Linear Signed-Rank Tests for Paired Survival Data Subject to a Common Censoring Time

In this paper we consider rank-based tests for paired survival data, in which pair members are subject to the same right censoring time. Linear signed-rank tests have already been developed for the two-treatment problem in which pair members receive the opposite treatments. Assuming a bivariate accelerated failure time model, we extend this class of linear signed-rank tests to the case of multiple covariates, making this methodology applicable to more complicated experimental designs. These tests can be reformulated as weighted sums of contigency table measures, giving an alternative method of computation and intuitive view of how these tests work. A simulation study of their small-sample performance relative to other tests demonstrates that the linear signed-rank tests have greater power in cases of moderately to highly correlated data.     

Adjusting and Comparing Survival Curves by Means of an Additive Risk Model

Survival curves may be adjusted for covariates using Aalen's additive risk model. Survival curves may be compared by taking the ratio of two adjusted survival curves; the ratio is denoted the generalized relative survival rate. Adjusting both survival curves for all but one of a common set of covariates gives the partial relative survival rate, which measures the covariate-specific contribution to the generalized relative survival rate. The generalized and partial relative survival rates have interpretations similar to the traditional relative survival rates frequently used in cancer epidemiology. In fact, the traditional relative survival rate can be generalized to a regression context using the additive risk model. This population-adjusted relative survival rate is an alternative and useful method for removing confounding effects of age, cohorts, and sex. The authors use a data set of malignant melanoma patients diagnosed from 1965 to 1974 in Norway. The 25-year survival of 1967 individuals is studied.     

Parameter Orthogonality in Mixed Regression Models for Survival Data

The implications of parameter orthogonality for the robustness of survival regression models are considered. The question of which of the proportional hazards or the accelerated life families of models would be more appropriate for analysis is usually ignored, and the proportional hazards family is applied, particularly in medicine, for convenience. Accelerated life models have conventionally been used in reliability applications. We propose a one-parameter family mixture survival model which includes both the accelerated life and the proportional hazards models. By orthogonalizing relative to the mixture parameter, we can show that, for small effects of the covariates, the regression parameters under the alternative families agree to within a constant. This recovers a known misspecification result. We use notions of parameter orthogonality to explore robustness to other types of misspecification including misspecified base-line hazards. The results hold in the presence of censoring. We also study the important question of when proportionality matters.     

Ordered Tests for Right–Censored Survival Data

In comparative clinical trials or animal carcinogenesis studies, the effect of increasing dose levels of an agent or an increasing number of additional modalities are frequently evaluated on the prolonged survival time of patients with a particular disease. It is of particular interest to test the ordered alternative that a treatment level increase leads to better survival. This paper considers an ordered test based on the two–sample weighted Kaplan–Meier statistics (Pepe & Fleming, 1989, 1991). It evaluates asymptotic relative efficiencies of the proposed ordered weighted Kaplan–Meier test, the competing ordered weighted logrank test (Liu et al., 1993) and modified ordered logrank test (Liu & Tsai, 1999) under Lehmann alternatives, for various piecewise exponential survival distributions. Finally, it demonstrates the proposed test on an appropriate dataset.     

Testing for covariate balance using quantile regression and resampling methods

Consistency of propensity score matching estimators hinges on the propensity score's ability to balance the distributions of covariates in the pools of treated and non-treated units. Conventional balance tests merely check for differences in covariates’ means, but cannot account for differences in higher moments. For this reason, this paper proposes balance tests which test for differences in the entire distributions of continuous covariates based on quantile regression (to derive Kolmogorov–Smirnov and Cramer–von-Mises–Smirnov-type test statistics) and resampling methods (for inference). Simulations suggest that these methods are very powerful and capture imbalances related to higher moments when conventional balance tests fail to do so.     

