The promise of genomic medicine to transform healthcare and improve health will not be fully realized until discoveries become relevant to and available for use by diverse populations and their clinicians. As part of the IGNITE II network, we are proposing two prospective randomized pragmatic genotype-guided clinical trials (GUARDD-US and ADOPT-PGx) to determine the impact of implementing genetic testing on hypertension, depression, and pain therapies. GUARDD-US: Chronic kidney disease (CKD) is associated with hypertension. People with African ancestry (AAs) have the highest risk of CKD and kidney failure, the highest prevalence of hypertension, and the lowest rate of blood pressure (BP) control. While this disparity is in part due to social determinants, ancestry has biological underpinnings and APOL1 high-risk genetic variants, nearly exclusive found in AAs, increase kidney failure risk 10-fold. We propose a genotype-guided trial to determine the effect of early vs. delayed knowledge of a positive APOL1 genotyping result on 3-month systolic blood pressure (SBP). The trial aims to recruit 5435 African Americans with hypertension, with or without CKD, randomized to immediate versus delayed return of APOL1 genetic testing. In those who are APOL1 negative, we will also conduct a pilot study to test the impact of pharmacogenetic (PGx) testing on SBP. Secondary outcomes include 6-month SBP, in CKD patients, on medications ordered, renal diagnosis and testing patient psycho-behavioral outcomes, cost effectiveness, and the effect of PGX guided hypertension management on SBP. ADOPT-PGx: Pain and depression are conditions that impact substantial proportions of the US population. The treatment of acute and chronic pain is challenged by the difficulty of finding effective therapies while minimizing the risk of adverse effects or opioid addiction. For depression, there are few clinically relevant predictors of successful treatment, which results in inadequate therapy for many patients. Both opioid and antidepressant prescriptions can be guided by PGx data based on existing guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC). We propose a prospective randomized pragmatic genotype-guided clinical trial that tests the effect of genotype-guided therapy in three scenarios of patients: acute post-surgical pain, chronic pain, and depression. For each scenario, participants will be randomized to genotype-guided drug therapy versus usual approaches to drug therapy selection. Changes in patient reported outcomes representing pain and depression control using standard PROMIS scales define the primary endpoints. Secondary analyses include safety endpoints, changes in overall well-being, and economic impact represented by differences in healthcare utilization. We expect the successful results from these clinical trials will provide critical evidence needed to drive the implementation of genomic medicine across broad demographics of patient ...