Assessing multiple endpoints with ordered alternatives

Nonparametric approaches to the analysis of multiple endpoints in clinical studies can be of particular value when the endpoints are heterogeneous or distributional assumptions are suspect. We describe a multivariate Terpstra-Jonckheere U-statistic for assessing multiple endpoints with ordered alternatives, and illustrate its use with data arising from a recent clinical study.     

CUSUM Hypothesis Tests and Alternative Response Probabilities for Finite Poisson Trials

This article develops a new cumulative sum statistic to identify aberrant behavior in a sequentially administered multiple-choice standardized examination. The examination responses can be described as finite Poisson trials, and the statistic can be used for other applications which fit this framework. The standardized examination setting uses a maximum likelihood estimate of examinee ability and an item response theory model. Aberrant and non aberrant probabilities are computed by an odds ratio analogous to risk adjusted CUSUM schemes. The significance level of a hypothesis test, where the null hypothesis is non-aberrant examinee behavior, is computed with Markov chains. A smoothing process is used to spread probabilities across the Markov states. The practicality of the approach to detect aberrant examinee behavior is demonstrated with results from both simulated and empirical data.     

A network algorithm for the exact treatment of the 2×k contingency table

A common statistical problem encountered in biomedical research is to test the hypothesis that the parameters of k binomial populations are all equal. An exact test of significance of this hypothesis is possible in principle, the appropriate null distribution being a normalized product of k binomial coefficients. However, the problem of computing the tail area of this distribution can be formidable since it requires the enumeration of all sets of k binomial coefficients whose product is less than a given constant. Existing algorithms, all of which rely on explicit enumeration to generate feasible binomial coefficients     

Issues in blinded sample size re-estimation

The utility of blinded sample size re-estimation for clinical trials depends on the ability to estimate variability without providing information about the true treatment difference, and on some reasonable assurance that the method is not likely to cause the sample size to be increased when the treatment effect is better than anticipated. We show that violations of these properties are unlikely to occur in practice.     

Probability computations for an extension of the geometric distribution

An extension of the stochastic process associated with the geometric distribution is presented. Combinatorial arguments are used to derive probabilities for various events of interest. Probabilities are approximated by evaluating truncated series. Bounds on the errors of approximation are developed. An example is presented and some additional applications are noted.     

Tables of the cramér-von mises distributions

Tables of the one- and two-sample unweighted Cramer-von Mises statistics are given, and compared with the limiting distribution. The two-sample statistic may be useful in (for example) clinical trials when a proportional hazards assumption (which leads to the use of the log-rank test) is unjustified: see, for example, Schumacher (1984). It is often possible to stop clinical trials early if the Cramer-von Mises test (rather than say, the log-rank test) is employed.     

A structured framework for assessing sensitivity to missing data assumptions in longitudinal clinical trials

The objective of this research was to demonstrate a framework for drawing inference from sensitivity analyses of incomplete longitudinal clinical trial data via a re‐analysis of data from a confirmatory clinical trial in depression. A likelihood‐based approach that assumed missing at random (MAR) was the primary analysis. Robustness to departure from MAR was assessed by comparing the primary result to those from a series of analyses that employed varying missing not at random (MNAR) assumptions (selection models, pattern mixture models and shared parameter models) and to MAR methods that used inclusive models. The key sensitivity analysis used multiple imputation assuming that after dropout the trajectory of drug‐treated patients was that of placebo treated patients with a similar outcome history (placebo multiple imputation). This result was used as the worst reasonable case to define the lower limit of plausible values for the treatment contrast. The endpoint contrast from the primary analysis was ? 2.79 (p = .013). In placebo multiple imputation, the result was ? 2.17. Results from the other sensitivity analyses ranged from ? 2.21 to ? 3.87 and were symmetrically distributed around the primary result. Hence, no clear evidence of bias from missing not at random data was found. In the worst reasonable case scenario, the treatment effect was 80% of the magnitude of the primary result. Therefore, it was concluded that a treatment effect existed. The structured sensitivity framework of using a worst reasonable case result based on a controlled imputation approach with transparent and debatable assumptions supplemented a series of plausible alternative models under varying assumptions was useful in this specific situation and holds promise as a generally useful framework. Copyright © 2012 John Wiley & Sons, Ltd.     

Robust inference from multiple test statistics via permutations: a better alternative to the single test statistic approach for randomized trials

Formal inference in randomized clinical trials is based on controlling the type I error rate associated with a single pre‐specified statistic. The deficiency of using just one method of analysis is that it depends on assumptions that may not be met. For robust inference, we propose pre‐specifying multiple test statistics and relying on the minimum p‐value for testing the null hypothesis of no treatment effect. The null hypothesis associated with the various test statistics is that the treatment groups are indistinguishable. The critical value for hypothesis testing comes from permutation distributions. Rejection of the null hypothesis when the smallest p‐value is less than the critical value controls the type I error rate at its designated value. Even if one of the candidate test statistics has low power, the adverse effect on the power of the minimum p‐value statistic is not much. Its use is illustrated with examples. We conclude that it is better to rely on the minimum p‐value rather than a single statistic particularly when that single statistic is the logrank test, because of the cost and complexity of many survival trials. Copyright © 2013 John Wiley & Sons, Ltd.     

Blinded sample size re-estimation in clinical trials comparing several treatments

An important question that arises in clinical trials is how many additional observations, if any, are required beyond those originally planned. This has satisfactorily been answered in the case of two-treatment double-blind clinical experiments. However, one may be interested in comparing a new treatment with its competitors, which may be more than one. This problem is addressed in this investigation involving responses from arbitrary distributions, in which the mean and the variance are not functionally related. First, a solution in determining the initial sample size for specified level of significance and power at a specified alternative is obtained. Then it is shown that when the initial sample size is large, the nominal level of significance and the power at the pre-specified alternative are fairly robust for the proposed sample size re-estimation procedure. An application of the results is made to the blood coagulation functionality problem considered by Kropf et al. [Multiple comparisons of treatments with stable multivariate tests in a two-stage adaptive design, including a test for non-inferiority, Biom. J. 42(8) (2000), pp. 951–965].     

Lower posterior death probabilities from a quick medical response in road traffic accidents

Introduction: We use data from Spain on roads and motorways traffic accidents in May 2004 to quantify the statistical association between quick medical response time and mortality rate. Method: Probit and logit parameters are estimated by a Bayesian method in which samples from the posterior densities are obtained through an MCMC simulation scheme. We provide posterior credible intervals and posterior partial effects of a quick medical response at several time levels over which we express our prior beliefs. Results: A reduction of 5 min, from a 25-min response-time level, is associated with lower posterior probabilities of death in roads and motorways accidents of 24% and 30%, respectively.