Browsing by Author "Tuteja, Sony"
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Item APOL1 Risk Variants, Acute Kidney Injury, and Death in Participants With African Ancestry Hospitalized With COVID-19 From the Million Veteran Program(American Medical Association, 2022) Hung, Adriana M.; Shah, Shailja C.; Bick, Alexander G.; Yu, Zhihong; Chen, Hua-Chang; Hunt, Christine M.; Wendt, Frank; Wilson, Otis; Greevy, Robert A.; Chung, Cecilia P.; Suzuki, Ayako; Ho, Yuk-Lam; Akwo, Elvis; Polimanti, Renato; Zhou, Jin; Reaven, Peter; Tsao, Philip S.; Gaziano, J. Michael; Huffman, Jennifer E.; Joseph, Jacob; Luoh, Shiuh-Wen; Iyengar, Sudha; Chang, Kyong-Mi; Casas, Juan P.; Matheny, Michael E.; O'Donnell, Christopher J.; Cho, Kelly; Tao, Ran; Susztak, Katalin; Robinson-Cohen, Cassianne; Tuteja, Sony; Siew, Edward D.; VA Million Veteran Program COVID-19 Science Initiative; Medicine, School of MedicineImportance: Coronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates. Objective: Individuals with African ancestry with 2 copies of apolipoprotein L1 (APOL1) variants G1 or G2 (high-risk group) have significantly increased rates of kidney disease. We tested the hypothesis that the APOL1 high-risk group is associated with a higher-risk of COVID-19-associated AKI and death. Design, setting, and participants: This retrospective cohort study included 990 participants with African ancestry enrolled in the Million Veteran Program who were hospitalized with COVID-19 between March 2020 and January 2021 with available genetic information. Exposures: The primary exposure was having 2 APOL1 risk variants (RV) (APOL1 high-risk group), compared with having 1 or 0 risk variants (APOL1 low-risk group). Main outcomes and measures: The primary outcome was AKI. The secondary outcomes were stages of AKI severity and death. Multivariable logistic regression analyses adjusted for preexisting comorbidities, medications, and inpatient AKI risk factors; 10 principal components of ancestry were performed to study these associations. We performed a subgroup analysis in individuals with normal kidney function prior to hospitalization (estimated glomerular filtration rate ≥60 mL/min/1.73 m2). Results: Of the 990 participants with African ancestry, 905 (91.4%) were male with a median (IQR) age of 68 (60-73) years. Overall, 392 (39.6%) patients developed AKI, 141 (14%) developed stages 2 or 3 AKI, 28 (3%) required dialysis, and 122 (12.3%) died. One hundred twenty-five (12.6%) of the participants were in the APOL1 high-risk group. Patients categorized as APOL1 high-risk group had significantly higher odds of AKI (adjusted odds ratio [OR], 1.95; 95% CI, 1.27-3.02; P = .002), higher AKI severity stages (OR, 2.03; 95% CI, 1.37-2.99; P < .001), and death (OR, 2.15; 95% CI, 1.22-3.72; P = .007). The association with AKI persisted in the subgroup with normal kidney function (OR, 1.93; 95% CI, 1.15-3.26; P = .01). Data analysis was conducted between February 2021 and April 2021. Conclusions and relevance: In this cohort study of veterans with African ancestry hospitalized with COVID-19 infection, APOL1 kidney risk variants were associated with higher odds of AKI, AKI severity, and death, even among individuals with prior normal kidney function.Item Best-worst scaling methodology to evaluate constructs of the Consolidated Framework for Implementation Research: application to the implementation of pharmacogenetic testing for antidepressant therapy.(BMC, 2022-05-14) Salloum, Ramzi G.; Bishop, Jeffrey R.; Elchynski, Amanda L.; Smith, D. Max; Rowe, Elizabeth; Blake, Kathryn V.; Limdi, Nita A.; Aquilante, Christina L.; Bates, Jill; Beitelshees, Amber L.; Cipriani, Amber; Duong, Benjamin Q.; Empey, Philip E.; Formea, Christine M.; Hicks, J. Kevin; Mroz, Pawel; Oslin, David; Pasternak, Amy L.; Petry, Natasha; Ramsey, Laura B.; Schlichte, Allyson; Swain, Sandra M.; Ward, Kristen M.; Wiisanen, Kristin; Skaar, Todd C.; Van Driest, Sara L.; Cavallari, Larisa H.; Tuteja, SonyBACKGROUND: Despite the increased demand for pharmacogenetic (PGx) testing to guide antidepressant use, little is known about how to implement testing in clinical practice. Best-worst scaling (BWS) is a stated preferences technique for determining the relative importance of alternative scenarios and is increasingly being used as a healthcare assessment tool, with potential applications in implementation research. We conducted a BWS experiment to evaluate the relative importance of implementation factors for PGx testing to guide antidepressant use. METHODS: We surveyed 17 healthcare organizations that either had implemented or were in the process of implementing PGx testing for antidepressants. The survey included a BWS experiment to evaluate the relative importance of Consolidated Framework for Implementation Research (CFIR) constructs from the perspective of implementing sites. RESULTS: Participating sites varied on their PGx testing platform and methods for returning recommendations to providers and patients, but they were