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.     

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 Competing Risks by Using Bayesian Smoothing

We consider the competing risks set-up. In many practical situations, the conditional probability of the cause of failure given the failure time is of direct interest. We propose to model the competing risks by the overall hazard rate and the conditional probabilities rather than the cause-specific hazards. We adopt a Bayesian smoothing approach for both quantities of interest. Illustrations are given at the end.     

Score tests for independence in semiparametric competing risks models

A popular model for competing risks postulates the existence of a latent unobserved failure time for each risk. Assuming that these underlying failure times are independent is attractive since it allows standard statistical tools for right-censored lifetime data to be used in the analysis. This paper proposes simple independence score tests for the validity of this assumption when the individual risks are modeled using semiparametric proportional hazards regressions. It assumes that covariates are available, making the model identifiable. The score tests are derived for alternatives that specify that copulas are responsible for a possible dependency between the competing risks. The test statistics are constructed by adding to the partial likelihoods for the individual risks an explanatory variable for the dependency between the risks. A variance estimator is derived by writing the score function and the Fisher information matrix for the marginal models as stochastic integrals. Pitman efficiencies are used to compare test statistics. A simulation study and a numerical example illustrate the methodology proposed in this paper.     

Testing dependence between the failure time and failure modes: An application of enlarged filtration

The model of independent competing risks provides no information for the assessment of competing failure modes if the failure mechanisms underlying these modes are coupled. Models for dependent competing risks in the literature can be distinguished on the basis of the functional behaviour of the conditional probability of failure due to a particular failure mode given that the failure time exceeds a fixed time, as a function of time. There is an interesting link between monotonicity of such conditional probability and dependence between failure time and failure mode, via crude hazard rates. In this paper, we propose tests for testing the dependence between failure time and failure mode using the crude hazards and using the conditional probabilities mentioned above. We establish the equivalence between the two approaches and provide an asymptotically efficient weight function under a sequence of local alternatives. The tests are applied to simulated data and to mortality follow-up data.     

Bayesian Analysis of Masked Series System Lifetime Data

The problem of analyzing series system lifetime data with masked or partial information on cause of failure is recent, compared to that of the standard competing risks model. A generic Gibbs sampling scheme is developed in this article towards a Bayesian analysis for a general parametric competing risks model with masked cause of failure data. The masking probabilities are not subjected to the symmetry assumption and independent Dirichlet priors are used to marginalize these nuisance parameters. The developed methodology is illustrated for the case where the components of a series system have independent log-Normal life distributions by employing independent Normal-Gamma priors for these component lifetime parameters. The Gibbs sampling scheme developed for the required analysis can also be used to provide a Bayesian analysis of data arising from the conventional competing risks model of independent log-Normals, which interestingly has so far remained by and large neglected in the literature. The developed methodology is deployed to analyze a masked lifetime data of PS/2 computer systems.     

An improper form of Weibull distribution for competing risks analysis with Bayesian approach

ABSTRACT

In survival analysis, individuals may fail due to multiple causes of failure called competing risks setting. Parametric models such as Weibull model are not improper that ignore the assumption of multiple failure times. In this study, a novel extension of Weibull distribution is proposed which is improper and then can incorporate to the competing risks framework. This model includes the original Weibull model before a pre-specified time point and an exponential form for the tail of the time axis. A Bayesian approach is used for parameter estimation. A simulation study is performed to evaluate the proposed model. The conducted simulation study showed identifiability and appropriate convergence of the proposed model. The proposed model and the 3-parameter Gompertz model, another improper parametric distribution, are fitted to the acute lymphoblastic leukemia dataset.     

Mark-specific hazard ratio model with missing multivariate marks

An objective of randomized placebo-controlled preventive HIV vaccine efficacy (VE) trials is to assess the relationship between vaccine effects to prevent HIV acquisition and continuous genetic distances of the exposing HIVs to multiple HIV strains represented in the vaccine. The set of genetic distances, only observed in failures, is collectively termed the ‘mark.’ The objective has motivated a recent study of a multivariate mark-specific hazard ratio model in the competing risks failure time analysis framework. Marks of interest, however, are commonly subject to substantial missingness, largely due to rapid post-acquisition viral evolution. In this article, we investigate the mark-specific hazard ratio model with missing multivariate marks and develop two inferential procedures based on (i) inverse probability weighting (IPW) of the complete cases, and (ii) augmentation of the IPW estimating functions by leveraging auxiliary data predictive of the mark. Asymptotic properties and finite-sample performance of the inferential procedures are presented. This research also provides general inferential methods for semiparametric density ratio/biased sampling models with missing data. We apply the developed procedures to data from the HVTN 502 ‘Step’ HIV VE trial.     

Parametric Modeling for Survival with Competing Risks and Masked Failure Causes

We consider a life testing situation in which systems are subject to failure from independent competing risks. Following a failure, immediate (stage-1) procedures are used in an attempt to reach a definitive diagnosis. If these procedures fail to result in a diagnosis, this phenomenon is called masking. Stage-2 procedures, such as failure analysis or autopsy, provide definitive diagnosis for a sample of the masked cases. We show how stage-1 and stage-2 information can be combined to provide statistical inference about (a) survival functions of the individual risks, (b) the proportions of failures associated with individual risks and (c) probability, for a specified masked case, that each of the masked competing risks is responsible for the failure. Our development is based on parametric distributional assumptions and the special case for which the failure times for the competing risks have a Weibull distribution is discussed in detail.     

