112 results on '"Pratt VM"'
Search Results
2. Implementation of a pharmacogenomics consult service to support the INGENIOUS trial
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Eadon, MT, primary, Desta, Z, additional, Levy, KD, additional, Decker, BS, additional, Pierson, RC, additional, Pratt, VM, additional, Callaghan, JT, additional, Rosenman, MB, additional, Carpenter, JS, additional, Holmes, AM, additional, McDonald, CA, additional, Benson, EA, additional, Patil, AS, additional, Vuppalanchi, R, additional, Gufford, BT, additional, Dave, N, additional, Robarge, JD, additional, Hyder, MA, additional, Haas, DM, additional, Kreutz, RP, additional, Dexter, PR, additional, Skaar, TC, additional, and Flockhart, DA, additional
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- 2016
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3. Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting
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Kalman, LV, primary, Agúndez, JAG, additional, Appell, M Lindqvist, additional, Black, JL, additional, Bell, GC, additional, Boukouvala, S, additional, Bruckner, C, additional, Bruford, E, additional, Caudle, K, additional, Coulthard, SA, additional, Daly, AK, additional, Tredici, AL Del, additional, den Dunnen, JT, additional, Drozda, K, additional, Everts, RE, additional, Flockhart, D, additional, Freimuth, RR, additional, Gaedigk, A, additional, Hachad, H, additional, Hartshorne, T, additional, Ingelman‐Sundberg, M, additional, Klein, TE, additional, Lauschke, VM, additional, Maglott, DR, additional, McLeod, HL, additional, McMillin, GA, additional, Meyer, UA, additional, Müller, DJ, additional, Nickerson, DA, additional, Oetting, WS, additional, Pacanowski, M, additional, Pratt, VM, additional, Relling, MV, additional, Roberts, A, additional, Rubinstein, WS, additional, Sangkuhl, K, additional, Schwab, M, additional, Scott, SA, additional, Sim, SC, additional, Thirumaran, RK, additional, Toji, LH, additional, Tyndale, RF, additional, van Schaik, RHN, additional, Whirl‐Carrillo, M, additional, Yeo, KTJ, additional, and Zanger, UM, additional
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- 2015
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4. Bioelectronic sensor technology for detection of cystic fibrosis and hereditary hemochromatosis mutations.
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Bernacki SH, Farkas DH, Shi W, Chan V, Liu Y, Beck JC, Bailey KS, Pratt VM, Monaghan KG, Matteson KJ, Schaefer FV, Friez M, Shrimpton AE, and Stenzel TT
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- 2003
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5. Development of a Multifaceted Program for Pharmacogenetics Adoption at an Academic Medical Center: Practical Considerations and Lessons Learned.
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Shugg T, Tillman EM, Breman AM, Hodge JC, McDonald CA, Ly RC, Rowe EJ, Osei W, Smith TB, Schwartz PH, Callaghan JT, Pratt VM, Lynch S, Eadon MT, and Skaar TC
- Abstract
In 2019, Indiana University launched the Precision Health Initiative to enhance the institutional adoption of precision medicine, including pharmacogenetics (PGx) implementation, at university-affiliated practice sites across Indiana. The overarching goal of this PGx implementation program was to facilitate the sustainable adoption of genotype-guided prescribing into routine clinical care. To accomplish this goal, we pursued the following specific objectives: (i) to integrate PGx testing into existing healthcare system processes; (ii) to implement drug-gene pairs with high-level evidence and educate providers and pharmacists on established clinical management recommendations; (iii) to engage key stakeholders, including patients to optimize the return of results for PGx testing; (iv) to reduce health disparities through the targeted inclusion of underrepresented populations; (v) and to track third-party reimbursement. This tutorial details our multifaceted PGx implementation program, including descriptions of our interventions, the critical challenges faced, and the major program successes. By describing our experience, we aim to assist other clinical teams in achieving sustainable PGx implementation in their health systems., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2024
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6. Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators.
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Skaar TC, Myers RA, Fillingim RB, Callaghan JT, Cicali E, Eadon MT, Elwood EN, Ginsburg GS, Lynch S, Nguyen KA, Obeng AO, Park H, Pratt VM, Rosenman M, Sadeghpour A, Shuman S, Singh R, Tillman EM, Volpi S, Wiisanen K, Winterstein AG, Horowitz CR, Voora D, Orlando L, Chakraborty H, Van Driest S, Peterson JF, Cavallari LA, Johnson JA, and Dexter PR
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- Adult, Female, Humans, Male, Middle Aged, Pain Management methods, Pain Measurement, Pharmacogenomic Testing, Precision Medicine methods, Analgesics, Opioid therapeutic use, Analgesics, Opioid adverse effects, Chronic Pain drug therapy, Cytochrome P-450 CYP2D6 genetics, Cytochrome P-450 CYP2D6 metabolism
- Abstract
Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2024
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7. DPYD Genotyping Recommendations: A Joint Consensus Recommendation of the Association for Molecular Pathology, American College of Medical Genetics and Genomics, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European Society for Pharmacogenomics and Personalized Therapy, Pharmacogenomics Knowledgebase, and Pharmacogene Variation Consortium.
