Data depth‐based nonparametric scale tests

Liu and Singh (1993, 2006) introduced a depth‐based d‐variate extension of the nonparametric two sample scale test of Siegel and Tukey (1960). Liu and Singh (2006) generalized this depth‐based test for scale homogeneity of k ≥ 2 multivariate populations. Motivated by the work of Gastwirth (1965), we propose k sample percentile modifications of Liu and Singh's proposals. The test statistic is shown to be asymptotically normal when k = 2, and compares favorably with Liu and Singh (2006) if the underlying distributions are either symmetric with light tails or asymmetric. In the case of skewed distributions considered in this paper the power of the proposed tests can attain twice the power of the Liu‐Singh test for d ≥ 1. Finally, in the k‐sample case, it is shown that the asymptotic distribution of the proposed percentile modified Kruskal‐Wallis type test is χ² with k ? 1 degrees of freedom. Power properties of this k‐sample test are similar to those for the proposed two sample one. The Canadian Journal of Statistics 39: 356–369; 2011 © 2011 Statistical Society of Canada     

A Semi‐parametric Transformation Frailty Model for Semi‐competing Risks Survival Data

In the analysis of semi‐competing risks data interest lies in estimation and inference with respect to a so‐called non‐terminal event, the observation of which is subject to a terminal event. Multi‐state models are commonly used to analyse such data, with covariate effects on the transition/intensity functions typically specified via the Cox model and dependence between the non‐terminal and terminal events specified, in part, by a unit‐specific shared frailty term. To ensure identifiability, the frailties are typically assumed to arise from a parametric distribution, specifically a Gamma distribution with mean 1.0 and variance, say, σ². When the frailty distribution is misspecified, however, the resulting estimator is not guaranteed to be consistent, with the extent of asymptotic bias depending on the discrepancy between the assumed and true frailty distributions. In this paper, we propose a novel class of transformation models for semi‐competing risks analysis that permit the non‐parametric specification of the frailty distribution. To ensure identifiability, the class restricts to parametric specifications of the transformation and the error distribution; the latter are flexible, however, and cover a broad range of possible specifications. We also derive the semi‐parametric efficient score under the complete data setting and propose a non‐parametric score imputation method to handle right censoring; consistency and asymptotic normality of the resulting estimators is derived and small‐sample operating characteristics evaluated via simulation. Although the proposed semi‐parametric transformation model and non‐parametric score imputation method are motivated by the analysis of semi‐competing risks data, they are broadly applicable to any analysis of multivariate time‐to‐event outcomes in which a unit‐specific shared frailty is used to account for correlation. Finally, the proposed model and estimation procedures are applied to a study of hospital readmission among patients diagnosed with pancreatic cancer.     

Reference‐based sensitivity analysis for time‐to‐event data

The analysis of time‐to‐event data typically makes the censoring at random assumption, ie, that—conditional on covariates in the model—the distribution of event times is the same, whether they are observed or unobserved (ie, right censored). When patients who remain in follow‐up stay on their assigned treatment, then analysis under this assumption broadly addresses the de jure, or “while on treatment strategy” estimand. In such cases, we may well wish to explore the robustness of our inference to more pragmatic, de facto or “treatment policy strategy,” assumptions about the behaviour of patients post‐censoring. This is particularly the case when censoring occurs because patients change, or revert, to the usual (ie, reference) standard of care. Recent work has shown how such questions can be addressed for trials with continuous outcome data and longitudinal follow‐up, using reference‐based multiple imputation. For example, patients in the active arm may have their missing data imputed assuming they reverted to the control (ie, reference) intervention on withdrawal. Reference‐based imputation has two advantages: (a) it avoids the user specifying numerous parameters describing the distribution of patients' postwithdrawal data and (b) it is, to a good approximation, information anchored, so that the proportion of information lost due to missing data under the primary analysis is held constant across the sensitivity analyses. In this article, we build on recent work in the survival context, proposing a class of reference‐based assumptions appropriate for time‐to‐event data. We report a simulation study exploring the extent to which the multiple imputation estimator (using Rubin's variance formula) is information anchored in this setting and then illustrate the approach by reanalysing data from a randomized trial, which compared medical therapy with angioplasty for patients presenting with angina.     