consistent in ranking several CFIR constructs as most important for implementation: patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and identification of champions. CONCLUSIONS: This study demonstrates the feasibility of using choice experiments to systematically evaluate the relative importance of implementation determinants from the perspective of implementing organizations. BWS findings can inform other organizations interested in implementing PGx testing for mental health. Further, this study demonstrates the application of BWS to PGx, the findings of which may be used by other organizations to inform implementation of PGx testing for mental health disorders.Item CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention in Diverse Clinical Settings.(Journal of the American Heart Association, 2022-02-15) Beitelshees, Amber L.; Thomas, Cameron D.; Empey, Philip E.; Stouffer, George A.; Angiolillo, Dominick J.; Franchi, Francesco; Tuteja, Sony; Limdi, Nita A.; Lee, James C.; Duarte, Julio D.; Kreutz, Rolf P.; Skaar, Todd C.; Coons, James C.; Giri, Jay; McDonough, Caitrin W.; Rowland, Rachel; Stevenson, James M.; Thai, Thuy; Vesely, Mark R.; Wellen, Jacob T.; Johnson, Julie A.; Winterstein, Almut G.; Cavallari, Larisa H.; Lee, Craig R.Background Studies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss-of-function (LOF) variant carriers versus non-carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real-world outcomes with the clinical implementation of CYP2C19-guided antiplatelet therapy after PCI. Methods and Results Data from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a CYP2C19 LOF variant. The primary outcome was the composite of major atherothrombotic events (all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life-threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39-0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71-1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele. Conclusions Real-world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.Item Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection(Nature, 2020-11) Beitelshees, Amber L.; Stevenson, James M.; El Rouby, Nihal; Dillon, Chrisly; Empey, Philip E.; Fielstein, Elliot M.; Johnson, Julie A.; Limdi, Nita A.; Ong, Henry H.; Franchi, Francesco; Angiolillo, Dominick P.; Peterson, Joshua F.; Rosenman, Marc B.; Skaar, Todd C.; Tuteja, Sony; Cavallari, Larisa H.; Medicine, School of MedicinePurpose Genotype-guided antiplatelet therapy is increasingly being incorporated into clinical care. The purpose of this study is to determine the extent to which patients initially genotyped for CYP2C19 to guide antiplatelet therapy were prescribed additional medications affected by CYP2C19. Methods We assembled a cohort of patients from eight sites performing CYP2C19 genotyping to inform antiplatelet therapy. Medication orders were evaluated from time of genotyping through one year. The primary endpoint was the proportion of patients prescribed two or more CYP2C19 substrates. Secondary endpoints were the proportion of patients with a drug–genotype interaction and time to receiving a CYP2C19 substrate. Results Nine thousand one hundred ninety-one genotyped patients (17% nonwhite) with a mean age of 68 ± 3 years were evaluated; 4701 (51%) of patients received two or more CYP2C19 substrates and 3835 (42%) of patients had a drug–genotype interaction. The average time between genotyping and CYP2C19 substrate other than antiplatelet therapy was 25 ± 10 days. Conclusions More than half of patients genotyped in the setting of CYP2C19-guided antiplatelet therapy received another medication impacted by CYP2C19 in the following year. Given that genotype is stable for a patient’s lifetime, this finding has implications for cost effectiveness, patient care, and treatment outcomes beyond the indication for which it was originally performed.Item Evaluation of Potential Racial Disparities in CYP2C19-Guided P2Y12 Inhibitor Prescribing After Percutaneous Coronary Intervention(Wiley, 2023) Cavallari, Larisa H.; Limdi, Nita A.; Beitelshees, Amber L.; Lee, James C.; Duarte, Julio D.; Franchi, Francesco; Tuteja, Sony; Giri, Jay; Empey, Philip E.; Kreutz, Rolf P.; Skaar, Todd C.; Allen, John M.; Coons, James C.; Gong, Yan; McDonough, Caitrin W.; Stevenson, James M.; Thomas, Cameron D.; Johnson, Julie A.; Stouffer, George A.; Angiolillo, Dominick J.; Lee, Craig R.; IGNITE Network; Pharmacology and Toxicology, School of MedicineBlack patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y12 inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI. Patients from 9 sites that performed clinical CYP2C19 genotyping after PCI were included. Alternative therapy (e.g., prasugrel or ticagrelor) was recommended for CYP2C19 no-function allele carriers, in whom clopidogrel is predicted to be less effective. The primary outcome was choice of P2Y12 inhibitor (clopidogrel vs. alternative therapy) based on genotype. Of 3,342 patients included, 2,448 (73%) were White, and 659 (20%) were