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.     

A general joint model for longitudinal measurements and competing risks survival data with heterogeneous random effects

This article studies a general joint model for longitudinal measurements and competing risks survival data. The model consists of a linear mixed effects sub-model for the longitudinal outcome, a proportional cause-specific hazards frailty sub-model for the competing risks survival data, and a regression sub-model for the variance–covariance matrix of the multivariate latent random effects based on a modified Cholesky decomposition. The model provides a useful approach to adjust for non-ignorable missing data due to dropout for the longitudinal outcome, enables analysis of the survival outcome with informative censoring and intermittently measured time-dependent covariates, as well as joint analysis of the longitudinal and survival outcomes. Unlike previously studied joint models, our model allows for heterogeneous random covariance matrices. It also offers a framework to assess the homogeneous covariance assumption of existing joint models. A Bayesian MCMC procedure is developed for parameter estimation and inference. Its performances and frequentist properties are investigated using simulations. A real data example is used to illustrate the usefulness of the approach.     

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.     

A Multi-state Piecewise Exponential Model of Hospital Outcomes after Injury

To allow more accurate prediction of hospital length of stay (LOS) after serious injury or illness, a multi-state model is proposed, in which transitions from the hospitalized state to three possible outcome states (home, long-term care, or death) are assumed to follow constant rates for each of a limited number of time periods. This results in a piecewise exponential (PWE) model for each outcome. Transition rates may be affected by time-varying covariates, which can be estimated from a reference database using standard statistical software and Poisson regression. A PWE model combining the three outcomes allows prediction of LOS. Records of 259,941 injured patients from the US Nationwide Inpatient Sample were used to create such a multi-state PWE model with four time periods. Hospital mortality and LOS for patient subgroups were calculated from this model, and time-varying covariate effects were estimated. Early mortality was increased by anatomic injury severity or penetrating mechanism, but these effects diminished with time; age and male sex remained strong predictors of mortality in all time periods. Rates of discharge home decreased steadily with time, while rates of transfer to long-term care peaked at five days. Predicted and observed LOS and mortality were similar for multiple subgroups. Conceptual background and methods of calculation are discussed and demonstrated. Multi-state PWE models may be useful to describe hospital outcomes, especially when many patients are not discharged home.     

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.     

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.     

Quantile regression for competing risks analysis under case-cohort design

The case-cohort design brings cost reduction in large cohort studies. In this paper, we consider a nonlinear quantile regression model for censored competing risks under the case-cohort design. Two different estimation equations are constructed with or without the covariates information of other risks included, respectively. The large sample properties of the estimators are obtained. The asymptotic covariances are estimated by using a fast resampling method, which is useful to consider further inferences. The finite sample performance of the proposed estimators is assessed by simulation studies. Also a real example is used to demonstrate the application of the proposed methods.     

Modeling low birth weights using threshold regression: results for U. S. birth data

Babies born live under 2,500 g or with a gestational age under 37 weeks are often inadequately developed and have elevated risks of infant mortality, congenital malformations, mental retardation, and other physical and neurological impairments. In this paper, we model birth weight as a first hitting time (FHT) of a birthing boundary in a Wiener process representing fetal development. We associate the parameters of the process and boundary with covariates describing maternal characteristics and the birthing environment using a relatively new regression methodology called threshold regression. Two FHT models for birth weight are developed. One is a mixture model and the other a competing risks model. These models are tested in a case demonstration using a 4%-systematic sample of the more than four million live births in the United States in 2002. An extensive data set for these births was provided by the National Center for Health Statistics. The focus of this paper is on the conceptual framework, models and methodology. A full empirical study is deferred to a later occasion.     

Using quantile regression for duration analysis

Summary Quantile regression methods are emerging as a popular technique in econometrics and biometrics for exploring the distribution of duration data. This paper discusses quantile regression for duration analysis allowing for a flexible specification of the functional relationship and of the error distribution. Censored quantile regression addresses the issue of right censoring of the response variable which is common in duration analysis. We compare quantile regression to standard duration models. Quantile regression does not impose a proportional effect of the covariates on the hazard over the duration time. However, the method cannot take account of time-varying covariates and it has not been extended so far to allow for unobserved heterogeneity and competing risks. We also discuss how hazard rates can be estimated using quantile regression methods. This paper benefitted from the helpful comments by an anonymous referee. Due to space constraints, we had to omit the details of the empirical application. These can be found in the long version of this paper, Fitzenberger and Wilke (2005). We gratefully acknowledge financial support by the German Research Foundation (DFG) through the research project ‘Microeconometric modelling of unemployment durations under consideration of the macroeconomic situation’. Thanks are due to Xuan Zhang for excellent research assistance. All errors are our sole responsibility.     

