Rank Tests for Matched Survival Data

In a clinical trial with the time to an event as the outcome of interest, we may randomize a number of matched subjects, such as litters, to different treatments. The number of treatments equals the number of subjects per litter, two in the case of twins. In this case, the survival times of matched subjects could be dependent. Although the standard rank tests, such as the logrank and Wilcoxon tests, for independent samples may be used to test the equality of marginal survival distributions, their standard error should be modified to accommodate the possible dependence of survival times between matched subjects. In this paper we propose a method of calculating the standard error of the rank tests for paired two-sample survival data. The method is naturally extended to that for K-sample tests under dependence.     

Simple nonparametric tests for a known standard survival based on censored data

It is often of interest in survival analysis to test whether the distribution of lifetimes from which the sample under study was derived is the same as a reference distribution. The latter can be specified on the basis of previous studies or on subject matter considerations. In this paper several tests are developed for the above hypothesis, suitable for right-censored observations. The tests are based on modifications of Moses' one-sample limits of some classical two-sample rank tests. The asymptotic distributions of the test statistics are derived, consistency is established for alternatives which are stochastically ordered with respect to the null, and Pitman asymptotic efficiencies are calculated relative to competing tests. Simulated power comparisons are reported. An example is given with data on the survival times of lung cancer patients.     

Asymptotic separability in sensitivity analysis

In an observational study in which each treated subject is matched to several untreated controls by using observed pretreatment covariates, a sensitivity analysis asks how hidden biases due to unobserved covariates might alter the conclusions. The bounds required for a sensitivity analysis are the solution to an optimization problem. In general, this optimization problem is not separable, in the sense that one cannot find the needed optimum by performing a separate optimization in each matched set and combining the results. We show, however, that this optimization problem is asymptotically separable, so that when there are many matched sets a separate optimization may be performed in each matched set and the results combined to yield the correct optimum with negligible error. This is true when the Wilcoxon rank sum test or the Hodges-Lehmann aligned rank test is applied in matching with multiple controls. Numerical calculations show that the asymptotic approximation performs well with as few as 10 matched sets. In the case of the rank sum test, a table is given containing the separable solution. With this table, only simple arithmetic is required to conduct the sensitivity analysis. The method also supplies estimates, such as the Hodges-Lehmann estimate, and confidence intervals associated with rank tests. The method is illustrated in a study of dropping out of US high schools and the effects on cognitive test scores.     

Linear rank tests for censored survival data

We describe a class of rank test procedures for the two-sample problem with right censored survival data. The class of tests is directly generalized from the linear rank tests by assigning each observation a rank according to its corresponding Wilcoxon scores. It allows a flexible choice of score functions, in particular, those powerful against scale differences between the two survival distributions. Monte Carlo simulations have shown that some members of this class have great power in detecting crossing-curve alternatives (alternatives where underlying survival curves cross over). The class also contains tests essentially equivalent to the Gehan-Wilcoxon and the logrank tests.     

A new method for the comparison of survival distributions

The assessment of overall homogeneity of time‐to‐event curves is a key element in survival analysis in biomedical research. The currently commonly used testing methods, e.g. log‐rank test, Wilcoxon test, and Kolmogorov–Smirnov test, may have a significant loss of statistical testing power under certain circumstances. In this paper we propose a new testing method that is robust for the comparison of the overall homogeneity of survival curves based on the absolute difference of the area under the survival curves using normal approximation by Greenwood's formula. Monte Carlo simulations are conducted to investigate the performance of the new testing method compared against the log‐rank, Wilcoxon, and Kolmogorov–Smirnov tests under a variety of circumstances. The proposed new method has robust performance with greater power to detect the overall differences than the log‐rank, Wilcoxon, and Kolmogorov–Smirnov tests in many scenarios in the simulations. Furthermore, the applicability of the new testing approach is illustrated in a real data example from a kidney dialysis trial. Copyright © 2009 John Wiley & Sons, Ltd.     

Comparison of unweighted and weighted rank based tests for an ordered alternative in randomized complete block designs

In randomized complete block designs, a monotonic relationship among treatment groups may already be established from prior information, e.g., a study with different dose levels of a drug. The test statistic developed by Page and another from Jonckheere and Terpstra are two unweighted rank based tests used to detect ordered alternatives when the assumptions in the traditional two-way analysis of variance are not satisfied. We consider a new weighted rank based test by utilizing a weight for each subject based on the sample variance in computing the new test statistic. The new weighted rank based test is compared with the two commonly used unweighted tests with regard to power under various conditions. The weighted test is generally more powerful than the two unweighted tests when the number of treatment groups is small to moderate.     

Linear signed rank tests for hultivariate location

Previously proposed linear signed rank tests for multivariate location are not invariant under linear transformations of the observations, The asymptotic relative efficiencies of the tests 2 with respect to Hotelling's T²test depend on the direction of shift and the covariance matrix of the alternative distributions. For distributions with highly correlated components, the efficiencies of some of these tests can be arbitrarily low; they approach zero for certain multivariate normal alternatives, This article proposes a transformation of the data to be performed prior to standard linear signed rank tests, The resulting procedures have attractive power and efficiency properties compared to the original tests, In particular, for elliptically symmetric contiguous alternafives, the efficiencies of the new tests equal those of corresponding univariate linear signed rank tests with respect to the t test.     