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Pratt VM, Cavallari LH, Fulmer ML, Gaedigk A, Hachad H, Ji Y, Kalman LV, Ly RC, Moyer AM, Scott SA, Turner AJ, van Schaik RHN, Whirl-Carrillo M, and Weck KE
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- Humans, Genotype, Knowledge Bases, Consensus, Pharmacogenomic Testing methods, Pharmacogenomic Testing standards, Alleles, Genotyping Techniques methods, Dihydrouracil Dehydrogenase (NADP) genetics, Pharmacogenetics methods, Precision Medicine methods, Precision Medicine standards
- Abstract
The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum set of variant alleles (tier 1) and an extended list of variant alleles (tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. The goal of this Working Group is to promote standardization of PGx testing across clinical laboratories. This document will focus on clinical DPYD PGx testing that may be applied to all dihydropyrimidine dehydrogenase-related medications. These recommendations are not to be interpreted as prescriptive but to provide a reference guide., Competing Interests: Disclosure Statement The University of North Carolina Medical Genetics Laboratory, RPRD Diagnostics, AccessDx Laboratory, and the Stanford Medicine Clinical Genomics Laboratory are fee-for-service clinical laboratories that offer clinical pharmacogenomic testing. V.M.P. is the director of Scientific Affairs for Agena Bioscience, is a member of the Pharmacogene Variation Consortium (PharmVar) Steering Committee and PharmVar CYP2C and CYP3A Gene Expert Panels, and is the Association for Molecular Pathology liaison to the National Academy of Medicine Roundtable on Genomics and Precision Health. L.H.C. is supported by NIH/National Human Genome Research Institute (NHGRI) grant U01 HG007269 and NIH/National Center for Advancing Translational Sciences grant UL1 TR001427 and serves on the Clinical Pharmacogenetics Implementation Consortium (CPIC) steering committee. A.G. is the director of PharmVar, a member of CPIC, and a member of the CPIC and Pharmacogenomics Clinical Annotation Tool Scientific Advisory Boards. H.H. is an employee of AccessDx Holdings and serves on the CPIC Scientific Advisory Board and on the PharmVar CYP2D6 Gene Expert Panel. Y.J. serves as the Vice Chair of the American College of Medical Genetics and Genomics (ACMG) Membership Committee. R.C.L. is a member of the PharmVar CYP2D6 Gene Expert Panel. A.M.M. is a member of the College of American Pathologists (CAP)/ACMG Biochemical and Molecular Genetics Committee and Pharmacogenetics Workgroup, the PharmVar CYP2D6 Gene Expert Panel, the ClinGen Pharmacogenomics (PGx) Working Group, and the ClinPGx Scientific Advisory Board. S.A.S. serves on the steering committees of CPIC and PharmVar and is a member of the PharmVar CYP2C Gene Expert Panel. A.J.T.'s efforts are supported in part by RPRD Diagnostics, an independent clinical laboratory offering pharmacogenetic testing services; she also serves on the PharmVar CYP1A2, CYP2D6, DPYD, and NUDT15 Gene Expert Panels. R.H.N.v.S. is a member of the Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, is a board member and past president of the European Society for Pharmacogenomics and Personalized Therapy, serves on the PharmVar CYP3A Gene Expert Panel, and is a member of the CPIC Scientific Advisory Board. M.W.-C. is supported by NIH/NHGRI/National Institute of Child Health and Human Development/National Institute on Drug Abuse grant U24 HG010615 and NIH/NHGRI grant U24 HG013077, is a co-investigator of CPIC, is co–principal investigator and director of the Pharmacogenomics Knowledgebase, and serves on the steering committee and multiple Gene Expert Panels for PharmVar. K.E.W. serves as the CAP liaison to the National Academy of Medicine Roundtable on Genomics and Precision Health. The remaining authors have declared no related conflicts of interest., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2024
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8. Overcoming Barriers to Discovery and Implementation of Equitable Pharmacogenomic Testing in Oncology.
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Shriver SP, Adams D, McKelvey BA, McCune JS, Miles D, Pratt VM, Ashcraft K, McLeod HL, Williams H, and Fleury ME
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- Humans, Pharmacogenetics, Genetic Testing, Medical Oncology, Pharmacogenomic Testing, Precision Medicine
- Abstract
Pharmacogenomics (PGx), the study of inherited genomic variation and drug response or safety, is a vital tool in precision medicine. In oncology, testing to identify PGx variants offers patients the opportunity for customized treatments that can minimize adverse effects and maximize the therapeutic benefits of drugs used for cancer treatment and supportive care. Because individuals of shared ancestry share specific genetic variants, PGx factors may contribute to outcome disparities across racial and ethnic categories when genetic ancestry is not taken into account or mischaracterized in PGx research, discovery, and application. Here, we examine how the current scientific understanding of the role of PGx in differential oncology safety and outcomes may be biased toward a greater understanding and more complete clinical implementation of PGx for individuals of European descent compared with other genetic ancestry groups. We discuss the implications of this bias for PGx discovery, access to care, drug labeling, and patient and provider understanding and use of PGx approaches. Testing for somatic genetic variants is now the standard of care in treatment of many solid tumors, but the integration of PGx into oncology care is still lacking despite demonstrated actionable findings from PGx testing, reduction in avoidable toxicity and death, and return on investment from testing. As the field of oncology is poised to expand and integrate germline genetic variant testing, it is vital that PGx discovery and application are equitable for all populations. Recommendations are introduced to address barriers to facilitate effective and equitable PGx application in cancer care.
