期刊
STATISTICS IN BIOPHARMACEUTICAL RESEARCH
卷 5, 期 1, 页码 54-66出版社
AMER STATISTICAL ASSOC
DOI: 10.1080/19466315.2012.756662
关键词
Bootstrap estimate; Delta method; Multivariate random coefficients models; Power; Preclinical Alzheimer's disease (AD); Randomized clinical trials (RCT); Sample size
资金
- National Institute on Aging (NIA) [R01 AG034119, R01 AG029672, R01 AG038651]
- NIA [P50 AG05681, P01 AG03991, P01AG26276, U01 AG032438]
Clinical trials in early-stage Alzheimer's disease (AD) are reaching a bottleneck because none of the current disease markers changes appreciably early in the disease process and therefore a huge sample is required to adequately power such trials. We propose a method to combine multiple markers so that the longitudinal rate of progression can be improved. The criterion is to maximize the probability that the combined marker will be decreased over time (assuming a negative mean slope for each marker). We propose estimating the weights of markers in the optimum combination and a confidence interval estimate of the combined rate of progression through the maximum likelihood estimates and a bootstrap procedure. We conduct simulations to assess the performance of our estimates and compare our approach with the first principal component from a principal component analysis. The proposed method is applied to a real-world sample of individuals with preclinical AD to combine measures from two cognitive domains. The combined cognitive marker is finally used to design future clinical trials on preclinical AD, demonstrating a significant reduction in the sample sizes needed to power such trials when compared with individual markers alone.
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