Diagnostic tests for bias of estimating equations in weighted regression with missing covariates

The authors propose two tests, one parametric and the other semiparametric, for testing bias of estimating equations in weighted regression with partially missing covariates when the primary regression model is correctly specified. More generally, the proposed tests may be thought of as a diagnostic tool for the combined package of the primary regression model and the missingness assumptions. The asymptotic null distributions of the two test statistics are derived under the assumption of missingness at random for the partially missing covariates. A small scale simulation study completes the work.     

Testing for the parametric component of partially linear EV models under random censorship

This paper investigates the hypothesis test of the parametric component in partially linear errors-in-variables (EV) model with random censorship. We construct two test statistics based on the difference of the corrected residual sum of squares and empirical likelihood ratio under the null and alternative hypotheses. It is shown that the limiting distributions of the proposed test statistics are both weighted sum of independent standard chi-squared distribution with one degree of freedom under the null hypothesis. Based on the adjusted test statistics, we further develop two new types of test procedures. Finite sample performance of the proposed test procedures is evaluated by extensive simulation studies.     

Empirical Likelihood Inference of the Partial Linear Isotonic Errors-in-variables Regression Models with Missing Data

This article is concerned with statistical inference of the partial linear isotonic regression model missing response and measurement errors in covariates. We proposed an empirical likelihood ratio test statistics and show that it has a limiting weighted chi-square distribution. An adjusted empirical likelihood ratio statistic, which is shown to have a limiting standard central chi-square distribution, is then proposed further. A maximum empirical likelihood estimator is also developed. A simulation study is conducted to examine the finite-sample property of proposed procedure.     

Nonparametric Tests for Stratum Effects in the Cox Model

Thispaper considers the stratified proportional hazards model witha focus on the assessment of stratum effects. The assessmentof such effects is often of interest, for example, in clinicaltrials. In this case, two relevant tests are the test of stratuminteraction with covariates and the test of stratum interactionwith baseline hazard functions. For the test of stratum interactionwith covariates, one can use the partial likelihood method (Kalbfleischand Prentice, 1980; Lin, 1994). For the test of stratum interactionwith baseline hazard functions, however, there seems to be noformal test available. We consider this problem and propose aclass of nonparametric tests. The asymptotic distributions ofthe tests are derived using the martingale theory. The proposedtests can also be used for survival comparisons which need tobe adjusted for covariate effects. The method is illustratedwith data from a lung cancer clinical trial.     

A log rank type test in observational survival studies with stratified sampling

In randomized clinical trials, the log rank test is often used to test the null hypothesis of the equality of treatment-specific survival distributions. In observational studies, however, the ordinary log rank test is no longer guaranteed to be valid. In such studies we must be cautious about potential confounders; that is, the covariates that affect both the treatment assignment and the survival distribution. In this paper, two cases were considered: the first is when it is believed that all the potential confounders are captured in the primary database, and the second case where a substudy is conducted to capture additional confounding covariates. We generalize the augmented inverse probability weighted complete case estimators for treatment-specific survival distribution proposed in Bai et al. (Biometrics 69:830–839, 2013) and develop the log rank type test in both cases. The consistency and double robustness of the proposed test statistics are shown in simulation studies. These statistics are then applied to the data from the observational study that motivated this research.     

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.     

Conditional Studentized Survival Tests for Randomly Censored Models

It is shown that in the case of heterogenous censoring distributions Studentized survival tests can be carried out as conditional permutation tests given the order statistics and their censoring status. The result is based on a conditional central limit theorem for permutation statistics. It holds for linear test statistics as well as for sup-statistics. The procedure works under one of the following general circumstances for the two-sample problem: the unbalanced sample size case, highly censored data, certain non-convergent weight functions or under alternatives. For instance, the two-sample log rank test can be carried out asymptotically as a conditional test if the relative amount of uncensored observations vanishes asymptotically as long as the number of uncensored observations becomes infinite. Similar results hold whenever the sample sizes and are unbalanced in the sense that and hold.     

