Statistical methods for dependent competing risks

Many biological and medical studies have as a response of interest the time to occurrence of some event,X, such as the occurrence of cessation of smoking, conception, a particular symptom or disease, remission, relapse, death due to some specific disease, or simply death. Often it is impossible to measureX due to the occurrence of some other competing event, usually termed a competing risk. This competing event may be the withdrawal of the subject from the study (for whatever reason), death from some cause other than the one of interest, or any eventuality that precludes the main event of interest from occurring. Usually the assumption is made that all such censoring times and lifetimes are independent. In this case one uses either the Kaplan-Meier estimator or the Nelson-Aalen estimator to estimate the survival function. However, if the competing risk or censoring times are not independent ofX, then there is no generally acceptable way to estimate the survival function. There has been considerable work devoted to this problem of dependent competing risks scattered throughout the statistical literature in the past several years and this paper presents a survey of such work.     

Efficient estimation for the proportional hazards model with competing risks and current status data

The proportional hazards model is the most commonly used model in regression analysis of failure time data and has been discussed by many authors under various situations (Kalbfleisch & Prentice, 2002. The Statistical Analysis of Failure Time Data, Wiley, New York). This paper considers the fitting of the model to current status data when there exist competing risks, which often occurs in, for example, medical studies. The maximum likelihood estimates of the unknown parameters are derived and their consistency and convergence rate are established. Also we show that the estimates of regression coefficients are efficient and have asymptotically normal distributions. Simulation studies are conducted to assess the finite sample properties of the estimates and an illustrative example is provided. The Canadian Journal of Statistics © 2009 Statistical Society of Canada     

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.     

Joint modeling of degradation and failure time data

This paper surveys some approaches to model the relationship between failure time data and covariate data like internal degradation and external environmental processes. These models which reflect the dependency between system state and system reliability include threshold models and hazard-based models. In particular, we consider the class of degradation–threshold–shock models (DTS models) in which failure is due to the competing causes of degradation and trauma. For this class of reliability models we express the failure time in terms of degradation and covariates. We compute the survival function of the resulting failure time and derive the likelihood function for the joint observation of failure times and degradation data at discrete times. We consider a special class of DTS models where degradation is modeled by a process with stationary independent increments and related to external covariates through a random time scale and extend this model class to repairable items by a marked point process approach. The proposed model class provides a rich conceptual framework for the study of degradation–failure issues.     

Accelerated failure time models for the analysis of competing risks

Competing risks are common in clinical cancer research, as patients are subject to multiple potential failure outcomes, such as death from the cancer itself or from complications arising from the disease. In the analysis of competing risks, several regression methods are available for the evaluation of the relationship between covariates and cause-specific failures, many of which are based on Cox’s proportional hazards model. Although a great deal of research has been conducted on estimating competing risks, less attention has been devoted to linear regression modeling, which is often referred to as the accelerated failure time (AFT) model in survival literature. In this article, we address the use and interpretation of linear regression analysis with regard to the competing risks problem. We introduce two types of AFT modeling framework, where the influence of a covariate can be evaluated in relation to either a cause-specific hazard function, referred to as cause-specific AFT (CS-AFT) modeling in this study, or the cumulative incidence function of a particular failure type, referred to as crude-risk AFT (CR-AFT) modeling. Simulation studies illustrate that, as in hazard-based competing risks analysis, these two models can produce substantially different effects, depending on the relationship between the covariates and both the failure type of principal interest and competing failure types. We apply the AFT methods to data from non-Hodgkin lymphoma patients, where the dataset is characterized by two competing events, disease relapse and death without relapse, and non-proportionality. We demonstrate how the data can be analyzed and interpreted, using linear competing risks regression models.     

The Bernstein–von Mises theorem in semiparametric competing risks models

Semiparametric Bayesian models are nowadays a popular tool in event history analysis. An important area of research concerns the investigation of frequentist properties of posterior inference. In this paper, we propose novel semiparametric Bayesian models for the analysis of competing risks data and investigate the Bernstein–von Mises theorem for differentiable functionals of model parameters. The model is specified by expressing the cause-specific hazard as the product of the conditional probability of a failure type and the overall hazard rate. We take the conditional probability as a smooth function of time and leave the cumulative overall hazard unspecified. A prior distribution is defined on the joint parameter space, which includes a beta process prior for the cumulative overall hazard. We first develop the large-sample properties of maximum likelihood estimators by giving simple sufficient conditions for them to hold. Then, we show that, under the chosen priors, the posterior distribution for any differentiable functional of interest is asymptotically equivalent to the sampling distribution derived from maximum likelihood estimation. A simulation study is provided to illustrate the coverage properties of credible intervals on cumulative incidence functions.     

