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Two-Stage Designs for Gene–Disease Association Studies

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Summary.

The goal of this article is to describe a two-stage design that maximizes the power to detect gene-disease associations when the principal design constraint is the total cost, represented by the total number of gene evaluations rather than the total number of individuals. In the first stage, all genes of interest are evaluated on a subset of individuals. The most promising genes are then evaluated on additional subjects in the second stage. This will eliminate wastage of resources on genes unlikely to be associated with disease based on the results of the first stage. We consider the case where the genes are correlated and the case where the genes are independent. Using simulation results, it is shown that, as a general guideline when the genes are independent or when the correlation is small, utilizing 75% of the resources in stage 1 to screen all the markers and evaluating the most promising 10% of the markers with the remaining resources provides near-optimal power for a broad range of parametric configurations. This translates to screening all the markers on approximately one quarter of the required sample size in stage 1.
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Keywords: Cost constraint; Gaussian approximation; Optimal design; Power

Document Type: Research Article

Affiliations: 1: Department of Epidemiology and Biostatistics, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, U.S.A. 2: Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, U.S.A.

Publication date: 2002-03-01

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