Statistical analysis of right-censored failure-time data with partially specified hazard rates

This paper discusses the analysis of right-censored failure-time data in which the failure rate may have different forms in different time intervals. Such data occur naturally, for example, in demography studies and leukemia research, and a number of methods for the analysis have been proposed in the literature. However, most methods are purely parametric or nonparametric. Matthews and Farewell (1982), for example, discussed this problem and proposed a method for testing a constant failure rate against a failure rate involving a change point. To estimate an absolute limit on the attainable human life span, Zelterman (1992) discussed a hazard function that has different parametric forms over different time intervals. We consider a different situation in which the hazard function may follow a parametric form before a change point and is completely unknown after the change point. To test the existence of the change point, a modified maximal-censored-likelihood-ratio test is proposed and its asymptotic properties are studied. A bootstrap method is described for finding critical values of the proposed test. Simulation results indicate that the test performs well.     

Covariates in multipath change‐point problems: Modelling and consistency of the MLE

Although the single‐path change‐point problem has been extensively treated in the statistical literature, its multipath counterpart has largely been ignored. In the multipath change‐point setting, it is often of interest to assess the impact of covariates on the change point itself as well as on the parameters before and after the change point. This paper is concerned only with the inclusion of covariates in the change‐point distribution. This is achieved through the hazard of change. Maximum likelihood estimation is discussed and consistency of the maximum likelihood estimators established.     

A test for abrupt change in hazard regression models with Weibull baselines

We develop a likelihood ratio test for an abrupt change point in Weibull hazard functions with covariates, including the two-piece constant hazard as a special case. We first define the log-likelihood ratio test statistic as the supremum of the profile log-likelihood ratio process over the interval which may contain an unknown change point. Using local asymptotic normality (LAN) and empirical measure, we show that the profile log-likelihood ratio process converges weakly to a quadratic form of Gaussian processes. We determine the critical values of the test and discuss how the test can be used for model selection. We also illustrate the method using the Chronic Granulomatous Disease (CGD) data.     

Estimation of a change point in the hazard rate of Lindley model under right censoring

In this article, we consider a single change point model for a sudden change in the hazard rate of Lindley distribution to model right-censored survival data. We derive the quantile function to generate random numbers from the proposed distribution by using the Lambert function. The maximum likelihood estimation method is used to estimate parameters of the change point model. A simulation study is also carried out to analyze the performance of the estimators. To validate our findings, a dataset on bone marrow transplant for patients of acute lymphoblastic leukemia is analyzed using the proposed model and is compared with the existing exponential single change point model.     

Estimation of a Change Point in a Hazard Function Based on Censored Data

The hazard function plays an important role in reliability or survival studies since it describes the instantaneous risk of failure of items at a time point, given that they have not failed before. In some real life applications, abrupt changes in the hazard function are observed due to overhauls, major operations or specific maintenance activities. In such situations it is of interest to detect the location where such a change occurs and estimate the size of the change. In this paper we consider the problem of estimating a single change point in a piecewise constant hazard function when the observed variables are subject to random censoring. We suggest an estimation procedure that is based on certain structural properties and on least squares ideas. A simulation study is carried out to compare the performance of this estimator with two estimators available in the literature: an estimator based on a functional of the Nelson-Aalen estimator and a maximum likelihood estimator. The proposed least squares estimator tums out to be less biased than the other two estimators, but has a larger variance. We illustrate the estimation method on some real data sets.     

Detecting change in a hazard regression model with right-censoring

The hazard function plays an important role in survival analysis and reliability, since it quantifies the instantaneous failure rate of an individual at a given time point t, given that this individual has not failed before t. In some applications, abrupt changes in the hazard function are observed, and it is of interest to detect the location of such a change. In this paper, we consider testing of existence of a change in the parameters of an exponential regression model, based on a sample of right-censored survival times and the corresponding covariates. Likelihood ratio type tests are proposed and non-asymptotic bounds for the type II error probability are obtained. When the tests lead to acceptance of a change, estimators for the location of the change are proposed. Non-asymptotic upper bounds of the underestimation and overestimation probabilities are obtained. A short simulation study illustrates these results.     

Detecting multiple change points in piecewise constant hazard functions

The National Cancer Institute (NCI) suggests a sudden reduction in prostate cancer mortality rates, likely due to highly successful treatments and screening methods for early diagnosis. We are interested in understanding the impact of medical breakthroughs, treatments, or interventions, on the survival experience for a population. For this purpose, estimating the underlying hazard function, with possible time change points, would be of substantial interest, as it will provide a general picture of the survival trend and when this trend is disrupted. Increasing attention has been given to testing the assumption of a constant failure rate against a failure rate that changes at a single point in time. We expand the set of alternatives to allow for the consideration of multiple change-points, and propose a model selection algorithm using sequential testing for the piecewise constant hazard model. These methods are data driven and allow us to estimate not only the number of change points in the hazard function but where those changes occur. Such an analysis allows for better understanding of how changing medical practice affects the survival experience for a patient population. We test for change points in prostate cancer mortality rates using the NCI Surveillance, Epidemiology, and End Results dataset.     