A Model Validation Procedure when Covariate Data are Missing at Random

Abstract. In the presence of missing covariates, standard model validation procedures may result in misleading conclusions. By building generalized score statistics on augmented inverse probability weighted complete‐case estimating equations, we develop a new model validation procedure to assess the adequacy of a prescribed analysis model when covariate data are missing at random. The asymptotic distribution and local alternative efficiency for the test are investigated. Under certain conditions, our approach provides not only valid but also asymptotically optimal results. A simulation study for both linear and logistic regression illustrates the applicability and finite sample performance of the methodology. Our method is also employed to analyse a coronary artery disease diagnostic dataset.     

Maximum of the weighted Kaplan–Meier tests for the two-sample censored data

In this paper, some versatile test procedures are considered, which are useful for the case where the association of survival functions is unclear. These procedures are based on a maximum of a class of the weighted Kaplan–Meier statistics. The weight functions used in the procedures account for both the censored and non-censored data points. Numerical simulations with these weight functions show that, under various levels of censoring, the proposed procedures perform well across a wide range of alternative configurations. Implementation of the proposed procedures is illustrated in a real data example.     

Goodness-of-fit tests for general linear models with covariates missed at random

In this paper, we consider a model checking problem for general linear models with randomly missing covariates. Two types of score type tests with inverse probability weight, which is estimated by parameter and nonparameter methods respectively, are proposed to this goodness of fit problem. The asymptotic properties of the test statistics are developed under the null and local alternative hypothesis. Simulation study is carried out to present the performance of the sizes and powers of the tests. We illustrate the proposed method with a data set on monozygotic twins.     

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.     

Nonparametric Covariate-Adjusted Association Tests Based on the Generalized Kendall's Tau()

Identifying the risk factors for comorbidity is important in psychiatric research. Empirically, studies have shown that testing multiple, correlated traits simultaneously is more powerful than testing a single trait at a time in association analysis. Furthermore, for complex diseases, especially mental illnesses and behavioral disorders, the traits are often recorded in different scales such as dichotomous, ordinal and quantitative. In the absence of covariates, nonparametric association tests have been developed for multiple complex traits to study comorbidity. However, genetic studies generally contain measurements of some covariates that may affect the relationship between the risk factors of major interest (such as genes) and the outcomes. While it is relatively easy to adjust these covariates in a parametric model for quantitative traits, it is challenging for multiple complex traits with possibly different scales. In this article, we propose a nonparametric test for multiple complex traits that can adjust for covariate effects. The test aims to achieve an optimal scheme of adjustment by using a maximum statistic calculated from multiple adjusted test statistics. We derive the asymptotic null distribution of the maximum test statistic, and also propose a resampling approach, both of which can be used to assess the significance of our test. Simulations are conducted to compare the type I error and power of the nonparametric adjusted test to the unadjusted test and other existing adjusted tests. The empirical results suggest that our proposed test increases the power through adjustment for covariates when there exist environmental effects, and is more robust to model misspecifications than some existing parametric adjusted tests. We further demonstrate the advantage of our test by analyzing a data set on genetics of alcoholism.     

Choice of parametric models in survival analysis: applications to monotherapy for epilepsy and cerebral palsy

Summary. In the analysis of medical survival data, semiparametric proportional hazards models are widely used. When the proportional hazards assumption is not tenable, these models will not be suitable. Other models for covariate effects can be useful. In particular, we consider accelerated life models, in which the effect of covariates is to scale the quantiles of the base-line distribution. Solomon and Hutton have suggested that there is some robustness to misspecification of survival regression models. They showed that the relative importance of covariates is preserved under misspecification with assumptions of small coefficients and orthogonal transformation of covariates. We elucidate these results by applications to data from five trials which compare two common anti-epileptic drugs (carbamazepine versus sodium valporate monotherapy for epilepsy) and to survival of a cohort of people with cerebral palsy. Results on the robustness against model misspecification depend on the assumptions of small coefficients and on the underlying distribution of the data. These results hold in cerebral palsy but do not hold in epilepsy data which have early high hazard rates. The orthogonality of coefficients is not important. However, the choice of model is important for an estimation of the magnitude of effects, particularly if the base-line shape parameter indicates high initial hazard rates.     

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.