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

基本信息

批准号：
7892558
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
项目类别：
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/7892558
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 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

项目摘要

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.

描述（由申请人提供）：Perera博士的长期职业目标是实施临床药物遗传学测试，这是临床护理中必不可少的一部分。随着药物遗传学研究的爆炸式增长，可以显而易见将药物遗传学用于临床护理的机会。华法林一直是研究的长期目标，因为其治疗指数狭窄和严重的副作用。当前，已经开发出使用CYP2C9和VKORC1中使用遗传变异的算法来预测高加索人和亚洲人的华法林维持剂量。但是，影响非洲裔美国人的剂量的变异程度和指导剂量的算法尚未研究。为了实现这一目标，Perera博士将首先确定非裔美国人中CYP2C9和VKORC1的遗传单倍型结构。通过使用识别推定功能区域的比较基因组学和软件，可以将重新取证范围缩小到最有可能产生信息丰富的SNP的区域。接下来，将使用单倍型标记的SNP以及非遗传因素来开发一种预测算法，用于该人群中的维持剂量。 Perera博士与合作的医生一起将招募非裔美国人的抗凝患者，并收集基因型数据和非遗传信息。回归分析将用于得出剂量算法以预测维持剂量。将招募第二个患者队列以测试该算法的预测能力。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之间的相关性。最后，她将通过非裔美国人骨科患者的试点研究评估临床结果。将进行这项研究以确定可行性的各个方面。诸如治疗INR和不良事件的结果将确定，以帮助开发良好的临床试验。将进行其他成本效益的分析，以确定该算法在临床护理中的实用性。拟议的研究既是及时的，也是必要的，以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）：华法林的准确剂量对临床医生和机构都至关重要。因此，开发一种可以预测非裔美国人的华法林剂量的算法，目前研究不足，将大大改善众多医疗领域的临床实践。这样的研究将有助于将药物遗传学发现转化为临床实践。