On computing estimates of a change-point in the Weibull regression hazard model

The hazard function describes the instantaneous rate of failure at a time t, given that the individual survives up to t. In applications, the effect of covariates produce changes in the hazard function. When dealing with survival analysis, it is of interest to identify where a change point in time has occurred. In this work, covariates and censored variables are considered in order to estimate a change-point in the Weibull regression hazard model, which is a generalization of the exponential model. For this more general model, it is possible to obtain maximum likelihood estimators for the change-point and for the parameters involved. A Monte Carlo simulation study shows that indeed, it is possible to implement this model in practice. An application with clinical trial data coming from a treatment of chronic granulomatous disease is also included.     

Confidence intervals for the first crossing point of two hazard functions

The phenomenon of crossing hazard rates is common in clinical trials with time to event endpoints. Many methods have been proposed for testing equality of hazard functions against a crossing hazards alternative. However, there has been relatively few approaches available in the literature for point or interval estimation of the crossing time point. The problem of constructing confidence intervals for the first crossing time point of two hazard functions is considered in this paper. After reviewing a recent procedure based on Cox proportional hazard modeling with Box-Cox transformation of the time to event, a nonparametric procedure using the kernel smoothing estimate of the hazard ratio is proposed. The proposed procedure and the one based on Cox proportional hazard modeling with Box-Cox transformation of the time to event are both evaluated by Monte–Carlo simulations and applied to two clinical trial datasets.     

Non‐parametric Bayesian Intensity Model: Exploring Time‐to‐Event Data on Two Time Scales

Time‐to‐event data have been extensively studied in many areas. Although multiple time scales are often observed, commonly used methods are based on a single time scale. Analysing time‐to‐event data on two time scales can offer a more extensive insight into the phenomenon. We introduce a non‐parametric Bayesian intensity model to analyse two‐dimensional point process on Lexis diagrams. After a simple discretization of the two‐dimensional process, we model the intensity by a one‐dimensional piecewise constant hazard functions parametrized by the change points and corresponding hazard levels. Our prior distribution incorporates a built‐in smoothing feature in two dimensions. We implement posterior simulation using the reversible jump Metropolis–Hastings algorithm and demonstrate the applicability of the method using both simulated and empirical survival data. Our approach outperforms commonly applied models by borrowing strength in two dimensions.     

Estimating the turning point of a bathtub-shaped failure distribution

The turning point of a hazard rate function is useful in assessing the hazard in the useful life phase and helps to determine and plan appropriate burn-in, maintenance, and repair policies and strategies. For many bathtub-shaped distributions, the turning point is unique, and the hazard varies little in the useful life phase. We investigate the performance of an empirical estimator for the turning point in the case of the modified Weibull distribution, a bathtub-shaped generalization of the Weibull distribution, that has been found to be useful in reliability engineering and other areas concerned with life-time data. We illustrate the theory by means of an example, and also conduct a simulation study to assess the performance of the estimator in practice.     

Bayesian adaptive patient enrollment restriction to identify a sensitive subpopulation using a continuous biomarker in a randomized phase 2 trial

With the development of molecular targeted drugs, predictive biomarkers have played an increasingly important role in identifying patients who are likely to receive clinically meaningful benefits from experimental drugs (i.e., sensitive subpopulation) even in early clinical trials. For continuous biomarkers, such as mRNA levels, it is challenging to determine cutoff value for the sensitive subpopulation, and widely accepted study designs and statistical approaches are not currently available. In this paper, we propose the Bayesian adaptive patient enrollment restriction (BAPER) approach to identify the sensitive subpopulation while restricting enrollment of patients from the insensitive subpopulation based on the results of interim analyses, in a randomized phase 2 trial with time‐to‐endpoint outcome and a single biomarker. Applying a four‐parameter change‐point model to the relationship between the biomarker and hazard ratio, we calculate the posterior distribution of the cutoff value that exhibits the target hazard ratio and use it for the restriction of the enrollment and the identification of the sensitive subpopulation. We also consider interim monitoring rules for termination because of futility or efficacy. Extensive simulations demonstrated that our proposed approach reduced the number of enrolled patients from the insensitive subpopulation, relative to an approach with no enrollment restriction, without reducing the likelihood of a correct decision for next trial (no‐go, go with entire population, or go with sensitive subpopulation) or correct identification of the sensitive subpopulation. Additionally, the four‐parameter change‐point model had a better performance over a wide range of simulation scenarios than a commonly used dichotomization approach. Copyright © 2016 John Wiley & Sons, Ltd.     

Semiparametric lack-of-fit tests in an additive hazard regression model

In the semiparametric additive hazard regression model of McKeague and Sasieni (Biometrika 81: 501–514), the hazard contributions of some covariates are allowed to change over time, without parametric restrictions (Aalen model), while the contributions of other covariates are assumed to be constant. In this paper, we develop tests that help to decide which of the covariate contributions indeed change over time. The remaining covariates may be modelled with constant hazard coefficients, thus reducing the number of curves that have to be estimated nonparametrically. Several bootstrap tests are proposed. The behavior of the tests is investigated in a simulation study. In a practical example, the tests consistently identify covariates with constant and with changing hazard contributions.     

