Adaptive Neyman's smooth tests of homogeneity of two samples of survival data

The problem of testing whether two samples of possibly right-censored survival data come from the same distribution is considered. The aim is to develop a test which is capable of detection of a wide spectrum of alternatives. A new class of tests based on Neyman's embedding idea is proposed. The null hypothesis is tested against a model where the hazard ratio of the two survival distributions is expressed by several smooth functions. A data-driven approach to the selection of these functions is studied. Asymptotic properties of the proposed procedures are investigated under fixed and local alternatives. Small-sample performance is explored via simulations which show that the power of the proposed tests appears to be more robust than the power of some versatile tests previously proposed in the literature (such as combinations of weighted logrank tests, or Kolmogorov–Smirnov tests).     

Validation of A Heteroscedastic Hazards Regression Model

A Cox-type regression model accommodating heteroscedasticity, with a power factor of the baseline cumulative hazard, is investigated for analyzing data with crossing hazards behavior. Since the approach of partial likelihood cannot eliminate the baseline hazard, an overidentified estimating equation (OEE) approach is introduced in the estimation procedure. Its by-product, a model checking statistic, is presented to test for the overall adequacy of the heteroscedastic model. Further, under the heteroscedastic model setting, we propose two statistics to test the proportional hazards assumption. Implementation of this model is illustrated in a data analysis of a cancer clinical trial.     

Delayed treatment effects,treatment switching and heterogeneous patient populations: How to design and analyze RCTs in oncology

In the analysis of survival times, the logrank test and the Cox model have been established as key tools, which do not require specific distributional assumptions. Under the assumption of proportional hazards, they are efficient and their results can be interpreted unambiguously. However, delayed treatment effects, disease progression, treatment switchers or the presence of subgroups with differential treatment effects may challenge the assumption of proportional hazards. In practice, weighted logrank tests emphasizing either early, intermediate or late event times via an appropriate weighting function may be used to accommodate for an expected pattern of non-proportionality. We model these sources of non-proportional hazards via a mixture of survival functions with piecewise constant hazard. The model is then applied to study the power of unweighted and weighted log-rank tests, as well as maximum tests allowing different time dependent weights. Simulation results suggest a robust performance of maximum tests across different scenarios, with little loss in power compared to the most powerful among the considered weighting schemes and huge power gain compared to unfavorable weights. The actual sources of non-proportional hazards are not obvious from resulting populationwise survival functions, highlighting the importance of detailed simulations in the planning phase of a trial when assuming non-proportional hazards.We provide the required tools in a software package, allowing to model data generating processes under complex non-proportional hazard scenarios, to simulate data from these models and to perform the weighted logrank tests.     

Comparison of Nonparametric Regression Curves by Spline Smoothing

In this article, procedures are proposed to test the hypothesis of equality of two or more regression functions. Tests are proposed by p-values, first under homoscedastic regression model, which are derived using fiducial method based on cubic spline interpolation. Then, we construct a test in the heteroscedastic case based on Fisher's method of combining independent tests. We study the behaviors of the tests by simulation experiments, in which comparisons with other tests are also given. The proposed tests have good performances. Finally, an application to a data set are given to illustrate the usefulness of the proposed test in practice.     

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.     

Comparison of failure probabilities in the presence of competing risks

Typically, differences in the effect of treatment on competing risks are compared by a weighted log-rank test. This test compares the cause specific hazard rates between the groups. Often the test does not agree with the impressions gained from plots of the cumulative incidence functions. Here we discuss several K-sample tests allowing us to directly compare cumulative incidence functions. These include tests based on the weighted integrated difference between the subdistribution hazards or cumulative incidence functions, Kolmogorov-Smirnov type test, and Renyi type test. In addition to unadjusted comparison techniques, tests based on the regression modeling of the cumulative incidence functions are considered. A simulation study is used to compare the various tests and to assess their power against different alternatives. The methods are illustrated using real data examples.     

Frailty Models and Rank Tests

Connections are established between the theories of weighted logrank tests and of frailty models. These connections arise because omission of a balanced covariate from a proportional hazards model generally leads to a model with non-proportional hazards, for which the simple logrank test is no longer optimal. The optimal weighting function and the asymptotic relative efficiencies of the simple logrank test and of the optimally weighted logrank test relative to the adjusted test that would be used if the covariate values were known, are expressible in terms of the Laplace transform of the hazard ratio for the distribution of the omitted covariate. For example if this hazard ratio has a gamma distribution, the optimal test is a member of the G class introduced by Harrington and Fleming (1982). We also consider positive stable, inverse Gaussian, displaced Poisson and two-point frailty distribution. Results are obtained for parametric and nonparametric tests and are extended to include random censoring. We show that the loss of efficiency from omitting a covariate is generally more important than the additional loss due to misspecification of the resulting non-proportional hazards model as a proportional hazards model. However two-point frailty distributions can provide exceptions to this rule. Censoring generally increases the efficiency of the simple logrank test to the adjusted logrank test.     

