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.

佩雷拉博士的长期职业目标是实施临床药物遗传学测试作为不可或缺的一部分 临床护理。随着药物遗传学研究的爆炸式发展， 药物遗传学应用于临床治疗已经变得显而易见。长期以来，战争一直是 由于其狭窄的治疗指数和严重的副作用，研究。目前，算法使用 CYP 2C 9和VKORC 1的遗传变异已被开发用于预测华法林的维持剂量， 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CYP 2C 9和VKORC 1的遗传单倍型结构。采用比较 基因组学和软件识别推定的功能区域，重测序可以缩小到区域 最有可能产生信息丰富的SNP。接下来，单倍型标记的SNP沿着非遗传因素将被应用于 用于开发该人群维持剂量的预测算法。佩雷拉医生，沿着 合作医生将招募非洲裔美国抗凝患者，收集基因型数据， 非遗传信息。将使用回归分析推导出给药算法，以预测 维持剂量将招募第二组患者以测试该预测能力。 算法患者将根据经验给药，这是护理标准;然而， 将确定预测和观察的维持剂量。最后，她将评估临床结果 通过对非裔美国骨科患者的试点研究。本研究将确定 可行性方面。将确定结局，如至治疗性INR的时间和不良事件， 协助开展有效的临床试验。将进行额外的成本效益分析， 确定该算法在临床护理中的实用性。建议的研究是及时和必要的， 填补现有知识的空白，并影响遗传药理学向临床实践的真实的转化。 这些研究有可能改变医学的实践方式。 相关性（参见说明）： 华法林的准确剂量对临床医生和机构都至关重要。因此，发展一个 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， 极大地改善了许多医疗领域的临床实践。这样的研究将有助于引导 将药物遗传学发现转化为临床实践。