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.     

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.     

Asymptotic efficiency of a competing risks model: A two-sample case

A generalized Cox regression model is studied for the covariance analysis of competing risks data subject to independent random censoring. The information of the maximum partial likelihood estimates is compared with that of maximum likelihood estimates assuming a log linear hazard function.The method of generalized variance is used to define the efficiency of estimation between the two models. This is then applied to two-sample problems with two exponentially censoring rates. Numerical results are summarized ane presented graphically.The detailed results indicate that the semi-parametric model wrks well for a higher rate of censoring. A method of generalizing the result to type 1 censoring and the efficiency of estimating the coefficient of the covariate are discussecd. A brief account of using the results to help design experiments is also given.     

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.

     

Tests for comparison of competing risks under the additive risk model

It is of interest that researchers study competing risks in which subjects may fail from any one of k causes. Comparing any two competing risks with covariate effects is very important in medical studies. In this paper, we develop tests for comparing cause-specific hazard rates and cumulative incidence functions at specified covariate levels under the additive risk model by a weighted difference of estimates of cumulative cause-specific hazard rates. Motivated by McKeague et al. (2001), we construct simultaneous confidence bands for the difference of two conditional cumulative incidence functions as a useful graphical tool. In addition, we conduct a simulation study, and the simulation result shows that the proposed procedure has a good finite sample performance. A melanoma data set in clinical trial is used for the purpose of illustration.     

Inference for a simple step-stress model with progressively censored competing risks data from Weibull distribution

In reliability analysis, it is common to consider several causes, either mechanical or electrical, those are competing to fail a unit. These causes are called “competing risks.” In this paper, we consider the simple step-stress model with competing risks for failure from Weibull distribution under progressive Type-II censoring. Based on the proportional hazard model, we obtain the maximum likelihood estimates (MLEs) of the unknown parameters. The confidence intervals are derived by using the asymptotic distributions of the MLEs and bootstrap method. For comparison, we obtain the Bayesian estimates and the highest posterior density (HPD) credible intervals based on different prior distributions. Finally, their performance is discussed through simulations.     

Semiparametric analysis of mixture regression models with competing risks data

In the analysis of competing risks data, cumulative incidence function is a useful summary of the overall crude risk for a failure type of interest. Mixture regression modeling has served as a natural approach to performing covariate analysis based on this quantity. However, existing mixture regression methods with competing risks data either impose parametric assumptions on the conditional risks or require stringent censoring assumptions. In this article, we propose a new semiparametric regression approach for competing risks data under the usual conditional independent censoring mechanism. We establish the consistency and asymptotic normality of the resulting estimators. A simple resampling method is proposed to approximate the distribution of the estimated parameters and that of the predicted cumulative incidence functions. Simulation studies and an analysis of a breast cancer dataset demonstrate that our method performs well with realistic sample sizes and is appropriate for practical use.     

Hypotheses Tests of Strain-specific Vaccine Efficacy Adjusted for Covariate Effects

In the evaluation of efficacy of a vaccine to protect against disease caused by finitely many diverse infectious pathogens, it is often important to assess if vaccine protection depends on variations of the exposing pathogen. This problem can be formulated under a competing risks model where the endpoint event is the infection and the cause of failure is the infecting strain type determined after the infection is diagnosed. The strain-specific vaccine efficacy is defined as one minus the cause-specific hazard ratio (vaccine/placebo). This paper develops some simple procedures for testing if the vaccine affords protection against various strains and if and how the strain-specific vaccine efficacy depends on the type of exposing strain, adjusting for covariate effects. The Cox proportional hazards model is used to relate the cause-specific outcomes to explanatory variables. The finite sample properties of proposed tests are studied through simulations and are shown to have good performances. The tests developed are applied to the data collected from an oral cholera vaccine trial.     

Regression analysis of competing risks data via semi-parametric additive hazard model

When the subjects in a study possess different demographic and disease characteristics and are exposed to more than one types of failure, a practical problem is to assess the covariate effects on each type of failure as well as on all-cause failure. The most widely used method is to employ the Cox models on each cause-specific hazard and the all-cause hazard. It has been pointed out that this method causes the problem of internal inconsistency. To solve such a problem, the additive hazard models have been advocated. In this paper, we model each cause-specific hazard with the additive hazard model that includes both constant and time-varying covariate effects. We illustrate that the covariate effect on all-cause failure can be estimated by the sum of the effects on all competing risks. Using data from a longitudinal study on breast cancer patients, we show that the proposed method gives simple interpretation of the final results, when the primary covariate effect is constant in the additive manner on each cause-specific hazard. Based on the given additive models on the cause-specific hazards, we derive the inferences for the adjusted survival and cumulative incidence functions.     

