Bayesian gamma frailty models for survival data with semi-competing risks and treatment switching

Motivated from a colorectal cancer study, we propose a class of frailty semi-competing risks survival models to account for the dependence between disease progression time, survival time, and treatment switching. Properties of the proposed models are examined and an efficient Gibbs sampling algorithm using the collapsed Gibbs technique is developed. A Bayesian procedure for assessing the treatment effect is also proposed. The deviance information criterion (DIC) with an appropriate deviance function and Logarithm of the pseudomarginal likelihood (LPML) are constructed for model comparison. A simulation study is conducted to examine the empirical performance of DIC and LPML and as well as the posterior estimates. The proposed method is further applied to analyze data from a colorectal cancer study.     

A dependent Dirichlet process model for survival data with competing risks

In this paper, we first propose a dependent Dirichlet process (DDP) model using a mixture of Weibull models with each mixture component resembling a Cox model for survival data. We then build a Dirichlet process mixture model for competing risks data without regression covariates. Next we extend this model to a DDP model for competing risks regression data by using a multiplicative covariate effect on subdistribution hazards in the mixture components. Though built on proportional hazards (or subdistribution hazards) models, the proposed nonparametric Bayesian regression models do not require the assumption of constant hazard (or subdistribution hazard) ratio. An external time-dependent covariate is also considered in the survival model. After describing the model, we discuss how both cause-specific and subdistribution hazard ratios can be estimated from the same nonparametric Bayesian model for competing risks regression. For use with the regression models proposed, we introduce an omnibus prior that is suitable when little external information is available about covariate effects. Finally we compare the models’ performance with existing methods through simulations. We also illustrate the proposed competing risks regression model with data from a breast cancer study. An R package “DPWeibull” implementing all of the proposed methods is available at CRAN.

     

Stratified proportional subdistribution hazards model with covariate-adjusted censoring weight for case-cohort studies

The case-cohort study design is widely used to reduce cost when collecting expensive covariates in large cohort studies with survival or competing risks outcomes. A case-cohort study dataset consists of two parts: (a) a random sample and (b) all cases or failures from a specific cause of interest. Clinicians often assess covariate effects on competing risks outcomes. The proportional subdistribution hazards model directly evaluates the effect of a covariate on the cumulative incidence function under the non-covariate-dependent censoring assumption for the full cohort study. However, the non-covariate-dependent censoring assumption is often violated in many biomedical studies. In this article, we propose a proportional subdistribution hazards model for case-cohort studies with stratified data with covariate-adjusted censoring weight. We further propose an efficient estimator when extra information from the other causes is available under case-cohort studies. The proposed estimators are shown to be consistent and asymptotically normal. Simulation studies show (a) the proposed estimator is unbiased when the censoring distribution depends on covariates and (b) the proposed efficient estimator gains estimation efficiency when using extra information from the other causes. We analyze a bone marrow transplant dataset and a coronary heart disease dataset using the proposed method.     

A 3-parameter Gompertz distribution for survival data with competing risks,with an application to breast cancer data

The cumulative incidence function is of great importance in the analysis of survival data when competing risks are present. Parametric modeling of such functions, which are by nature improper, suggests the use of improper distributions. One frequently used improper distribution is that of Gompertz, which captures only monotone hazard shapes. In some applications, however, subdistribution hazard estimates have been observed with unimodal shapes. An extension to the Gompertz distribution is presented which can capture unimodal as well as monotone hazard shapes. Important properties of the proposed distribution are discussed, and the proposed distribution is used to analyze survival data from a breast cancer clinical trial.     

A Mass Redistribution Algorithm for Right Censored and Left Truncated Time to Event Data

Failure times are often right-censored and left-truncated. In this paper we give a mass redistribution algorithm for right-censored and/or left-truncated failure time data. We show that this algorithm yields the Kaplan-Meier estimator of the survival probability. One application of this algorithm in modeling the subdistribution hazard for competing risks data is studied. We give a product-limit estimator of the cumulative incidence function via modeling the subdistribution hazard. We show by induction that this product-limit estimator is identical to the left-truncated version of Aalen-Johansen (1978) estimator for the cumulative incidence function.     