Analyzing panel count data with a dependent observation process and a terminal event

Panel count data occur in many fields and a number of approaches have been developed. However, most of these approaches are for situations where there is no terminal event and the observation process is independent of the underlying recurrent event process unconditionally or conditional on the covariates. In this paper, we discuss a more general situation where the observation process is informative and there exists a terminal event which precludes further occurrence of the recurrent events of interest. For the analysis, a semiparametric transformation model is presented for the mean function of the underlying recurrent event process among survivors. To estimate the regression parameters, an estimating equation approach is proposed in which an inverse survival probability weighting technique is used. The asymptotic distribution of the proposed estimates is provided. Simulation studies are conducted and suggest that the proposed approach works well for practical situations. An illustrative example is provided. The Canadian Journal of Statistics 41: 174–191; 2013 © 2012 Statistical Society of Canada     

A linear transformation model for multivariate interval‐censored failure time data

This paper discusses multivariate interval‐censored failure time data observed when several correlated survival times of interest exist and only interval censoring is available for each survival time. Such data occur in many fields, for instance, studies of the development of physical symptoms or diseases in several organ systems. A marginal inference approach was used to create a linear transformation model and applied to bivariate interval‐censored data arising from a diabetic retinopathy study and an AIDS study. The results of simulation studies that were conducted to evaluate the performance of the presented approach suggest that it performs well. The Canadian Journal of Statistics 41: 275–290; 2013 © 2013 Statistical Society of Canada     

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.     

Planning and analyzing clinical trials with competing risks: Recommendations for choosing appropriate statistical methodology

In the analysis of time‐to‐event data, competing risks occur when multiple event types are possible, and the occurrence of a competing event precludes the occurrence of the event of interest. In this situation, statistical methods that ignore competing risks can result in biased inference regarding the event of interest. We review the mechanisms that lead to bias and describe several statistical methods that have been proposed to avoid bias by formally accounting for competing risks in the analyses of the event of interest. Through simulation, we illustrate that Gray's test should be used in lieu of the logrank test for nonparametric hypothesis testing. We also compare the two most popular models for semiparametric modelling: the cause‐specific hazards (CSH) model and Fine‐Gray (F‐G) model. We explain how to interpret estimates obtained from each model and identify conditions under which the estimates of the hazard ratio and subhazard ratio differ numerically. Finally, we evaluate several model diagnostic methods with respect to their sensitivity to detect lack of fit when the CSH model holds, but the F‐G model is misspecified and vice versa. Our results illustrate that adequacy of model fit can strongly impact the validity of statistical inference. We recommend analysts incorporate a model diagnostic procedure and contingency to explore other appropriate models when designing trials in which competing risks are anticipated.     

Pseudo Self-Consistent Estimation of a Copula Model with Informative Censoring

Abstract.  We consider the case where a terminal event censors a non-terminal event, but not vice versa. When the events are dependent, estimation of the distribution of the non-terminal event is a competing risks problem, while estimation of the distribution of the terminal event is not. The dependence structure of the event times is formulated with the gamma frailty copula on the upper wedge, with the marginal distributions unspecified. With a consistent estimator of the association parameter, pseudo self-consistency equations are derived and adapted to the semiparametric model. Existence, uniform consistency and weak convergence of the new estimator for the marginal distribution of the non-terminal event is established using theories of empirical processes, U -statistics and Z -estimation. The potential practical utility of the methodology is illustrated with simulated and real data sets.     

Duration analysis in longitudinal studies with intermittent observation times and losses to followup

We consider the analysis of spell durations observed in event history studies where members of the study panel are seen intermittently. Challenges for analysis arise because losses to followup are frequently related to previous event history, and spells typically overlap more than one observation period. We provide methods of estimation based on inverse probability of censoring weighting for parametric and semiparametric Cox regression models. Selection of panel members through a complex survey design is also addressed, and the methods are illustrated in an analysis of jobless spell durations based on data from the Statistics Canada Survey of Labour and Income Dynamics. The Canadian Journal of Statistics 40: 1–21; 2012 © 2012 Statistical Society of Canada     

A Note on Dirichlet One-Armed Bandits

One of the two independent stochastic processes (or ‘arms’) is selected and observed sequentially at each of n(≤ ∝) stages. Arm 1 yields observations identically distributed with unknown probability measure P with a Dirichlet process prior whereas observations from arm 2 have known probability measure Q. Future observations are discounted and at stage m, the payoff is a _m(≥0) times the observation Z _m at that stage. The objective is to maximize the total expected payoff. Clayton and Berry (1985) consider this problem when a _m equals 1 for m ≤ n and 0 for m > n(< ∝) In this paper, the Clayton and Berry (1985) results are extended to the case of regular discount sequences of horizon n, which may also be infinite. The results are illustrated with numerical examples. In case of geometric discounting, the results apply to a bandit with many independent unknown Dirichlet arms.     

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.     