Heterogeneity and varying effect in hazards regression

In the analysis of survival data, when nonproportional hazards are encountered, the Cox model is often extended to allow for a time-dependent effect by accommodating a varying coefficient. This extension, however, cannot resolve the nonproportionality caused by heterogeneity. In contrast, the heteroscedastic hazards regression (HHR) model is capable of modeling heterogeneity and thus can be applied when dealing with nonproportional hazards. In this paper, we study the application of the HHR model possibly equipped with varying coefficients. An LRR (logarithm of relative risk) plot is suggested when investigating the need to impose varying coefficients. Constancy and degeneration in the plot are used as diagnostic criteria. For the HHR model, a ‘piecewise effect’ (PE) analysis and an ‘average effect’ (AE) analysis are introduced. For the PE setting, we propose a score-type test for covariate-specific varying coefficients. The Stanford Heart Transplant data are analyzed for illustration. In the case of degeneration being destroyed by a polynomial covariate, piecewise constancy and/or monotonicity of the LRRs is considered as an alternative criterion based on the PE analysis. Finally, under the framework of the varying-coefficient HHR model, the meanings of the PE and AE analyses, along with their dynamic interpretation, are discussed.     

Rank invariant tests with left truncated and interval censored data

Peto and Peto (1972) have studied rank invariant tests to compare two survival curves for right censored data. We apply their tests, including the logrank test and the generalized Wilcoxon test, to left truncated and interval censored data. The significance levels of the tests are approximated by Monte Carlo permutation tests. Simulation studies are conducted to show their size and power under different distributional differences. In particular, the logrank test works well under the Cox proportional hazards alternatives, as for the usual right censored data. The methods are illustrated by the analysis of the Massachusetts Health Care Panel Study dataset.     

Partitioned log-rank tests for the overall homogeneity of hazard rate functions

In survival analysis, it is routine to test equality of two survival curves, which is often conducted by using the log-rank test. Although it is optimal under the proportional hazards assumption, the log-rank test is known to have little power when the survival or hazard functions cross. To test the overall homogeneity of hazard rate functions, we propose a group of partitioned log-rank tests. By partitioning the time axis and taking the supremum of the sum of two partitioned log-rank statistics over different partitioning points, the proposed test gains enormous power for cases with crossing hazards. On the other hand, when the hazards are indeed proportional, our test still maintains high power close to that of the optimal log-rank test. Extensive simulation studies are conducted to compare the proposed test with existing methods, and three real data examples are used to illustrate the commonality of crossing hazards and the advantages of the partitioned log-rank tests.     

Comparing Two Survival Time Distributions: An Investigation of Several Weight Functions for the Weighted Logrank Statistic

In survival analysis, it is often of interest to test whether or not two survival time distributions are equal, specifically in the presence of censored data. One very popular test statistic utilized in this testing procedure is the weighted logrank statistic. Much attention has been focused on finding flexible weight functions to use within the weighted logrank statistic, and we propose yet another. We demonstrate our weight function to be more stable than one of the most popular, which is given by Fleming and Harrington, by means of asymptotic normal tests, bootstrap tests and permutation tests performed on two datasets with a variety of characteristics.     

Weighted Mean Survival Test Statistics: a Class of Distance Tests for Censored Survival Data

A class of test statistics is introduced which is sensitive against the alternative of stochastic ordering in the two-sample censored data problem. The test statistics for evaluating a cumulative weighted difference in survival distributions are developed while taking into account the imbalances in base-line covariates between two groups. This procedure can be used to test the null hypothesis of no treatment effect, especially when base-line hazards cross and prognostic covariates need to be adjusted. The statistics are semiparametric, not rank based, and can be written as integrated weighted differences in estimated survival functions, where these survival estimates are adjusted for covariate imbalances. The asymptotic distribution theory of the tests is developed, yielding test procedures that are shown to be consistent under a fixed alternative. The choice of weight function is discussed and relies on stability and interpretability considerations. An example taken from a clinical trial for acquired immune deficiency syndrome is presented.     

Weighted Logrank Permutation Tests for Randomly Right Censored Life Science Data

In biomedical research, weighted logrank tests are frequently applied to compare two samples of randomly right censored survival times. We address the question how to combine a number of weighted logrank statistics to achieve good power of the corresponding survival test for a whole linear space or cone of alternatives, which are given by hazard rates. This leads to a new class of semiparametric projection tests that are motivated by likelihood ratio tests for an asymptotic model. We show that these tests can be carried out as permutation tests and discuss their asymptotic properties. A simulation study together with the analysis of a classical data set illustrates the advantages.     

Using Auxiliary Time-Dependent Covariates to Recover Information in Nonparametric Testing with Censored Data

Murrayand Tsiatis (1996) described a weighted survival estimate thatincorporates prognostic time-dependent covariate informationto increase the efficiency of estimation. We propose a test statisticbased on the statistic of Pepe and Fleming (1989, 1991) thatincorporates these weighted survival estimates. As in Pepe andFleming, the test is an integrated weighted difference of twoestimated survival curves. This test has been shown to be effectiveat detecting survival differences in crossing hazards settingswhere the logrank test performs poorly. This method uses stratifiedlongitudinal covariate information to get more precise estimatesof the underlying survival curves when there is censored informationand this leads to more powerful tests. Another important featureof the test is that it remains valid when informative censoringis captured by the incorporated covariate. In this case, thePepe-Fleming statistic is known to be biased and should not beused. These methods could be useful in clinical trials with heavycensoring that include collection over time of covariates, suchas laboratory measurements, that are prognostic of subsequentsurvival or capture information related to censoring.     

