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.     

Semiparametric model for semi-competing risks data with application to breast cancer study

For many forms of cancer, patients will receive the initial regimen of treatments, then experience cancer progression and eventually die of the disease. Understanding the disease process in patients with cancer is essential in clinical, epidemiological and translational research. One challenge in analyzing such data is that death dependently censors cancer progression (e.g., recurrence), whereas progression does not censor death. We deal with the informative censoring by first selecting a suitable copula model through an exploratory diagnostic approach and then developing an inference procedure to simultaneously estimate the marginal survival function of cancer relapse and an association parameter in the copula model. We show that the proposed estimators possess consistency and weak convergence. We use simulation studies to evaluate the finite sample performance of the proposed method, and illustrate it through an application to data from a study of early stage breast cancer.     

Maximum likelihood analysis of semicompeting risks data with semiparametric regression models

The “semicompeting risks” include a terminal event and a non-terminal event. The terminal event may censor the non-terminal event but not vice versa. Because times to the two events are usually correlated, the non-terminal event is subject to dependent/informative censoring by the terminal event. We seek to conduct marginal regressions and joint association analyses for the two event times under semicompeting risks. The proposed method is based on the modeling setup where the semiparametric transformation models are assumed for marginal regressions, and a copula model is assumed for the joint distribution. We propose a nonparametric maximum likelihood approach for inferences, which provides a martingale representation for the score function and an analytical expression for the information matrix. Direct theoretical developments and computational implementation are allowed for the proposed approach. Simulations and a real data application demonstrate the utility of the proposed methodology.     

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.     

Estimation of the joint survival function for successive duration times under double-truncation and right-censoring

ABSTRACT

In incident cohort studies, survival data often include subjects who have had an initiate event at recruitment and may potentially experience two successive events (first and second) during the follow-up period. When disease registries or surveillance systems collect data based on incidence occurring within a specific calendar time interval, the initial event is usually subject to double truncation. Furthermore, since the second duration process is observable only if the first event has occurred, double truncation and dependent censoring arise. In this article, under the two sampling biases with an unspecified distribution of truncation variables, we propose a nonparametric estimator of the joint survival function of two successive duration times using the inverse-probability-weighted (IPW) approach. The consistency of the proposed estimator is established. Based on the estimated marginal survival functions, we also propose a two-stage estimation procedure for estimating the parameters of copula model. The bootstrap method is used to construct confidence interval. Numerical studies demonstrate that the proposed estimation approaches perform well with moderate sample sizes.     

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.     

Regression analysis of informative current status data with the semiparametric linear transformation model

Many methods have been developed in the literature for regression analysis of current status data with noninformative censoring and also some approaches have been proposed for semiparametric regression analysis of current status data with informative censoring. However, the existing approaches for the latter situation are mainly on specific models such as the proportional hazards model and the additive hazard model. Corresponding to this, in this paper, we consider a general class of semiparametric linear transformation models and develop a sieve maximum likelihood estimation approach for the inference. In the method, the copula model is employed to describe the informative censoring or relationship between the failure time of interest and the censoring time, and Bernstein polynomials are used to approximate the nonparametric functions involved. The asymptotic consistency and normality of the proposed estimators are established, and an extensive simulation study is conducted and indicates that the proposed approach works well for practical situations. In addition, an illustrative example is provided.     

A copula model for marked point processes

Many chronic diseases feature recurring clinically important events. In addition, however, there often exists a random variable which is realized upon the occurrence of each event reflecting the severity of the event, a cost associated with it, or possibly a short term response indicating the effect of a therapeutic intervention. We describe a novel model for a marked point process which incorporates a dependence between continuous marks and the event process through the use of a copula function. The copula formulation ensures that event times can be modeled by any intensity function for point processes, and any multivariate model can be specified for the continuous marks. The relative efficiency of joint versus separate analyses of the event times and the marks is examined through simulation under random censoring. An application to data from a recent trial in transfusion medicine is given for illustration.     

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.     

Flexible Modeling in the Koziol-Green Model by a Copula Function

In survival analysis, the classical Koziol-Green random censorship model is commonly used to describe informative censoring. Hereby, it is assumed that the distribution of the censoring time is a power of the distribution of the survival time. In this article, we extend this model by assuming a general function between these distributions. We determine this function from a relationship between the observable random variables which is described by a copula family that depends on an unknown parameter θ. For this setting, we develop a semi-parametric estimator for the distribution of the survival time in which we propose a pseudo-likelihood estimator for the copula parameter θ. As results, we show first the consistency and asymptotic normality of the estimator for θ. Afterwards, we prove the weak convergence of the process associated to the semi-parametric distribution estimator. Furthermore, we investigate the finite sample performance of these estimators through a simulation study and finally apply it to a practical data set on survival with malignant melanoma.     

