Survival analysis using inverse probability of treatment weighted methods based on the generalized propensity score

In survival analysis, treatment effects are commonly evaluated based on survival curves and hazard ratios as causal treatment effects. In observational studies, these estimates may be biased due to confounding factors. The inverse probability of treatment weighted (IPTW) method based on the propensity score is one of the approaches utilized to adjust for confounding factors between binary treatment groups. As a generalization of this methodology, we developed an exact formula for an IPTW log‐rank test based on the generalized propensity score for survival data. This makes it possible to compare the group differences of IPTW Kaplan–Meier estimators of survival curves using an IPTW log‐rank test for multi‐valued treatments. As causal treatment effects, the hazard ratio can be estimated using the IPTW approach. If the treatments correspond to ordered levels of a treatment, the proposed method can be easily extended to the analysis of treatment effect patterns with contrast statistics. In this paper, the proposed method is illustrated with data from the Kyushu Lipid Intervention Study (KLIS), which investigated the primary preventive effects of pravastatin on coronary heart disease (CHD). The results of the proposed method suggested that pravastatin treatment reduces the risk of CHD and that compliance to pravastatin treatment is important for the prevention of CHD. Copyright © 2009 John Wiley & Sons, Ltd.     

Analysis of Type-II hybrid censored competing risks data

Kundu and Gupta [Analysis of hybrid life-tests in presence of competing risks. Metrica. 2007;65:159–170] provided the analysis of Type-I hybrid censored competing risks data, when the lifetime distributions of the competing cause of failures follows exponential distribution. In this paper, we consider the analysis of Type-II hybrid censored competing risks data. It is assumed that latent lifetime distributions of the competing causes of failures follow independent exponential distributions with different scale parameters. It is observed that the maximum likelihood estimators of the unknown parameters do not always exist. We propose the modified estimators of the scale parameters, which coincide with the corresponding maximum likelihood estimators when they exist, and asymptotically they are equivalent. We obtain the exact distribution of the proposed estimators. Using the exact distributions of the proposed estimators, associated confidence intervals are obtained. The asymptotic and bootstrap confidence intervals of the unknown parameters are also provided. Further, Bayesian inference of some unknown parametric functions under a very flexible Beta-Gamma prior is considered. Bayes estimators and associated credible intervals of the unknown parameters are obtained using the Monte Carlo method. Extensive Monte Carlo simulations are performed to see the effectiveness of the proposed estimators and one real data set has been analysed for the illustrative purposes. It is observed that the proposed model and the method work quite well for this data set.     

Vertical modeling: analysis of competing risks data with a cure fraction

In this paper, we extend the vertical modeling approach for the analysis of survival data with competing risks to incorporate a cure fraction in the population, that is, a proportion of the population for which none of the competing events can occur. The proposed method has three components: the proportion of cure, the risk of failure, irrespective of the cause, and the relative risk of a certain cause of failure, given a failure occurred. Covariates may affect each of these components. An appealing aspect of the method is that it is a natural extension to competing risks of the semi-parametric mixture cure model in ordinary survival analysis; thus, causes of failure are assigned only if a failure occurs. This contrasts with the existing mixture cure model for competing risks of Larson and Dinse, which conditions at the onset on the future status presumably attained. Regression parameter estimates are obtained using an EM-algorithm. The performance of the estimators is evaluated in a simulation study. The method is illustrated using a melanoma cancer data set.

     

Estimation of the bivariate distribution function for censored gap times

In many medical studies, patients may experience several events during follow-up. The times between consecutive events (gap times) are often of interest and lead to problems that have received much attention recently. In this work, we consider the estimation of the bivariate distribution function for censored gap times. Some related problems such as the estimation of the marginal distribution of the second gap time and the conditional distribution are also discussed. In this article, we introduce a nonparametric estimator of the bivariate distribution function based on Bayes’ theorem and Kaplan–Meier survival function and explore the behavior of the four estimators through simulations. Real data illustration is included.     

