The implementation of a pharmacogenomics-based algorithm for warfarin dosing

佩雷拉博士的长期职业目标是将临床药物遗传学测试作为不可或缺的一部分来实施 临床护理的基础上。随着药物遗传学研究的爆炸性增长，推动使用 药物遗传学在临床护理中的应用已经变得显而易见。华法林长期以来一直是 研究因其治疗指标狭窄，副作用严重。目前，算法使用 已开发出CYP2C9和VKORC1的遗传变异来预测华法林在中国的维持剂量 高加索人和亚洲人。然而，影响非裔美国人剂量的变异程度和 指导给药的算法还有待研究。为了实现这一目标，佩雷拉博士将首先确定 非裔美国人CYP2C9和VKORC1的遗传单倍型结构。通过使用比较 基因组学和识别假定功能区域的软件，重新测序可以缩小到区域 最有可能产生信息量大的SNPs。接下来，单倍型标记SNPs以及非遗传因素将被 用于开发该人群中维持剂量的预测算法。佩雷拉博士和 合作的医生，将招募非裔美国人抗凝患者，并收集基因数据和 非遗传信息。将使用回归分析来推导出剂量算法来预测 维持量。第二批患者将被招募来测试这一预测能力 算法。患者将根据经验给药，护理标准也是如此；然而，患者之间的相关性 将确定预测和观测的维持量。最后，她将评估临床结果。 通过对非裔美国人整形外科患者进行的一项试点研究。这项研究将进行以确定 可行性方面。结果，如治疗INR的时间和不良事件将确定为 协助开展强有力的临床试验。我们会进行额外的成本效益分析，以 确定该算法在临床护理中的实用性。拟议的研究既及时又必要，以 填补现有知识的空白，并影响药物遗传学真正转化为临床实践。 这类研究有可能改变人们行医的方式。 相关性(请参阅说明)： 华法林的准确剂量对临床医生和机构都是至关重要的。因此，AN的发展 预测非裔美国人华法林剂量的算法，目前正在研究中的人群，将 极大地改善了众多医疗领域的临床实践。这样的研究将有助于引导人们 将药物遗传学研究成果转化为临床实践。

Dr. Perera's long-term career goal is to implement clinical pharmacogenetic testing as an indispensable part of clinical care. With the explosion of pharmacogenetic research, the opportunity to advance the use of pharmacogenetics into clinical care has become apparent. Warfarin has been a long-standing target of research because of its narrow therapeutic index and serious side effect profile. Currently, algorithms using genetic variants in CYP2C9 and VKORC1 have been developed to predict maintenance dose of warfarin in Caucasians and Asians. However, the extent of variation that affects dose in African Americans and an algorithm to guide dosing have yet to be investigated. In pursuit of this goal, Dr. Perera will first determine the genetic haplotype structure of CYP2C9 and VKORC1 in African Americans. By using comparative genomics and software that identifies putative functional regions, resequencing can be narrowed to areas most likely to yield informative SNPs. Next, haplotype-tagging SNPs along with non-genetic factors will be used to develop a predictive algorithm for maintenance dose in this population. Dr. Perera, along with collaborating physicians, will recruit African American anticoagulation patients and collect genotype data and non-genetic information. Regression analysis will be used to derive a dosing algorithm to predict maintenance dose. A second cohort of patients will be recruited to test the predictive power of this algorithm. Patient will be dosed empirically, as is standard of care; however, the correlation between predicted and observed maintenance dose will be determined. Lastly, she will evaluate the clinical outcomes through a pilot study in African American orthopedic patients. This study will be conducted to determine aspects of feasibility. Outcomes such as time to therapeutic INR and adverse events will be determined to assist in the development of a well-power clinical trial. Additional cost-effective analysis will be conducted to determine the utility of this algorithm in clinical care. The proposed research is both timely and necessary to fill gaps in the current knowledge and to affect real translation of pharmacogenetics into clinical practice. Such studies have the potential to change the way medicine is practiced. RELEVANCE (See instructions): The accurate dosing of warfarin is critical to both clinicians and institutions. Therefore the development of an algorithm that would predict warfarin dose in African Americans, a currently under-studied population, would greatly improve clinical practice in numerous medical fields. Such research will help lead the way to the translation of pharmacogenetic findings into clinical practice.