The identifiability of the mixed proportional hazards competing risks model

Summary. We prove identification of dependent competing risks models in which each risk has a mixed proportional hazard specification with regressors, and the risks are dependent by way of the unobserved heterogeneity, or frailty, components. We show that the conditions for identification given by Heckman and Honoré can be relaxed. We extend the results to the case in which multiple spells are observed for each subject.     

Estimation in a competing risks proportional hazards model under length-biased sampling with censoring

What population does the sample represent? The answer to this question is of crucial importance when estimating a survivor function in duration studies. As is well-known, in a stationary population, survival data obtained from a cross-sectional sample taken from the population at time $t_0$ represents not the target density $f(t)$ but its length-biased version proportional to $tf(t)$ , for $t>0$ . The problem of estimating survivor function from such length-biased samples becomes more complex, and interesting, in presence of competing risks and censoring. This paper lays out a sampling scheme related to a mixed Poisson process and develops nonparametric estimators of the survivor function of the target population assuming that the two independent competing risks have proportional hazards. Two cases are considered: with and without independent censoring before length biased sampling. In each case, the weak convergence of the process generated by the proposed estimator is proved. A well-known study of the duration in power for political leaders is used to illustrate our results. Finally, a simulation study is carried out in order to assess the finite sample behaviour of our estimators.     

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 proportional hazards model for the analysis of doubly censored competing risks data

ABSTRACT

Competing risks data are common in medical research in which lifetime of individuals can be classified in terms of causes of failure. In survival or reliability studies, it is common that the patients (objects) are subjected to both left censoring and right censoring, which is refereed as double censoring. The analysis of doubly censored competing risks data in presence of covariates is the objective of this study. We propose a proportional hazards model for the analysis of doubly censored competing risks data, using the hazard rate functions of Gray (1988 Gray, R.J. (1988). A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann. Statist. 16:1141–1154.[Crossref], [Web of Science ®] , [Google Scholar]), while focusing upon one major cause of failure. We derive estimators for regression parameter vector and cumulative baseline cause specific hazard rate function. Asymptotic properties of the estimators are discussed. A simulation study is conducted to assess the finite sample behavior of the proposed estimators. We illustrate the method using a real life doubly censored competing risks data.     

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     

The proportional hazards model: applications in epidemiology

Cox's (1972) Proportioal hazards failure time model, already widely used in the analysis of clinical trials, also provides an elegant formalization of the epidemiologic concept of relative risk. When used to compare the disease experience of a study cohort with that of an external control population, it generalizes the notions of the standardized morbidity ratio (SMR) and the proportional morbidity ratio (PMR). For studies in which matched sets of cases and controls are sampled retrospectively from the population at risk, the model provides a flexible tool for the regression analysis of multiple risk factors.     

Bayesian estimation of a proportional hazards model for double-censored durations

Double-censored data consist of uncensored, left- and right-censored observations and occur in survival time analysis. In this paper, parametric Bayes estimation is investigated for a proportional hazards model with durations subject to double-censoring. We prove consistency and asymptotic normality of the posterior mean with the Bernstein–von Mises theorem. In addition, we estimate asymptotic standard errors. A simulation study shows that the finite-sample performance is similar to that of the maximum likelihood estimator. Finally, the proposed model is applied to rating transition data. The analysis suggests that an upgrade of a rating increases the duration in that class by about 10 days on average.     

Quantile estimation in the proportional hazards model of random censorship

The asymptotic theory is given for quantile estimation in the proportional hazards model of random censorship. In this model, the tail of the censoring distribution function is some power of the tail of the survival distribution function. The quantile estimator is based on the maximum likelihood estimator for the survival time distribution, due to Abdushukurov, Cheng and Lin.     

Sample size calculation for a proportional hazards mixture cure model with nonbinary covariates

Sample size calculation is a critical issue in clinical trials because a small sample size leads to a biased inference and a large sample size increases the cost. With the development of advanced medical technology, some patients can be cured of certain chronic diseases, and the proportional hazards mixture cure model has been developed to handle survival data with potential cure information. Given the needs of survival trials with potential cure proportions, a corresponding sample size formula based on the log-rank test statistic for binary covariates has been proposed by Wang et al. [25]. However, a sample size formula based on continuous variables has not been developed. Herein, we presented sample size and power calculations for the mixture cure model with continuous variables based on the log-rank method and further modified it by Ewell's method. The proposed approaches were evaluated using simulation studies for synthetic data from exponential and Weibull distributions. A program for calculating necessary sample size for continuous covariates in a mixture cure model was implemented in R.     

Sensitivity analysis for unmeasured confounding in a marginal structural Cox proportional hazards model

Sensitivity analysis for unmeasured confounding should be reported more often, especially in observational studies. In the standard Cox proportional hazards model, this requires substantial assumptions and can be computationally difficult. The marginal structural Cox proportional hazards model (Cox proportional hazards MSM) with inverse probability weighting has several advantages compared to the standard Cox model, including situations with only one assessment of exposure (point exposure) and time-independent confounders. We describe how simple computations provide sensitivity for unmeasured confounding in a Cox proportional hazards MSM with point exposure. This is achieved by translating the general framework for sensitivity analysis for MSMs by Robins and colleagues to survival time data. Instead of bias-corrected observations, we correct the hazard rate to adjust for a specified amount of unmeasured confounding. As an additional bonus, the Cox proportional hazards MSM is robust against bias from differential loss to follow-up. As an illustration, the Cox proportional hazards MSM was applied in a reanalysis of the association between smoking and depression in a population-based cohort of Norwegian adults. The association was moderately sensitive for unmeasured confounding.     