A jackknife-based versatile test for two-sample problems with right-censored data

For testing the equality of two survival functions, the weighted logrank test and the weighted Kaplan–Meier test are the two most widely used methods. Actually, each of these tests has advantages and defects against various alternatives, while we cannot specify in advance the possible types of the survival differences. Hence, how to choose a single test or combine a number of competitive tests for indicating the diversities of two survival functions without suffering a substantial loss in power is an important issue. Instead of directly using a particular test which generally performs well in some situations and poorly in others, we further consider a class of tests indexed by a weighted parameter for testing the equality of two survival functions in this paper. A delete-1 jackknife method is implemented for selecting weights such that the variance of the test is minimized. Some numerical experiments are performed under various alternatives for illustrating the superiority of the proposed method. Finally, the proposed testing procedure is applied to two real-data examples as well.     

A non-parametric statistic for testing conditional heteroscedasticity for unobserved component models

When prediction intervals are constructed using unobserved component models (UCM), problems can arise due to the possible existence of components that may or may not be conditionally heteroscedastic. Accurate coverage depends on correctly identifying the source of the heteroscedasticity. Different proposals for testing heteroscedasticity have been applied to UCM; however, in most cases, these procedures are unable to identify the heteroscedastic component correctly. The main issue is that test statistics are affected by the presence of serial correlation, causing the distribution of the statistic under conditional homoscedasticity to remain unknown. We propose a nonparametric statistic for testing heteroscedasticity based on the well-known Wilcoxon''s rank statistic. We study the asymptotic validation of the statistic and examine bootstrap procedures for approximating its finite sample distribution. Simulation results show an improvement in the size of the homoscedasticity tests and a power that is clearly comparable with the best alternative in the literature. We also apply the test on real inflation data. Looking for the presence of a conditionally heteroscedastic effect on the error terms, we arrive at conclusions that almost all cases are different than those given by the alternative test statistics presented in the literature.     

Precedence-type test based on Kaplan–Meier estimator of cumulative distribution function

In this paper, we introduce a precedence-type test based on Kaplan–Meier estimator of cumulative distribution function (CDF) for testing the hypothesis that two distribution functions are equal against a stochastically ordered hypothesis. This test is an alternative to the precedence life-test proposed first by Nelson (1963). After deriving the null distribution of the test statistic, we present its exact power function under the Lehmann alternative, and compare the exact power as well as simulated power (under location-shift) of the proposed test with other precedence-type tests. Next, we extend this test to the case of progressively Type-II censored data. Critical values for some combination of sample sizes and progressive censoring schemes are presented. We then examine the power properties of this test procedure and compare them to those of the weighted precedence and weighted maximal precedence tests under a location-shift alternative by means of Monte Carlo simulations. Finally, we present two examples to illustrate all the test procedures discussed here, and then make some concluding remarks.     

Data-driven smooth tests of the proportional hazards assumption

A new test of the proportional hazards assumption in the Cox model is proposed. The idea is based on Neyman’s smooth tests. The Cox model with proportional hazards (i.e. time-constant covariate effects) is embedded in a model with a smoothly time-varying covariate effect that is expressed as a combination of some basis functions (e.g., Legendre polynomials, cosines). Then the smooth test is the score test for significance of these artificial covariates. Furthermore, we apply a modification of Schwarz’s selection rule to choosing the dimension of the smooth model (the number of the basis functions). The score test is then used in the selected model. In a simulation study, we compare the proposed tests with standard tests based on the score process.     

Proportional cause-specific reversed hazards model

The proportional reversed hazards model explains the multiplicative effect of covariates on the baseline reversed hazard rate function of lifetimes. In the present study, we introduce a proportional cause-specific reversed hazards model. The proposed regression model facilitates the analysis of failure time data with multiple causes of failure under left censoring. We estimate the regression parameters using a partial likelihood approach. We provide Breslow's type estimators for the cumulative cause-specific reversed hazard rate functions. Asymptotic properties of the estimators are discussed. Simulation studies are conducted to assess their performance. We illustrate the applicability of the proposed model using a real data set.     

Tests for Equality of Survival Distributions Against Non-Location Alternatives

We propose new two andk-sample tests for evaluating the equality of survival distributions against alternatives that include crossing of survival functions, and proportional and monotone hazard ratios. The tests allow for right censored data. The asymptotic power against local alternatives is investigated. Simulation results demonstrate that the new tests are more powerful than known tests when survival functions cross. We apply the tests to a well known study of chemo- and radio-therapy conducted by the Gastrointestinal Tumor Study Group. TheP-values for both proposed tests are much smaller than for other known tests.