Competing risks model for clustered data based on the subdistribution hazards with spatial random effects

In some applications, the clustered survival data are arranged spatially such as clinical centers or geographical regions. Incorporating spatial variation in these data not only can improve the accuracy and efficiency of the parameter estimation, but it also investigates the spatial patterns of survivorship for identifying high-risk areas. Competing risks in survival data concern a situation where there is more than one cause of failure, but only the occurrence of the first one is observable. In this paper, we considered Bayesian subdistribution hazard regression models with spatial random effects for the clustered HIV/AIDS data. An intrinsic conditional autoregressive (ICAR) distribution was employed to model the areal spatial random effects. Comparison among competing models was performed by the deviance information criterion. We illustrated the gains of our model through application to the HIV/AIDS data and the simulation studies.KEYWORDS: Competing risks, subdistribution hazard, cumulative incidence function, spatial random effect, Markov chain Monte Carlo     

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.     

Reinforced urns and the subdistribution beta‐Stacy process prior for competing risks analysis

In this paper, we introduce the subdistribution beta‐Stacy process, a novel Bayesian nonparametric process prior for subdistribution functions useful for the analysis of competing risks data. In particular, we (i) characterize this process from a predictive perspective by means of an urn model with reinforcement, (ii) show that it is conjugate with respect to right‐censored data, and (iii) highlight its relations with other prior processes for competing risks data. Additionally, we consider the subdistribution beta‐Stacy process prior in a nonparametric regression model for competing risks data, which, contrary to most others available in the literature, is not based on the proportional hazards assumption.     

A competing risks model for correlated data based on the subdistribution hazard

Family-based follow-up study designs are important in epidemiology as they enable investigations of disease aggregation within families. Such studies are subject to methodological complications since data may include multiple endpoints as well as intra-family correlation. The methods herein are developed for the analysis of age of onset with multiple disease types for family-based follow-up studies. The proposed model expresses the marginalized frailty model in terms of the subdistribution hazards (SDH). As with Pipper and Martinussen’s (Scand J Stat 30:509–521, 2003) model, the proposed multivariate SDH model yields marginal interpretations of the regression coefficients while allowing the correlation structure to be specified by a frailty term. Further, the proposed model allows for a direct investigation of the covariate effects on the cumulative incidence function since the SDH is modeled rather than the cause specific hazard. A simulation study suggests that the proposed model generally offers improved performance in terms of bias and efficiency when a sufficient number of events is observed. The proposed model also offers type I error rates close to nominal. The method is applied to a family-based study of breast cancer when death in absence of breast cancer is considered a competing risk.     

Applying a marginalized frailty model to competing risks

The marginalized frailty model is often used for the analysis of correlated times in survival data. When only two correlated times are analyzed, this model is often referred to as the Clayton–Oakes model [7,22]. With time-to-event data, there may exist multiple end points (competing risks) suggesting that an analysis focusing on all available outcomes is of interest. The purpose of this work is to extend the single risk marginalized frailty model to the multiple risk setting via cause-specific hazards (CSH). The methods herein make use of the marginalized frailty model described by Pipper and Martinussen [24]. As such, this work uses the martingale theory to develop a likelihood based on estimating equations and observed histories. The proposed multivariate CSH model yields marginal regression parameter estimates while accommodating the clustering of outcomes. The multivariate CSH model can be fitted using a data augmentation algorithm described by Lunn and McNeil [21] or by fitting a series of single risk models for each of the competing risks. An example of the application of the multivariate CSH model is provided through the analysis of a family-based follow-up study of breast cancer with death in absence of breast cancer as a competing risk.     