A Novel Method to Calculate Mean Survival Time for Time-to-Event Data

In the analysis of time-to-event data, restricted mean survival time has been well investigated in the literature and provided by many commercial software packages, while calculating mean survival time remains as a challenge due to censoring or insufficient follow-up time. Several researchers have proposed a hybrid estimator of mean survival based on the Kaplan–Meier curve with an extrapolated tail. However, this approach often leads to biased estimate due to poor estimate of the parameters in the extrapolated “tail” and the large variability associated with the tail of the Kaplan–Meier curve due to small set of patients at risk. Two key challenges in this approach are (1) where the extrapolation should start and (2) how to estimate the parameters for the extrapolated tail. The authors propose a novel approach to calculate mean survival time to address these two challenges. In the proposed approach, an algorithm is used to search if there are any time points where the hazard rates change significantly. The survival function is estimated by the Kaplan–Meier method prior to the last change point and approximated by an exponential function beyond the last change point. The parameter in the exponential function is estimated locally. Mean survival time is derived based on this survival function. The simulation and case studies demonstrated the superiority of the proposed approach.     

Shape Constrained Non‐parametric Estimators of the Baseline Distribution in Cox Proportional Hazards Model

Abstract. We investigate non‐parametric estimation of a monotone baseline hazard and a decreasing baseline density within the Cox model. Two estimators of a non‐decreasing baseline hazard function are proposed. We derive the non‐parametric maximum likelihood estimator and consider a Grenander type estimator, defined as the left‐hand slope of the greatest convex minorant of the Breslow estimator. We demonstrate that the two estimators are strongly consistent and asymptotically equivalent and derive their common limit distribution at a fixed point. Both estimators of a non‐increasing baseline hazard and their asymptotic properties are obtained in a similar manner. Furthermore, we introduce a Grenander type estimator for a non‐increasing baseline density, defined as the left‐hand slope of the least concave majorant of an estimator of the baseline cumulative distribution function, derived from the Breslow estimator. We show that this estimator is strongly consistent and derive its asymptotic distribution at a fixed point.     

Wavelet Analysis of Change Points in Nonparametric Hazard Rate Models Under Random Censorship

In this article, we consider detection and estimation of change points in nonparametric hazard rate models. Wavelet methods are utilized to develop a testing procedure for change points detection. The asymptotic properties of the test statistic are explored. When there exist change points in hazard function, we also propose estimators for the number, the locations, and the jump sizes of the change points. The asymptotic properties of these estimators are systematically derived. Some simulation examples are conducted to assess the finite sample performance of the proposed approach and to make comparisons with some existing methods. A real data analysis is provided to illustrate the new approach.     

Hazard-based nonparametric survivor function estimation

Summary.  A representation is developed that expresses the bivariate survivor function as a function of the hazard function for truncated failure time variables. This leads to a class of nonparametric survivor function estimators that avoid negative mass. The transformation from hazard function to survivor function is weakly continuous and compact differentiable, so that such properties as strong consistency, weak convergence to a Gaussian process and bootstrap applicability for a hazard function estimator are inherited by the corresponding survivor function estimator. The set of point mass assignments for a survivor function estimator is readily obtained by using a simple matrix calculation on the set of hazard rate estimators. Special cases arise from a simple empirical hazard rate estimator, and from an empirical hazard rate estimator following the redistribution of singly censored observations within strips. The latter is shown to equal van der Laan's repaired nonparametric maximum likelihood estimator, for which a Greenwood-like variance estimator is given. Simulation studies are presented to compare the moderate sample performance of various nonparametric survivor function estimators.     

Generalizing the standardized hazard ratio to multivariate proportional hazards regression,with an application to clinical~genomic studies

The standardized hazard ratio for univariate proportional hazards regression is generalized as a scalar to multivariate proportional hazards regression. Estimators of the standardized log hazard ratio are developed, with corrections for bias and for regression to the mean in high-dimensional analyses. Tests of point and interval null hypotheses and confidence intervals are constructed. Cohort sampling study designs, commonly used in prospective–retrospective clinical genomic studies, are accommodated.     

The mixed gamma ageing model in life data analysis

Parametric and non-parametric lifetime data analyses in practical applications require sensitive tools if non-monotonic ageing properties (trend changes) are to be examined. The well known bathtub-shaped hazard rate is a special model for describing a trend change in ageing properties over time. The identification of trend changes in the hazard rate can be supported by graphical tools. This paper discusses the combined application of graphical tools and parametric estimation in the flexible mixed gamma distribution family to identify trend changes and model bathtub-shaped hazard rates.     

Semiparametric Sequential Testing for Multiple Change Points in Piecewise Constant Hazard Functions with Long-Term Survivors

In this article, we consider parameter estimation in the hazard rate with multiple change points in the presence of long-term survivors. We combine two methods: maximum likelihood based and martingale based, to estimate the change points in the hazard rate for right censored survival data that accounts for long-term survivors. A simulation study is carried out to compare the performance of estimators. The method is applied to analyze two real datasets.