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.     

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.     

Non-parametric Tests for Recurrent Events under Competing Risks

Abstract.  We consider a data set on nosocomial infections of patients hospitalized in a French intensive care facility. Patients may suffer from recurrent infections of different types and they also have a high risk of death. To deal with such situations, a model of recurrent events with competing risks and a terminal event is introduced. Our aim was to compare the occurrence rates of two types of events. For this purpose, we propose two tests: one to detect if the occurrence rate of a given type of event increases with time; a second to detect if the instantaneous probability of experiencing an event of a given type is always greater than the one of another type. The asymptotic properties of the test statistics are derived and Monte Carlo methods are used to study the power of the tests. Finally, the procedures developed are applied to the French nosocomial infections data set.     

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.     

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 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.     

Analysis of progressively type-I interval censored competing risks data for a class of an exponential distribution

ABSTRACT

In this paper, we consider some problems of point estimation and point prediction when the competing risks data from a class of exponential distribution are progressive type-I interval censored. The maximum likelihood estimation and mid-point approximation method are proposed for the estimations of parameters. Also several point predictors of censored units such as the maximum likelihood predictor, the best unbiased predictor and the conditional median predictor are obtained. The methods discussed here are applied when the lifetime distributions of the latent failure times are independent and Weibull-distributed. Finally a simulation study is given by using Monte-Carlo simulations to compare the performances of the different methods and one data analysis has been presented for illustrative purposes.     

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.     

A class of observation-driven random coefficient INAR(1) processes based on negative binomial thinning

Integer-valued time series models and their applications have attracted a lot of attention over the last years. In this paper, we introduce a class of observation-driven random coefficient integer-valued autoregressive processes based on negative binomial thinning, where the autoregressive parameter depends on the observed values of the previous moment. Basic probability and statistics properties of the process are established. The unknown parameters are estimated by the conditional least squares and empirical likelihood methods. Specially, we consider three aspects of the empirical likelihood method: maximum empirical likelihood estimate, confidence region and EL test. The performance of the two estimation methods is compared through simulation studies. Finally, an application to a real data example is provided.     

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.     

The response functions for competing risks

The competing risks data consist of a pair (T,δ) where T≧0 can be interpreted as the failure time and δ as the identifier of the risk causing the failure. In many practical situations, the main interest lies in studying the inter-relationships between the probability structures of the failure time under various risks. Here, we consider two risks and propose the Junctional relationships between the probability structure of (T,δ=1) and (T,δ=2) by time-dependent scale and shape shifts. Also, a model which raptures the relative aging of a unit under the two risks is proposed. The necessary theory for confidence estimation of these shift functions is developed. These techniques are illustrated through several data sets available in the literature.     

Comparison of estimators in nested case–control studies with multiple outcomes

Reuse of controls in a nested case-control (NCC) study has not been considered feasible since the controls are matched to their respective cases. However, in the last decade or so, methods have been developed that break the matching and allow for analyses where the controls are no longer tied to their cases. These methods can be divided into two groups; weighted partial likelihood (WPL) methods and full maximum likelihood methods. The weights in the WPL can be estimated in different ways and four estimation procedures are discussed. In addition, we address modifications needed to accommodate left truncation. A full likelihood approach is also presented and we suggest an aggregation technique to decrease the computation time. Furthermore, we generalize calibration for case-cohort designs to NCC studies. We consider a competing risks situation and compare WPL, full likelihood and calibration through simulations and analyses on a real data example.     

The Geometric Birnbaum-Saunders regression model with cure rate

In this paper, we propose a cure rate survival model by assuming the number of competing causes of the event of interest follows the Geometric distribution and the time to event follow a Birnbaum Saunders distribution. We consider a frequentist analysis for parameter estimation of a Geometric Birnbaum Saunders model with cure rate. Finally, to analyze a data set from the medical area.     

An EM type estimation procedure for the destructive exponentially weighted Poisson regression cure model under generalized gamma lifetime

In this paper, we assume the number of competing causes to follow an exponentially weighted Poisson distribution. By assuming the initial number of competing causes can undergo destruction and that the population of interest has a cure fraction, we develop the EM algorithm for the determination of the MLEs of the model parameters of such a general cure model. This model is more flexible than the promotion time cure model and also provides an interesting and realistic interpretation of the biological mechanism of the occurrence of an event of interest. Instead of assuming a particular parametric distribution for the lifetime, we assume the lifetime to belong to the wider class of generalized gamma distribution. This allows us to carry out a model discrimination to select a parsimonious lifetime distribution that provides the best fit to the data. Within the EM framework, a two-way profile likelihood approach is proposed to estimate the shape parameters. An extensive Monte Carlo simulation study is carried out to demonstrate the performance of the proposed estimation method. Model discrimination is carried out by means of the likelihood ratio test and information-based methods. Finally, a data on melanoma is analyzed for illustrative purpose.     

A Discrete-Time Multilevel Mixture Model for Event History Data with Long-Term Survivors,with an Application to an Analysis of Contraceptive Sterilization in Bangladesh

Event history models typically assume that the entire population is at risk of experiencing the event of interest throughout the observation period. However, there will often be individuals, referred to as long-term survivors, who may be considered a priori to have a zero hazard throughout the study period. In this paper, a discrete-time mixture model is proposed in which the probability of long-term survivorship and the timing of event occurrence are modelled jointly. Another feature of event history data that often needs to be considered is that they may come from a population with a hierarchical structure. For example, individuals may be nested within geographical regions and individuals in the same region may have similar risks of experiencing the event of interest due to unobserved regional characteristics. Thus, the discrete-time mixture model is extended to allow for clustering in the likelihood and timing of an event within regions. The model is further extended to allow for unobserved individual heterogeneity in the hazard of event occurrence. The proposed model is applied in an analysis of contraceptive sterilization in Bangladesh. The results show that a woman's religion and education level affect her probability of choosing sterilization, but not when she gets sterilized. There is also evidence of community-level variation in sterilization timing, but not in the probability of sterilization.     

New flexible models generated by gamma random variables for lifetime modeling

In this paper we introduce a new three-parameter exponential-type distribution. The new distribution is quite flexible and can be used effectively in modeling survival data and reliability problems. It can have constant, decreasing, increasing, upside-down bathtub and bathtub-shaped hazard rate functions. It also generalizes some well-known distributions. We discuss maximum likelihood estimation of the model parameters for complete sample and for censored sample. Additionally, 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 follows the proposed distribution. Maximum likelihood estimation of the model parameters of the new cure rate survival model is discussed for complete sample and censored sample. Two applications to real data are provided to illustrate the flexibility of the new model in practice.     

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.     

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 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.     

Progressively Type-I interval censored competing risks data for the proportional hazards family

In this article, we consider some problems of estimation and prediction when progressive Type-I interval censored competing risks data are from the proportional hazards family. The maximum likelihood estimators of the unknown parameters are obtained. Based on gamma priors, the Lindely's approximation and importance sampling methods are applied to obtain Bayesian estimators under squared error and linear–exponential loss functions. Several classical and Bayesian point predictors of censored units are provided. Also, based on given producer's and consumer's risks accepting sampling plans are considered. Finally, the simulation study is given by Monte Carlo simulations to evaluate the performances of the different methods.