The goals of this project are to identify strategies to improve the integration of genomic testing, reporting, and use into the clinical workflow of patient care. Over the last decade, we have acquired the infrastructure and expertise to support genetic testing, reporting, alerting, educating, and returning results. We will now leverage our past accomplishments and our genomics-enabled learning health system (gLHS) to share implementation strategies, conduct two selected intervention projects network-wide and evaluate their impact, and share gLHS tools and resources that can be broadly adopted. To facilitate this work, we are proposing two pragmatic randomized stepped wedge clinical trials: one focused on implementing DPYD testing and one on APOL1 testing. In patients receiving fluoropyrimidine chemotherapies, DPYD testing and genetic-guided dose adjustments reduce the severe toxicities caused by these drugs. In many other countries, DPYD testing is standard of care; in the US, it is beginning to be used in some clinics, but needs additional leadership and effective strategies to overcome the barriers and facilitate broad adoption. APOL1 variants contribute to the development and progression of chronic kidney disease and disparate outcomes in patients with African ancestry. APOL1 testing, together with joint decision making with the patient and provider, helps to manage risk factors that contribute to poor chronic kidney disease outcomes. These trials represent two distinct genetic tests and disciplines of medicine, are tests that are ready for broad implementation, can be implemented in most health care systems, and address disparate healthcare outcomes. The two proposed clinical trials will serve as a platform to implement innovative solutions to drive genomic medicine uptake. We propose that an initial set of solutions would reasonably include EHR-based clinical decision support, educating providers, simplifying genetic test ordering, and streamlining processes to improve insurance reimbursement rates. Following the initial implementation, we will evaluate the success of the strategies and refine and integrate additional improvements in two subsequent rounds of iterative implementation. In order to fully accommodate the selected projects, our implementation team includes experts in genetics, counseling, informatics, pharmacology, bioethics, learning health systems, economics, implementation science and many disciplines of medicine that have a productive track record of working together. Our previous implementation work has led to the identification and resolution of many barriers to genomic medicine. The insights gained from our learning health system, provider and patient feedback, informatics analyses, workflow logistics, and laboratory challenges provide initial basis for our initial interventions; they will also provide immediate strategies for other health care systems to learn from our experience. Upon completion of these trials, we expe...