Wiley Laura K, Vanhouten Jacob P, Samuels David C, Aldrich Melinda C, Roden Dan M, Peterson Josh F, Denny Joshua C
Div. of Biomedical Informatics and Personalized Med., University of Colorado, 13001 E. 17th Pl. MS F-563 Aurora, CO 80045, USA,
Pac Symp Biocomput. 2017;22:545-556. doi: 10.1142/9789813207813_0050.
The blood thinner warfarin has a narrow therapeutic range and high inter- and intra-patient variability in therapeutic doses. Several studies have shown that pharmacogenomic variants help predict stable warfarin dosing. However, retrospective and randomized controlled trials that employ dosing algorithms incorporating pharmacogenomic variants under perform in African Americans. This study sought to determine if: 1) including additional variants associated with warfarin dose in African Americans, 2) predicting within single ancestry groups rather than a combined population, or 3) using percentage African ancestry rather than observed race, would improve warfarin dosing algorithms in African Americans. Using BioVU, the Vanderbilt University Medical Center biobank linked to electronic medical records, we compared 25 modeling strategies to existing algorithms using a cohort of 2,181 warfarin users (1,928 whites, 253 blacks). We found that approaches incorporating additional variants increased model accuracy, but not in clinically significant ways. Race stratification increased model fidelity for African Americans, but the improvement was small and not likely to be clinically significant. Use of percent African ancestry improved model fit in the context of race misclassification.
血液稀释剂华法林的治疗窗较窄，治疗剂量在患者之间和患者自身的变异性都很高。多项研究表明，药物基因组变异有助于预测华法林的稳定给药剂量。然而，采用纳入药物基因组变异的给药算法的回顾性研究和随机对照试验在非裔美国人中表现不佳。本研究旨在确定：1）纳入与非裔美国人华法林剂量相关的其他变异；2）在单一血统群体而非混合群体中进行预测；或3）使用非洲血统百分比而非观察到的种族，是否会改善非裔美国人的华法林给药算法。利用范德比尔特大学医学中心与电子病历相关联的生物样本库BioVU，我们使用2181名华法林使用者（1928名白人、253名黑人）的队列，将25种建模策略与现有算法进行了比较。我们发现，纳入其他变异的方法提高了模型准确性，但在临床上并无显著意义。种族分层提高了非裔美国人模型的保真度，但改善幅度较小，可能在临床上也无显著意义。在种族误分类的情况下，使用非洲血统百分比改善了模型拟合。