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- 2024
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9. 2024 Updates to American Medical Association's Current Procedural Terminology Codes for Oncology Panel Testing.
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Pratt VM
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- United States, Humans, Medical Oncology, American Medical Association, Current Procedural Terminology
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Competing Interests: Disclosure Statement None declared.
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- 2024
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10. The INGENIOUS trial: Impact of pharmacogenetic testing on adverse events in a pragmatic clinical trial.
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Eadon MT, Rosenman MB, Zhang P, Fulton CR, Callaghan JT, Holmes AM, Levy KD, Gupta SK, Haas DM, Vuppalanchi R, Benson EA, Kreutz RP, Tillman EM, Shugg T, Pierson RC, Gufford BT, Pratt VM, Zang Y, Desta Z, Dexter PR, and Skaar TC
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- Humans, Aripiprazole, Norepinephrine, Serotonin, Drug-Related Side Effects and Adverse Reactions genetics, Pharmacogenomic Testing
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Adverse drug events (ADEs) account for a significant mortality, morbidity, and cost burden. Pharmacogenetic testing has the potential to reduce ADEs and inefficacy. The objective of this INGENIOUS trial (NCT02297126) analysis was to determine whether conducting and reporting pharmacogenetic panel testing impacts ADE frequency. The trial was a pragmatic, randomized controlled clinical trial, adapted as a propensity matched analysis in individuals (N = 2612) receiving a new prescription for one or more of 26 pharmacogenetic-actionable drugs across a community safety-net and academic health system. The intervention was a pharmacogenetic testing panel for 26 drugs with dosage and selection recommendations returned to the health record. The primary outcome was occurrence of ADEs within 1 year, according to modified Common Terminology Criteria for Adverse Events (CTCAE). In the propensity-matched analysis, 16.1% of individuals experienced any ADE within 1-year. Serious ADEs (CTCAE level ≥ 3) occurred in 3.2% of individuals. When combining all 26 drugs, no significant difference was observed between the pharmacogenetic testing and control arms for any ADE (Odds ratio 0.96, 95% CI: 0.78-1.18), serious ADEs (OR: 0.91, 95% CI: 0.58-1.40), or mortality (OR: 0.60, 95% CI: 0.28-1.21). However, sub-group analyses revealed a reduction in serious ADEs and death in individuals who underwent pharmacogenotyping for aripiprazole and serotonin or serotonin-norepinephrine reuptake inhibitors (OR 0.34, 95% CI: 0.12-0.85). In conclusion, no change in overall ADEs was observed after pharmacogenetic testing. However, limitations incurred during INGENIOUS likely affected the results. Future studies may consider preemptive, rather than reactive, pharmacogenetic panel testing., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2023
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11. CYP3A4 and CYP3A5 Genotyping Recommendations: A Joint Consensus Recommendation of the Association for Molecular Pathology, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European Society for Pharmacogenomics and Personalized Therapy, and Pharmacogenomics Knowledgebase.
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Pratt VM, Cavallari LH, Fulmer ML, Gaedigk A, Hachad H, Ji Y, Kalman LV, Ly RC, Moyer AM, Scott SA, van Schaik RHN, Whirl-Carrillo M, and Weck KE
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- Humans, Genotype, Consensus, Pathology, Molecular, Pharmacists, Pathologists, Pharmacogenetics, Cytochrome P-450 CYP3A genetics
- Abstract
The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum panel of variant alleles (tier 1) and an extended panel of variant alleles (tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. The goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This document will focus on clinical CYP3A4 and CYP3A5 PGx testing that may be applied to all CYP3A4- and CYP3A5-related medications. These recommendations are not to be interpreted as prescriptive but to provide a reference guide., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. All rights reserved.)
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- 2023
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12. PharmVar GeneFocus: CYP3A5.
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Rodriguez-Antona C, Savieo JL, Lauschke VM, Sangkuhl K, Drögemöller BI, Wang D, van Schaik RHN, Gilep AA, Peter AP, Boone EC, Ramey BE, Klein TE, Whirl-Carrillo M, Pratt VM, and Gaedigk A
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- Humans, Immunosuppressive Agents therapeutic use, Pharmacogenetics, Cyclosporine, Genotype, Cytochrome P-450 CYP3A genetics, Tacrolimus
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The Pharmacogene Variation Consortium (PharmVar) catalogs star (*) allele nomenclature for the polymorphic human CYP3A5 gene. Genetic variation within the CYP3A5 gene locus impacts the metabolism of several clinically important drugs, including the immunosuppressants tacrolimus, sirolimus, cyclosporine, and the benzodiazepine midazolam. Variable CYP3A5 activity is of clinical importance regarding tacrolimus metabolism. This GeneFocus provides a CYP3A5 gene summary with a focus on aspects regarding standardized nomenclature. In addition, this review also summarizes recent changes and updates, including the retirement of several allelic variants and provides an overview of how PharmVar CYP3A5 star allele nomenclature is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC)., (© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.)
