Improved precision in the analysis of randomized trials with survival outcomes,without assuming proportional hazards

We present a new estimator of the restricted mean survival time in randomized trials where there is right censoring that may depend on treatment and baseline variables. The proposed estimator leverages prognostic baseline variables to obtain equal or better asymptotic precision compared to traditional estimators. Under regularity conditions and random censoring within strata of treatment and baseline variables, the proposed estimator has the following features: (i) it is interpretable under violations of the proportional hazards assumption; (ii) it is consistent and at least as precise as the Kaplan–Meier and inverse probability weighted estimators, under identifiability conditions; (iii) it remains consistent under violations of independent censoring (unlike the Kaplan–Meier estimator) when either the censoring or survival distributions, conditional on covariates, are estimated consistently; and (iv) it achieves the nonparametric efficiency bound when both of these distributions are consistently estimated. We illustrate the performance of our method using simulations based on resampling data from a completed, phase 3 randomized clinical trial of a new surgical treatment for stroke; the proposed estimator achieves a 12% gain in relative efficiency compared to the Kaplan–Meier estimator. The proposed estimator has potential advantages over existing approaches for randomized trials with time-to-event outcomes, since existing methods either rely on model assumptions that are untenable in many applications, or lack some of the efficiency and consistency properties (i)–(iv). We focus on estimation of the restricted mean survival time, but our methods may be adapted to estimate any treatment effect measure defined as a smooth contrast between the survival curves for each study arm. We provide R code to implement the estimator.

     

Strong consistency of presmoothed Kaplan–Meier integrals when covariables are present

It is known that the Kaplan–Meier estimation may be improved via presmoothing methods. In this article, we introduce an extended presmoothed Kaplan–Meier estimator in the presence of covariates. The main result is the strong consistency of general empirical integrals based on such an estimator. As applications, one can obtain a consis-tent multivariate empirical distribution under censoring, and also can obtain a consistent estimation of regression parameters. We illustrate the new estimation methods through simulations and real data analysis.     

Double robust estimation in longitudinal marginal structural models

In this article we consider estimation of causal parameters in a marginal structural model for the discrete intensity of the treatment specific counting process (e.g. hazard of a treatment specific survival time) based on longitudinal observational data on treatment, covariates and survival. We define three estimators: the inverse probability of treatment weighted (IPTW) estimator, the maximum likelihood estimator (MLE), and a double robust (DR) estimator. The DR estimator is obtained by following a general methodology for constructing double robust estimating functions in censored data models as described in van der Laan and Robins (Unified Methods for Censored Longitudinal Data and Causality, 2002). The double-robust estimator is consistent and asymptotically linear when either the treatment mechanism or the partial likelihood of the observed data is consistently estimated. We illustrate the superiority of the DR estimator relative to the IPTW and ML estimators in a simulation study. The proposed methodology is also applied to estimate the causal effect of exercise on physical functioning in a longitudinal study of seniors in Sonoma County.     

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.     

Estimation of the Average Survival Function Using a Censored Data Regression Model

In the presence of covariates information, assuming the linear relationship between a transformation of survival time and covariates, we propose a new estimator of survival function and show its consistency. In addition, a comparison of the proposed estimator with the product-limit estimator introduced by Kaplan and Meier (1958) is performed through Monte Carlo simulation studies. We illustrate the proposed estimator with the updated Stanford heart transplant data.     

Sample size calculations for single-arm survival studies using transformations of the Kaplan–Meier estimator

In single-arm clinical trials with survival outcomes, the Kaplan–Meier estimator and its confidence interval are widely used to assess survival probability and median survival time. Since the asymptotic normality of the Kaplan–Meier estimator is a common result, the sample size calculation methods have not been studied in depth. An existing sample size calculation method is founded on the asymptotic normality of the Kaplan–Meier estimator using the log transformation. However, the small sample properties of the log transformed estimator are quite poor in small sample sizes (which are typical situations in single-arm trials), and the existing method uses an inappropriate standard normal approximation to calculate sample sizes. These issues can seriously influence the accuracy of results. In this paper, we propose alternative methods to determine sample sizes based on a valid standard normal approximation with several transformations that may give an accurate normal approximation even with small sample sizes. In numerical evaluations via simulations, some of the proposed methods provided more accurate results, and the empirical power of the proposed method with the arcsine square-root transformation tended to be closer to a prescribed power than the other transformations. These results were supported when methods were applied to data from three clinical trials.     

