Two-stage designs in case-control association analysis
➤ Gửi thông báo lỗi ⚠️ Báo cáo tài liệu vi phạmNội dung chi tiết: Two-stage designs in case-control association analysis
Two-stage designs in case-control association analysis
Two-stage designs in case-control association analysisYijunZuo1, GuohuaZou2, and Hongyu Zhao3"1D^pjii.i.n)eiil.oLSjatbJi^-dnd Probability, Michigan St Two-stage designs in case-control association analysistate. University. East Lansing,MI 48824, USA2Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100080, p. R. China3Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520, USA★Corresponding author:Hongyu Zhao, Ph.D.Departme Two-stage designs in case-control association analysisnt of Epidemiology and Public HealthYale University School of Medicine60 College StreetNew Haven. CT 06520-8034Phone: (203) 785-6271Fax: (203) 785-691Two-stage designs in case-control association analysis
2Email: hongvu.zhaofaiyale.edu.AbstractDNA pooling is a cost effective approach for collecting information on marker allele frequency in genetic studiTwo-stage designs in case-control association analysisYijunZuo1, GuohuaZou2, and Hongyu Zhao3"1D^pjii.i.n)eiil.oLSjatbJi^-dnd Probability, Michigan St Two-stage designs in case-control association analysisaccurate and informative individual genotyping. In this paper, 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 trul Two-stage designs in case-control association analysisy disease-associated markers are ranked among the top after second stage analysis. We have derived analytical results on the proportion of markers toTwo-stage designs in case-control association analysis
be selected for second stage analysis. For example, to detect disease-associated markers with an allele frequency difference of 0.05 between the casesTwo-stage designs in case-control association analysisYijunZuo1, GuohuaZou2, and Hongyu Zhao3"1D^pjii.i.n)eiil.oLSjatbJi^-dnd Probability, Michigan St Two-stage designs in case-control association analysis 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 Two-stage designs in case-control association analysis 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 isTwo-stage designs in case-control association analysis
a high probability that at least one disease-associated marker is ranked among the top when the allele frequency differences between the cases and conTwo-stage designs in case-control association analysisYijunZuo1, GuohuaZou2, and Hongyu Zhao3"1D^pjii.i.n)eiil.oLSjatbJi^-dnd Probability, Michigan St Two-stage designs in case-control association analysis Therefore, (he two-stage design with DNA pooling as a screening tool offers an efficient strategy in genome-wide association studies, even when the measurement errors associated with DNA pooling are non-negligible. For any disease model, we find that all the statistical results essentially depend o Two-stage designs in case-control association analysisn the population allele frequency and the allele frequency differences between the cases and controls at the disease-associated markers. The general cTwo-stage designs in case-control association analysis
onclusions hold whether the second stage uses an entirely independent sample or includes both the samples used in the first stage as well as an indepeTwo-stage designs in case-control association analysisYijunZuo1, GuohuaZou2, and Hongyu Zhao3"1D^pjii.i.n)eiil.oLSjatbJi^-dnd Probability, Michigan St Two-stage designs in case-control association analysissociation studies3IntroductionGenome-wide case-control association study is a promising approach to identifying disease genes (Risch 2000). For a specific marker, allele frequency difference between cases and controls may indicate potential association between this marker and disease, although other Two-stage designs in case-control association analysis factors (e.g. population stratification) may account for the observed difference. Allele frequencies among the cases and controls can be obtained eitTwo-stage designs in case-control association analysis
her through individual genotyping or DNA pooling. Although individual genotyping provides more accurate estimates of allele frequencies and allows forTwo-stage designs in case-control association analysisYijunZuo1, GuohuaZou2, and Hongyu Zhao3"1D^pjii.i.n)eiil.oLSjatbJi^-dnd Probability, Michigan St Two-stage designs in case-control association analysisidual genotyping needs to collect data from hundreds of thousands markers for each person.In the absence of measurement errors associated with DNA pooling, there would be no difference between using DNA pooling or individual genotyping for the estimation of allele frequency. However, one major limit Two-stage designs in case-control association analysisation of the current DNA pooling technologies is indeed the errors associated with measuring allele frequencies in the pooled samples. Recent researchTwo-stage designs in case-control association analysis
suggests that for a given pooled DNA sample, the standard deviation of the estimated allele frequency is between 1% and 4% (cf., Buetow et al. 2001, Two-stage designs in case-control association analysisYijunZuo1, GuohuaZou2, and Hongyu Zhao3"1D^pjii.i.n)eiil.oLSjatbJi^-dnd Probability, Michigan St Two-stage designs in case-control association analysisallele-specific extension or minisequencing from a primer adjacent to the site of the SNP, the standard deviation4ranged from 1% to 4% depending on the specific markers being tested. Our recent studies have found that the errors of this magnitude may have a large effect on the power of case-control Two-stage designs in case-control association analysisassociation studies using DNA pooling as the sole source for genotyping (see Zou and Zhao 2004 for unrelated population samples and Zou and Zhao 2005Two-stage designs in case-control association analysis
for family samples). Therefore, a two-stage design where DNA pooling is used as a screening tool followed by individual genotyping for validation in aTwo-stage designs in case-control association analysisYijunZuo1, GuohuaZou2, and Hongyu Zhao3"1D^pjii.i.n)eiil.oLSjatbJi^-dnd Probability, Michigan St Two-stage designs in case-control association analysis 2002, Sham et al. 2002). In such a design, the first stage evaluates a very large number (e.g. one million) of markers using DNA pooling, and only the most promising ones are selected and studied in the second stage through individual genotyping. Similar two-stage designs have been considered by El Two-stage designs in case-control association analysisston (1994) and Elston et al. (1996) in the context of linkage analysis, and by Satagopan et al. (2002, 2003, 2004) in the context of association studTwo-stage designs in case-control association analysis
ies. However, these studies primarily assumed that individual genotyping is used in both stages, which may not be as cost-effective as using DNA pooliTwo-stage designs in case-control association analysisYijunZuo1, GuohuaZou2, and Hongyu Zhao3"1D^pjii.i.n)eiil.oLSjatbJi^-dnd Probability, Michigan St Two-stage designs in case-control association analysisg tool in the first stage, the following issues need to be addressed:(i)How many markers should be chosen after the first stage so that there is a high probability that all or some of the disease-associated markers are included in the individual genotyping (second) stage?3https://khothuvien.cori!(ii Two-stage designs in case-control association analysis)What is the statistical power that a disease-associated marker is identified when the overall false positive rate is appropriately controlled for?(iiTwo-stage designs in case-control association analysis
i)When the primary goal is to ensure that some of the disease-associated markers are ranked among the top L markers after the two-stage analysis, whatTwo-stage designs in case-control association analysisYijunZuo1, GuohuaZou2, and Hongyu Zhao3"1D^pjii.i.n)eiil.oLSjatbJi^-dnd Probability, Michigan StTwo-stage designs in case-control association analysisYijunZuo1, GuohuaZou2, and Hongyu Zhao3"1D^pjii.i.n)eiil.oLSjatbJi^-dnd Probability, Michigan StGọi ngay
Chat zalo
Facebook