Semiparametric regression methods for temporal processes subject to multiple sources of censoring

Process regression methodology is underdeveloped relative to the frequency with which pertinent data arise. In this article, the response-190 is a binary indicator process representing the joint event of being alive and remaining in a specific state. The process is indexed by time (e.g., time since diagnosis) and observed continuously. Data of this sort occur frequently in the study of chronic disease. A general area of application involves a recurrent event with non-negligible duration (e.g., hospitalization and associated length of hospital stay) and subject to a terminating event (e.g., death). We propose a semiparametric multiplicative model for the process version of the probability of being alive and in the (transient) state of interest. Under the proposed methods, the regression parameter is estimated through a procedure that does not require estimating the baseline probability. Unlike the majority of process regression methods, the proposed methods accommodate multiple sources of censoring. In particular, we derive a computationally convenient variant of inverse probability of censoring weighting based on the additive hazards model. We show that the regression parameter estimator is asymptotically normal, and that the baseline probability function estimator converges to a Gaussian process. Simulations demonstrate that our estimators have good finite sample performance. We apply our method to national end-stage liver disease data. The Canadian Journal of Statistics 48: 222–237; 2020 © 2019 Statistical Society of Canada     

A copula model for bivariate hybrid censored survival data with application to the MACS study

A copula model for bivariate survival data with hybrid censoring is proposed to study the association between survival time of individuals infected with HIV and persistence time of infection with an additional virus. Survival with HIV is right censored and the persistence time of the additional virus is subject to interval censoring case 1. A pseudo-likelihood method is developed to study the association between the two event times under such hybrid censoring. Asymptotic consistency and normality of the pseudo-likelihood estimator are established based on empirical process theory. Simulation studies indicate good performance of the estimator with moderate sample size. The method is applied to a motivating HIV study which investigates the effect of GB virus type C (GBV-C) co-infection on survival time of HIV infected individuals.     

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.     

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.     

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.     

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.     

Non‐parametric Copula Estimation Under Bivariate Censoring

In this paper, we consider non‐parametric copula inference under bivariate censoring. Based on an estimator of the joint cumulative distribution function, we define a discrete and two smooth estimators of the copula. The construction that we propose is valid for a large range of estimators of the distribution function and therefore for a large range of bivariate censoring frameworks. Under some conditions on the tails of the distributions, the weak convergence of the corresponding copula processes is obtained in l^∞([0,1]²). We derive the uniform convergence rates of the copula density estimators deduced from our smooth copula estimators. Investigation of the practical behaviour of these estimators is performed through a simulation study and two real data applications, corresponding to different censoring settings. We use our non‐parametric estimators to define a goodness‐of‐fit procedure for parametric copula models. A new bootstrap scheme is proposed to compute the critical values.     

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.     

Likelihood-Based Inference for Semi-Competing Risks

Consider semi-competing risks data (two times to concurrent events are studied but only one of them is right-censored by the other one) where the link between the times Y and C to non-terminal and terminal events, respectively, is modeled by a family of Archimedean copulas. Moreover, both Y and C are submitted to an independent right censoring variable D. We propose to estimate the parameter of the copula and some resulting survival functions using a pseudo maximum likelihood approach. The main advantage of this procedure is that it extends to multidimensional parameters copulas. We perform simulations to study the behavior of our estimation procedure and its impact on other related estimators and we apply our method to real data coming from a study on the Hodgkin disease.     

Estimating treatment effects on the marginal recurrent event mean in the presence of a terminating event

In biomedical studies where the event of interest is recurrent (e.g., hospitalization), it is often the case that the recurrent event sequence is subject to being stopped by a terminating event (e.g., death). In comparing treatment options, the marginal recurrent event mean is frequently of interest. One major complication in the recurrent/terminal event setting is that censoring times are not known for subjects observed to die, which renders standard risk set based methods of estimation inapplicable. We propose two semiparametric methods for estimating the difference or ratio of treatment-specific marginal mean numbers of events. The first method involves imputing unobserved censoring times, while the second methods uses inverse probability of censoring weighting. In each case, imbalances in the treatment-specific covariate distributions are adjusted out through inverse probability of treatment weighting. After the imputation and/or weighting, the treatment-specific means (then their difference or ratio) are estimated nonparametrically. Large-sample properties are derived for each of the proposed estimators, with finite sample properties assessed through simulation. The proposed methods are applied to kidney transplant data.