Comparing waiting times in a multi-stage model: A log-rank approach

A proper log-rank test for comparing two waiting (i.e. sojourn, gap) times under right censored data has been absent in the survival literature. The classical log-rank test provides a biased comparison even under independent right censoring since the censoring induced on the time since state entry depends on the entry time unless the hazards are semi-Markov. We develop test statistics for comparing K waiting time distributions from a multi-stage model in which censoring and waiting times may be dependent upon the transition history in the multi-stage model. To account for such dependent censoring, the proposed test statistics utilize an inverse probability of censoring weighted (IPCW) approach previously employed to define estimators for the cumulative hazard and survival function for waiting times in multi-stage models. We develop the test statistics as analogues to K-sample log-rank statistics for failure time data, and weak convergence to a Gaussian limit is demonstrated. A simulation study demonstrates the appropriateness of the test statistics in designs that violate typical independence assumptions for multi-stage models, under which naive test statistics for failure time data perform poorly, and illustrates the superiority of the test under proportional hazards alternatives to a Mann–Whitney type test. We apply the test statistics to an existing data set of burn patients.     

Combined multiple testing by censored empirical likelihood

We propose a new procedure for combining multiple tests in samples of right-censored observations. The new method is based on multiple constrained censored empirical likelihood where the constraints are formulated as linear functionals of the cumulative hazard functions. We prove a version of Wilks’ theorem for the multiple constrained censored empirical likelihood ratio, which provides a simple reference distribution for the test statistic of our proposed method. A useful application of the proposed method is, for example, examining the survival experience of different populations by combining different weighted log-rank tests. Real data examples are given using the log-rank and Gehan-Wilcoxon tests. In a simulation study of two sample survival data, we compare the proposed method of combining tests to previously developed procedures. The results demonstrate that, in addition to its computational simplicity, the combined test performs comparably to, and in some situations more reliably than previously developed procedures. Statistical software is available in the R package ‘emplik’.     

Generalized Log-Rank Tests for Interval-Censored Failure Time Data

Abstract.  Several non-parametric test procedures have been proposed for incomplete survival data: interval-censored failure time data. However, most of them have unknown asymptotic properties with heuristically derived and/or complicated variance estimation. This article presents a class of generalized log-rank tests for this type of survival data and establishes their asymptotics. The methods are evaluated using simulation studies and illustrated by a set of real data from a cancer study.     

Fitting Cox Models with Doubly Censored Data Using Spline‐Based Sieve Marginal Likelihood

In some applications, the failure time of interest is the time from an originating event to a failure event while both event times are interval censored. We propose fitting Cox proportional hazards models to this type of data using a spline‐based sieve maximum marginal likelihood, where the time to the originating event is integrated out in the empirical likelihood function of the failure time of interest. This greatly reduces the complexity of the objective function compared with the fully semiparametric likelihood. The dependence of the time of interest on time to the originating event is induced by including the latter as a covariate in the proportional hazards model for the failure time of interest. The use of splines results in a higher rate of convergence of the estimator of the baseline hazard function compared with the usual non‐parametric estimator. The computation of the estimator is facilitated by a multiple imputation approach. Asymptotic theory is established and a simulation study is conducted to assess its finite sample performance. It is also applied to analyzing a real data set on AIDS incubation time.     

Testing equality of survival distributions when the population marks are missing

This paper introduces a nonparametric approach for testing the equality of two or more survival distributions based on right censored failure times with missing population marks for the censored observations. The standard log-rank test is not applicable here because the population membership information is not available for the right censored individuals. We propose to use the imputed population marks for the censored observations leading to fractional at-risk sets that can be used in a two sample censored data log-rank test. We demonstrate with a simple example that there could be a gain in power by imputing population marks (the proposed method) for the right censored individuals compared to simply removing them (which also would maintain the right size). Performance of the imputed log-rank tests obtained this way is studied through simulation. We also obtain an asymptotic linear representation of our test statistic. Our testing methodology is illustrated using a real data set.     

