The implementation of a pharmacogenomics-based algorithm for warfarin dosing

基于药物基因组学的华法林给药算法的实施

• 批准号: 8261454
• 负责人: Minoli A Perera
• 金额: $ 12.03万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261454
• 关键词: 6-Mercaptopurine; Accounting; Address; Adverse effects; Adverse event; Affect; African American; Age; Algorithms; Anticoagulation; Area; Asians; Binding Sites; Biological Assay; CYP2C9 gene; Cancer-Predisposing Gene; Candidate Disease Gene; Caring; Caucasians; Caucasoid Race; Clinic; Clinical; Clinical Trials; Code; Collaborations; Computer software; Conduct Clinical Trials; Consult; Cost Effectiveness Analysis; DNA Resequencing; Data; Decision Modeling; Development; Dose; ERBB2 gene; Economics; Educational Curriculum; Elements; Evaluation; Explosion; Feasibility Studies; Future; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Goals; Haplotypes; Institution; Instruction; International Normalized Ratio; Introns; Investigation; Investments; Knowledge; Lead; Linear Models; Literature; Logistics; Maintenance; Medical; Medicine; Methods; Orthopedic Surgery procedures; Orthopedics; Outcome; Outpatients; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Phenotype; Physicians; Pilot Projects; Population; Population Study; Predictive Factor; Prophylactic treatment; Prospective Studies; Randomized Clinical Trials; Recruitment Activity; Regression Analysis; Research; Research Design; Research Infrastructure; Research Personnel; Roche brand of trastuzumab; Savings; Science; Services; Societies; Structure; Surgeon; Surveys; Targeted Research; Testing; Therapeutic; Therapeutic Index; Time; Training; Translations; Variant; Venous Thrombosis; Warfarin; base; career; clinical care; clinical practice; clinically relevant; cohort; comparative; comparative genomics; cost; dosage; ethnic difference; experience; genetic variant; improved; malignant breast neoplasm; medical schools; non-genetic; novel; patient oriented research; patient population; pharmacogenetic testing; phrases; programs; sex; standard of care; success; thiopurine methyltransferase; tool; triphenylmethylphosphonium; tumor

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.

Perera博士的长期职业目标是将临床药物遗传学测试作为必不可少的部分实施 临床护理。随着药物遗传学研究的爆炸式增长，有机会推进使用 药物遗传学进入临床护理已变得显而易见。华法林一直是 由于其狭窄的治疗指数和严重的副作用概况而进行的研究。当前，使用算法 CYP2C9和VKORC1中的遗传变异已开发出来预测华法林的维持剂量 高加索人和亚洲人。但是，影响非裔美国人剂量的变异程度 指导剂量的算法尚未研究。为了实现这一目标，佩雷拉博士将首先确定 非裔美国人中CYP2C9和VKORC1的遗传单倍型结构。通过使用比较 识别推定功能区域的基因组学和软件，可以将重新取证范围缩小到区域 最有可能产生信息丰富的SNP。接下来，将单倍型标记为SNP以及非遗传因素将是 用于开发一种用于维持剂量的预测算法。佩雷拉博士 合作医师，将招募非裔美国人抗凝患者并收集基因型数据，并 非遗传信息。回归分析将用于得出剂量算法以预测 维护剂量。将招募第二个患者队列来测试此类的预测能力 算法。患者将按照护理标准进行经验服用；但是， 将确定预测和观察到的维持剂量。最后，她将评估临床结果 通过对非裔美国人骨科患者的试点研究。将进行这项研究以确定 可行性的各个方面。诸如治疗INR和不良事件等时间的结果将被确定为 协助开发能力临床试验。将进行其他成本效益的分析 确定该算法在临床护理中的效用。拟议的研究既及时又是必要的 填补当前知识的空白，并影响药物遗传学对临床实践的真实翻译。 这样的研究有可能改变医学的实践方式。 相关性（请参阅说明）： 对华法林的准确剂量对临床医生和机构都至关重要。因此 可以预测非裔美国人的华法林剂量的算法，目前人口不足，将 在众多医疗领域中，大大改善了临床实践。这样的研究将有助于领导 将药物遗传学发现转化为临床实践。