Bringing game theory to hypothesis testing: Establishing finite sample bounds on inference

Small sample properties are of fundamental interest when only limited data is avail- able. Exact inference is limited by constraints imposed by speci.c nonrandomized tests and of course also by lack of more data. These e¤ects can be separated as we propose to evaluate a test by comparing its type II error to the minimal type II error among all tests for the given sample. Game theory is used to establish this minimal type II error, the associated randomized test is characterized as part of a Nash equilibrium of a .ctitious game against nature. We use this method to investigate sequential tests for the di¤erence between two means when outcomes are constrained to belong to a given bounded set. Tests of inequality and of noninferiority are included. We .nd that inference in terms of type II error based on a balanced sample cannot be improved by sequential sampling or even by observing counter factual evidence providing there is a reasonable gap between the hypotheses.Exact, distribution-free, nonparametric, independent samples, matched pairs, Z test, unavoidable type II error, noninferiority, LeeX

Classification accuracy comparison: hypothesis tests and the use of confidence intervals in evaluations of difference, equivalence and non-inferiority

The comparison of classification accuracy statements has generally been based upon tests of difference or inequality when other scenarios and approaches may be more appropriate. Procedures for evaluating two scenarios with interest focused on the similarity in accuracy values, non-inferiority and equivalence, are outlined following a discussion of tests of difference (inequality). It is also suggested that the confidence interval of the difference in classification accuracy may be used as well as or instead of conventional hypothesis testing to reveal more information about the disparity in the classification accuracy values compared

Testing for equivalence: an intersection-union permutation solution

The notion of testing for equivalence of two treatments is widely used in clinical trials, pharmaceutical experiments,bioequivalence and quality control. It is essentially approached within the intersection-union (IU) principle. According to this principle the null hypothesis is stated as the set of effects lying outside a suitably established interval and the alternative as the set of effects lying inside that interval. The solutions provided in the literature are mostly based on likelihood techniques, which in turn are rather difficult to handle, except for cases lying within the regular exponential family and the invariance principle. The main goal of present paper is to go beyond most of the limitations of likelihood based methods, i.e. to work in a nonparametric setting within the permutation frame. To obtain practical solutions, a new IU permutation test is presented and discussed. A simple simulation study for evaluating its main properties, and three application examples are also presented.Comment: 21 pages, 2 figure

Comparison of serious inhaler technique errors made by device-naïve patients using three different dry powder inhalers: a randomised, crossover, open-label study

Background: Serious inhaler technique errors can impair drug delivery to the lungs. This randomised, crossover, open-label study evaluated the proportion of patients making predefined serious errors with Pulmojet compared with Diskus and Turbohaler dry powder inhalers. Methods: Patients ≥18 years old with asthma and/or COPD who were current users of an inhaler but naïve to the study devices were assigned to inhaler technique assessment on Pulmojet and either Diskus or Turbohaler in a randomised order. Patients inhaled through empty devices after reading the patient information leaflet. If serious errors potentially affecting dose delivery were recorded, they repeated the inhalations after watching a training video. Inhaler technique was assessed by a trained nurse observer and an electronic inhalation profile recorder. Results: Baseline patient characteristics were similar between randomisation arms for the Pulmojet-Diskus (n = 277) and Pulmojet-Turbohaler (n = 144) comparisons. Non-inferiority in the proportions of patients recording no nurse-observed serious errors was demonstrated for both Pulmojet versus Diskus, and Pulmojet versus Turbohaler; therefore, superiority was tested. Patients were significantly less likely to make ≥1 nurse-observed serious errors using Pulmojet compared with Diskus (odds ratio, 0.31; 95 % CI, 0.19–0.51) or Pulmojet compared with Turbohaler (0.23; 0.12–0.44) after reading the patient information leaflet with additional video instruction, if required. Conclusions These results suggest Pulmojet is easier to learn to use correctly than the Turbohaler or Diskus for current inhaler users switching to a new dry powder inhaler

Modified World Health Organization Hand Rub Formulations Comply with European Efficacy Requirements for Preoperative Surgical Hand Preparations