Finding local departures from a parametric model using nonparametric regression

Goodness-of-fit evaluation of a parametric regression model is often done through hypothesis testing, where the fit of the model of interest is compared statistically to that obtained under a broader class of models. Nonparametric regression models are frequently used as the latter type of model, because of their flexibility and wide applicability. To date, this type of tests has generally been performed globally, by comparing the parametric and nonparametric fits over the whole range of the data. However, in some instances it might be of interest to test for deviations from the parametric model that are localized to a subset of the data. In this case, a global test will have low power and hence can miss important local deviations. Alternatively, a naive testing approach that discards all observations outside the local interval will suffer from reduced sample size and potential overfitting. We therefore propose a new local goodness-of-fit test for parametric regression models that can be applied to a subset of the data but relies on global model fits, and propose a bootstrap-based approach for obtaining the distribution of the test statistic. We compare the new approach with the global and the naive tests, both theoretically and through simulations, and illustrate its practical behavior in an application. We find that the local test has a better ability to detect local deviations than the other two tests.     

Intermediate clinical events,surrogate markers and survival

This paper investigates one- and two-sample problems comparing survival times when an individual may experience an intermediate event prior to death or reaching some well defined endpoint. The intermediate event may be polychotomous. Patients experiencing the intermediate event may have an altered survival distribution after the intermediate event. Score tests are derived for testing if the occurrence of the intermediate event actually alters survival. These models have implications for evaluating therapies without randomization as well as strengthening the log rank test for comparing two survival distributions. The exact distribution of the score tests can be found by conditioning on both the waiting time and occurrence of the intermedate event.Deceased     

A Distribution Free Test for the Equality of Scales

Situations where scale parameters are not nuisance factors to be controlled but outcomes to be explained arise in many contexts such as quality control, agricultural production systems, experimental education, the pharmaceutical industry and biology. Tests for homogeneity of variances are often of interest also as a preliminary to analysis of variance, dose-response modelling or discriminant analysis. The literature on tests for the equality of scales is vast. A test which usually stands out in terms of power and robustness against non normality is the modified Levene W50 test, however in the literature no test is found to be the most powerful one for every distribution. The goal of the article is to propose an effective method for comparing scales. More precisely, we propose a test for the equality of scales that, even though was not the most powerful one for every distribution, it has good overall performance under every type of distribution. This test has the form of a combined resampling test. It is important to note that non combined tests show good performance only in particular contexts. Size and power of the proposed test are studied via simulation and compared with many other robust tests for scale. A practical application to industrial quality control is discussed.     

Estimating treatment effects on the marginal recurrent event mean in the presence of a terminating event

In biomedical studies where the event of interest is recurrent (e.g., hospitalization), it is often the case that the recurrent event sequence is subject to being stopped by a terminating event (e.g., death). In comparing treatment options, the marginal recurrent event mean is frequently of interest. One major complication in the recurrent/terminal event setting is that censoring times are not known for subjects observed to die, which renders standard risk set based methods of estimation inapplicable. We propose two semiparametric methods for estimating the difference or ratio of treatment-specific marginal mean numbers of events. The first method involves imputing unobserved censoring times, while the second methods uses inverse probability of censoring weighting. In each case, imbalances in the treatment-specific covariate distributions are adjusted out through inverse probability of treatment weighting. After the imputation and/or weighting, the treatment-specific means (then their difference or ratio) are estimated nonparametrically. Large-sample properties are derived for each of the proposed estimators, with finite sample properties assessed through simulation. The proposed methods are applied to kidney transplant data.     

The analysis of multivariate recurrent events with partially missing event types

In many clinical studies, subjects are at risk of experiencing more than one type of potentially recurrent event. In some situations, however, the occurrence of an event is observed, but the specific type is not determined. We consider the analysis of this type of incomplete data when the objectives are to summarize features of conditional intensity functions and associated treatment effects, and to study the association between different types of event. Here we describe a likelihood approach based on joint models for the multi-type recurrent events where parameter estimation is obtained from a Monte-Carlo EM algorithm. Simulation studies show that the proposed method gives unbiased estimators for regression coefficients and variance–covariance parameters, and the coverage probabilities of confidence intervals for regression coefficients are close to the nominal level. When the distribution of the frailty variable is misspecified, the method still provides estimators of the regression coefficients with good properties. The proposed method is applied to a motivating data set from an asthma study in which exacerbations were to be sub-typed by cellular analysis of sputum samples as eosinophilic or non-eosinophilic.     