Black. More Black than White patients had a no-function allele (34.3% vs. 29.7%, P = 0.024). At hospital discharge following PCI, 44.2% of Black and 44.0% of White no-function allele carriers were prescribed alternative therapy. At the time of the last follow-up within 12 months, numerically fewer Black (51.8%) than White (56.7%) no-function allele carriers were prescribed alternative therapy (P = 0.190). However, the difference was not significant after accounting for other factors associated with P2Y12 inhibitor selection (odds ratio 0.79, 95% confidence interval 0.58-1.08). Alternative therapy use did not differ between Black (14.3%) and White (16.7%) patients without a no-function allele (P = 0.232). Among real-world patients who received CYP2C19 testing after PCI, P2Y12 inhibitor prescribing rates did not differ between Black and White patients. Our data suggest an absence of racial disparity in genotype-guided antiplatelet prescribing among patients receiving CYP2C19 testing.Item Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.(Wiley, 2021-03) Lee, Craig R.; Thomas, Cameron D.; Beitelshees, Amber L.; Tuteja, Sony; Empey, Philip E.; Lee, James C.; Limdi, Nita A.; Duarte, Julio D.; Skaar, Todd C.; Chen, Yiqing; Cook, Kelsey J.; Coons, James C.; Dillon, Chrisly; Franchi, Francesco; Giri, Jay; Gong, Yan; Kreutz, Rolf P.; McDonough, Caitrin W.; Stevenson, James M.; Weck, Karen E.; Angiolillo, Dominick J.; Johnson, Julie A.; Stouffer, George A.; Cavallari, Larisa H.Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.Item Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing(Springer Nature, 2019-10) Cavallari, Larisa H.; Van Driest, Sara L.; Prows, Cynthia A.; Bishop, Jeffrey R.; Limdi, Nita A.; Pratt, Victoria M.; Ramsey, Laura B.; Smith, D. Max; Tuteja, Sony; Duong, Benjamin Q.; Hicks, J. Kevin; Lee, James C.; Obeng, Aniwaa Owusu; Beitelshees, Amber L.; Bell, Gillian C.; Blake, Kathryn; Crona, Daniel J.; Dressler, Lynn; Gregg, Ryan A.; Hines, Lindsay J.; Scott, Stuart A.; Shelton, Richard C.; Weitzel, Kristin Wiisanen; Johnson, Julie A.; Peterson, Josh F.; Empey, Philip E.; Skaar, Todd C.; Medical and Molecular Genetics, School of MedicinePURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.Item Multi-site investigation of strategies for the implementation of CYP2C19 genotype-guided antiplatelet therapy(Wiley, 2018) Empey, Philip E.; Stevenson, James M.; Tuteja, Sony; Weitzel, Kristin W.; Angiolillo, Dominick J.; Beitelshees, Amber L.; Coons, James C.; Duarte, Julio D.; Franchi, Francesco; Jeng, Linda J. B.; Johnson, Julie A.; Kreutz, Rolf P.; Limdi, Nita A.; Maloney, Kristin A.; Obeng, Aniwaa Owusu; Peterson, Josh F.; Petry, Natasha; Pratt, Victoria M.; Rollini, Fabiana; Scott, Stuart A.; Skaar, Todd C.; Vesely, Mark R.; Stouffer, George A.; Wilke, Russell A.; Cavallari, Larisa H.; Lee, Craig R.; Medicine, School of MedicineCYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes which are both related to CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions. This article is protected by copyright.Item Multisite evaluation of institutional processes and implementation determinants for pharmacogenetic testing to guide antidepressant therapy.(Wiley, 2022-02) Tuteja, Sony; Salloum, Ramzi G.; Elchynski, Amanda L.; Smith, D. Max; Rowe, Elizabeth; Blake, Kathryn V.; Limdi, Nita A.; Aquilante, Christina L.; Bates, Jill; Beitelshees, Amber L.; Cipriani, Amber; Duong, Benjamin Q.; Empey, Philip E.; Formea, Christine M.; Hicks, J. Kevin; Mroz, Pawel; Oslin, David; Pasternak, Amy L.; Petry, Natasha; Ramsey, Allyson; Swain, Sandra M.; Ward, Kristen M.; Wiisanen, Kristin; Skaar, Todd C.; Van Driest, Sara L.; Cavallari, Larisa H.; Bishop, Jeffrey R.There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best-worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx-guided pharmacotherapy for antidepressant management.Item Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing(Elsevier, 2021) Duarte, Julio D.; Dalton, Rachel; Elchynski, Amanda L.; Smith, D. Max; Cicali, Emily J.; Lee, James C.; Duong, Benjamin Q.; Petry, Natasha J.; Aquilante, Christina L.; Beitelshees, Amber L.; Empey, Philip E.; Johnson, Julie A.; Obeng, Aniwaa Owusu; Pasternak, Amy L.; Pratt, Victoria M.; Ramsey, Laura B.; Tuteja, Sony; Van Driest, Sara L.; Wiisanen, Kristin; Hicks, J. Kevin; Cavallari, Larisa H.; IGNITE Network Pharmacogenetics Working Group; Medical and Molecular Genetics, School of MedicinePurpose: The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear. Methods: In this report, we compare and contrast implementation strategies for pre-emptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates. Results: We found that while pre-emptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Finally, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for pre-emptive PGx testing remain low. Conclusion: These findings should inform the establishment of future implementation efforts at institutions considering a pre-emptive PGx testing program.