公共衛生學院: 流行病學與預防醫學研究所指導教授: 林菀俞梁芸婕Liang, Yun-ChiehYun-ChiehLiang2017-03-032018-06-292017-03-032018-06-292015http://ntur.lib.ntu.edu.tw//handle/246246/273811由於次世代定序 (next-generation sequencing, NGS) 的發展，遺傳學家發現，尋找次要等位基因頻率小於1% 的罕見致病變異 (rare causal variants) 有助於瞭解複雜疾病的成因。在家族研究中一個簡單且常用的研究設計為收集病例親本三元體 (case-parent trios) 資料。若研究者可同時獲得族群對照 (population controls) 資料，使用此資訊於三元體資料可改善統計方法的檢定力。於分析病例親本三元體資料時，傳遞不平衡檢定 (transmission disequilibrium test) 是一廣為人知的方法。其已被延伸至偵測罕見變異關聯上，稱作rvTDT。由於rvTDT是條件式的方法 (conditioning approach)，此法可穩健處理族群分層 (population stratification) 的問題。然而，條件的過程中可能損害其檢定力。針對病例親本三元體資料，本文提出「條件式適性P值結合法」，簡稱conADA。吾人首先截斷P值較大的變異，使得此法較不受中立變異混入之影響。此外，由於檢定統計量乃條件於親本基因型所建構，在族群分層出現時依然可產生正確的統計推論。As the development of next-generation sequencing technologies, geneticists found that rare causal variants (minor allele frequency (MAF) < 1%) detection can help to uncover the etiology of complex diseases. Recruiting case-parent trios is a simple and popular study design in family-based studies. If researchers can also obtain data from population controls, utilizing unrelated controls in trios can improve the power of a statistical method. The transmission disequilibrium test (TDT) is a well-known method to analyze case-parent trio data. It has been extended to rare-variant association testing (referred to as ‘rvTDT’ hereafter), and is robust to population stratification because of its conditioning approach. However, power loss may occur in the conditioning process. We here propose a ‘conditioning adaptive combination of P-values method’ (abbreviated as ‘conADA’). By first truncating the variants with larger P-values, it is robust to the inclusion of neutral variants. Moreover, because the test statistic is developed by conditioning on parental genotypes, conADA generates valid statistical inference in the presence of population stratification.3108988 bytesapplication/pdf論文公開時間: 2015/9/14論文使用權限: 同意有償授權(權利金給回饋本人)中立變異次世代定序患病子代罕見變異Neutral variantsnext-generation sequencingaffected offspringrare variantsthesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/273811/1/ntu-104-R02849013-1.pdf