estimation with Missing Censoring Times for the Generalized Koziol–Green Model

ABSTRACT

When analyzing time-to-event data, there are various situations in which right censoring times for unfailed units are missing. In that context, by taking a supplementary sample of a convenient percentage of unfailed units, we propose a semi-parametric method for estimating a survival function under the natural extension of the Koziol–Green model to double random censoring. Some large sample properties of this estimator are derived. We prove uniform strong consistency and asymptotic weak convergence to a Gaussian process. A simulation study is also presented in order to analyze the behavior of the proposed estimator.     

Additive risks regression model for middle censored exponentiated-exponential lifetime data

Jammalamadaka and Mangalam introduced middle censoring which refers to data arising in situations, where the exact lifetime becomes unobservable if it falls within a random censoring interval. In the present article, we propose an additive risks regression model for a lifetime data subject to middle censoring, where the lifetimes are assumed to follow exponentiated exponential distribution. The regression parameters are estimated using the Expectation-Maximization algorithm. Asymptotic normality of the estimator is proposed. We report a simulation study to assess the finite sample properties of the estimator. We then analyze a real-life data on survival times of larynx cancer patients studied by Karduan.     

Marginal Regression Analysis for Semi-Competing Risks Data Under Dependent Censoring

Abstract.  Multiple events data are commonly seen in medical applications. There are two types of events, namely terminal and non-terminal. Statistical analysis for non-terminal events is complicated due to dependent censoring. Consequently, joint modelling and inference are often needed to avoid the problem of non-identifiability. This article considers regression analysis for multiple events data with major interest in a non-terminal event such as disease progression. We generalize the technique of artificial censoring, which is a popular way to handle dependent censoring, under flexible model assumptions on the two types of events. The proposed method is applied to analyse a data set of bone marrow transplantation.