Parametric inference for quantile event times with adjustment for covariates on competing risks data

ABSTRACT

We propose parametric inferences for quantile event times with adjustment for covariates on competing risks data. We develop parametric quantile inferences using parametric regression modeling of the cumulative incidence function from the cause-specific hazard and direct approaches. Maximum likelihood inferences are developed for estimation of the cumulative incidence function and quantiles. We develop the construction of parametric confidence intervals for quantiles. Simulation studies show that the proposed methods perform well. We illustrate the methods using early stage breast cancer data.     

Regression analysis of competing risks data via semi-parametric additive hazard model

When the subjects in a study possess different demographic and disease characteristics and are exposed to more than one types of failure, a practical problem is to assess the covariate effects on each type of failure as well as on all-cause failure. The most widely used method is to employ the Cox models on each cause-specific hazard and the all-cause hazard. It has been pointed out that this method causes the problem of internal inconsistency. To solve such a problem, the additive hazard models have been advocated. In this paper, we model each cause-specific hazard with the additive hazard model that includes both constant and time-varying covariate effects. We illustrate that the covariate effect on all-cause failure can be estimated by the sum of the effects on all competing risks. Using data from a longitudinal study on breast cancer patients, we show that the proposed method gives simple interpretation of the final results, when the primary covariate effect is constant in the additive manner on each cause-specific hazard. Based on the given additive models on the cause-specific hazards, we derive the inferences for the adjusted survival and cumulative incidence functions.     

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.     

A new parametric family for modelling cumulative incidence functions: application to breast cancer data

Summary.  Competing risks situations can be encountered in many research areas such as medicine, social science and engineering. The main stream of analyses of those competing risks data has been nonparametric or semiparametric in the statistical literature. We propose a new parametric family to parameterize the cumulative incidence function completely. The new distribution is sufficiently flexible to fit various shapes of hazard patterns in survival data and increases the efficiency of the cumulative incidence estimates over the distribution-free approaches. A simple two-sample parametric test statistic is also proposed to compare the cumulative incidence functions between two groups at a given time point. The new parametric approach is illustrated by using breast cancer data sets from the National Surgical Adjuvant Breast and Bowel Project.     

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.     

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.     

Tests for comparison of competing risks under the additive risk model

It is of interest that researchers study competing risks in which subjects may fail from any one of k causes. Comparing any two competing risks with covariate effects is very important in medical studies. In this paper, we develop tests for comparing cause-specific hazard rates and cumulative incidence functions at specified covariate levels under the additive risk model by a weighted difference of estimates of cumulative cause-specific hazard rates. Motivated by McKeague et al. (2001), we construct simultaneous confidence bands for the difference of two conditional cumulative incidence functions as a useful graphical tool. In addition, we conduct a simulation study, and the simulation result shows that the proposed procedure has a good finite sample performance. A melanoma data set in clinical trial is used for the purpose of illustration.     

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.     

Proportional cause-specific reversed hazards model

The proportional reversed hazards model explains the multiplicative effect of covariates on the baseline reversed hazard rate function of lifetimes. In the present study, we introduce a proportional cause-specific reversed hazards model. The proposed regression model facilitates the analysis of failure time data with multiple causes of failure under left censoring. We estimate the regression parameters using a partial likelihood approach. We provide Breslow's type estimators for the cumulative cause-specific reversed hazard rate functions. Asymptotic properties of the estimators are discussed. Simulation studies are conducted to assess their performance. We illustrate the applicability of the proposed model using a real data set.     

A simulation study on the confidence interval procedures of some mean cumulative function estimators

Recurrence data are collected to study the recurrent events in biological, physical, and other systems. Quantities of interest include the mean cumulative number of events and the mean cumulative cost of the events. The mean cumulative function (MCF) can be estimated using non-parametric (NP) methods or by fitting parametric models, and many procedures have been suggested to construct the confidence intervals (CIs) for the MCF. This paper summarizes the results of a large simulation study that was designed to compare five CI procedures for both NP and parametric estimation. When performing parametric estimation, we assume the power law non-homogeneous Poisson process (NHPP) model. Our results include the evaluation of these procedures when they are used for window-observation recurrence data where recurrence histories of some systems are available only in observation windows with gaps in between.     