Multistate Survival Models as Transient Electrical Networks

In multistate survival analysis, the sojourn of a patient through various clinical states is shown to correspond to the diffusion of 1 C of electrical charge through an electrical network. The essential comparison has differentials of probability for the patient to correspond to differentials of charge, and it equates clinical states to electrical nodes. Indeed, if the death state of the patient corresponds to the sink node of the circuit, then the transient current that would be seen on an oscilloscope as the sink output is a plot of the probability density for the survival time of the patient. This electrical circuit analogy is further explored by considering the simplest possible survival model with two clinical states, alive and dead (sink), that incorporates censoring and truncation. The sink output seen on an oscilloscope is a plot of the Kaplan–Meier mass function. Thus, the Kaplan–Meier estimator finds motivation from the dynamics of current flow, as a fundamental physical law, rather than as a nonparametric maximum likelihood estimate (MLE). Generalization to competing risks settings with multiple death states (sinks) leads to cause‐specific Kaplan–Meier submass functions as outputs at sink nodes. With covariates present, the electrical analogy provides for an intuitive understanding of partial likelihood and various baseline hazard estimates often used with the proportional hazards model.     

Nonparametric estimation of quantile functions for randomly right censored data

In this paper we compare four nonparametric quantile function estimators for randomly right censored data: the Kaplan–Meier estimator, the linearly interpolated Kaplan–Meier estimator, the kernel-type survival function estimator, and the Bézier curve smoothing estimator. Also, we compare several kinds of confidence intervals of quantiles for four nonparametric quantile function estimators.     

ON THE ESTIMATION OF SURVIVAL FUNCTION UNDER RANDOM CENSORSHIP

ABSTRACT

The paper deals with an improvement of the well-known Kaplan–Meier estimator of survival function when the censoring mechanism is random and independent of the failure times. Small sample size properties of the new estimator, as well as the original Kaplan–Meier estimator are inspected by means of Monte Carlo simulations. It follows from the simulations that the proposed estimator prevails with respect to some basic statistical characteristics.     

A weighted Harrell–Davis distance test with applications to censored data

Consider the standard treatment-control model with a time-to-event endpoint. We propose a novel interpretable test statistic from a quantile function point of view. The large sample consistency of our estimator is proven for fixed bandwidth values theoretically and validated empirically. A Monte Carlo simulation study also shows that given small sample sizes, utilization of a tuning parameter through the application of a smooth quantile function estimator shows an improvement in efficiency in terms of the MSE when compared to direct application of classic Kaplan–Meier survival function estimator. The procedure is finally illustrated via an application to epithelial ovarian cancer data.     

The Jackknife estimate of covariance of two Kaplan–Meier integrals with covariables

In this paper the Jackknife estimate of covariance of two Kaplan–Meier integrals with covariates is introduced. Its strong consistency is established under mild conditions. Several applications of the estimator are discussed.     

Product-limit Estimators and Cox Regression with Missing Censoring Information

The Kaplan–Meier estimator of a survival function requires that the censoring indicator is always observed. A method of survival function estimation is developed when the censoring indicators are missing completely at random (MCAR). The resulting estimator is a smooth functional of the Nelson–Aalen estimators of certain cumulative transition intensities. The asymptotic properties of this estimator are derived. A simulation study shows that the proposed estimator has greater efficiency than competing MCAR-based estimators. The approach is extended to the Cox model setting for the estimation of a conditional survival function given a covariate.     

Generalized M-estimation for the accelerated failure time model

The accelerated failure time (AFT) model is an important regression tool to study the association between failure time and covariates. In this paper, we propose a robust weighted generalized M (GM) estimation for the AFT model with right-censored data by appropriately using the Kaplan–Meier weights in the GM–type objective function to estimate the regression coefficients and scale parameter simultaneously. This estimation method is computationally simple and can be implemented with existing software. Asymptotic properties including the root-n consistency and asymptotic normality are established for the resulting estimator under suitable conditions. We further show that the method can be readily extended to handle a class of nonlinear AFT models. Simulation results demonstrate satisfactory finite sample performance of the proposed estimator. The practical utility of the method is illustrated by a real data example.     

Survival estimation through the cumulative hazard function with monotone natural cubic splines

In this paper we explore the estimation of survival probabilities via a smoothed version of the survival function, in the presence of censoring. We investigate the fit of a natural cubic spline on the cumulative hazard function under appropriate constraints. Under the proposed technique the problem reduces to a restricted least squares one, leading to convex optimization. The approach taken in this paper is evaluated and compared via simulations to other known methods such as the Kaplan Meier and the logspline estimator. Our approach is easily extended to address estimation of survival probabilities in the presence of covariates when the proportional hazards model assumption holds. In this case the method is compared to a restricted cubic spline approach that involves maximum likelihood. The proposed approach can be also adjusted to accommodate left censoring.     

