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研究生:邱品琇
研究生(外文):Pin-Hsiu Chiu
論文名稱:病例對照研究中哈溫平衡檢定結果對基因型與疾病關係影響之研究
論文名稱(外文):The Testing of Hardy-Weinberg Equilibrium and the Estimation of the Association between a Single SNP and A Disease in Case-Control Studies
指導教授:林逸芬
指導教授(外文):I-Feng Lin
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:公共衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:82
中文關鍵詞:病例對照研究哈溫平衡檢定勝算比
外文關鍵詞:case-control studyHardy-Weinberg Equilibriumodds ratio
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研究背景與目標:
病例對照設計(case-control studies)經常被用在基因與疾病的相關性研究,勝算比(odds ratio;OR)則為量化相關性幅度(magnitude of the effect)的一個重要指標。在發表這類結果的期刊文章中,常可見研究者例行性的對基因型分布做哈溫平衡(Hardy-Weinberg Equilibrium)檢定,若檢定結果不推翻哈溫平衡的虛無假說,研究者一般認為所選取的樣本是合適的,足以代表母體的基因型分布,則後續勝算比的估計較可相信。本研究主要目的在藉由統計模擬的方式來探討當對照組符合哈溫平衡時,哈溫平衡檢定的結果與勝算比估計值之關係。
研究方法:
設定不同的病例組及對照組個別之對偶基因頻率(Allele frequency),比較三種不同選樣情境,不同遺傳模式包含累加性(Additive)、隱性(Recessive)、顯性(Dominant)及乘積性(Multiplicative)模式以及疾病與基因沒有相關性的情形(即真實勝算比為1),在不同的真實勝算比不同樣本數的情況下,檢定每一次模擬之哈溫平衡情形並觀察勝算比之估計值。
結果與結論:
當選樣誤差或是基因型定型誤差(genotyping error)存在時,勝算比估計值會偏離真實值,然而此時對照組基因型分布哈溫平衡的檢定還是會顯示未達統計意義,病例組基因型分布的哈溫平衡檢定結果,則有可能會接受或拒絕虛無假設。而在不同遺傳模式下,當病例組存在選樣誤差時,基因型分布在哈溫平衡檢定的結果也都可能會有拒絕或接受虛無假設的情形。病例對照相關研究中,無法充分提供勝算比是否正確估計的訊息。在病例組偏離哈溫平衡的情境下,哈溫平衡檢定結果為拒絕虛無假設的次數會隨著樣本數增加而增加。哈溫平衡會受到族群融合、選樣誤差等因素之影響。因此在基因型的病例對照研究中,例行性的檢定對照組基因型分布是否偏離哈溫平衡,進而依此做為勝算比的估計是否有效的依據是不夠充分的。且在病歷對照研究中,病例組基因型分布檢定結果與勝算比顯著性之間沒有絕對的關聯性。
有些研究者認為病例組及對照組的基因型分佈必須符合哈溫平衡,其結果才為可信的,但根據本研究參數設定的結果,病例組及對照組的基因型分佈要同時符合哈溫平衡,且還要遵守四種遺傳模式卻是非常困難的,只有在乘積性遺傳模式之下,才比較可能會發生。
Background:
In genetic association studies, the case-control design is often used to investigate the relationship between a disease and a single nucleotide polymorphism (SNP). The odds ratio (OR) provides a measure of the strength of the association. The Hardy-Weinberg Equilibrium (HWE) is usually tested. Some researchers have zero tolerance for a testing result of departures from HWE in both cases and controls. On the other hands, some suggested that testing for HWE could be a useful tool for rapid gene hunting. There is little studies focused on how the test results of HWE related to the estimates of OR.

Objective:
The purpose of this study is to investigate the relationship of the results of HWE test for the genotype of the cases and the estimates of ORs given the controls are in HWE. The effects of allele frequencies, magnitude of association, and sample size were evaluated through a simulation study.