A 3-parameter Gompertz distribution for survival data with competing risks,with an application to breast cancer data

The cumulative incidence function is of great importance in the analysis of survival data when competing risks are present. Parametric modeling of such functions, which are by nature improper, suggests the use of improper distributions. One frequently used improper distribution is that of Gompertz, which captures only monotone hazard shapes. In some applications, however, subdistribution hazard estimates have been observed with unimodal shapes. An extension to the Gompertz distribution is presented which can capture unimodal as well as monotone hazard shapes. Important properties of the proposed distribution are discussed, and the proposed distribution is used to analyze survival data from a breast cancer clinical trial.     

Semiparametric estimation of the cumulative incidence function under competing risks and left-truncated sampling

In this article, we propose semiparametric methods to estimate the cumulative incidence function of two dependent competing risks for left-truncated and right-censored data. The proposed method is based on work by Huang and Wang (1995). We extend previous model by allowing for a general parametric truncation distribution and a third competing risk before recruitment. Based on work by Vardi (1989), several iterative algorithms are proposed to obtain the semiparametric estimates of cumulative incidence functions. The asymptotic properties of the semiparametric estimators are derived. Simulation results show that a semiparametric approach assuming the parametric truncation distribution is correctly specified produces estimates with smaller mean squared error than those obtained in a fully nonparametric model.     

On heteroscedastic hazards regression models: theory and application

A class of non-proportional hazards regression models is considered to have hazard specifications consisting of a power form of cross-effects on the base-line hazard function. The primary goal of these models is to deal with settings in which heterogeneous distribution shapes of survival times may be present in populations characterized by some observable covariates. Although effects of such heterogeneity can be explicitly seen through crossing cumulative hazards phenomena in k -sample problems, they are barely visible in a one-sample regression setting. Hence, heterogeneity of this kind may not be noticed and, more importantly, may result in severely misleading inference. This is because the partial likelihood approach cannot eliminate the unknown cumulative base-line hazard functions in this setting. For coherent statistical inferences, a system of martingale processes is taken as a basis with which, together with the method of sieves, an overidentified estimating equation approach is proposed. A Pearson's χ² type of goodness-of-fit testing statistic is derived as a by-product. An example with data on gastric cancer patients' survival times is analysed.     

Estimation and interpretation of models of absolute risk from epidemiologic data,including family-based studies

Absolute risk is the chance that a person with given risk factors and free of the disease of interest at age a will be diagnosed with that disease in the interval (a, a + τ]. Absolute risk is sometimes called cumulative incidence. Absolute risk is a “crude” risk because it is reduced by the chance that the person will die of competing causes of death before developing the disease of interest. Cohort studies admit flexibility in modeling absolute risk, either by allowing covariates to affect the cause-specific relative hazards or to affect the absolute risk itself. An advantage of cause-specific relative risk models is that various data sources can be used to fit the required components. For example, case–control data can be used to estimate relative risk and attributable risk, and these can be combined with registry data on age-specific composite hazard rates for the disease of interest and with national data on competing hazards of mortality to estimate absolute risk. Family-based designs, such as the kin-cohort design and collections of pedigrees with multiple affected individuals can be used to estimate the genotype-specific hazard of disease. Such analyses must be adjusted for ascertainment, and failure to take into account residual familial risk, such as might be induced by unmeasured genetic variants or by unmeasured behavioral or environmental exposures that are correlated within families, can lead to overestimates of mutation-specific absolute risk in the general population.     

