The implementation of a pharmacogenomics-based algorithm for warfarin dosing

描述（由申请人提供）：Perera博士的长期职业目标是将临床药物遗传学检测作为临床护理不可或缺的一部分。随着药物遗传学研究的爆炸式增长，将药物遗传学应用于临床护理的机会已经变得明显。华法林由于其狭窄的治疗指数和严重的副作用，一直是研究的长期目标。目前，使用CYP2C9和VKORC1基因变异的算法已被开发用于预测白种人和亚洲人华法林维持剂量。然而，影响非裔美国人剂量的变异程度和指导剂量的算法还有待研究。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，重测序可以缩小到最有可能产生信息性snp的区域。接下来，单倍型标记snp以及非遗传因素将用于开发该人群维持剂量的预测算法。佩雷拉博士将与合作医生一起招募非裔美国抗凝患者，并收集基因型数据和非遗传信息。回归分析将用于推导预测维持剂量的给药算法。第二组患者将被招募来测试该算法的预测能力。病人将根据经验给药，这是标准的护理；然而，预测和观察到的维持剂量之间的相关性将被确定。最后，她将通过对非裔美国骨科患者的试点研究来评估临床结果。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被确定，以协助发展良好的临床试验。将进行额外的成本效益分析，以确定该算法在临床护理中的效用。提出的研究是及时和必要的，以填补目前的知识空白，并影响药物遗传学真正转化为临床实践。这样的研究有可能改变医学实践的方式。相关性（见说明书）：华法林的准确剂量对临床医生和机构都至关重要。因此，开发一种预测非裔美国人（目前研究不足的人群）华法林剂量的算法，将极大地改善许多医学领域的临床实践。这样的研究将有助于引导药物遗传学研究成果转化为临床实践。

DESCRIPTION (provided by applicant): 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.