Methods:
Varying scenarios with different susceptibility-allele frequencies in cases and controls, different sets of ORs, and different sample sizes were simulated. One thousand datasets were generated for each scenario and mean estimated ORs, 95% significant rate, and the significance of the HWE test were reported.

Results and Conclusions:
Given the genotypes of the controls are in HWE, the results of HWE test for the genotypes of the cases may be acceptance or rejections when the estimates of ORs deviate from the true values because of selection bias. The same results revealed in four different modes of inheritance as well. When the disease-genotype association exists, the HWE tests were not necessarily significant, and the results may be affected by many conditions, include sample sizes, selection bias, and genotyping errors. Therefore, the HWE test cannot be used to justify the validity of the OR estimates in case-control studies. There is no absolute relation between the results of HWE test and the significance of the estimate of ORs.
Some researcher think the genotypes of both the case and the control have to be in HWE. According to the process of parameter settings, the situation may only occur in the multiplicative effect.
第一章 緒論 1
第一節 研究背景 2
第二節 研究動機與目的 3
第三節 哈溫平衡檢定(HARDY-WEINBERG EQUILIBRIUM TEST) 5
一、哈溫平衡檢定用於病例對照研究中 7
二、哈溫平衡檢定之相關文獻探討 8
第四節 病歷對照研究之遺傳模式(MODE OF INHERITANCE) 11
第二章 研究方法 12
第一節 研究架構 13
第二節 模擬研究之參數設定 14
一、第一大類模擬之真實情境下參數設定 14
二、第二大類模擬之真實情境下參數設定 17
第三節 模擬研究設計 19
第三章 研究結果 21
第一節 哈溫平衡檢定結果與勝算比估計值之關係 23
一、真實情況下,病例組符合哈溫平衡之情境 23
二、真實情況下,病例組偏離哈溫平衡之情境 27
第二節 樣本數對哈溫平衡檢定之影響 29
第三節 病例組基因型分布檢定結果與勝算比顯著性之關係 30
第四章 討論與結論 33
第一節 結論 34
第二節 研究之限制 36
參考文獻 37
圖表 38
1.Gyorffy B, Kocsis I, Va´sa´rhelyi B. Biallelic genotype distributions in papers published in Gut between 1998 and 2003: altered conclusions after recalculating the Hardy-Weinberg equilibrium. Gut 2004;53:614-6.
2.Gyorffy B, Kocsis I, Vasarhelyi B. Missed calculations and new conclusions: re-calculation of genotype distribution data published in Journal of Investigative Dermatology, 1998–2003. Journal of Investigative Dermatology 2004;122:644-6.
3.Kocsis I, Gyorffy B, Nemeth E, et al. Examination of Hardy-Weinberg equilibrium in papers of Kidney International: an underused tool. Kidney international 2004;65:1956-8.
4.Kocsis I, Vasarhelyi B, Gyorffy A, et al. Reanalysis of genotype distributions published in Neurology between 1999 and 2002. AAN Enterprises, 2004:357-8.
5.Salanti G, Amountza G, Ntzani EE, et al. Hardy–Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. European journal of human genetics 2005;13:840-8.
6.Chen J, Chatterjee N. Exploiting Hardy-Weinberg equilibrium for efficient screening of single SNP associations from case-control studies. Hum Hered 2007;63:196-204.
7.Zou GY, Donner A. The Merits of Testing Hardy-Weinberg Equilibrium in the Analysis of Unmatched Case-Control Data: A Cautionary Note. Annals of Human Genetics 2006;70:923-33.
8.Lee WC. Searching for disease-susceptibility loci by testing for Hardy-Weinberg disequilibrium in a gene bank of affected individuals. American Journal of Epidemiology 2003;158:397-400.
9.Nemeth E, Vasarhelyi B, Gyorffy B, et al. Unreported Deviations of Genotype Distributions from Hardy-Weinberg Equilibrium in Articles Published in Critical Care Medicine Between 1999 and 2003. Critical Care Medicine 2004;32:1431.
10.Hosmer DW, Lemeshow S. Applied logistic regression. Wiley-Interscience, 2004.
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