Power and sample size considerations in clinical trials with competing risk endpoints

In clinical trials with a time-to-event endpoint, subjects are often at risk for events other than the one of interest. When the occurrence of one type of event precludes observation of any later events or alters the probably of subsequent events, the situation is one of competing risks. During the planning stage of a clinical trial with competing risks, it is important to take all possible events into account. This paper gives expressions for the power and sample size for competing risks based on a flexible parametric Weibull model. Nonuniform accrual to the study is considered and an allocation ratio other than one may be used. Results are also provided for the case where two or more of the competing risks are of primary interest.     

Competing risks model with random censoring on the leff

We consider a model involvingk competing risks when the random variables of interest (risks) are censored from the left with the unobservable random variable. The nonparametrical estimators for survival functions of risks are presented and the estimators are strongly approximated with the best rates by appropriate Gaussian processes.     

Modeling potential time to event data with competing risks

Patients receiving radical prostatectomy are at risk of metastasis or prostate cancer related death, and often need repeated clinical evaluations to determine whether additional adjuvant or salvage therapies are needed. Since the prostate cancer is a slowly progressing disease, and these additional therapies come with significant side effects, it is important for clinical decision making purposes to estimate a patient’s risk of cancer metastasis, in the presence of a competing risk by death, under the hypothetical condition that the patient does not receive any additional therapy. In observational studies, patients may receive additional therapy by choice; the time to metastasis without any therapy is often a potential outcome and not always observed. We study the competing risks model of Fine and Gray (J Am Stat Assoc, 94:496–509, 1999) with adjustment for treatment choice by inverse probability censoring weighting (IPCW). The model can be fit using standard software for partial likelihood with double IPCW weights. The proposed methodology is used in a prostate cancer study to predict the post-prostatectomy cumulative incidence probability of cancer metastasis without additional adjuvant or salvage therapies.     

Multiple imputation of censored survival data in the presence of missing covariates using restricted mean survival time

Missing covariates data with censored outcomes put a challenge in the analysis of clinical data especially in small sample settings. Multiple imputation (MI) techniques are popularly used to impute missing covariates and the data are then analyzed through methods that can handle censoring. However, techniques based on MI are available to impute censored data also but they are not much in practice. In the present study, we applied a method based on multiple imputation by chained equations to impute missing values of covariates and also to impute censored outcomes using restricted survival time in small sample settings. The complete data were then analyzed using linear regression models. Simulation studies and a real example of CHD data show that the present method produced better estimates and lower standard errors when applied on the data having missing covariate values and censored outcomes than the analysis of the data having censored outcome but excluding cases with missing covariates or the analysis when cases with missing covariate values and censored outcomes were excluded from the data (complete case analysis).     

On correlation rank screening for ultra-high dimensional competing risks data

In recent years, numerous feature screening schemes have been developed for ultra-high dimensional standard survival data with only one failure event. Nevertheless, existing literature pays little attention to related investigations for competing risks data, in which subjects suffer from multiple mutually exclusive failures. In this article, we develop a new marginal feature screening for ultra-high dimensional time-to-event data to allow for competing risks. The proposed procedure is model-free, and robust against heavy-tailed distributions and potential outliers for time to the type of failure of interest. Apart from this, it is invariant to any monotone transformation of event time of interest. Under rather mild assumptions, it is shown that the newly suggested approach possesses the ranking consistency and sure independence screening properties. Some numerical studies are conducted to evaluate the finite-sample performance of our method and make a comparison with its competitor, while an application to a real data set is provided to serve as an illustration.     

Modeling marginal features in studies of recurrent events in the presence of a terminal event

We study models for recurrent events with special emphasis on the situation where a terminal event acts as a competing risk for the recurrent events process and where there may be gaps between periods during which subjects are at risk for the recurrent event. We focus on marginal analysis of the expected number of events and show that an Aalen–Johansen type estimator proposed by Cook and Lawless is applicable in this situation. A motivating example deals with psychiatric hospital admissions where we supplement with analyses of the marginal distribution of time to the competing event and the marginal distribution of the time spent in hospital. Pseudo-observations are used for the latter purpose.

