Step-up procedures for non-inferiority tests with multiple experimental treatments.

Non-inferiority (NI) trials are becoming more popular. The NI of a new treatment compared with a standard treatment is established when the new treatment maintains a substantial fraction of the treatment effect of the standard treatment. A valid NI trial is also required to show assay sensitivity, the demonstration of the standard treatment having the expected effect with a size comparable to those reported in previous placebo-controlled studies. A three-arm NI trial is a clinical study that includes a new treatment, a standard treatment and a placebo. Most of the statistical methods developed for three-arm NI trials are designed for the existence of only one new treatment. Recently, a single-step procedure was developed to deal with NI trials with multiple new treatments with the overall familywise error rate controlled at a specified level. In this article, we extend the single-step procedure to two new step-up procedures for NI trials with multiple new treatments. A comparative study of test power shows that both proposed step-up procedures provide a significant improvement of power when compared to the single-step procedure. One of the two proposed step-up procedures also allows the flexibility of allocating different error rates between the sensitivity hypothesis and the NI hypotheses so that the assignment of fewer patients to the placebo becomes possible when designing NI trials. We illustrate the new procedures using data from a clinical trial.

Recursive confidence band construction for an unknown distribution function.

Given a sample X1,...,Xn of independent observations from an unknown continuous distribution function F, the problem of constructing a confidence band for F is considered, which is a fundamental problem in statistical inference. This confidence band provides simultaneous inferences on all quantiles and also on all of the cumulative probabilities of the distribution, and so they are among the most important inference procedures that address the issue of multiplicity. A fully nonparametric approach is taken where no assumptions are made about the distribution function F. Historical approaches to this problem, such as Kolmogorov's famous () procedure, represent some of the earliest inference methodologies that address the issue of multiplicity. This is because a confidence band at a given confidence level 1-α allows inferences on all of the quantiles of the distribution, and also on all of the cumulative probabilities, at that specified confidence level. In this paper it is shown how recursive methodologies can be employed to construct both one-sided and two-sided confidence bands of various types. The first approach operates by putting bounds on the cumulative probabilities at the data points, and a recursive integration approach is described. The second approach operates by providing bounds on certain specified quantiles of the distribution, and its implementation using recursive summations of multinomial probabilities is described. These recursive methodologies are illustrated with examples, and R code is available for their implementation.

Normal probability plots with confidence.

Normal probability plots are widely used as a statistical tool for assessing whether an observed simple random sample is drawn from a normally distributed population. The users, however, have to judge subjectively, if no objective rule is provided, whether the plotted points fall close to a straight line. In this paper, we focus on how a normal probability plot can be augmented by intervals for all the points so that, if the population distribution is normal, then all the points should fall into the corresponding intervals simultaneously with probability 1-α. These simultaneous 1-α probability intervals provide therefore an objective mean to judge whether the plotted points fall close to the straight line: the plotted points fall close to the straight line if and only if all the points fall into the corresponding intervals. The powers of several normal probability plot based (graphical) tests and the most popular nongraphical Anderson-Darling and Shapiro-Wilk tests are compared by simulation. Based on this comparison, recommendations are given in Section 3 on which graphical tests should be used in what circumstances. An example is provided to illustrate the methods.

Simultaneous inference for several quantiles of a normal population with applications.

A common statistical problem is to make inference about the mean of a normally distributed population. While the mean and the variance are important quantities, many real problems require information on certain quantiles of the population which combine both the mean and variance. Motivated by two recent applications, we consider simultaneous inference for more than one quantile of interest. In this paper, a set of exact 1-α level simultaneous confidence intervals for several quantiles of a normally distributed population is constructed, based on a simple random sample from that population. The critical constants for achieving an exact 1-α simultaneous coverage probability can be computed efficiently using numerical quadrature involving only a one-dimensional integral combined with standard search algorithms. The proposed methods are illustrated with an example. Several further research problems are identified.

Extension of three-arm non-inferiority studies to trials with multiple new treatments.

Non-inferiority (NI) trials are becoming increasingly popular. The main purpose of NI trials is to assert the efficacy of a new treatment compared with an active control by demonstrating that the new treatment maintains a substantial fraction of the treatment effect of the control. Most of the statistical testing procedures in this area have been developed for three-arm NI trials in which a new treatment is compared with an active control in the presence of a placebo. However, NI trials frequently involve comparisons of several new treatments with a control, such as in studies involving different doses of a new drug or different combinations of several new drugs. In seeking an adequate testing procedure for such cases, we use a new approach that modifies existing testing procedures to cover circumstances in which several new treatments are present. We also give methods and algorithms to produce the optimal sample size configuration. In addition, we also discuss the advantages of using different margins for the assay sensitivity test between the active control and the placebo and the NI test between the new treatments and the active control. We illustrate the new approach by using data from a clinical trial.

Operability region equivalence: simultaneous confidence bands for the equivalence of two regression models over restricted regions.

In many scientific problems the purpose of comparing two linear regression models is to demonstrate that they have only negligible differences and so can be regarded as being practically equivalent. The frequently used statistical approach of testing the homogeneity null hypothesis of the two models by using a partial F test is not appropriate for this purpose. In this paper, a simultaneous confidence band is proposed which provides an upper bound on the largest possible difference between the two models, in units of the standard error of the observations, over a given region of the covariates. This is demonstrated to be a more practical method for assessing the equivalence of the two regression models.