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- 2022
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13. Building Evidence for Clinical Use of Pharmacogenomics and Reimbursement for Testing.
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Cavallari LH and Pratt VM
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- Genotype, Pharmacogenetics
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- 2022
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14. Implementing a pragmatic clinical trial to tailor opioids for acute pain on behalf of the IGNITE ADOPT PGx investigators.
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Cavallari LH, Cicali E, Wiisanen K, Fillingim RB, Chakraborty H, Myers RA, Blake KV, Asiyanbola B, Baye JF, Bronson WH, Cook KJ, Elwood EN, Gray CF, Gong Y, Hines L, Kannry J, Kucher N, Lynch S, Nguyen KA, Obeng AO, Pratt VM, Prieto HA, Ramos M, Sadeghpour A, Singh R, Rosenman M, Starostik P, Thomas CD, Tillman E, Dexter PR, Horowitz CR, Orlando LA, Peterson JF, Skaar TC, Van Driest SL, Volpi S, Voora D, Parvataneni HK, and Johnson JA
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- Humans, Codeine administration & dosage, Cytochrome P-450 CYP2D6 genetics, Cytochrome P-450 CYP2D6 metabolism, Hydrocodone administration & dosage, Practice Patterns, Physicians', Prospective Studies, Tramadol administration & dosage, Acute Pain diagnosis, Acute Pain drug therapy, Analgesics, Opioid administration & dosage, Pain, Postoperative diagnosis, Pain, Postoperative drug therapy
- Abstract
Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2022
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15. Characterization of Reference Materials for TPMT and NUDT15: A GeT-RM Collaborative Project.
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Pratt VM, Wang WY, Boone EC, Broeckel U, Cody N, Edelmann L, Gaedigk A, Lynnes TC, Medeiros EB, Moyer AM, Mitchell MW, Scott SA, Starostik P, Turner A, and Kalman LV
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- Alleles, DNA genetics, Haplotypes, Humans, Genetic Testing, Methyltransferases genetics, Pharmacogenetics, Pyrophosphatases genetics
- Abstract
Pharmacogenetic testing is increasingly provided by clinical and research laboratories; however, only a limited number of quality control and reference materials are currently available for many of the TPMT and NUDT15 variants included in clinical tests. To address this need, the Division of Laboratory Systems, Centers for Disease Control and Prevention-based Genetic Testing Reference Material (GeT-RM) coordination program, in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Institute for Medical Research, has characterized 19 DNA samples derived from Coriell cell lines. DNA samples were distributed to four volunteer testing laboratories for genotyping using a variety of commercially available and laboratory developed tests and/or Sanger sequencing. Of the 12 samples characterized for TPMT, newly identified variants include TPMT∗2, ∗6, ∗12, ∗16, ∗21, ∗24, ∗32, ∗33, and ∗40; for the 7 NUDT15 reference material samples, newly identified variants are NUDT15∗2, ∗3, ∗4, ∗5, ∗6, and ∗9. In addition, a novel haplotype, TPMT∗46, was identified in this study. Preexisting data on an additional 11 Coriell samples, as well as some supplemental testing, were used to create comprehensive reference material panels for TPMT and NUDT15. These publicly available and well-characterized materials can be used to support the quality assurance and quality control programs of clinical laboratories performing clinical pharmacogenetic testing., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2022
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16. TPMT and NUDT15 Genotyping Recommendations: A Joint Consensus Recommendation of the Association for Molecular Pathology, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European Society for Pharmacogenomics and Personalized Therapy, and Pharmacogenomics Knowledgebase.
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Pratt VM, Cavallari LH, Fulmer ML, Gaedigk A, Hachad H, Ji Y, Kalman LV, Ly RC, Moyer AM, Scott SA, van Schaik RHN, Whirl-Carrillo M, and Weck KE
- Subjects
- Consensus, Genotype, Humans, Knowledge Bases, Methyltransferases, Pathologists, Pharmacists, Pathology, Molecular, Pharmacogenetics, Pyrophosphatases genetics
- Abstract
The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This article provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This article focuses on clinical TPMT and NUDT15 PGx testing, which may be applied to all thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15)-related medications. These recommendations are not to be interpreted as prescriptive, but to provide a reference guide., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2022
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17. Design and rationale of GUARDD-US: A pragmatic, randomized trial of genetic testing for APOL1 and pharmacogenomic predictors of antihypertensive efficacy in patients with hypertension.