     

Marginal Means/Rates Models for Multiple Type Recurrent Event Data

Recurrent events are frequently observed in biomedical studies, and often more than one type of event is of interest. Follow-up time may be censored due to loss to follow-up or administrative censoring. We propose a class of semi-parametric marginal means/rates models, with a general relative risk form, for assessing the effect of covariates on the censored event processes of interest. We formulate estimating equations for the model parameters, and examine asymptotic properties of the parameter estimators. Finite sample properties of the regression coefficients are examined through simulations. The proposed methods are applied to a retrospective cohort study of risk factors for preschool asthma.     

Regression analysis of restricted mean survival time based on pseudo-observations for competing risks data

Competing risks data often occur in many medical follow-up studies. When the survival time is the outcome variable, the restricted mean survival time has heuristic and clinically meaningful interpretation. In this article, we propose a class of regression models for the restricted mean survival time in the competing risks setting. We adopt a technique of pseudo-observations to develop estimating equation approaches for the model parameters and establish asymptotic properties of the resulting estimators. The finite-sample behavior of the proposed method is evaluated through simulation studies, and an application to the Women’s Interagency HIV Study is provided.     

The competing risks analysis for parallel and series systems using Type-II progressive censoring

Abstract

Recently, the study of the lifetime of systems in reliability and survival analysis in the presence of several causes of failure (competing risks) has attracted attention in the literature. In this paper, series and parallel systems with exponential lifetime for each item of the system are considered. Several causes of failure independently affect lifetime distributions and observations of failure times of the systems are considered under progressive Type-II censored scheme. For series systems, the maximum likelihood estimates of parameters are computed and confidence intervals for parameters of the model are obtained using Fisher information matrix. For parallel systems, the generalized EM algorithm which uses the Newton-Raphson algorithm inside the EM algorithm is used to compute the maximum likelihood estimates of parameters. Also, the standard errors of the maximum likelihood estimates are computed by using the supplemented EM algorithm. The simulation study confirms the good performance of the introduced approach.     

Reinforced urns and the subdistribution beta‐Stacy process prior for competing risks analysis

In this paper, we introduce the subdistribution beta‐Stacy process, a novel Bayesian nonparametric process prior for subdistribution functions useful for the analysis of competing risks data. In particular, we (i) characterize this process from a predictive perspective by means of an urn model with reinforcement, (ii) show that it is conjugate with respect to right‐censored data, and (iii) highlight its relations with other prior processes for competing risks data. Additionally, we consider the subdistribution beta‐Stacy process prior in a nonparametric regression model for competing risks data, which, contrary to most others available in the literature, is not based on the proportional hazards assumption.     

Assessing the treatment effect in a randomized controlled trial with extensive non‐adherence: the EVOLVE trial

Intention‐to‐treat (ITT) analysis is widely used to establish efficacy in randomized clinical trials. However, in a long‐term outcomes study where non‐adherence to study drug is substantial, the on‐treatment effect of the study drug may be underestimated using the ITT analysis. The analyses presented herein are from the EVOLVE trial, a double‐blind, placebo‐controlled, event‐driven cardiovascular outcomes study conducted to assess whether a treatment regimen including cinacalcet compared with placebo in addition to other conventional therapies reduces the risk of mortality and major cardiovascular events in patients receiving hemodialysis with secondary hyperparathyroidism. Pre‐specified sensitivity analyses were performed to assess the impact of non‐adherence on the estimated effect of cinacalcet. These analyses included lag‐censoring, inverse probability of censoring weights (IPCW), rank preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE). The relative hazard (cinacalcet versus placebo) of mortality and major cardiovascular events was 0.93 (95% confidence interval 0.85, 1.02) using the ITT analysis; 0.85 (0.76, 0.95) using lag‐censoring analysis; 0.81 (0.70, 0.92) using IPCW; 0.85 (0.66, 1.04) using RPSFTM and 0.85 (0.75, 0.96) using IPE. These analyses, while not providing definitive evidence, suggest that the intervention may have an effect while subjects are receiving treatment. The ITT method remains the established method to evaluate efficacy of a new treatment; however, additional analyses should be considered to assess the on‐treatment effect when substantial non‐adherence to study drug is expected or observed. Copyright © 2015 John Wiley & Sons, Ltd.     

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).     

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.     

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.     

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.     

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.