Modelling Survival Events with Longitudinal Covariates Measured with Error

In survival analysis, time-dependent covariates are usually present as longitudinal data collected periodically and measured with error. The longitudinal data can be assumed to follow a linear mixed effect model and Cox regression models may be used for modelling of survival events. The hazard rate of survival times depends on the underlying time-dependent covariate measured with error, which may be described by random effects. Most existing methods proposed for such models assume a parametric distribution assumption on the random effects and specify a normally distributed error term for the linear mixed effect model. These assumptions may not be always valid in practice. In this article, we propose a new likelihood method for Cox regression models with error-contaminated time-dependent covariates. The proposed method does not require any parametric distribution assumption on random effects and random errors. Asymptotic properties for parameter estimators are provided. Simulation results show that under certain situations the proposed methods are more efficient than the existing methods.     

A flexible parametric survival model for fitting time to event data in clinical trials

Time‐to‐event data are common in clinical trials to evaluate survival benefit of a new drug, biological product, or device. The commonly used parametric models including exponential, Weibull, Gompertz, log‐logistic, log‐normal, are simply not flexible enough to capture complex survival curves observed in clinical and medical research studies. On the other hand, the nonparametric Kaplan Meier (KM) method is very flexible and successful on catching the various shapes in the survival curves but lacks ability in predicting the future events such as the time for certain number of events and the number of events at certain time and predicting the risk of events (eg, death) over time beyond the span of the available data from clinical trials. It is obvious that neither the nonparametric KM method nor the current parametric distributions can fulfill the needs in fitting survival curves with the useful characteristics for predicting. In this paper, a full parametric distribution constructed as a mixture of three components of Weibull distribution is explored and recommended to fit the survival data, which is as flexible as KM for the observed data but have the nice features beyond the trial time, such as predicting future events, survival probability, and hazard function.     

Estimation of partially linear single-index additive hazards model with current status data

In this paper, we introduce a partially linear single-index additive hazards model with current status data. Both the unknown link function of the single-index term and the cumulative baseline hazard function are approximated by B-splines under a monotonicity constraint on the latter. The sieve method is applied to estimate the nonparametric and parametric components simultaneously. We show that, when the nonparametric link function is an exact B-spline, the resultant estimator of regression parameter vector is asymptotically normal and achieves the semiparametric information bound and the rate of convergence of the estimator for the cumulative baseline hazard function is optimal. Simulation studies are presented to examine the finite sample performance of the proposed estimation method. For illustration, we apply the method to a clinical dataset with current status outcome.     

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 Mass Redistribution Algorithm for Right Censored and Left Truncated Time to Event Data

Failure times are often right-censored and left-truncated. In this paper we give a mass redistribution algorithm for right-censored and/or left-truncated failure time data. We show that this algorithm yields the Kaplan-Meier estimator of the survival probability. One application of this algorithm in modeling the subdistribution hazard for competing risks data is studied. We give a product-limit estimator of the cumulative incidence function via modeling the subdistribution hazard. We show by induction that this product-limit estimator is identical to the left-truncated version of Aalen-Johansen (1978) estimator for the cumulative incidence function.     

Competing risks model for clustered data based on the subdistribution hazards with spatial random effects

In some applications, the clustered survival data are arranged spatially such as clinical centers or geographical regions. Incorporating spatial variation in these data not only can improve the accuracy and efficiency of the parameter estimation, but it also investigates the spatial patterns of survivorship for identifying high-risk areas. Competing risks in survival data concern a situation where there is more than one cause of failure, but only the occurrence of the first one is observable. In this paper, we considered Bayesian subdistribution hazard regression models with spatial random effects for the clustered HIV/AIDS data. An intrinsic conditional autoregressive (ICAR) distribution was employed to model the areal spatial random effects. Comparison among competing models was performed by the deviance information criterion. We illustrated the gains of our model through application to the HIV/AIDS data and the simulation studies.KEYWORDS: Competing risks, subdistribution hazard, cumulative incidence function, spatial random effect, Markov chain Monte Carlo