Regression Analysis for Multistate Models Based on a Pseudo-value Approach, with Applications to Bone Marrow Transplantation Studies

Abstract.  Typically, regression analysis for multistate models has been based on regression models for the transition intensities. These models lead to highly nonlinear and very complex models for the effects of covariates on state occupation probabilities. We present a technique that models the state occupation or transition probabilities in a multistate model directly. The method is based on the pseudo-values from a jackknife statistic constructed from non-parametric estimators for the probability in question. These pseudo-values are used as outcome variables in a generalized estimating equation to obtain estimates of model parameters. We examine this approach and its properties in detail for two special multistate model probabilities, the cumulative incidence function in competing risks and the current leukaemia-free survival used in bone marrow transplants. The latter is the probability a patient is alive and in either a first or second post-transplant remission. The techniques are illustrated on a dataset of leukaemia patients given a marrow transplant. We also discuss extensions of the model that are of current research interest.     

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.     

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.

     

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.     

An additive subdistribution hazard model for competing risks data

The cumulative incidence function plays an important role in assessing its treatment and covariate effects with competing risks data. In this article, we consider an additive hazard model allowing the time-varying covariate effects for the subdistribution and propose the weighted estimating equation under the covariate-dependent censoring by fitting the Cox-type hazard model for the censoring distribution. When there exists some association between the censoring time and the covariates, the proposed coefficients’ estimations are unbiased and the large-sample properties are established. The finite-sample properties of the proposed estimators are examined in the simulation study. The proposed Cox-weighted method is applied to a competing risks dataset from a Hodgkin's disease study.     

Bayesian analysis for partially complete time and type of failure data

In this paper, we consider the Bayesian analysis of competing risks data, when the data are partially complete in both time and type of failures. It is assumed that the latent cause of failures have independent Weibull distributions with the common shape parameter, but different scale parameters. When the shape parameter is known, it is assumed that the scale parameters have Beta–Gamma priors. In this case, the Bayes estimates and the associated credible intervals can be obtained in explicit forms. When the shape parameter is also unknown, it is assumed that it has a very flexible log-concave prior density functions. When the common shape parameter is unknown, the Bayes estimates of the unknown parameters and the associated credible intervals cannot be obtained in explicit forms. We propose to use Markov Chain Monte Carlo sampling technique to compute Bayes estimates and also to compute associated credible intervals. We further consider the case when the covariates are also present. The analysis of two competing risks data sets, one with covariates and the other without covariates, have been performed for illustrative purposes. It is observed that the proposed model is very flexible, and the method is very easy to implement in practice.     

Pseudo-observations for competing risks with covariate dependent censoring

Regression analysis for competing risks data can be based on generalized estimating equations. For the case with right censored data, pseudo-values were proposed to solve the estimating equations. In this article we investigate robustness of the pseudo-values against violation of the assumption that the probability of not being lost to follow-up (un-censored) is independent of the covariates. Modified pseudo-values are proposed which rely on a correctly specified regression model for the censoring times. Bias and efficiency of these methods are compared in a simulation study. Further illustration of the differences is obtained in an application to bone marrow transplantation data and a corresponding sensitivity analysis.     

Flexible parametric estimation technique for a competing risks model with unobserved heterogeneity: a Monte Carlo study

We analyse a flexible parametric estimation technique for a competing risks (CR) model with unobserved heterogeneity, by extending a local mixed proportional hazard single risk model for continuous duration time to a local mixture CR (LMCR) model for discrete duration time. The state-specific local hazard function for the LMCR model is per definition a valid density function if we have either one or two destination states. We conduct Monte Carlo experiments to compare the estimated parameters of the LMCR model, and to compare the estimated parameters of a CR model based on a Heckman–Singer-type (HS-type) technique, with the data-generating process parameters. The Monte Carlo results show that the LMCR model performs better or at least as good as the HS-type model with respect to the estimated structure parameters in most of the cases, but relatively poorer with respect to the estimated duration-dependence parameters.     

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.     

A competing risks approach for nonparametric estimation of transition probabilities in a non-Markov illness-death model

Competing risks model time to first event and type of first event. An example from hospital epidemiology is the incidence of hospital-acquired infection, which has to account for hospital discharge of non-infected patients as a competing risk. An illness-death model would allow to further study hospital outcomes of infected patients. Such a model typically relies on a Markov assumption. However, it is conceivable that the future course of an infected patient does not only depend on the time since hospital admission and current infection status but also on the time since infection. We demonstrate how a modified competing risks model can be used for nonparametric estimation of transition probabilities when the Markov assumption is violated.     

Hazards regression for freemium products and services: a competing risks approach

We propose a competing risks approach to analyse customer behaviours in freemium products and services. The event of interest is when a customer starts to pay for additional features or functionalities. The observation of such an event may be preempted by an event where the customer quits using the product before paying and consuming the additional features or functionalities. One such freemium service is the online game category. The Fine-Gray regression model was implemented for an online game player activity data to study how covariates affect the paying hazard. Some covariates are hypothesized to have different discrete effects at multiple change points. We extend the model to allow for possible change points in the analysis.