Statistical considerations in clinical trial design with event-free survival as the primary efficacy endpoint

In late-phase confirmatory clinical trials in the oncology field, time-to-event (TTE) endpoints are commonly used as primary endpoints for establishing the efficacy of investigational therapies. Among these TTE endpoints, overall survival (OS) is always considered as the gold standard. However, OS data can take years to mature, and its use for measurement of efficacy can be confounded by the use of post-treatment rescue therapies or supportive care. Therefore, to accelerate the development process and better characterize the treatment effect of new investigational therapies, other TTE endpoints such as progression-free survival and event-free survival (EFS) are applied as primary efficacy endpoints in some confirmatory trials, either as a surrogate for OS or as a direct measure of clinical benefits. For evaluating novel treatments for acute myeloid leukemia, EFS has been gradually recognized as a direct measure of clinical benefits. However, the application of an EFS endpoint is still controversial mainly due to the debate surrounding definition of treatment failure (TF) events. In this article, we investigate the EFS endpoint with the most conservative definition for the timing of TF, which is Day 1 since randomization. Specifically, the corresponding non-proportional hazard pattern of the EFS endpoint is investigated with both analytical and numerical approaches.     

Multivariate Approach for Comparative Evaluations of Customer Satisfaction with Application to Transport Services

In problems related to evaluations of products or services (e.g. in customer satisfaction analysis) the main difficulties concern the synthesis of the information, which is necessary for the presence of several evaluators and many response variables (aspects under evaluation). In this article, the problem of determining and comparing the satisfaction of different groups of customers, in the presence of multivariate response variables and using the results of pairwise comparisons is addressed. Within the framework of group ranking methods and multi criteria decision making theory, a new approach, based on nonparametric techniques, for evaluating group satisfaction in a multivariate framework is proposed and the concept of Multivariate Relative Satisfaction is defined. An application to the evaluation of public transport services, like the railway service and the urban bus service, by students of the University of Ferrara (Italy) is also discussed.     

Estimation of error probabilities in stochastic dominance

The process of using data to infer the existence of stochastic dominance is subject to sampling error. Kroll and Levy (1980), among others, have presented simulation results for several normal and lognormal distributions which show high error probabilities for a wide range of parameter values. This paper continues this line of research and uses simulation to estimate error probabilities. Distributions considered are a pair of normals and a pair of lognormals. Analysis of these distributions is made computationally feasible through theoretical results which reduce the number of parameters of the pair of distributions from four to two.     

A robust test for autocorrelation in the presence of a structural break in variance

It has been known that when there is a break in the variance (unconditional heteroskedasticity) of the error term in linear regression models, a routine application of the Lagrange multiplier (LM) test for autocorrelation can cause potentially significant size distortions. We propose a new test for autocorrelation that is robust in the presence of a break in variance. The proposed test is a modified LM test based on a generalized least squares regression. Monte Carlo simulations show that the new test performs well in finite samples and it is especially comparable to other existing heteroskedasticity-robust tests in terms of size, and much better in terms of power.     

A comparative study of confidence intervals for negative binomial proportion

In this paper, we investigate four existing and three new confidence interval estimators for the negative binomial proportion (i.e., proportion under inverse/negative binomial sampling). An extensive and systematic comparative study among these confidence interval estimators through Monte Carlo simulations is presented. The performance of these confidence intervals are evaluated in terms of their coverage probabilities and expected interval widths. Our simulation studies suggest that the confidence interval estimator based on saddlepoint approximation is more appealing for large coverage levels (e.g., nominal level≤1% ) whereas the score confidence interval estimator is more desirable for those commonly used coverage levels (e.g., nominal level>1% ). We illustrate these confidence interval construction methods with a real data set from a maternal congenital heart disease study.     

Numerical evaluation of tests based on different heteroskedasticity-consistent covariance matrix estimators

This article considers the issue of performing tests in linear heteroskedastic models when the test statistic employs a consistent variance estimator. Several different estimators are considered, namely: HC0, HC1, HC2, HC3, and their bias-adjusted versions. The numerical evaluation is performed using numerical integration methods; the Imhof algorithm is used to that end. The results show that bias-adjustment of variance estimators used to construct test statistics delivers more reliable tests when they are performed for the HC0 and HC1 estimators, but the same does not hold for the HC3 estimator. Overall, the most reliable test is the HC3-based one.     

A permutation alternative and other test procedures for spatially correlated data in one-way anova

Research in many disciplines involves data with spatially correlated observations. Spatial dependence violates the independent errors assumption required for techniques such as the standard one-way analysis of variance for a completely randomized design. The testing methodology within the correlated errors approach has not been investigated within a spatial context. For one-way fixed effects analysis of variance, a permutation test and tests associated with the correlated errors approach are investigated through simulation. No single test was superior with respect to both power and size but the standard Wald F test and a simple adjustment to it performed well overall.     

Adaptive designs for single‐arm phase II trials in oncology

Clinical phase II trials in oncology are conducted to determine whether the activity of a new anticancer treatment is promising enough to merit further investigation. Two‐stage designs are commonly used for this situation to allow for early termination. Designs proposed in the literature so far have the common drawback that the sample sizes for the two stages have to be specified in the protocol and have to be adhered to strictly during the course of the trial. As a consequence, designs that allow a higher extent of flexibility are desirable. In this article, we propose a new adaptive method that allows an arbitrary modification of the sample size of the second stage using the results of the interim analysis or external information while controlling the type I error rate. If the sample size is not changed during the trial, the proposed design shows very similar characteristics to the optimal two‐stage design proposed by Chang et al. (Biometrics 1987; 43:865–874). However, the new design allows the use of mid‐course information for the planning of the second stage, thus meeting practical requirements when performing clinical phase II trials in oncology. Copyright © 2012 John Wiley & Sons, Ltd.     

Truncation invariant copulas and a testing procedure

ABSTRACT

The class of bivariate copulas that are invariant under truncation with respect to one variable is considered. A simulation algorithm for the members of the class and a novel construction method are presented. Moreover, inspired by a stochastic interpretation of the members of such a class, a procedure is suggested to check whether the dependence structure of a given data set is truncation invariant. The overall performance of the procedure has been illustrated on both simulated and real data.     

邓小平社会主义核心价值观教育思想探析

以泰州某大跨度连续梁桥的静动载试验为例，建立ANSYS和桥梁博士模型进行静动力有限元数值计算。将试验结果与模型计算值进行比较，试验结果表明,该桥结构刚度和承载能力满足设计要求。