Statistical analysis of dependent competing risks model in accelerated life testing under progressively hybrid censoring using copula function

This article considers statistical analysis of dependent competing risks model from Weibull distribution in accelerated life testing, in which copula function is used to examine the dependence structure between competing failure modes. We derive the maximum likelihood estimates, the approximate, and Bootstrap confidence intervals of the parameters. The effects of different dependence structures on the estimates of parameters are investigated. The simulation is given to compare the performance of the estimates when the competing failure modes are dependent with those when the failure modes are independent. Finally, one dataset was used for illustrative purpose in conclusion.     

On a deconvolution problem under competing risks

Bagai and Prakasa Rao [Analysis of survival data with two dependent competing risks. Biometr J. 1992;7:801–814] considered a competing risks model with two dependent risks. The two risks are initially independent but dependence arises because of the additive effect of an independent risk on the two initially independent risks. They showed that the ratio of failure rates are identifiable in the nonparametric set-up. In this paper, we consider it as a measurement error/deconvolution problem and suggest a nonparametric kernel-type estimator for the ratio of two failure rates. The local error properties of the proposed estimator are studied. Simulation studies show the efficacy of the proposed estimator.     

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.

     

Assessing component reliability using lifetime data from systems

ABSTRACT

In this paper, we introduce a competing risks model for the lifetimes of components that differs from the classical competing risks models by the fact that it is not directly observable which component has failed. We propose two statistical methods for estimating the reliability of components from failure data on a system. Our methods are applied to simulated failure data, in order to illustrate the performance of the methods.     

Statistical analysis of competing risks model from Marshall–Olkin extended Chen distribution under adaptive progressively interval censoring with random removals

In this paper, a new censoring scheme named by adaptive progressively interval censoring scheme is introduced. The competing risks data come from Marshall–Olkin extended Chen distribution under the new censoring scheme with random removals. We obtain the maximum likelihood estimators of the unknown parameters and the reliability function by using the EM algorithm based on the failure data. In addition, the bootstrap percentile confidence intervals and bootstrap-t confidence intervals of the unknown parameters are obtained. To test the equality of the competing risks model, the likelihood ratio tests are performed. Then, Monte Carlo simulation is conducted to evaluate the performance of the estimators under different sample sizes and removal schemes. Finally, a real data set is analyzed for illustration purpose.     

Bayesian analysis of bivariate competing risks models with covariates

Bivariate exponential models have often been used for the analysis of competing risks data involving two correlated risk components. Competing risks data consist only of the time to failure and cause of failure. In situations where there is positive probability of simultaneous failure, possibly the most widely used model is the Marshall–Olkin (J. Amer. Statist. Assoc. 62 (1967) 30) bivariate lifetime model. This distribution is not absolutely continuous as it involves a singularity component. However, the likelihood function based on the competing risks data is then identifiable, and any inference, Bayesian or frequentist, can be carried out in a straightforward manner. For the analysis of absolutely continuous bivariate exponential models, standard approaches often run into difficulty due to the lack of a fully identifiable likelihood (Basu and Ghosh; Commun. Statist. Theory Methods 9 (1980) 1515). To overcome the nonidentifiability, the usual frequentist approach is based on an integrated likelihood. Such an approach is implicit in Wada et al. (Calcutta Statist. Assoc. Bull. 46 (1996) 197) who proved some related asymptotic results. We offer in this paper an alternative Bayesian approach. Since systematic prior elicitation is often difficult, the present study focuses on Bayesian analysis with noninformative priors. It turns out that with an appropriate reparameterization, standard noninformative priors such as Jeffreys’ prior and its variants can be applied directly even though the likelihood is not fully identifiable. Two noninformative priors are developed that consist of Laplace's prior for nonidentifiable parameters and Laplace's and Jeffreys's priors for identifiable parameters. The resulting Bayesian procedures possess some frequentist optimality properties as well. Finally, these Bayesian methods are illustrated with analyses of a data set originating out of a lung cancer clinical trial conducted by the Eastern Cooperative Oncology Group.     

Inference for cumulative incidence on discrete failure times with competing risks

In the competing risks analysis, most inferences have been developed based on continuous failure time data. However, failure times are sometimes observed as being discrete. We propose nonparametric inferences for the cumulative incidence function for pure discrete data with competing risks. When covariate information is available, we propose semiparametric inferences for direct regression modelling of the cumulative incidence function for grouped discrete failure time data with competing risks. Simulation studies show that the procedures perform well. The proposed methods are illustrated with a study of contraceptive use in Indonesia.     

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.     

Identifiability of masking probabilities in competing risks models with emphasis on Weibull models

Abstract

Lifetime data with masked failure causes arise in both reliability engineering and epidemiology. The phenomenon of masking occurs when a subject is exposed to multiple risks. A competing risks model with masking probabilities is widely used for the masked failure data. However, in many cases, the model suffers from an identification problem. We show that the identifiability of masking probabilities depends on both the structure of data and the cause-specific hazard functions. Motivated by this result, two existing solutions are reviewed and further improved.     

A Class of Non-parametric Tests in the Competing Risks Model for Comparing Two Samples

We consider a model when a process involving the production of elements is under inspection. The elements have possible failures due to competing risks. We assume the availability of a data set of failure times, D₁, obtained when the process is under control. Our main goal is to test if the failure rates in D₁ are equal to or less than the failure rates in another data set D₂, against "undesirable" neighbouring alternatives. A class of tests based on a two-dimensional vector statistic is obtained. Linear test statistics with weight functions giving optimal local asymptotic power are derived. Martingale techniques are used. An example illustrates the derivation of reasonable tests     

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.