Statistical power to detect violation of the proportional hazards assumption when using the Cox regression model

The use of the Cox proportional hazards regression model is wide-spread. A key assumption of the model is that of proportional hazards. Analysts frequently test the validity of this assumption using statistical significance testing. However, the statistical power of such assessments is frequently unknown. We used Monte Carlo simulations to estimate the statistical power of two different methods for detecting violations of this assumption. When the covariate was binary, we found that a model-based method had greater power than a method based on cumulative sums of martingale residuals. Furthermore, the parametric nature of the distribution of event times had an impact on power when the covariate was binary. Statistical power to detect a strong violation of the proportional hazards assumption was low to moderate even when the number of observed events was high. In many data sets, power to detect a violation of this assumption is likely to be low to modest.     

Uniqueness of permuted treatment estimator distributions in the proportional hazards model

We discuss findings regarding the permutation distributions of treatment effect estimators in the proportional hazards model. For fixed sample size n, we will prove that all uncensored and untied event times yield the same permutation distribution of treatment effect estimators in the proportional hazards model. In other words this distribution is irrelevant with respect to the actual event times. We will show several uniqueness properties under different conditions. These properties are useful for small sample permutation tests and also helpful to large sample cases.     

Maximum likelihood estimation in the proportional hazards model of random censorship

The maximum likelihood estimator (MLE) for the survival function S_Tunder the proportional hazards model of censorship is derived and shown to differ from the Abdushukurov-Cheng-Lin estimator when the class of allowable distributions includes all continuous and discrete distributions. The estimators are compared via an example. The MLE is calculated using a Newton-Raphson iterative procedure and implemented via a FORTRAN algorithm.     

Comparison of goodness of fit tests for the cox proportional hazards model

The proportional hazards regression model of Cox(1972) is widely used in analyzing survival data. We examine several goodness of fit tests for checking the proportionality of hazards in the Cox model with two-sample censored data, and compare the performance of these tests by a simulation study. The strengths and weaknesses of the tests are pointed out. The effects of the extent of random censoring on the size and power are also examined. Results of a simulation study demonstrate that Gill and Schumacher's test is most powerful against a broad range of monotone departures from the proportional hazards assumption, but it may not perform as well fail for alternatives of nonmonotone hazard ratio. For the latter kind of alternatives, Andersen's test may detect patterns of irregular changes in hazards.     

On estimation of covariate-specific residual time quantiles under the proportional hazards model

Estimation and inference in time-to-event analysis typically focus on hazard functions and their ratios under the Cox proportional hazards model. These hazard functions, while popular in the statistical literature, are not always easily or intuitively communicated in clinical practice, such as in the settings of patient counseling or resource planning. Expressing and comparing quantiles of event times may allow for easier understanding. In this article we focus on residual time, i.e., the remaining time-to-event at an arbitrary time t given that the event has yet to occur by t. In particular, we develop estimation and inference procedures for covariate-specific quantiles of the residual time under the Cox model. Our methods and theory are assessed by simulations, and demonstrated in analysis of two real data sets.     

Performance of goodness-of-fit tests for the Cox proportional hazards model with time-varying covariates

There are few readily-implemented tests for goodness-of-fit for the Cox proportional hazards model with time-varying covariates. Through simulations, we assess the power of tests by Cox (J R Stat Soc B (Methodol) 34(2):187–220, 1972), Grambsch and Therneau (Biometrika 81(3):515–526, 1994), and Lin et al. (Biometrics 62:803–812, 2006). Results show that power is highly variable depending on the time to violation of proportional hazards, the magnitude of the change in hazard ratio, and the direction of the change. Because these characteristics are unknown outside of simulation studies, none of the tests examined is expected to have high power in real applications. While all of these tests are theoretically interesting, they appear to be of limited practical value.     

Analysis of a continuous-time proportional hazard model using discrete duration data

Many economic duration variables are often available only up to intervals, and not up to exact points. However, continuous time duration models are conceptually superior to discrete ones. Hence, in duration analyses, one faces a situation with discrete data and a continuous model. This paper discusses (i) the asymptotic bias of a conventional approximation procedure in which a discrete duration is treated as an exact observation; and (ii) the efficiency of a correct maximum likelihood estimator which appropriately accounts for the discrete nature of the data.     

Analysis of a continuous-time proportional hazard model using discrete duration data

Many economic duration variables are often available only up to intervals, and not up to exact points. However, continuous time duration models are conceptually superior to discrete ones. Hence, in duration analyses, one faces a situation with discrete data and a continuous model. This paper discusses (i) the asymptotic bias of a conventional approximation procedure in which a discrete duration is treated as an exact observation; and (ii) the efficiency of a correct maximum likelihood estimator which appropriately accounts for the discrete nature of the data.