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BMC Proceedings

, 3:S40

First Online: 15 December 2009DOI: 10.1186-1753-6561-3-S7-S40

Cite this article as: Parkhomenko, E., Tritchler, D., Lemire, M. et al. BMC Proc 2009 3Suppl 7: S40. doi:10.1186-1753-6561-3-S7-S40


In high-dimensional studies such as genome-wide association studies, the correction for multiple testing in order to control total type I error results in decreased power to detect modest effects. We present a new analytical approach based on the higher criticism statistic that allows identification of the presence of modest effects. We apply our method to the genome-wide study of rheumatoid arthritis provided in the Genetic Analysis Workshop 16 Problem 1 data set. There is evidence for unknown bias in this study that could be explained by the presence of undetected modest effects. We compared the asymptotic and empirical thresholds for the higher criticism statistic. Using the asymptotic threshold we detected the presence of modest effects genome-wide. We also detected modest effects using 90 percentile of the empirical null distribution as a threshold; however, there is no such evidence when the 95 and 99 percentiles were used. While the higher criticism method suggests that there is some evidence for modest effects, interpreting individual single-nucleotide polymorphisms with significant higher criticism statistics is of undermined value. The goal of higher criticism is to alert the researcher that genetic effects remain to be discovered and to promote the use of more targeted and powerful studies to detect the remaining effects.

List of abbreviations usedHCHigher criticism

NARACNorth American Rheumatoid Arthritis Consortium

PDFProbability density function

RARheumatoid arthritis

SNPSingle-nucleotide polymorphism.

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Author: Elena Parkhomenko - David Tritchler - Mathieu Lemire - Pingzhao Hu - Joseph Beyene


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