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.

     

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.     

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.     

Identification of Longitudinal Biomarkers in Survival Analysis for Competing Risks Data

In recent years, joint analysis of longitudinal measurements and survival data has received much attention. However, previous work has primarily focused on a single failure type for the event time. In this article, we consider joint modeling of repeated measurements and competing risks failure time data to allow for more than one distinct failure type in the survival endpoint so we fit a cause-specific hazards sub-model to allow for competing risks, with a separate latent association between longitudinal measurements and each cause of failure. Besides, previous work does not focus on the hypothesis to test a separate latent association between longitudinal measurements and each cause of failure. In this article, we derive a score test to identify longitudinal biomarkers or surrogates for a time to event outcome in competing risks data. With a carefully chosen definition of complete data, the maximum likelihood estimation of the cause-specific hazard functions is performed via an EM algorithm. We extend this work and allow random effects to be present in both the longitudinal biomarker and underlying survival function. The random effects in the biomarker are introduced via an explicit term while the random effect in the underlying survival function is introduced by the inclusion of frailty into the model.

We use simulations to explore how the number of individuals, the number of time points per individual and the functional form of the random effects from the longitudinal biomarkers considering heterogeneous baseline hazards in individuals influence the power to detect the association of a longitudinal biomarker and the survival time.     

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.     

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.     

A Bayesian approach to mixture cure models with spatial frailties for population‐based cancer relative survival data

As the treatments of cancer progress, a certain number of cancers are curable if diagnosed early. In population‐based cancer survival studies, cure is said to occur when mortality rate of the cancer patients returns to the same level as that expected for the general cancer‐free population. The estimates of cure fraction are of interest to both cancer patients and health policy makers. Mixture cure models have been widely used because the model is easy to interpret by separating the patients into two distinct groups. Usually parametric models are assumed for the latent distribution for the uncured patients. The estimation of cure fraction from the mixture cure model may be sensitive to misspecification of latent distribution. We propose a Bayesian approach to mixture cure model for population‐based cancer survival data, which can be extended to county‐level cancer survival data. Instead of modeling the latent distribution by a fixed parametric distribution, we use a finite mixture of the union of the lognormal, loglogistic, and Weibull distributions. The parameters are estimated using the Markov chain Monte Carlo method. Simulation study shows that the Bayesian method using a finite mixture latent distribution provides robust inference of parameter estimates. The proposed Bayesian method is applied to relative survival data for colon cancer patients from the Surveillance, Epidemiology, and End Results (SEER) Program to estimate the cure fractions. The Canadian Journal of Statistics 40: 40–54; 2012 © 2012 Statistical Society of Canada     

Accelerated hazards mixture cure model

We propose a new cure model for survival data with a surviving or cure fraction. The new model is a mixture cure model where the covariate effects on the proportion of cure and the distribution of the failure time of uncured patients are separately modeled. Unlike the existing mixture cure models, the new model allows covariate effects on the failure time distribution of uncured patients to be negligible at time zero and to increase as time goes by. Such a model is particularly useful in some cancer treatments when the treat effect increases gradually from zero, and the existing models usually cannot handle this situation properly. We develop a rank based semiparametric estimation method to obtain the maximum likelihood estimates of the parameters in the model. We compare it with existing models and methods via a simulation study, and apply the model to a breast cancer data set. The numerical studies show that the new model provides a useful addition to the cure model literature.     

A marginal regression model for multivariate failure time data with a surviving fraction

A marginal regression approach for correlated censored survival data has become a widely used statistical method. Examples of this approach in survival analysis include from the early work by Wei et al. (J Am Stat Assoc 84:1065–1073, 1989) to more recent work by Spiekerman and Lin (J Am Stat Assoc 93:1164–1175, 1998). This approach is particularly useful if a covariate’s population average effect is of primary interest and the correlation structure is not of interest or cannot be appropriately specified due to lack of sufficient information. In this paper, we consider a semiparametric marginal proportional hazard mixture cure model for clustered survival data with a surviving or “cure” fraction. Unlike the clustered data in previous work, the latent binary cure statuses of patients in one cluster tend to be correlated in addition to the possible correlated failure times among the patients in the cluster who are not cured. The complexity of specifying appropriate correlation structures for the data becomes even worse if the potential correlation between cure statuses and the failure times in the cluster has to be considered, and thus a marginal regression approach is particularly attractive. We formulate a semiparametric marginal proportional hazards mixture cure model. Estimates are obtained using an EM algorithm and expressions for the variance–covariance are derived using sandwich estimators. Simulation studies are conducted to assess finite sample properties of the proposed model. The marginal model is applied to a multi-institutional study of local recurrences of tonsil cancer patients who received radiation therapy. It reveals new findings that are not available from previous analyses of this study that ignored the potential correlation between patients within the same institution.     

On Non-parametric Estimation of the Survival Function with Competing Risks

The non-parametric maximum likelihood estimators (MLEs) are derived for survival functions associated with individual risks or system components in a reliability framework. Lifetimes are observed for systems that contain one or more of those components. Analogous to a competing risks model, the system is assumed to fail upon the first instance of any component failure; i.e. the system is configured in series. For any given risk or component type, the asymptotic distribution is shown to depend explicitly on the unknown survival function of the other risks, as well as the censoring distribution. Survival functions with increasing failure rate are investigated as a special case. The order restricted MLE is shown to be consistent under mild assumptions of the underlying component lifetime distributions.     

