Browsing by Author "Nicholas, R."

In recent years adaptive seamless phase II/III designs (ASDs) allowing treatment or dose selection at an interim analysis have gained much attention because of their potential to save development costs and to shorten time-to-market of a new compound compared to conventional drug development programmes with separate trials for individual phases. In this paper, we describe an ASD with treatment selection based on early outcome data, specifically considering the situation where no final outcomes are observed at the time of the interim analysis. Bringing together combination tests for adaptive designs and the closure principle for multiple testing, control of the familywise type I error rate in the strong sense is achieved. Furthermore, a simulation model is proposed based on standardized test statistics that allows the generation of virtual trials for a variety of outcomes. We use this simulation model to investigate the actual type I error rate of the proposed testing procedure and find that the familywise type I error rate is controlled as expected. The method is often conservative, with the degree of conservatism depending on the correlation between early and late outcome, the true mean values of the early outcome in the different treatment groups and the selection rule. The investigations are motivated and illustrated by an application of the proposed design and simulation model to progressive multiple sclerosis. Copyright (C) 2011 John Wiley & Sons, Ltd.

Objective: The sonographic findings of chronic cerebrospinal venous insufficiency (CCSVI) are used by some as selection criteria for venography. We performed a systematic review to establish the prevalence and strength of association between sonographic CCSVI and multiple sclerosis (MS). Method: Two reviewers searched PubMed and EMBASE from 1948 to date using the keywords 'chronic cerebrospinal venous insufficiency' according to PRISMA guidelines. Results: Four cross-sectional studies met the criteria for inclusion. The prevalence of CCSVI ranged from 7% to 100% in MS patients and from 2% to 36% in healthy controls. Diagnostic odds ratios for MS varied between 2 and 26, 499 (I(2)=94%). Sensitivities of CCSVI for MS varied between 7% and 100% (I(2)=98%). Specificities varied between 64% and 100% (I(2)=95%). Conclusion: There is substantial variation in the strength of association between CCSVI and MS beyond that explained by demographic differences or sonographer training. Reliable evidence on which to base decisions requires sonographic consensus and assessment of the reproducibility of individual criteria between trained sonographers.