Empirical likelihood method for the multivariate accelerated failure time models

In applications, multivariate failure time data appears when each study subject may potentially experience several types of failures or recurrences of a certain phenomenon, or failure times may be clustered. Three types of marginal accelerated failure time models dealing with multiple events data, recurrent events data and clustered events data are considered. We propose a unified empirical likelihood inferential procedure for the three types of models based on rank estimation method. The resulting log-empirical likelihood ratios are shown to possess chi-squared limiting distributions. The properties can be applied to do tests and construct confidence regions without the need to solve the rank estimating equations nor to estimate the limiting variance-covariance matrices. The related computation is easy to implement. The proposed method is illustrated by extensive simulation studies and a real example.     

Nonparametric analysis of treatment effects with missing observations

This paper develops a test for comparing treatment effects when observations are missing at random for repeated measures data on independent subjects. It is assumed that missingness at any occasion follows a Bernoulli distribution. It is shown that the distribution of the vector of linear rank statistics depends on the unknown parameters of the probability law that governs missingness, which is absent in the existing conditional methods employing rank statistics. This dependence is through the variance–covariance matrix of the vector of linear ranks. The test statistic is a quadratic form in the linear rank statistics when the variance–covariance matrix is estimated. The limiting distribution of the test statistic is derived under the null hypothesis. Several methods of estimating the unknown components of the variance–covariance matrix are considered. The estimate that produces stable empirical Type I error rate while maintaining the highest power among the competing tests is recommended for implementation in practice. Simulation studies are also presented to show the advantage of the proposed test over other rank-based tests that do not account for the randomness in the missing data pattern. Our method is shown to have the highest power while also maintaining near-nominal Type I error rates. Our results clearly illustrate that even for an ignorable missingness mechanism, the randomness in the pattern of missingness cannot be ignored. A real data example is presented to highlight the effectiveness of the proposed method.     

Generalized Mann–Whitney Type Tests for Microarray Experiments

New statistical procedures are introduced to analyse typical microRNA expression data sets. For each separate microRNA expression, the null hypothesis to be tested is that there is no difference between the distributions of the expression in different groups. The test statistics are then constructed having certain type of alternatives in mind. To avoid strong (parametric) distributional assumptions, the alternatives are formulated using probabilities of different orders of pairs or triples of observations coming from different groups, and the test statistics are then constructed using corresponding several‐sample U‐statistics, natural estimates of these probabilities. Classical several‐sample rank test statistics, such as the Kruskal–Wallis and Jonckheere–Terpstra tests, are special cases in our approach. Also, as the number of variables (microRNAs) is huge, we confront a serious simultaneous testing problem. Different approaches to control the family‐wise error rate or the false discovery rate are shortly discussed, and it is shown how the Chen–Stein theorem can be used to show that family‐wise error rate can be controlled for cluster‐dependent microRNAs under weak assumptions. The theory is illustrated with an analysis of real data, a microRNA expression data set on Finnish (aggressive and non‐aggressive) prostate cancer patients and their controls.     

Multivariate two‐sample permutation tests for trials with multiple time‐to‐event outcomes

Clinical trials involving multiple time‐to‐event outcomes are increasingly common. In this paper, permutation tests for testing for group differences in multivariate time‐to‐event data are proposed. Unlike other two‐sample tests for multivariate survival data, the proposed tests attain the nominal type I error rate. A simulation study shows that the proposed tests outperform their competitors when the degree of censored observations is sufficiently high. When the degree of censoring is low, it is seen that naive tests such as Hotelling's T² outperform tests tailored to survival data. Computational and practical aspects of the proposed tests are discussed, and their use is illustrated by analyses of three publicly available datasets. Implementations of the proposed tests are available in an accompanying R package.     

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.     

A fast Monte Carlo expectation–maximization algorithm for estimation in latent class model analysis with an application to assess diagnostic accuracy for cervical neoplasia in women with atypical glandular cells

In this article, we use a latent class model (LCM) with prevalence modeled as a function of covariates to assess diagnostic test accuracy in situations where the true disease status is not observed, but observations on three or more conditionally independent diagnostic tests are available. A fast Monte Carlo expectation–maximization (MCEM) algorithm with binary (disease) diagnostic data is implemented to estimate parameters of interest; namely, sensitivity, specificity, and prevalence of the disease as a function of covariates. To obtain standard errors for confidence interval construction of estimated parameters, the missing information principle is applied to adjust information matrix estimates. We compare the adjusted information matrix-based standard error estimates with the bootstrap standard error estimates both obtained using the fast MCEM algorithm through an extensive Monte Carlo study. Simulation demonstrates that the adjusted information matrix approach estimates the standard error similarly with the bootstrap methods under certain scenarios. The bootstrap percentile intervals have satisfactory coverage probabilities. We then apply the LCM analysis to a real data set of 122 subjects from a Gynecologic Oncology Group study of significant cervical lesion diagnosis in women with atypical glandular cells of undetermined significance to compare the diagnostic accuracy of a histology-based evaluation, a carbonic anhydrase-IX biomarker-based test and a human papillomavirus DNA test.     