Large‐sample tests of extreme‐value dependence for multivariate copulas

Starting from the characterization of extreme‐value copulas based on max‐stability, large‐sample tests of extreme‐value dependence for multivariate copulas are studied. The two key ingredients of the proposed tests are the empirical copula of the data and a multiplier technique for obtaining approximate p‐values for the derived statistics. The asymptotic validity of the multiplier approach is established, and the finite‐sample performance of a large number of candidate test statistics is studied through extensive Monte Carlo experiments for data sets of dimension two to five. In the bivariate case, the rejection rates of the best versions of the tests are compared with those of the test of Ghoudi et al. (1998) recently revisited by Ben Ghorbal et al. (2009). The proposed procedures are illustrated on bivariate financial data and trivariate geological data. The Canadian Journal of Statistics 39: 703–720; 2011. © 2011 Statistical Society of Canada     

A linear transformation model for multivariate interval‐censored failure time data

This paper discusses multivariate interval‐censored failure time data observed when several correlated survival times of interest exist and only interval censoring is available for each survival time. Such data occur in many fields, for instance, studies of the development of physical symptoms or diseases in several organ systems. A marginal inference approach was used to create a linear transformation model and applied to bivariate interval‐censored data arising from a diabetic retinopathy study and an AIDS study. The results of simulation studies that were conducted to evaluate the performance of the presented approach suggest that it performs well. The Canadian Journal of Statistics 41: 275–290; 2013 © 2013 Statistical Society of Canada     

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     

Flexible modelling of simultaneously interval censored and truncated time‐to‐event data

This paper deals with the analysis of data from a HET‐CAM^VT experiment. From a statistical perspective, such data yield many challenges. First of all, the data are typically time‐to‐event like data, which are at the same time interval censored and right truncated. In addition, one has to cope with overdispersion as well as clustering. Traditional analysis approaches ignore overdispersion and clustering and summarize the data into a continuous score that can be analysed using simple linear models. In this paper, a novel combined frailty model is developed that simultaneously captures all of the aforementioned statistical challenges posed by the data. Copyright © 2015 John Wiley & Sons, Ltd.     

One‐Way anova for Functional Data via Globalizing the Pointwise F‐test

In this paper, we propose and study a new global test, namely, GPF test, for the one‐way anova problem for functional data, obtained via globalizing the usual pointwise F‐test. The asymptotic random expressions of the test statistic are derived, and its asymptotic power is investigated. The GPF test is shown to be root‐n consistent. It is much less computationally intensive than a parametric bootstrap test proposed in the literature for the one‐way anova for functional data. Via some simulation studies, it is found that in terms of size‐controlling and power, the GPF test is comparable with two existing tests adopted for the one‐way anova problem for functional data. A real data example illustrates the GPF test.     

Log‐rank permutation tests for trend: saddlepoint p‐values and survival rate confidence intervals

Suppose p + 1 experimental groups correspond to increasing dose levels of a treatment and all groups are subject to right censoring. In such instances, permutation tests for trend can be performed based on statistics derived from the weighted log‐rank class. This article uses saddlepoint methods to determine the mid‐P‐values for such permutation tests for any test statistic in the weighted log‐rank class. Permutation simulations are replaced by analytical saddlepoint computations which provide extremely accurate mid‐P‐values that are exact for most practical purposes and almost always more accurate than normal approximations. The speed of mid‐P‐value computation allows for the inversion of such tests to determine confidence intervals for the percentage increase in mean (or median) survival time per unit increase in dosage. The Canadian Journal of Statistics 37: 5‐16; 2009 © 2009 Statistical Society of Canada     

Goodness‐of‐fit testing based on a weighted bootstrap: A fast large‐sample alternative to the parametric bootstrap

