Project Summary The current administrative supplement request is for a 12-month extension with funding to complete the ongoing IGNITE Network pragmatic clinical trials, GUARDD-US and ADOPT PGx. The GUARDD-US and ADOPT PGx trials have been underway since July 2020 and February 2021, respectively. These trials will help 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, exclusively 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 clinical trial aims to recruit 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. 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. 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. A 12-month extension with funding is needed due to unanticipated network-wide delays in launching each trial and shutdowns due to COVID-19. The funding requested in this administrative supplement reflects the trial close-out needs and the costs associated with leading analyses and publication costs for 13 secondary manuscripts.