Testing for center effects on survival and competing risks outcomes using pseudo-value regression

In multi-center studies, the presence of a cluster effect leads to correlation among outcomes within a center and requires different techniques to handle such correlation. Testing for a cluster effect can serve as a pre-screening step to help guide the researcher towards the appropriate analysis. With time to event data, score tests have been proposed which test for the presence of a center effect on the hazard function. However, sometimes researchers are interested in directly modeling other quantities such as survival probabilities or cumulative incidence at a fixed time. We propose a test for the presence of a center effect acting directly on the quantity of interest using pseudo-value regression, and derive the asymptotic properties of our proposed test statistic. We examine the performance of our proposed test through simulation studies in both survival and competing risks settings. The proposed test may be more powerful than tests based on the hazard function in settings where the center effect is time-varying. We illustrate the test using a multicenter registry study of survival and competing risks outcomes after hematopoietic cell transplantation.

     

Nonparametric Two-Sample Tests of Longitudinal Data with Termination Events

In longitudinal data, observations of response variables occur at fixed or random time points, and can be stopped by a termination event. When comparing longitudinal data for two groups, such irregular observation behavior must be considered to yield suitable results. In this article, we propose the use of nonparametric tests based on the difference between weighted cumulative mean functions for comparing two mean functions with an adjustment for difference in the timing of termination events. We also derive the asymptotic null distributions of the test statistics and examine their small sample properties through simulations. We apply our method to data from a study of liver cirrhosis.     

A modified approximate method for analysis of degradation data

Estimation of the lifetime distribution of industrial components and systems yields very important information for manufacturers and consumers. However, obtaining reliability data is time consuming and costly. In this context, degradation tests are a useful alternative approach to lifetime and accelerated life tests in reliability studies. The approximate method is one of the most used techniques for degradation data analysis. It is very simple to understand and easy to implement numerically in any statistical software package. This paper uses time series techniques in order to propose a modified approximate method (MAM). The MAM improves the standard one in two aspects: (1) it uses previous observations in the degradation path as a Markov process for future prediction and (2) it is not necessary to specify a parametric form for the degradation path. Characteristics of interest such as mean or median time to failure and percentiles, among others, are obtained by using the modified method. A simulation study is performed in order to show the improved properties of the modified method over the standard one. Both methods are also used to estimate the failure time distribution of the fatigue-crack-growth data set.     

Bootstrap methods for single structural change tests: power versus corrected size and empirical illustration

This paper assesses the performance of tests for a single structural change at unknown date when regressors are stationary, trending and when they have a break in mean. Size and power of the test procedures are compared in a simulation setup particularly aimed at autoregressive models using their limiting distribution and some bootstrap approximations. The comparisons are performed using graphical methods, namely P value discrepancy plots and size–power curves. The simulation study gives some interesting insights to the test procedures. Indeed, it documents that tests based on the conventional asymptotic distribution are oversized in small samples. The size correction is achieved by some bootstrap methods which appear to possess reasonable size properties. For the power study, the proposed bootstrap method improves on the asymptotic approximations of some tests for heteroskedastic regression errors especially when there is a mean-shift in the regressors. This result has not been found for the case of i.i.d. errors where the bootstrap tests have the same power properties as the tests based on the asymptotic approximations. We finally study the relationship between two monthly US interest rates. The results show that such relationship has been altered by a regime-shift located in May 1981.     