Background. The World Health Organization (WHO) has published "Guidelines on Hand Hygiene in Health Care” recommending 2 hand rub formulations based on 80% vol/vol ethanol or 75% vol/vol isopropanol for local production in healthcare settings where commercial products are not available or are too expensive. Previous investigations have shown that neither formulation meets the efficacy requirements of European norm (EN) 12791, which is the most stringent available norm for surgical hand rub preparations. Even when modified with approximately 5% higher alcohol content, the formulations proved to be inferior to the reference of the norm when measured after 3 hours. Objective. Because the high glycerol content of the formulations was suspected to negatively influence their efficacy, additional investigations were performed with varying glycerol content. Methods. Modified formulations with higher alcohol concentration (mass instead of volume percentage) and lower glycerol concentration (0.725% instead of 1.45%) or without the addition of glycerol were evaluated for their conformity with the efficacy requirements of EN 12791, which demands noninferiority in comparison with a reference hand antisepsis procedure immediately and 3 hours after treatment on volunteers' hands. Design. Randomized Latin-square design. Setting. Microbiology laboratory of the Medical University of Vienna, Vienna, Austria. Participants. Twenty-five healthy volunteers. Results. Reducing the concentration of glycerol or omitting it completely rendered both WHO formulations noninferior to the reference, both immediately and 3 hours after surgical hand antisepsis. Conclusions. Both WHO-recommended formulations meet the efficacy requirements of EN 12791 by increasing their alcohol concentrations by 5%, prolonging their application to 5 minutes and reducing the glycerol concentration to 0.725

Classification accuracy comparison: hypothesis tests and the use of confidence intervals in evaluations of difference, equivalence and non-inferiority

The comparison of classification accuracy statements has generally been based upon tests of difference or inequality when other scenarios and approaches may be more appropriate. Procedures for evaluating two scenarios with interest focused on the similarity in accuracy values, non-inferiority and equivalence, are outlined following a discussion of tests of difference (inequality). It is also suggested that the confidence interval of the difference in classification accuracy may be used as well as or instead of conventional hypothesis testing to reveal more information about the disparity in the classification accuracy values compared

Methods of sample size calculation for clinical trials

Sample size calculations should be an important part of the design of a trial, but are researchers choosing sensible trial sizes? This thesis looks at ways of determining appropriate sample sizes for Normal, binary and ordinal data. The inadequacies of existing sample size and power calculation software and methods are considered, and new software is offered that will be of more use to researchers planning randomised clinical trials. The software includes the capacity to assess the power and required sample size for incomplete block crossover trial designs for Normal data. Following on from these the difference between calculated power for published trials and the actual results are investigated. As a result, the appropriateness of the standard equations to determine a sample size is questioned- in particular the effect of using a variance estimate based on a sample variance from a pilot study is considered. Taking into account the distribution of this statistic alternative approaches beyond power are considered that take into account the uncertainty in sample variance. Software is also presented that will allow these new types of sample size and Expected Power calculations to be carried out

Safety and efficacy of methylene blue combined with artesunate or amodiaquine for uncomplicated falciparum malaria

Besides existing artemisinin-based combination therapies, alternative safe, effective and affordable drug combinations against falciparum malaria are needed. Methylene blue (MB) was the first synthetic antimalarial drug ever used, and recent studies have been promising with regard to its revival in malaria therapy. The objective of this study was to assess the safety and efficacy of two MB-based malaria combination therapies, MB-artesunate (AS) and MB-amodiaquine (AQ), compared to the local standard of care, AS-AQ, in Burkina Faso. Open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria in Nouna, north-western Burkina Faso. Follow-up was for 28 days and analysis by intention-to-treat. The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. No drug-related serious adverse events and no deaths occurred. MB-containing regimens were associated with mild vomiting and dysuria. No early treatment failures were observed. Parasite clearance time differed significantly among groups and was the shortest with MB-AS. By day 14, the rates of adequate clinical and parasitological response after PCR-based correction for recrudescence were 87% for MB-AS, 100% for MB-AQ (p = 0.004), and 100% for AS-AQ (p = 0.003). By day 28, the respective figure was lowest for MB-AS (62%), intermediate for the standard treatment AS-AQ (82%; p = 0.015), and highest for MB-AQ (95%; p<0.001; p = 0.03). MB-AQ is a promising alternative drug combination against malaria in Africa. Moreover, MB has the potential to further accelerate the rapid parasite clearance of artemisinin-based combination therapies. More than a century after the antimalarial properties of MB had been described, its role in malaria control deserves closer attention. ClinicalTrials.gov NCT00354380

Computational Bayesian Methods Applied to Complex Problems in Bio and Astro Statistics

In this dissertation we apply computational Bayesian methods to three distinct problems. In the first chapter, we address the issue of unrealistic covariance matrices used to estimate collision probabilities. We model covariance matrices with a Bayesian Normal-Inverse-Wishart model, which we fit with Gibbs sampling. In the second chapter, we are interested in determining the sample sizes necessary to achieve a particular interval width and establish non-inferiority in the analysis of prevalences using two fallible tests. To this end, we use a third order asymptotic approximation. In the third chapter, we wish to synthesize evidence across multiple domains in measurements taken longitudinally across time, featuring a substantial amount of structurally missing data, and fit the model with Hamiltonian Monte Carlo in a simulation to analyze how estimates of a parameter of interest change across sample sizes