Two-stage designs in case-control association analysis

doi:10.1534/genetics.105.042648

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	Two-stage designs in case-control association analysis
	Zuo, Yijun ; Zou, Guohua ; Zhao, Hongyu
	2006-07-01
发表期刊	GENETICS
ISSN	0016-6731
卷号	173 期号:3 页码:1747-1760
摘要	DNA pooling is a cost-effective approach for collecting information on marker allele frequency in genetic studies. It is often suggested as a screening tool to identify a subset of candidate markers from a very large number of markers to be followed up by more accurate and informative individual genotyping. In this article, we investigate several statistical properties and design issues related to this two-stage design, including the selection of the candidate markers for second-stage analysis, statistical power of this design, and the probability that truly disease-associated markers are ranked among the top after second-stage analysis. We have derived analytical results on the proportion of markers to be selected for second-stage analysis. For example, to detect disease-associated markers with an allele frequency difference of 0.05 between the cases and controls through an initial sample of 1000 cases and 1000 controls, our results suggest that when the measurement errors are small (0.005), similar to 3% of the markers should be selected. For the statistical power to identify disease-associated markers, we find that the measurement errors associated with DNA pooling have little effect on its power. This is in contrast to the one-stage pooling scheme where measurement errors may have large effect on statistical power. As for the probability that the disease-associated markers are ranked among the top in the second stage, we show that there is a high probability that at least one disease-associated marker is ranked among the top when the allele frequency differences between the cases and controls are not < 0.05 for reasonably large sample sizes, even though the errors associated with DNA pooling in the first stage are not small. Therefore, the two-stage design with DNA pooling as a screening tool offers an efficient strategy in genomewide association studies, even when the measurement errors associated with DNA pooling are nonnegligible. For any disease model, we find that all the statistical results essentially depend on the population allele frequency and the allele frequency differences between the cases and controls at the disease-associated markers. The general conclusions hold whether the second stage uses an entirely independent sample or includes both the samples used in the first stage and an independent set of samples.
DOI	10.1534/genetics.105.042648
语种	英语
WOS研究方向	Genetics & Heredity
WOS类目	Genetics & Heredity
WOS记录号	WOS:000239629400046
出版者	GENETICS
引用统计
文献类型	期刊论文
条目标识符	http://ir.amss.ac.cn/handle/2S8OKBNM/3144
专题	中国科学院数学与系统科学研究院
通讯作者	Zhao, Hongyu
作者单位	1.Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA 2.Michigan State Univ, Dept Probabil & Stat, E Lansing, MI 48824 USA 3.Chinese Acad Sci, Acad Math & Syst Sci, Beijing 100080, Peoples R China
推荐引用方式 GB/T 7714	Zuo, Yijun,Zou, Guohua,Zhao, Hongyu. Two-stage designs in case-control association analysis[J]. GENETICS,2006,173(3):1747-1760.
APA	Zuo, Yijun,Zou, Guohua,&Zhao, Hongyu.(2006).Two-stage designs in case-control association analysis.GENETICS,173(3),1747-1760.
MLA	Zuo, Yijun,et al."Two-stage designs in case-control association analysis".GENETICS 173.3(2006):1747-1760.