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Eadon MT, Cavanaugh KL, Orlando LA, Christian D, Chakraborty H, Steen-Burrell KA, Merrill P, Seo J, Hauser D, Singh R, Beasley CM, Fuloria J, Kitzman H, Parker AS, Ramos M, Ong HH, Elwood EN, Lynch SE, Clermont S, Cicali EJ, Starostik P, Pratt VM, Nguyen KA, Rosenman MB, Calman NS, Robinson M, Nadkarni GN, Madden EB, Kucher N, Volpi S, Dexter PR, Skaar TC, Johnson JA, Cooper-DeHoff RM, and Horowitz CR
- Subjects
- Black or African American, Antihypertensive Agents, Apolipoprotein L1, Blood Pressure, Genetic Testing, Humans, Pharmacogenetics, Hypertension, Renal Insufficiency, Chronic
- Abstract
Rationale and Objective: APOL1 risk alleles are associated with increased cardiovascular and chronic kidney disease (CKD) risk. It is unknown whether knowledge of APOL1 risk status motivates patients and providers to attain recommended blood pressure (BP) targets to reduce cardiovascular disease., Study Design: Multicenter, pragmatic, randomized controlled clinical trial., Setting and Participants: 6650 individuals with African ancestry and hypertension from 13 health systems., Intervention: APOL1 genotyping with clinical decision support (CDS) results are returned to participants and providers immediately (intervention) or at 6 months (control). A subset of participants are re-randomized to pharmacogenomic testing for relevant antihypertensive medications (pharmacogenomic sub-study). CDS alerts encourage appropriate CKD screening and antihypertensive agent use., Outcomes: Blood pressure and surveys are assessed at baseline, 3 and 6 months. The primary outcome is change in systolic BP from enrollment to 3 months in individuals with two APOL1 risk alleles. Secondary outcomes include new diagnoses of CKD, systolic blood pressure at 6 months, diastolic BP, and survey results. The pharmacogenomic sub-study will evaluate the relationship of pharmacogenomic genotype and change in systolic BP between baseline and 3 months., Results: To date, the trial has enrolled 3423 participants., Conclusions: The effect of patient and provider knowledge of APOL1 genotype on systolic blood pressure has not been well-studied. GUARDD-US addresses whether blood pressure improves when patients and providers have this information. GUARDD-US provides a CDS framework for primary care and specialty clinics to incorporate APOL1 genetic risk and pharmacogenomic prescribing in the electronic health record., Trial Registration: ClinicalTrials.govNCT04191824., (Copyright © 2022. Published by Elsevier Inc.)
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- 2022
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18. Analytical Validation of a Computational Method for Pharmacogenetic Genotyping from Clinical Whole Exome Sequencing.
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Ly RC, Shugg T, Ratcliff R, Osei W, Lynnes TC, Pratt VM, Schneider BP, Radovich M, Bray SM, Salisbury BA, Parikh B, Sahinalp SC, Numanagić I, and Skaar TC
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- Cytochrome P-450 CYP3A genetics, DNA Copy Number Variations genetics, Genotype, High-Throughput Nucleotide Sequencing, Humans, Liver-Specific Organic Anion Transporter 1 genetics, Exome Sequencing, Cytochrome P-450 CYP2D6 genetics, Pharmacogenetics methods
- Abstract
Germline whole exome sequencing from molecular tumor boards has the potential to be repurposed to support clinical pharmacogenomics. However, accurately calling pharmacogenomics-relevant genotypes from exome sequencing data remains challenging. Accordingly, this study assessed the analytical validity of the computational tool, Aldy, in calling pharmacogenomics-relevant genotypes from exome sequencing data for 13 major pharmacogenes. Germline DNA from whole blood was obtained for 164 subjects seen at an institutional molecular solid tumor board. All subjects had whole exome sequencing from Ashion Analytics and panel-based genotyping from an institutional pharmacogenomics laboratory. Aldy version 3.3 was operationalized on the LifeOmic Precision Health Cloud with copy number fixed to two copies per gene. Aldy results were compared with those from genotyping for 56 star allele-defining variants within CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP4F2, DPYD, G6PD, NUDT15, SLCO1B1, and TPMT. Read depth was >100× for all variants except CYP3A4∗22. For 75 subjects in the validation cohort, all 3393 Aldy variant calls were concordant with genotyping. Aldy calls for 736 diplotypes containing alleles assessed by both platforms were also concordant. Aldy identified additional star alleles not covered by targeted genotyping for 139 diplotypes. Aldy accurately called variants and diplotypes for 13 major pharmacogenes, except for CYP2D6 variants involving copy number variations, thus allowing repurposing of whole exome sequencing to support clinical pharmacogenomics., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2022
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19. CYP2C8, CYP2C9, and CYP2C19 Characterization Using Next-Generation Sequencing and Haplotype Analysis: A GeT-RM Collaborative Project.
