DESCRIPTION (provided by applicant): Despite the hope that pharmacogenomics (PGx) will improve the risk-benefit ratio of certain medications, there is little empiric evidence about how PGx might impact patient outcomes such as drug safety and effectiveness. The research activities in this career development award will use simvastatin PGx as a model of the impact of genomic medicine on patient outcomes. Statins are cholesterol-lowering medications that have dramatically reduced the risk of cardiovascular disease (CVD) and death in millions of Americans. Statins can also cause muscle injury (myopathy) ranging from mild muscle aches to life-threatening rhabdomyolysis. Recently, genome-wide association studies have identified a locus in the SLCO1B1 gene that is associated with the risk of statin-associated myopathy. Up to twenty percent of Americans carry at least one copy of the C allele at SLCO1B1 rs4149056, which increases the risk of myopathy greater than four-fold. PGx testing for the SLCO1B1 locus might improve the safety of statin use in patient care. However, at the same time, SLCO1B1 testing may result in insufficient statin dosing for a given patient's level of CVD risk. To examine the impact of statin PGx on patient outcomes, this project will conduct a randomized controlled trial of SLCO1B1 testing in a Veteran patient population. First, metrics will be developed for statin-related patient outcomes in the VA health system. VA provider notes will be used to develop and validate a natural language processing algorithm to identify statin myopathy from text from the electronic health record. VA clinical and administrative data will be used to develop informatics-based approaches to categorize Veterans into American College of Cardiology/American Heart Association (ACC/AHA) CVD risk categorizes and determine whether their statin doses are appropriate for their level of CVD risk. These metrics will then be used as outcomes for a randomized controlled trial determining the impact of SLCO1B1 rs4149056 testing on statin safety and appropriate statin dosing among 408 VA primary care patients. Veterans at higher CVD risk will be randomized to undergo SLCO1B1 testing versus no testing in the course of usual primary care. After one year, the two groups will be compared regarding the occurrence of statin myopathy, cholesterol levels, and concordance with ACC/AHA guidelines for CVD prevention and PGx guidelines for simvastatin safety. In addition to gathering empiric evidence about the impact of statin PGx on Veteran health outcomes, this career development award includes mentorship, coursework, and seminars in translational genomics, PGx, and innovative randomized controlled trial design. The research and career development activities will prepare the applicant for his long-term goal of a research career in translational genomics that informs how genomic medicine might be used to improve Veteran health.