A Semi‐parametric Transformation Frailty Model for Semi‐competing Risks Survival Data

In the analysis of semi‐competing risks data interest lies in estimation and inference with respect to a so‐called non‐terminal event, the observation of which is subject to a terminal event. Multi‐state models are commonly used to analyse such data, with covariate effects on the transition/intensity functions typically specified via the Cox model and dependence between the non‐terminal and terminal events specified, in part, by a unit‐specific shared frailty term. To ensure identifiability, the frailties are typically assumed to arise from a parametric distribution, specifically a Gamma distribution with mean 1.0 and variance, say, σ². When the frailty distribution is misspecified, however, the resulting estimator is not guaranteed to be consistent, with the extent of asymptotic bias depending on the discrepancy between the assumed and true frailty distributions. In this paper, we propose a novel class of transformation models for semi‐competing risks analysis that permit the non‐parametric specification of the frailty distribution. To ensure identifiability, the class restricts to parametric specifications of the transformation and the error distribution; the latter are flexible, however, and cover a broad range of possible specifications. We also derive the semi‐parametric efficient score under the complete data setting and propose a non‐parametric score imputation method to handle right censoring; consistency and asymptotic normality of the resulting estimators is derived and small‐sample operating characteristics evaluated via simulation. Although the proposed semi‐parametric transformation model and non‐parametric score imputation method are motivated by the analysis of semi‐competing risks data, they are broadly applicable to any analysis of multivariate time‐to‐event outcomes in which a unit‐specific shared frailty is used to account for correlation. Finally, the proposed model and estimation procedures are applied to a study of hospital readmission among patients diagnosed with pancreatic cancer.     

Identification of longitudinal biomarkers for survival by a score test derived from a joint model of longitudinal and competing risks data

In this paper, we consider joint modelling of repeated measurements and competing risks failure time data. For competing risks time data, a semiparametric mixture model in which proportional hazards model are specified for failure time models conditional on cause and a multinomial model for the marginal distribution of cause conditional on covariates. We also derive a score test based on joint modelling of repeated measurements and competing risks failure time data to identify longitudinal biomarkers or surrogates for a time to event outcome in competing risks data.     

Analysis of Type-II hybrid censored competing risks data

Kundu and Gupta [Analysis of hybrid life-tests in presence of competing risks. Metrica. 2007;65:159–170] provided the analysis of Type-I hybrid censored competing risks data, when the lifetime distributions of the competing cause of failures follows exponential distribution. In this paper, we consider the analysis of Type-II hybrid censored competing risks data. It is assumed that latent lifetime distributions of the competing causes of failures follow independent exponential distributions with different scale parameters. It is observed that the maximum likelihood estimators of the unknown parameters do not always exist. We propose the modified estimators of the scale parameters, which coincide with the corresponding maximum likelihood estimators when they exist, and asymptotically they are equivalent. We obtain the exact distribution of the proposed estimators. Using the exact distributions of the proposed estimators, associated confidence intervals are obtained. The asymptotic and bootstrap confidence intervals of the unknown parameters are also provided. Further, Bayesian inference of some unknown parametric functions under a very flexible Beta-Gamma prior is considered. Bayes estimators and associated credible intervals of the unknown parameters are obtained using the Monte Carlo method. Extensive Monte Carlo simulations are performed to see the effectiveness of the proposed estimators and one real data set has been analysed for the illustrative purposes. It is observed that the proposed model and the method work quite well for this data set.     

Modelling and analysis of recall-based competing risks data

In this paper we consider the analysis of recall-based competing risks data. The chance of an individual recalling the exact time to event depends on the time of occurrence of the event and time of observation of the individual. In particular, it is assumed that the probability of recall depends on the time elapsed since the occurrence of an event. In this study we consider the likelihood-based inference for the analysis of recall-based competing risks data. The likelihood function is constructed by incorporating the information about the probability of recall. We consider the maximum likelihood estimation of parameters. Simulation studies are carried out to examine the performance of the estimators. The proposed estimation procedure is applied to a real life data set.     

Power and sample size considerations in clinical trials with competing risk endpoints

In clinical trials with a time-to-event endpoint, subjects are often at risk for events other than the one of interest. When the occurrence of one type of event precludes observation of any later events or alters the probably of subsequent events, the situation is one of competing risks. During the planning stage of a clinical trial with competing risks, it is important to take all possible events into account. This paper gives expressions for the power and sample size for competing risks based on a flexible parametric Weibull model. Nonuniform accrual to the study is considered and an allocation ratio other than one may be used. Results are also provided for the case where two or more of the competing risks are of primary interest.     

A New lifetime model for multivariate survival data with a surviving fraction

In this paper we propose a new lifetime model for multivariate survival data with a surviving fraction. We develop this model assuming that there are m types of unobservable competing risks, where each risk is related to a time of the occurrence of an event of interest. We explore the use of Markov chain Monte Carlo methods to develop a Bayesian analysis for the proposed model. We also perform a simulation study in order to analyse the frequentist coverage probabilities of credible interval derived from posteriors. Our modelling is illustrated through a real data set.