An additive subdistribution hazard model for competing risks data

The cumulative incidence function plays an important role in assessing its treatment and covariate effects with competing risks data. In this article, we consider an additive hazard model allowing the time-varying covariate effects for the subdistribution and propose the weighted estimating equation under the covariate-dependent censoring by fitting the Cox-type hazard model for the censoring distribution. When there exists some association between the censoring time and the covariates, the proposed coefficients’ estimations are unbiased and the large-sample properties are established. The finite-sample properties of the proposed estimators are examined in the simulation study. The proposed Cox-weighted method is applied to a competing risks dataset from a Hodgkin's disease study.     

Vertical modeling: analysis of competing risks data with a cure fraction

In this paper, we extend the vertical modeling approach for the analysis of survival data with competing risks to incorporate a cure fraction in the population, that is, a proportion of the population for which none of the competing events can occur. The proposed method has three components: the proportion of cure, the risk of failure, irrespective of the cause, and the relative risk of a certain cause of failure, given a failure occurred. Covariates may affect each of these components. An appealing aspect of the method is that it is a natural extension to competing risks of the semi-parametric mixture cure model in ordinary survival analysis; thus, causes of failure are assigned only if a failure occurs. This contrasts with the existing mixture cure model for competing risks of Larson and Dinse, which conditions at the onset on the future status presumably attained. Regression parameter estimates are obtained using an EM-algorithm. The performance of the estimators is evaluated in a simulation study. The method is illustrated using a melanoma cancer data set.

     

Penalized variable selection in competing risks regression

Penalized variable selection methods have been extensively studied for standard time-to-event data. Such methods cannot be directly applied when subjects are at risk of multiple mutually exclusive events, known as competing risks. The proportional subdistribution hazard (PSH) model proposed by Fine and Gray (J Am Stat Assoc 94:496–509, 1999) has become a popular semi-parametric model for time-to-event data with competing risks. It allows for direct assessment of covariate effects on the cumulative incidence function. In this paper, we propose a general penalized variable selection strategy that simultaneously handles variable selection and parameter estimation in the PSH model. We rigorously establish the asymptotic properties of the proposed penalized estimators and modify the coordinate descent algorithm for implementation. Simulation studies are conducted to demonstrate the good performance of the proposed method. Data from deceased donor kidney transplants from the United Network of Organ Sharing illustrate the utility of the proposed method.     

Flexible simulation of competing risks data following prespecified subdistribution hazards

In recent years different approaches for the analysis of time-to-event data in the presence of competing risks, i.e. when subjects can fail from one of two or more mutually exclusive types of event, were introduced. Different approaches for the analysis of competing risks data, focusing either on cause-specific or subdistribution hazard rates, were presented in statistical literature. Many new approaches use complicated weighting techniques or resampling methods, not allowing an analytical evaluation of these methods. Simulation studies often replace analytical comparisons, since they can be performed more easily and allow investigation of non-standard scenarios. For adequate simulation studies the generation of appropriate random numbers is essential. We present an approach to generate competing risks data following flexible prespecified subdistribution hazards. Event times and types are simulated using possibly time-dependent cause-specific hazards, chosen in a way that the generated data will follow the desired subdistribution hazards or hazard ratios, respectively.     

Applying competing risks regression models: an overview

In many clinical research applications the time to occurrence of one event of interest, that may be obscured by another??so called competing??event, is investigated. Specific interventions can only have an effect on the endpoint they address or research questions might focus on risk factors for a certain outcome. Different approaches for the analysis of time-to-event data in the presence of competing risks were introduced in the last decades including some new methodologies, which are not yet frequently used in the analysis of competing risks data. Cause-specific hazard regression, subdistribution hazard regression, mixture models, vertical modelling and the analysis of time-to-event data based on pseudo-observations are described in this article and are applied to a dataset of a cohort study intended to establish risk stratification for cardiac death after myocardial infarction. Data analysts are encouraged to use the appropriate methods for their specific research questions by comparing different regression approaches in the competing risks setting regarding assumptions, methodology and interpretation of the results. Notes on application of the mentioned methods using the statistical software R are presented and extensions to the presented standard methods proposed in statistical literature are mentioned.     