The process comparing the empirical cumulative distribution function of the sample with a parametric estimate of the cumulative distribution function is known as the empirical process with estimated parameters and has been extensively employed in the literature for goodness‐of‐fit testing. The simplest way to carry out such goodness‐of‐fit tests, especially in a multivariate setting, is to use a parametric bootstrap. Although very easy to implement, the parametric bootstrap can become very computationally expensive as the sample size, the number of parameters, or the dimension of the data increase. An alternative resampling technique based on a fast weighted bootstrap is proposed in this paper, and is studied both theoretically and empirically. The outcome of this work is a generic and computationally efficient multiplier goodness‐of‐fit procedure that can be used as a large‐sample alternative to the parametric bootstrap. In order to approximately determine how large the sample size needs to be for the parametric and weighted bootstraps to have roughly equivalent powers, extensive Monte Carlo experiments are carried out in dimension one, two and three, and for models containing up to nine parameters. The computational gains resulting from the use of the proposed multiplier goodness‐of‐fit procedure are illustrated on trivariate financial data. A by‐product of this work is a fast large‐sample goodness‐of‐fit procedure for the bivariate and trivariate t distribution whose degrees of freedom are fixed. The Canadian Journal of Statistics 40: 480–500; 2012 © 2012 Statistical Society of Canada     

Location‐invariant Multi‐sample U‐tests for Covariance Matrices with Large Dimension

For two or more multivariate distributions with common covariance matrix, test statistics for certain special structures of the common covariance matrix are presented when the dimension of the multivariate vectors may exceed the number of such vectors. The test statistics are constructed as functions of location‐invariant estimators defined as U‐statistics, and the corresponding asymptotic theory is used to derive the limiting distributions of the proposed tests. The properties of the test statistics are established under mild and practical assumptions, and the same are numerically demonstrated using simulation results with small or moderate sample sizes and large dimensions.     

Restricted mean survival time as a summary measure of time‐to‐event outcome

Many clinical research studies evaluate a time‐to‐event outcome, illustrate survival functions, and conventionally report estimated hazard ratios to express the magnitude of the treatment effect when comparing between groups. However, it may not be straightforward to interpret the hazard ratio clinically and statistically when the proportional hazards assumption is invalid. In some recent papers published in clinical journals, the use of restricted mean survival time (RMST) or τ ‐year mean survival time is discussed as one of the alternative summary measures for the time‐to‐event outcome. The RMST is defined as the expected value of time to event limited to a specific time point corresponding to the area under the survival curve up to the specific time point. This article summarizes the necessary information to conduct statistical analysis using the RMST, including the definition and statistical properties of the RMST, adjusted analysis methods, sample size calculation, information fraction for the RMST difference, and clinical and statistical meaning and interpretation. Additionally, we discuss how to set the specific time point to define the RMST from two main points of view. We also provide developed SAS codes to determine the sample size required to detect an expected RMST difference with appropriate power and reconstruct individual survival data to estimate an RMST reference value from a reported survival curve.     

Data Dependent Cells Chi‐Square Test With Recurrent Events

We consider a recurrent event wherein the inter‐event times are independent and identically distributed with a common absolutely continuous distribution function F. In this article, interest is in the problem of testing the null hypothesis that F belongs to some parametric family where the q‐dimensional parameter is unknown. We propose a general Chi‐squared test in which cell boundaries are data dependent. An estimator of the parameter obtained by minimizing a quadratic form resulting from a properly scaled vector of differences between Observed and Expected frequencies is used to construct the test. This estimator is known as the minimum chi‐square estimator. Large sample properties of the proposed test statistic are established using empirical processes tools. A simulation study is conducted to assess the performance of the test under parameter misspecification, and our procedures are applied to a fleet of Boeing 720 jet planes' air conditioning system failures.     

On a new goodness‐of‐fit process for families of copulas

A goodness‐of‐fit procedure is proposed for parametric families of copulas. The new test statistics are functionals of an empirical process based on the theoretical and sample versions of Spearman's dependence function. Conditions under which this empirical process converges weakly are seen to hold for many families including the Gaussian, Frank, and generalized Farlie–Gumbel–Morgenstern systems of distributions, as well as the models with singular components described by Durante [Durante ( 2007 ) Comptes Rendus Mathématique. Académie des Sciences. Paris, 344, 195–198]. Thanks to a parametric bootstrap method that allows to compute valid P‐values, it is shown empirically that tests based on Cramér–von Mises distances keep their size under the null hypothesis. Simulations attesting the power of the newly proposed tests, comparisons with competing procedures and complete analyses of real hydrological and financial data sets are presented. The Canadian Journal of Statistics 37: 80‐101; 2009 © 2009 Statistical Society of Canada     

A weighted log-rank test and associated effect estimator for cancer trials with delayed treatment effect