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Gaedigk A, Boone EC, Scherer SE, Lee SB, Numanagić I, Sahinalp C, Smith JD, McGee S, Radhakrishnan A, Qin X, Wang WY, Farrow EG, Gonzaludo N, Halpern AL, Nickerson DA, Miller NA, Pratt VM, and Kalman LV
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- Alleles, Genotype, Haplotypes genetics, Humans, Cytochrome P-450 CYP2C19 genetics, Cytochrome P-450 CYP2C8 genetics, Cytochrome P-450 CYP2C9 genetics, Genetic Testing, High-Throughput Nucleotide Sequencing
- Abstract
Pharmacogenetic tests typically target selected sequence variants to identify haplotypes that are often defined by star (∗) allele nomenclature. Due to their design, these targeted genotyping assays are unable to detect novel variants that may change the function of the gene product and thereby affect phenotype prediction and patient care. In the current study, 137 DNA samples that were previously characterized by the Genetic Testing Reference Material (GeT-RM) program using a variety of targeted genotyping methods were recharacterized using targeted and whole genome sequencing analysis. Sequence data were analyzed using three genotype calling tools to identify star allele diplotypes for CYP2C8, CYP2C9, and CYP2C19. The genotype calls from next-generation sequencing (NGS) correlated well to those previously reported, except when novel alleles were present in a sample. Six novel alleles and 38 novel suballeles were identified in the three genes due to identification of variants not covered by targeted genotyping assays. In addition, several ambiguous genotype calls from a previous study were resolved using the NGS and/or long-read NGS data. Diplotype calls were mostly consistent between the calling algorithms, although several discrepancies were noted. This study highlights the utility of NGS for pharmacogenetic testing and demonstrates that there are many novel alleles that are yet to be discovered, even in highly characterized genes such as CYP2C9 and CYP2C19., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. All rights reserved.)
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- 2022
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20. Clinical pharmacogenomic testing and reporting: A technical standard of the American College of Medical Genetics and Genomics (ACMG).
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Tayeh MK, Gaedigk A, Goetz MP, Klein TE, Lyon E, McMillin GA, Rentas S, Shinawi M, Pratt VM, and Scott SA
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- Genomics, Humans, Pharmacogenetics, Phenotype, United States, Genetics, Medical, Pharmacogenomic Testing
- Abstract
Pharmacogenomic testing interrogates germline sequence variants implicated in interindividual drug response variability to infer a drug response phenotype and to guide medication management for certain drugs. Specifically, discrete aspects of pharmacokinetics, such as drug metabolism, and pharmacodynamics, as well as drug sensitivity, can be predicted by genes that code for proteins involved in these pathways. Pharmacogenomics is unique and differs from inherited disease genetics because the drug response phenotype can be drug-dependent and is often unrecognized until an unexpected drug reaction occurs or a patient fails to respond to a medication. Genes and variants with sufficiently high levels of evidence and consensus may be included in a clinical pharmacogenomic test; however, result interpretation and phenotype prediction can be challenging for some genes and medications. This document provides a resource for laboratories to develop and implement clinical pharmacogenomic testing by summarizing publicly available resources and detailing best practices for pharmacogenomic nomenclature, testing, result interpretation, and reporting., Competing Interests: Conflict of Interest M.K.T., E.L., G.A.M., S.R., V.M.P., and S.A.S. serve as directors in clinical laboratories that perform a breadth of genetic and genomic analyses on a fee for service basis. The other authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
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- 2022
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21. Pharmacogenomics of Hypertension in CKD: The CKD-PGX Study.
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Eadon MT, Maddatu J, Moe SM, Sinha AD, Ferreira RM, Miller BW, Sher SJ, Su J, Pratt VM, Chapman AB, Skaar TC, and Moorthi RN
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- Cross-Sectional Studies, Humans, Pharmacogenetics, Prospective Studies, Hypertension complications, Renal Insufficiency, Chronic complications
- Abstract
Background: Patients with CKD often have uncontrolled hypertension despite polypharmacy. Pharmacogenomic drug-gene interactions (DGIs) may affect the metabolism or efficacy of antihypertensive agents. We report changes in hypertension control after providing a panel of 11 pharmacogenomic predictors of antihypertensive response., Methods: A prospective cohort with CKD and hypertension was followed to assess feasibility of pharmacogenomic testing implementation, self-reported provider utilization, and BP control. The analysis population included 382 subjects with hypertension who were genotyped for cross-sectional assessment of DGIs, and 335 subjects followed for 1 year to assess systolic BP (SBP) and diastolic BP (DBP)., Results: Most participants (58%) with uncontrolled hypertension had a DGI reducing the efficacy of one or more antihypertensive agents. Subjects with a DGI had 1.85-fold (95% CI, 1.2- to 2.8-fold) higher odds of uncontrolled hypertension, as compared with those without a DGI, adjusted for race, health system (safety-net hospital versus other locations), and advanced CKD (eGFR <30 ml/min). CYP2C9 -reduced metabolism genotypes were associated with losartan response and uncontrolled hypertension (odds ratio [OR], 5.2; 95% CI, 1.9 to 14.7). CYP2D6 -intermediate or -poor metabolizers had less frequent uncontrolled hypertension compared with normal metabolizers taking metoprolol or carvedilol (OR, 0.55; 95% CI, 0.3 to 0.95). In 335 subjects completing 1-year follow-up, SBP (-4.0 mm Hg; 95% CI, 1.6 to 6.5 mm Hg) and DBP (-3.3 mm Hg; 95% CI, 2.0 to 4.6 mm Hg) were improved. No significant difference in SBP or DBP change were found between individuals with and without a DGI., Conclusions: There is a potential role for the addition of pharmacogenomic testing to optimize antihypertensive regimens in patients with CKD.