Generalized Supremum Tests for the Equality of Cause Specific Hazard Rates

In this paper we propose two new classes of asymptotically distribution-free Renyi-type tests for testing the equality of two risks in a competing risk model with possible censoring. This work extends the work of Aly, Kochar and McKeague [1994, Journal of American Statistical Association, 89, 994–999] and many of the existing tests for this problem belong to these newly proposed classes. The asymptotic properties of the proposed tests are investigated. Simulation studies are done to compare the performance with existing tests. A competing risks data set is analyzed to demonstrate the usefulness of the procedure.     

Product-limit Estimators and Cox Regression with Missing Censoring Information

The Kaplan–Meier estimator of a survival function requires that the censoring indicator is always observed. A method of survival function estimation is developed when the censoring indicators are missing completely at random (MCAR). The resulting estimator is a smooth functional of the Nelson–Aalen estimators of certain cumulative transition intensities. The asymptotic properties of this estimator are derived. A simulation study shows that the proposed estimator has greater efficiency than competing MCAR-based estimators. The approach is extended to the Cox model setting for the estimation of a conditional survival function given a covariate.     

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.     

Local composite partial likelihood estimation for length-biased and right-censored data

Length-biased data, which are often encountered in engineering, economics and epidemiology studies, are generally subject to right censoring caused by the research ending or the follow-up loss. The structure of length-biased data is distinct from conventional survival data, since the independent censoring assumption is often violated due to the biased sampling. In this paper, a proportional hazard model with varying coefficients is considered for the length-biased and right-censored data. A local composite likelihood procedure is put forward for the estimation of unknown coefficient functions in the model, and large sample properties of the proposed estimators are also obtained. Additionally, an extensive simulation studies are conducted to assess the finite sample performance of the proposed method and a data set from the Academy Awards is analyzed.     

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.     

Proportional cause-specific reversed hazards model

The proportional reversed hazards model explains the multiplicative effect of covariates on the baseline reversed hazard rate function of lifetimes. In the present study, we introduce a proportional cause-specific reversed hazards model. The proposed regression model facilitates the analysis of failure time data with multiple causes of failure under left censoring. We estimate the regression parameters using a partial likelihood approach. We provide Breslow's type estimators for the cumulative cause-specific reversed hazard rate functions. Asymptotic properties of the estimators are discussed. Simulation studies are conducted to assess their performance. We illustrate the applicability of the proposed model using a real data set.     

A Smooth Test in Proportional Hazard Survival Models Using Local Partial Likelihood Fitting

Proportional hazard models for survival data, even though popular and numerically handy, suffer from the restrictive assumption that covariate effects are constant over survival time. A number of tests have been proposed to check this assumption. This paper contributes to this area by employing local estimates allowing to fit hazard models in which covariate effects are smoothly varying with time. A formal test is derived to check for proportional hazards against smooth hazards as alternative. The test proves to possess omnibus power in that it is powerful against arbitrary but smooth alternatives. Comparative simulations and two data examples accompany the presentation. Extensions are provided to multiple covariate settings, where the focus of interest is to decide which of the covariate effects vary with time.     

Impact of dependent left truncation in semiparametric competing risks methods: A simulation study

In this study, we investigated the robustness of the methods that account for independent left truncation when applied to competing risks settings with dependent left truncation. We specifically focused on the methods for the proportional cause-specific hazards model and the Fine–Gray model. Simulation experiments showed that these methods are not in general robust against dependent left truncation. The magnitude of the bias was analogous to the strength of the association between left truncation and failure times, the effect of the covariate on the competing cause of failure, and the baseline hazard of left truncation time.     

Continuous covariate frailty models for censored and truncated clustered data

Using some logarithmic and integral transformation we transform a continuous covariate frailty model into a polynomial regression model with a random effect. The responses of this mixed model can be ‘estimated’ via conditional hazard function estimation. The random error in this model does not have zero mean and its variance is not constant along the covariate and, consequently, these two quantities have to be estimated. Since the asymptotic expression for the bias is complicated, the two-large-bandwidth trick is proposed to estimate the bias. The proposed transformation is very useful for clustered incomplete data subject to left truncation and right censoring (and for complex clustered data in general). Indeed, in this case no standard software is available to fit the frailty model, whereas for the transformed model standard software for mixed models can be used for estimating the unknown parameters in the original frailty model. A small simulation study illustrates the good behavior of the proposed method. This method is applied to a bladder cancer data set.     

A new test for single against competing risks models in duration analysis

This paper shows that the single-risk duration model with two event types is a limiting case of bivariate dependent competing risks model, where the joint distribution of event times are degenerate. Then a new test is proposed for the null hypothesis of single risk against dependent competing risks model under the proportional hazard model assumption.     

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.