Pharmacogenomics Clinical Annotation Tool (PharmCAT)

摘要 美国每年约有200万例药物不良反应(ADR) 这造成了大约10万人死亡，损失超过300亿美元 每年。这些住院和死亡中的许多是可以预防的。开发 在开药前识别患者遗传变异的基础设施 已知会导致ADRS的是许多基因组药物实施的活跃领域 医疗保健组织和学术医疗中心。临床药物遗传学 实施联盟(CPIC)、美国食品和药物管理局(FDA)、 药物基因组学知识库(PharmGKB)等已经建立 关于基因-药物对的指南和建议，这些基因-药物对能够并已经导致 根据遗传变异开出修改的处方(S)。最大的挑战之一 在实施药物基因组学(PGx)时，提取基因组变异体并分配 可能的二倍型(每条染色体上有一个单倍型，包括星形等位基因定义) 来自测序和基因分型技术的遗传数据，以便应用 开处方的建议。在前者的成员之间的合作中 PGRN-统计分析资源(P-STAR)，PharmGKB，临床基因组 资源(Clingen)、电子病历和基因组学(Emerge)网络， 在实践中实施基因组学(IGNITE)、CPIC和其他，我们正在开发一种 提取PGx变体的软件工具PharmCAT，从已发表的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，推断双倍型，并生成 包括CPIC、FDA或其他临床指南的口译报告。《美国药典》 然后，可以使用报告为处方决策提供信息。此框架已命名为 药物基因组学临床注释工具包(PharmCAT)。最初的原型是 PharmCAT是由PharmGKB的软件开发人员根据 Teri Klein博士和软件开发人员及其团队在斯坦福大学的指导 以及宾夕法尼亚大学的玛丽莲·里奇博士和她的团队。在这辆U24 基因组学资源提案，我们的目标是进一步开发、测试和传播 将PharmCAT资源提供给科学界。这将使研究和 以标准化、可重复性、一致性的方式将PGx应用于临床护理 加快精准医疗PGx的临床实施。

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.