Semiparametric estimation of the cumulative incidence function under competing risks and left-truncated sampling

In this article, we propose semiparametric methods to estimate the cumulative incidence function of two dependent competing risks for left-truncated and right-censored data. The proposed method is based on work by Huang and Wang (1995). We extend previous model by allowing for a general parametric truncation distribution and a third competing risk before recruitment. Based on work by Vardi (1989), several iterative algorithms are proposed to obtain the semiparametric estimates of cumulative incidence functions. The asymptotic properties of the semiparametric estimators are derived. Simulation results show that a semiparametric approach assuming the parametric truncation distribution is correctly specified produces estimates with smaller mean squared error than those obtained in a fully nonparametric model.     

Weighted empirical likelihood for quantile regression with non ignorable missing covariates

In this paper, we propose an empirical likelihood-based weighted estimator of regression parameter in quantile regression model with non ignorable missing covariates. The proposed estimator is computationally simple and achieves semiparametric efficiency if the probability of missingness on the fully observed variables is correctly specified. The efficiency gain of the proposed estimator over the complete-case-analysis estimator is quantified theoretically and illustrated via simulation and a real data application.     

Nonparametric estimation of the cumulative intensities in an interval censored competing risks model

The nonparametric maximum likelihood estimation (NPMLE) of the distribution function from the interval censored (IC) data has been extensively studied in the extant literature. The NPMLE was also developed for the subdistribution functions in an IC competing risks model and in an illness-death model under various interval-censoring scenarios. But the important problem of estimation of the cumulative intensities (CIs) in the interval-censored models has not been considered previously. We develop the NPMLE of the CI in a simple alive/dead model and of the CIs in a competing risks model. Assuming that data are generated by a discrete and finite mixed case interval censoring mechanism we provide a discussion and the simulation study of the asymptotic properties of the NPMLEs of the CIs. In particular we show that they are asymptotically unbiased; in contrast the ad hoc estimators presented in extant literature are substantially biased. We illustrate our methods with the data from a prospective cohort study on the longevity of dental veneers.     

Bayesian Parametric Accelerated Failure Time Spatial Model and its Application to Prostate Cancer

Prostate cancer is the most common cancer diagnosed in American men and the second leading cause of death from malignancies. There are large geographical variation and racial disparities existing in the survival rate of prostate cancer. Much work on the spatial survival model is based on the proportional hazards model, but few focused on the accelerated failure time model. In this paper, we investigate the prostate cancer data of Louisiana from the SEER program and the violation of the proportional hazards assumption suggests the spatial survival model based on the accelerated failure time model is more appropriate for this data set. To account for the possible extra-variation, we consider spatially-referenced independent or dependent spatial structures. The deviance information criterion (DIC) is used to select a best fitting model within the Bayesian frame work. The results from our study indicate that age, race, stage and geographical distribution are significant in evaluating prostate cancer survival.     

Estimation of the marginal survival time in the presence of dependent competing risks using inverse probability of censoring weighted (IPCW) methods

In medical studies, there is interest in inferring the marginal distribution of a survival time subject to competing risks. The Kyushu Lipid Intervention Study (KLIS) was a clinical study for hypercholesterolemia, where pravastatin treatment was compared with conventional treatment. The primary endpoint was time to events of coronary heart disease (CHD). In this study, however, some subjects died from causes other than CHD or were censored due to loss to follow-up. Because the treatments were targeted to reduce CHD events, the investigators were interested in the effect of the treatment on CHD events in the absence of causes of death or events other than CHD. In this paper, we present a method for estimating treatment group-specific marginal survival curves of time-to-event data in the presence of dependent competing risks. The proposed method is a straightforward extension of the Inverse Probability of Censoring Weighted (IPCW) method to settings with more than one reason for censoring. The results of our analysis showed that the IPCW marginal incidence for CHD was almost the same as the lower bound for which subjects with competing events were assumed to be censored at the end of all follow-up. This result provided reassurance that the results in KLIS were robust to competing risks.