A generalized Fleming and Harrington's class of tests for interval‐censored data

The class $G^{\rho,\lambda }$ of weighted log‐rank tests proposed by Fleming & Harrington [Fleming & Harrington (1991) Counting Processes and Survival Analysis, Wiley, New York] has been widely used in survival analysis and is nowadays, unquestionably, the established method to compare, nonparametrically, k different survival functions based on right‐censored survival data. This paper extends the $G^{\rho,\lambda }$ class to interval‐censored data. First we introduce a new general class of rank based tests, then we show the analogy to the above proposal of Fleming & Harrington. The asymptotic behaviour of the proposed tests is derived using an observed Fisher information approach and a permutation approach. Aiming to make this family of tests interpretable and useful for practitioners, we explain how to interpret different choices of weights and we apply it to data from a cohort of intravenous drug users at risk for HIV infection. The Canadian Journal of Statistics 40: 501–516; 2012 © 2012 Statistical Society of Canada     

A unified sequential test procedure for simultaneous testing the equality of several binomial proportions to a specified standard

In this article, we propose a unified sequentially rejective test procedure for testing simultaneously the equality of several independent binomial proportions to a specified standard. The proposed test procedure is general enough to include some well-known multiple testing procedures such as the Ordinary Bonferroni procedure, Hochberg procedure and Rom procedure. It involves multiple tests of significance based on the simple binomial tests (exact or approximate) which can be easily found in many elementary standard statistics textbooks. Unlike the traditional Chi-square test of the overall hypothesis, the procedure can identify the subset of the binomial proportions, which are different from the prespecified standard with the control of the familywise type I error rate. Moreover, the power computation of the procedure is provided and the procedure is illustrated by two real examples from an ecological study and a carcinogenicity study.     

A nonparametric test for current status data with unequal censoring

Nonparametric tests for the comparison of different treatments based on current status data are proposed. For this problem, most methods proposed in the literature require that observation times on all subjects follow the same distribution. In other words, censoring distributions are identical between the treatment groups. In this paper, we focus on the situation where the censoring distributions may be different for subjects in different treatment groups and the test that can take this unequal censoring into account is given. The asymptotic distribution of the test proposed is derived. The method proposed is applied to data arising from a tumorigenicity experiment.     

Adjusted variable plots for Cox's proportional hazards regression model

Adjusted variable plots are useful in linear regression for outlier detection and for qualitative evaluation of the fit of a model. In this paper, we extend adjusted variable plots to Cox's proportional hazards model for possibly censored survival data. We propose three different plots: a risk level adjusted variable (RLAV) plot in which each observation in each risk set appears, a subject level adjusted variable (SLAV) plot in which each subject is represented by one point, and an event level adjusted variable (ELAV) plot in which the entire risk set at each failure event is represented by a single point. The latter two plots are derived from the RLAV by combining multiple points. In each point, the regression coefficient and standard error from a Cox proportional hazards regression is obtained by a simple linear regression through the origin fit to the coordinates of the pictured points. The plots are illustrated with a reanalysis of a dataset of 65 patients with multiple myeloma.     

Saddlepoint p-values for a class of tests for comparing competing risks with censored data

One of the general problems in clinical trials and mortality rates is the comparison of competing risks. Most of the test statistics used for independent and dependent risks with censored data belong to the class of weighted linear rank tests in its multivariate version. In this paper, we introduce the saddlepoint approximations as accurate and fast approximations for the exact p-values of this class of tests instead of the asymptotic and permutation simulated calculations. Real data examples and extensive simulation studies showed the accuracy and stability performance of the saddlepoint approximations over different scenarios of lifetime distributions, sample sizes and censoring.     

Sliced inverse regression for survival data

We apply the univariate sliced inverse regression to survival data. Our approach is different from the other papers on this subject. The right-censored observations are taken into account during the slicing of the survival times by assigning each of them with equal weight to all of the slices with longer survival. We test this method with different distributions for the two main survival data models, the accelerated lifetime model and Cox’s proportional hazards model. In both cases and under different conditions of sparsity, sample size and dimension of parameters, this non-parametric approach finds the data structure and can be viewed as a variable selector.     

Sample Size Calculation for Rank Tests Comparing K Survival Distributions

Rank tests, such as logrank or Wilcoxon rank sum tests, have been popularly used to compare survival distributions of two or more groups in the presence of right censoring. However, there has been little research on sample size calculation methods for rank tests to compare more than two groups. An existing method is based on a crude approximation, which tends to underestimate sample size, i.e., the calculated sample size has lower power than projected. In this paper we propose an asymptotically correct method and an approximate method for sample size calculation. The proposed methods are compared to other methods through simulation studies.