Non-parametric Tests for Recurrent Events under Competing Risks

Abstract.  We consider a data set on nosocomial infections of patients hospitalized in a French intensive care facility. Patients may suffer from recurrent infections of different types and they also have a high risk of death. To deal with such situations, a model of recurrent events with competing risks and a terminal event is introduced. Our aim was to compare the occurrence rates of two types of events. For this purpose, we propose two tests: one to detect if the occurrence rate of a given type of event increases with time; a second to detect if the instantaneous probability of experiencing an event of a given type is always greater than the one of another type. The asymptotic properties of the test statistics are derived and Monte Carlo methods are used to study the power of the tests. Finally, the procedures developed are applied to the French nosocomial infections data set.     

The k-sample problem in a multi-state model and testing transition probability matrices

The choice of multi-state models is natural in analysis of survival data, e.g., when the subjects in a study pass through different states like ‘healthy’, ‘in a state of remission’, ‘relapse’ or ‘dead’ in a health related quality of life study. Competing risks is another common instance of the use of multi-state models. Statistical inference for such event history data can be carried out by assuming a stochastic process model. Under such a setting, comparison of the event history data generated by two different treatments calls for testing equality of the corresponding transition probability matrices. The present paper proposes solution to this class of problems by assuming a non-homogeneous Markov process to describe the transitions among the health states. A class of test statistics are derived for comparison of \(k\) treatments by using a ‘weight process’. This class, in particular, yields generalisations of the log-rank, Gehan, Peto–Peto and Harrington–Fleming tests. For an intrinsic comparison of the treatments, the ‘leave-one-out’ jackknife method is employed for identifying influential observations. The proposed methods are then used to develop the Kolmogorov–Smirnov type supremum tests corresponding to the various extended tests. To demonstrate the usefulness of the test procedures developed, a simulation study was carried out and an application to the Trial V data provided by International Breast Cancer Study Group is discussed.     

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.     

Rank Tests for Clustered Survival Data

In a clinical trial, we may randomize subjects (called clusters) to different treatments (called groups), and make observations from multiple sites (called units) of each subject. In this case, the observations within each subject could be dependent, whereas those from different subjects are independent. If the outcome of interest is the time to an event, we may use the standard rank tests proposed for independent survival data, such as the logrank and Wilcoxon tests, to test the equality of marginal survival distributions, but their standard error should be modified to accommodate the possible intracluster correlation. In this paper we propose a method of calculating the standard error of the rank tests for two-sample clustered survival data. The method is naturally extended to that for K-sample tests under dependence.     

Additive–multiplicative rates model for recurrent events

Recurrent events are frequently encountered in biomedical studies. Evaluating the covariates effects on the marginal recurrent event rate is of practical interest. There are mainly two types of rate models for the recurrent event data: the multiplicative rates model and the additive rates model. We consider a more flexible additive–multiplicative rates model for analysis of recurrent event data, wherein some covariate effects are additive while others are multiplicative. We formulate estimating equations for estimating the regression parameters. The estimators for these regression parameters are shown to be consistent and asymptotically normally distributed under appropriate regularity conditions. Moreover, the estimator of the baseline mean function is proposed and its large sample properties are investigated. We also conduct simulation studies to evaluate the finite sample behavior of the proposed estimators. A medical study of patients with cystic fibrosis suffered from recurrent pulmonary exacerbations is provided for illustration of the proposed method.     

Efficiency improvement in a class of survival models through model-free covariate incorporation

In randomized clinical trials, we are often concerned with comparing two-sample survival data. Although the log-rank test is usually suitable for this purpose, it may result in substantial power loss when the two groups have nonproportional hazards. In a more general class of survival models of Yang and Prentice (Biometrika 92:1–17, 2005), which includes the log-rank test as a special case, we improve model efficiency by incorporating auxiliary covariates that are correlated with the survival times. In a model-free form, we augment the estimating equation with auxiliary covariates, and establish the efficiency improvement using the semiparametric theories in Zhang et al. (Biometrics 64:707–715, 2008) and Lu and Tsiatis (Biometrics, 95:674–679, 2008). Under minimal assumptions, our approach produces an unbiased, asymptotically normal estimator with additional efficiency gain. Simulation studies and an application to a leukemia study show the satisfactory performance of the proposed method.