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.     

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.     

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     

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.     

Reduced rank proportional hazards model for competing risks: An application to a breast cancer trial

In many cancer trials patients are at risk of recurrence and death after the appearance and the successful treatment of the first diagnosed tumour. In this situation competing risks models that model several competing causes of therapy or surgery failure are a natural framework to describe the evolution of the disease.Typically, regression models for competing risks outcomes are based on proportional hazards model for each of the cause-specific hazard rates. An immediate practical problem is then how to deal with the abundance of regression parameters. The aim of reduced rank proportional hazards models is to reduce the number of parameters that need to be estimated while at the same time keeping the distinction between different transitions. They have the advantage of describing the competing risks model in fewer parameters, cope with transitions where few events are present and facilitate the interpretation of these estimates.We shall illustrate the use of this technique on 2795 patients from a breast cancer trial (EORTC 10854).     

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.     

Testing transition probability matrix of a multi-state model with censored data

In this paper, we develop procedures to test hypotheses concerning transition probability matrices arising from certain nonhomogeneous Markov processes. It is assumed that the data consist of sample paths, some of which are observed until a certain terminal state, and the other paths are censored. Problems of this type arise in the context of multi-state models relevant to Health Related Quality of Life (HRQoL) and Competing Risks. The test statistic is based on the estimator for the associated intensity matrix. We show that the asymptotic null distribution of the proposed statistic is Gaussian, and demonstrate how the procedure can be adopted for HRQoL studies and competing risks model using real data sets. Finally, we establish that the test statistic for the HRQoL has greatest local asymptotic power against a sequence of proportional hazards alternatives converging to the null hypothesis.     

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.     

To move or not to move to find a new job: spatial duration time model with dynamic covariate effects

The aim of this paper is to show the flexibility and capacity of penalized spline smoothing as estimation routine for modelling duration time data. We analyse the unemployment behaviour in Germany between 2000 and 2004 using a massive database from the German Federal Employment Agency. To investigate dynamic covariate effects and differences between competing job markets depending on the distance between former and recent working place, a functional duration time model with competing risks is used. It is build upon a competing hazard function where some of the smooth covariate effects are allowed to vary with unemployment duration. The focus of our analysis is on contrasting the spatial, economic and individual covariate effects of the competing job markets and on analysing their general influence on the unemployed's re-employment probabilities. As a result of our analyses, we reveal differences concerning gender, age and education. We also discover an effect between the newly formed and the old West German states. Moreover, the spatial pattern between the considered job markets differs.     

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.     

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.

     

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.     

The random-effects proportional hazards model with grouped survival data: a comparison between the grouped continuous and continuation ratio versions

Summary.  When analysing grouped time survival data having a hierarchical structure it is often appropriate to assume a random-effects proportional hazards model for the latent continuous time and then to derive the corresponding grouped time model. There are two formally equivalent grouped time versions of the proportional hazards model obtained from different perspec-tives, known as the continuation ratio and the grouped continuous models. However, the two models require distinct estimation procedures and, more importantly, they differ substantially when extended to time-dependent covariates and/or non-proportional effects. The paper discusses these issues in the context of random-effects models, illustrating the main points with an application to a complex data set on job opportunities for a cohort of graduates.     

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.     

Competing risks simulation with the survsim R package

The goal of this work is to describe how the last version available of the survsim R package can be used to simulate a cohort in a competing risks context by means of a cause-specific hazards model following the ideas introduced by Beyersmann in 2009, and also allowing for individual heterogeneity through a random effect. An example of its application based on a real cohort will be discussed.     

Bounds on the covariate-time transformation for competing-risks survival analysis

A fundamental problem with the latent-time framework in competing risks is the lack of identifiability of the joint distribution. Given observed covariates along with assumptions as to the form of their effect, then identifiability may obtain. However it is difficult to check any assumptions about form since a more general model may lose identifiability. This paper considers a general framework for modelling the effect of covariates, with the single assumption that the copula dependency structure of the latent times is invariant to the covariates. This framework consists of a set of functions: the covariate-time transformations. The main result produces bounds on these functions, which are derived solely from the crude incidence functions. These bounds are a useful model checking tool when considering the covariate-time transformation resulting from any particular set of further assumptions. An example is given where the widely-used assumption of independent competing risks is checked.     

A competing risks derivation of a mixture model for the analysis of survival data

Boag (1949) and Berkson and Gage (1952) proposed a mixture model for the analysis of survival time data when aproportion of treated patients are cured. This paper presents a derivation of the Boag/Berkson-Gage mixture model as well as a eneralization of the model based on the theory of competing risks. The assumptions underlying the model are stated and discussed and a general likelihood function is obtained. Use of the model is illustrated ith data from the Stanford Heart Transplant Program.     

The alert-delay competing risks model for maintenance analysis

The paper considers the modelling of the dependency between corrective maintenance and condition-based preventive maintenance of complex repairable systems. A new model of dependent competing risks is proposed, called the alert-delay (AD) model. This model has different properties from that of the delay-time, repair-alert and proportional warning constant inspection models and happens to fit some data sets which could not be fitted by the previous models. The main features of the AD model are derived: probabilistic properties and statistical analysis. Simulation results and an application to real data are presented.     

Flexible competing risks regression modeling and goodness-of-fit

In this paper we consider different approaches for estimation and assessment of covariate effects for the cumulative incidence curve in the competing risks model. The classic approach is to model all cause-specific hazards and then estimate the cumulative incidence curve based on these cause-specific hazards. Another recent approach is to directly model the cumulative incidence by a proportional model (Fine and Gray, J Am Stat Assoc 94:496–509, 1999), and then obtain direct estimates of how covariates influences the cumulative incidence curve. We consider a simple and flexible class of regression models that is easy to fit and contains the Fine–Gray model as a special case. One advantage of this approach is that our regression modeling allows for non-proportional hazards. This leads to a new simple goodness-of-fit procedure for the proportional subdistribution hazards assumption that is very easy to use. The test is constructive in the sense that it shows exactly where non-proportionality is present. We illustrate our methods to a bone marrow transplant data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Through this data example we demonstrate the use of the flexible regression models to analyze competing risks data when non-proportionality is present in the data.