Testing for the Presence of a Cure Fraction in Clustered Interval‐Censored Survival Data

Clustered interval‐censored survival data are often encountered in clinical and epidemiological studies due to geographic exposures and periodic visits of patients. When a nonnegligible cured proportion exists in the population, several authors in recent years have proposed to use mixture cure models incorporating random effects or frailties to analyze such complex data. However, the implementation of the mixture cure modeling approaches may be cumbersome. Interest then lies in determining whether or not it is necessary to adjust the cured proportion prior to the mixture cure analysis. This paper mainly focuses on the development of a score for testing the presence of cured subjects in clustered and interval‐censored survival data. Through simulation, we evaluate the sampling distribution and power behaviour of the score test. A bootstrap approach is further developed, leading to more accurate significance levels and greater power in small sample situations. We illustrate applications of the test using data sets from a smoking cessation study and a retrospective study of early breast cancer patients.     

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.     

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.     

Analysis of interval censored competing risk data with missing causes of failure using pseudo values approach

Competing risks often occur when subjects may fail from one of several mutually exclusive causes. For example, when a patient suffering a cancer may die from other cause, we are interested in the effect of a certain covariate on the probability of dying of cancer at a certain time. Several approaches have been suggested to analyse competing risk data in the presence of complete information of failure cause. In this paper, our interest is to consider the occurrence of missing causes as well as interval censored failure time. There exist no method to discuss this problem. We applied a Klein–Andersen's pseudo-value approach [Klein, JP Andersen PK. Regression modeling of competing risks data based on pseudovalues of the cumulative incidence function. Biometrics. 2005;61:223–229] based on the estimated cumulative incidence function and a regression coefficient is estimated through a multiple imputation. We evaluate the suggested method by comparing with a complete case analysis in several simulation settings.     

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.     

Population-based absolute risk estimation with survey data

Absolute risk is the probability that a cause-specific event occurs in a given time interval in the presence of competing events. We present methods to estimate population-based absolute risk from a complex survey cohort that can accommodate multiple exposure-specific competing risks. The hazard function for each event type consists of an individualized relative risk multiplied by a baseline hazard function, which is modeled nonparametrically or parametrically with a piecewise exponential model. An influence method is used to derive a Taylor-linearized variance estimate for the absolute risk estimates. We introduce novel measures of the cause-specific influences that can guide modeling choices for the competing event components of the model. To illustrate our methodology, we build and validate cause-specific absolute risk models for cardiovascular and cancer deaths using data from the National Health and Nutrition Examination Survey. Our applications demonstrate the usefulness of survey-based risk prediction models for predicting health outcomes and quantifying the potential impact of disease prevention programs at the population level.     

The Poisson Generalized Linear Failure Rate Model

We formulate a new cure rate survival model by assuming that the number of competing causes of the event of interest has the Poisson distribution, and the time to this event has the generalized linear failure rate distribution. A new distribution to analyze lifetime data is defined from the proposed cure rate model, and its quantile function as well as a general expansion for the moments is derived. We estimate the parameters of the model with cure rate in the presence of covariates for censored observations using maximum likelihood and derive the observed information matrix. We obtain the appropriate matrices for assessing local influence on the parameter estimates under different perturbation schemes and present some ways to perform global influence analysis. The usefulness of the proposed cure rate survival model is illustrated in an application to real data.     

A weighted Poisson distribution and its application to cure rate models

The family of weighted Poisson distributions offers great flexibility in modeling discrete data due to its potential to capture over/under-dispersion by an appropriate selection of the weight function. In this paper, we introduce a flexible weighted Poisson distribution and further study its properties by using it in the context of cure rate modeling under a competing cause scenario. A special case of the new distribution is the COM-Poisson distribution which in turn encompasses the Bernoulli, Poisson, and geometric distributions; hence, many of the well-studied cure rate models may be seen as special cases of the proposed model. We focus on the estimation, through the maximum likelihood method, of the cured proportion and the properties of the failure time of the susceptibles/non cured individuals; a profile likelihood approach is also adopted for estimating the parameters of the weighted Poisson distribution. A Monte Carlo simulation study demonstrates the accuracy of the proposed inferential method. Finally, as an illustration, we fit the proposed model to a cutaneous melanoma data set.     

Weibull lagged effect step-stress model with competing risks

In many survival analysis studies, failure can come from one of several competing risks. Additionally, where survival times are lengthy, researchers can increase stress levels to cause units to fail faster. One type of accelerated testing is a step-stress test where the increase is presented in quantum jumps at predetermined time points. If the impact of the increase is not immediately attained, an interim lag period is modeled. In this article, we propose a two-competing risk step-stress model with a lag period where each independent risk follows a Weibull lifetime distribution, the interim lag period is linear, and the attainment point is assumed known. We obtain the maximum likelihood estimators and the observed information matrix; we construct confidence intervals and provide estimates of coverage probabilities using large sample theory, percentile bootstrap, and bias-corrected accelerated (BCa) bootstrap methods.     

The competing risks Cox model with auxiliary case covariates under weaker missing-at-random cause of failure

In the analysis of time-to-event data with multiple causes using a competing risks Cox model, often the cause of failure is unknown for some of the cases. The probability of a missing cause is typically assumed to be independent of the cause given the time of the event and covariates measured before the event occurred. In practice, however, the underlying missing-at-random assumption does not necessarily hold. Motivated by colorectal cancer molecular pathological epidemiology analysis, we develop a method to conduct valid analysis when additional auxiliary variables are available for cases only. We consider a weaker missing-at-random assumption, with missing pattern depending on the observed quantities, which include the auxiliary covariates. We use an informative likelihood approach that will yield consistent estimates even when the underlying model for missing cause of failure is misspecified. The superiority of our method over naive methods in finite samples is demonstrated by simulation study results. We illustrate the use of our method in an analysis of colorectal cancer data from the Nurses’ Health Study cohort, where, apparently, the traditional missing-at-random assumption fails to hold.