Pharmacogenomics Clinical Annotation Tool (PharmCAT)

摘要 美国每年发生约200万起药物不良反应（ADR）。 这导致大约10万人死亡，花费超过300亿美元 每年.其中许多住院和死亡是可以预防的。发展 基础设施，以便在开药前识别患者的遗传变异 已知引起ADR是基因组医学实施的活跃领域， 医疗保健组织和学术医疗中心。临床药物遗传学 美国食品药品监督管理局（FDA）、美国食品药品监督管理局（CPIC） 药物基因组学知识库（PharmGKB）和其他已建立 围绕基因药物对的指导方针和建议， 基于遗传变异的处方修改。的最大挑战之一 在实施药物基因组学（PGx）是提取基因组变异和分配 可能的双体型（每条染色体上一个单体型，包括星等位基因定义） 从测序和基因分型技术获得的基因数据中， 处方建议。在前者成员之间的合作中， PGRN-统计分析资源（P-STAR），PharmGKB，临床基因组 电子病历和基因组学（eMERGE）网络， 实施基因组学实践（IGNITE），CPIC和其他，我们正在开发一个 软件工具PharmCAT，用于提取PGx变体，从已发布的CPIC中的变体开始 指南，来自测序或基因分型技术产生的遗传数据集 （表示为.VCF文件），解释变异等位基因，推断二倍体型，并生成 解读报告，包括CPIC、FDA或其他临床指南。关于PharmCAT 然后，报告可用于通知处方决策。该框架被命名为 药物基因组学临床注释工具包（PharmCAT）。的最初原型 PharmCAT由PharmGKB的软件开发人员根据 Teri Klein博士和软件开发人员以及她在斯坦福大学的团队的指导下 以及宾夕法尼亚大学的玛丽莲里奇博士和她的团队。在U24 基因组学资源的建议，我们的目标是进一步开发，测试和传播 PharmCAT资源给科学界。这将使研究和 以标准化、可重复、一致的方式将PGx应用于临床护理 加快PGx临床实施，实现精准医疗。

ABSTRACT Approximately 2 million adverse drug reactions (ADRs) occur annually in the United States; this results in roughly 100,000 deaths and costs upwards of $30 billion dollars each year. Many of these hospitalizations and deaths are preventable. Developing the infrastructure to identify the genetic variants in patients before prescribing the medications known to cause ADRs is an active area of genomic medicine implementation at many health care organizations and academic medical centers. The Clinical Pharmacogenetics Implementation Consortium (CPIC), U.S Food & Drug Administration (FDA), the Pharmacogenomics Knowledgebase (PharmGKB) and others have established guidelines and recommendations surrounding gene-drug pairs that can and already lead to prescribing modifications based on genetic variant(s). One of the greatest challenges in implementing Pharmacogenomics (PGx) is extracting genomic variants and assigning possible diplotypes (one haplotype on each chromosome, including star-allele definitions) from genetic data derived from sequencing and genotyping technologies in order to apply the prescribing recommendations. In a collaboration between the members of the former PGRN-Statistical Analysis Resource (P-STAR), PharmGKB, the Clinical Genome Resource (ClinGen), the electronic Medical Records and Genomics (eMERGE) network, Implementing Genomics in Practice (IGNITE), CPIC, and others, we are developing a software tool, PharmCAT, to extract PGx variants, beginning with those in published CPIC guidelines, from a genetic dataset resulting from sequencing or genotyping technologies (represented as a .VCF file), interpret the variant alleles, infer diplotypes, and generate an interpretation report including CPIC, FDA, or other clinical guidance. The PharmCAT report can then be used to inform prescribing decisions. This framework has been named the Pharmacogenomics Clinical Annotation Toolkit (PharmCAT). The initial prototype of PharmCAT has been developed by software developers at PharmGKB under the direction of Dr. Teri Klein and software developers and her team at Stanford University as well as Dr. Marylyn Ritchie and her team at the University of Pennsylvania. In this U24 genomics resources proposal, our goals are to further develop, test, and disseminate the PharmCAT resource to the scientific community. This will enable the research and implementation of PGx into clinical care in a standardized, reproducible, consistent manner and accelerate PGx clinical implementation for precision medicine.