The standard log-rank test has been extended by adopting various weight functions. Cancer vaccine or immunotherapy trials have shown a delayed onset of effect for the experimental therapy. This is manifested as a delayed separation of the survival curves. This work proposes new weighted log-rank tests to account for such delay. The weight function is motivated by the time-varying hazard ratio between the experimental and the control therapies. We implement a numerical evaluation of the Schoenfeld approximation (NESA) for the mean of the test statistic. The NESA enables us to assess the power and to calculate the sample size for detecting such delayed treatment effect and also for a more general specification of the non-proportional hazards in a trial. We further show a connection between our proposed test and the weighted Cox regression. Then the average hazard ratio using the same weight is obtained as an estimand of the treatment effect. Extensive simulation studies are conducted to compare the performance of the proposed tests with the standard log-rank test and to assess their robustness to model mis-specifications. Our tests outperform the G^ρ,γ class in general and have performance close to the optimal test. We demonstrate our methods on two cancer immunotherapy trials.     

Two‐stage phase II survival trial design

Recently, molecularly targeted agents and immunotherapy have been advanced for the treatment of relapse or refractory cancer patients, where disease progression‐free survival or event‐free survival is often a primary endpoint for the trial design. However, methods to evaluate two‐stage single‐arm phase II trials with a time‐to‐event endpoint are currently processed under an exponential distribution, which limits application of real trial designs. In this paper, we developed an optimal two‐stage design, which is applied to the four commonly used parametric survival distributions. The proposed method has advantages compared with existing methods in that the choice of underlying survival model is more flexible and the power of the study is more adequately addressed. Therefore, the proposed two‐stage design can be routinely used for single‐arm phase II trial designs with a time‐to‐event endpoint as a complement to the commonly used Simon's two‐stage design for the binary outcome.     

Goodness‐of‐fit Test for Directional Data

In this paper, we study the problem of testing the hypothesis on whether the density f of a random variable on a sphere belongs to a given parametric class of densities. We propose two test statistics based on the L² and L¹ distances between a non‐parametric density estimator adapted to circular data and a smoothed version of the specified density. The asymptotic distribution of the L² test statistic is provided under the null hypothesis and contiguous alternatives. We also consider a bootstrap method to approximate the distribution of both test statistics. Through a simulation study, we explore the moderate sample performance of the proposed tests under the null hypothesis and under different alternatives. Finally, the procedure is illustrated by analysing a real data set based on wind direction measurements.     

Implications of random cut‐points theory for the Mann‐Whitney and binomial tests

Through random cut‐points theory, the author extends inference for ordered categorical data to the unspecified continuum underlying the ordered categories. He shows that a random cut‐point Mann‐Whitney test yields slightly smaller p‐values than the conventional test for most data. However, when at least P% of the data lie in one of the k categories (with P = 80 for k = 2, P = 67 for k = 3,…, P = 18 for k = 30), he also shows that the conventional test can yield much smaller p‐values, and hence misleadingly liberal inference for the underlying continuum. The author derives formulas for exact tests; for k = 2, the Mann‐Whitney test is but a binomial test.     

Subgroup Analysis with Time‐to‐Event Data Under a Logistic‐Cox Mixture Model

Subgroup detection has received increasing attention recently in different fields such as clinical trials, public management and market segmentation analysis. In these fields, people often face time‐to‐event data, which are commonly subject to right censoring. This paper proposes a semiparametric Logistic‐Cox mixture model for subgroup analysis when the interested outcome is event time with right censoring. The proposed method mainly consists of a likelihood ratio‐based testing procedure for testing the existence of subgroups. The expectation–maximization iteration is applied to improve the testing power, and a model‐based bootstrap approach is developed to implement the testing procedure. When there exist subgroups, one can also use the proposed model to estimate the subgroup effect and construct predictive scores for the subgroup membership. The large sample properties of the proposed method are studied. The finite sample performance of the proposed method is assessed by simulation studies. A real data example is also provided for illustration.     

Goodness‐of‐fit tests for the hyperbolic distribution

The authors give tests of fit for the hyperbolic distribution, based on the Cramér‐von Mises statistic W². They consider the general case with four parameters unknown, and some specific cases where one or two parameters are fixed. They give two examples using stock price data.