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- 2022
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22. Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers.
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Shugg T, Ly RC, Rowe EJ, Philips S, Hyder MA, Radovich M, Rosenman MB, Pratt VM, Callaghan JT, Desta Z, Schneider BP, and Skaar TC
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- Cytochrome P-450 CYP2D6 genetics, Drug Interactions, Germ Cells, Humans, Neoplasms drug therapy, Pharmacogenetics
- Abstract
Purpose: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer., Methods: Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes., Results: Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme., Conclusion: Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer., Competing Interests: Milan RadovichEmployment: Caris Life SciencesLeadership: Caris Life SciencesStock and Other Ownership Interests: LifeOmic, Macrogenics, Immunomedics, Tyme TechnologiesHonoraria: LillyResearch Funding: Lilly (Inst), Boston Biomedical (Inst), Foundation Medicine (Inst), Epic Sciences (Inst), Pfizer (Inst), Genentech (Inst)Patents, Royalties, Other Intellectual Property: Combination therapy for the treatment of TNBC with a PI3K pathway inhibitor that targets PI3KDelta and PI3KGamma (Inst)Travel, Accommodations, Expenses: LifeOmic, Caris Life Sciences Victoria M. PrattStock and Other Ownership Interests: Quest Diagnostics, LabCorpOther Relationship: Avalon Heathcare John T. CallaghanEmployment: IU healthStock and Other Ownership Interests: Lilly, Abbott/AbbVie, Stryker (I) Bryan P. SchneiderHonoraria: Lilly, Research to PracticeResearch Funding: Genentech/Roche, Pfizer, Foundation Medicine, Exact Sciences Todd C. SkaarHonoraria: Tabula Rasa HealthcareConsulting or Advisory Role: Indiana University HealthTravel, Accommodations, Expenses: Tabula Rasa HealthcareOther Relationship: NIHNo other potential conflicts of interest were reported.
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- 2022
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23. Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing.
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Duarte JD, Dalton R, Elchynski AL, Smith DM, Cicali EJ, Lee JC, Duong BQ, Petry NJ, Aquilante CL, Beitelshees AL, Empey PE, Johnson JA, Obeng AO, Pasternak AL, Pratt VM, Ramsey LB, Tuteja S, Van Driest SL, Wiisanen K, Hicks JK, and Cavallari LH
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- Drug Prescriptions, Genetic Testing, Humans, Precision Medicine methods, Pharmacogenetics methods, Pharmacogenomic Testing
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Purpose: 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., (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)
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- 2021
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24. Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.
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Levy KD, Blake K, Fletcher-Hoppe C, Franciosi J, Goto D, Hicks JK, Holmes AM, Kanuri SH, Madden EB, Musty MD, Orlando L, Pratt VM, Ramos M, Wu R, and Ginsburg GS
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- 2021
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25. Recommendations for Clinical CYP2D6 Genotyping Allele Selection: A Joint Consensus Recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and the European Society for Pharmacogenomics and Personalized Therapy.
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Pratt VM, Cavallari LH, Del Tredici AL, Gaedigk A, Hachad H, Ji Y, Kalman LV, Ly RC, Moyer AM, Scott SA, van Schaik RHN, Whirl-Carrillo M, and Weck KE
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- Gene Frequency, Humans, Laboratories, Clinical, Netherlands, Pathologists psychology, Pharmacists psychology, Societies, Medical, United States, Alleles, Consensus, Cytochrome P-450 CYP2D6 genetics, Genotype, Genotyping Techniques methods, Pharmacogenomic Testing standards, Precision Medicine standards
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The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing, and to determine a minimal set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations on a minimal panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories in designing assays for PGx testing. When developing these recommendations, the Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations with regard to PGx testing. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This document is focused on clinical CYP2D6 PGx testing that may be applied to all cytochrome P450 2D6-metabolized medications. These recommendations are not meant to be interpreted as prescriptive but to provide a reference guide for clinical laboratories that may be either implementing PGx testing or reviewing and updating their existing platform., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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26. PharmVar GeneFocus: CYP2C9.
