Pharmacogenomics Clinical Annotation Tool (PharmCAT)

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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.