Generalized Concept of Relative Risk and Wider Applications of the Proportional Hazards Model and the Kaplan–Meier Estimator

The concepts of relative risk and hazard ratio are generalized for ordinary ordinal and continuous response variables, respectively. Under the generalized concepts, the Cox proportional hazards model with the Breslow's and Efron's methods can be regarded as generalizations of the Mantel–Haenszel estimator for dealing with broader types of covariates and responses. When ordinal responses can be regarded as discretized observations of a hypothetical continuous variable, the estimated relative risks from the Cox model reflect the associations between the responses and covariates. Examples are given to illustrate the generalized concepts and wider applications of the Cox model and the Kaplan–Meier estimator.     

Coverage probabilities of nonparametric simultaneous confidence bands for a survival function

Simultaneous confidence bands provide a useful adjunct to the popular Kaplan–Meier product limit estimator for a survival function, particularly when results are displayed graphically. They allow an assessment of the magnitude of sampling errors and provide a graphical view of a formal goodness-of-fit test. In this paper we evaluate a modified version of Nair's (1981) simultaneous confidence bands. The modification is based on a logistic transformation of the Kaplan–Meier estimator. We show that the modified bands have some important practical advantages.     

An Alternative to Efron's Redistribution-of-Mass Construction of the Kaplan—Meier Estimator

Kaplan and Meier (1958) derived the nonparametric maximum likelihood estimator of the survival function for the case in which some survival times are right-censored. Efron (1967) proposed a redistribution-of-mass construction of the Kaplan—Meier estimator that emphasized and illustrated the contribution of the censored observations. This article presents an alternative construction that, unlike Efron's method, redistributes the mass initially associated with each censored observation directly to the uncensored observations. The proposed construction avoids distributing a given mass more than once and provides additional insight into the nature of the Kaplan—Meier estimator.     

On the use of extreme value tail modeling for generalized pairwise comparisons with censored outcomes

In randomized clinical trials, methods of pairwise comparisons such as the ‘Net Benefit’ or the ‘win ratio’ have recently gained much attention when interests lies in assessing the effect of a treatment as compared to a standard of care. Among other advantages, these methods are usually praised for delivering a treatment measure that can easily handle multiple outcomes of different nature, while keeping a meaningful interpretation for patients and clinicians. For time-to-event outcomes, a recent suggestion emerged in the literature for estimating these treatment measures by providing a natural handling of censored outcomes. However, this estimation procedure may lead to biased estimates when tails of survival functions cannot be reliably estimated using Kaplan–Meier estimators. The problem then extrapolates to the other outcomes incorporated in the pairwise comparison construction. In this work, we suggest to extend the procedure by the consideration of a hybrid survival function estimator that relies on an extreme value tail model through the Generalized Pareto distribution. We provide an estimator of treatment effect measures that notably improves on bias and remains easily apprehended for practical implementation. This is illustrated in an extensive simulation study as well as in an actual trial of a new cancer immunotherapy.     

The central limit theorem under semiparametric random censorship models

We study integrals for arbitrary Borel-measurable functions with respect to a semiparametric estimator of the distribution function in the random censorship model. Based on a representation of these integrals, which is similar to the one given by Stute for Kaplan–Meier integrals, a central limit theorem is established which generalizes a corresponding result of the Cheng and Lin estimator. It is shown that the semiparametric integral estimator is at least as efficient as the corresponding Kaplan–Meier integral estimator in terms of asymptotic variance if the correct semiparametric model is used. Furthermore, a necessary and sufficient condition for a strict gain in efficiency is stated. Finally, this asymptotic result is confirmed in a small simulation study under moderate sample sizes.     

On estimation of frequency data with censored observations

The problem of the estimation of mean frequency of events in the presence of censoring is important in assessing the efficacy, safety and cost of therapies. The mean frequency is typically estimated by dividing the total number of events by the total number of patients under study. This method, referred to in this paper as the ‘naïve estimator’, ignores the censoring. Other approaches available for this problem require many assumptions that are rarely acceptable. These include the assumption of independence, constant hazard rate over time and other similar distributional assumptions. In this paper a simple non‐parametric estimator based on the sum of the products of Kaplan–Meier estimators is proposed as an estimator of mean frequency, and its approximate variance and standard error are derived. An illustration is provided to show the derivation of the proposed estimator. Although the clinical trial setting is used in this paper, the problem has applications in other areas where survival analysis is used and recurrent events are studied. Copyright © 2003 John Wiley & Sons, Ltd.