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Sangkuhl K, Claudio-Campos K, Cavallari LH, Agundez JAG, Whirl-Carrillo M, Duconge J, Del Tredici AL, Wadelius M, Rodrigues Botton M, Woodahl EL, Scott SA, Klein TE, Pratt VM, Daly AK, and Gaedigk A
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- Alleles, Haplotypes genetics, Humans, Knowledge Bases, Pharmaceutical Preparations administration & dosage, Pharmacogenetics methods, Cytochrome P-450 CYP2C9 genetics, Polymorphism, Genetic genetics
- Abstract
The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C9 gene. Genetic variation within the CYP2C9 gene locus impacts the metabolism or bioactivation of many clinically important drugs, including nonsteroidal anti-inflammatory drugs, phenytoin, antidiabetic agents, and angiotensin receptor blockers. Variable CYP2C9 activity is of particular importance regarding efficacy and safety of warfarin and siponimod as indicated in their package inserts. This GeneFocus provides a comprehensive overview and summary of CYP2C9 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase and the Clinical Pharmacogenetics Implementation Consortium., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)
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- 2021
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27. Characterization of Reference Materials with an Association for Molecular Pathology Pharmacogenetics Working Group Tier 2 Status: CYP2C9, CYP2C19, VKORC1, CYP2C Cluster Variant, and GGCX: A GeT-RM Collaborative Project.
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Pratt VM, Turner A, Broeckel U, Dawson DB, Gaedigk A, Lynnes TC, Medeiros EB, Moyer AM, Requesens D, Vetrini F, and Kalman LV
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- Alleles, Genotype, Genotyping Techniques, Humans, Pharmacogenomic Testing, Carboxy-Lyases genetics, Cytochrome P-450 CYP2C19 genetics, Cytochrome P-450 CYP2C9 genetics, Cytochrome P-450 Enzyme System genetics, Pharmacogenetics methods, Pharmacogenomic Variants, Vitamin K Epoxide Reductases genetics
- Abstract
Pharmacogenetic testing is increasingly available from clinical and research laboratories. However, only a limited number of quality control and other reference materials are currently available for many of the variants that are tested. The Association for Molecular Pathology Pharmacogenetic Work Group has published a series of papers recommending alleles for inclusion in clinical testing. Several of the alleles were not considered for tier 1 because of a lack of reference materials. To address this need, the Division of Laboratory Systems, Centers for Disease Control and Prevention-based Genetic Testing Reference Material (GeT-RM) program, in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Institute for Medical Research, has characterized 18 DNA samples derived from Coriell cell lines. DNA samples were distributed to five volunteer testing laboratories for genotyping using three commercially available and laboratory developed tests. Several tier 2 variants, including CYP2C9∗13, CYP2C19∗35, the CYP2C cluster variant (rs12777823), two variants in VKORC1 (rs61742245 and rs72547529) related to warfarin resistance, and two variants in GGCX (rs12714145 and rs11676382) related to clotting factor activation, were identified among these samples. These publicly available materials complement the pharmacogenetic reference materials previously characterized by the GeT-RM program and will support the quality assurance and quality control programs of clinical laboratories that perform pharmacogenetic testing., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2021
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28. Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network.
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Ginsburg GS, Cavallari LH, Chakraborty H, Cooper-DeHoff RM, Dexter PR, Eadon MT, Ferket BS, Horowitz CR, Johnson JA, Kannry J, Kucher N, Madden EB, Orlando LA, Parker W, Peterson J, Pratt VM, Rakhra-Burris TK, Ramos MA, Skaar TC, Sperber N, Steen-Burrell KA, Van Driest SL, Voora D, Wiisanen K, Winterstein AG, and Volpi S
- Subjects
- Apolipoprotein L1, Electronic Health Records, Humans, Pharmacogenomic Testing, Precision Medicine, Decision Support Systems, Clinical, Genomics
- Abstract
Purpose: A critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions., Methods: The Implementing Genomics in Practice Pragmatic Trials Network (IGNITE PTN) was formed in 2018 to measure the clinical utility and cost-effectiveness of genomic medicine interventions, to assess approaches for real-world application of genomic medicine in diverse clinical settings, and to produce generalizable knowledge on clinical trials using genomic interventions. Five clinical sites and a coordinating center evaluated trial proposals and developed working groups to enable their implementation., Results: Two pragmatic clinical trials (PCTs) have been initiated, one evaluating genetic risk APOL1 variants in African Americans in the management of their hypertension, and the other to evaluate the use of pharmacogenetic testing for medications to manage acute and chronic pain as well as depression., Conclusion: IGNITE PTN is a network that carries out PCTs in genomic medicine; it is focused on diversity and inclusion of underrepresented minority trial participants; it uses electronic health records and clinical decision support to deliver the interventions. IGNITE PTN will develop the evidence to support (or oppose) the adoption of genomic medicine interventions by patients, providers, and payers.
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- 2021
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29. Multi-Institutional Implementation of Clinical Decision Support for APOL1, NAT2, and YEATS4 Genotyping in Antihypertensive Management.
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Schneider TM, Eadon MT, Cooper-DeHoff RM, Cavanaugh KL, Nguyen KA, Arwood MJ, Tillman EM, Pratt VM, Dexter PR, McCoy AB, Orlando LA, Scott SA, Nadkarni GN, Horowitz CR, and Kannry JL
- Abstract
(1) Background: Clinical decision support (CDS) is a vitally important adjunct to the implementation of pharmacogenomic-guided prescribing in clinical practice. A novel CDS was sought for the APOL1 , NAT2 , and YEATS4 genes to guide optimal selection of antihypertensive medications among the African American population cared for at multiple participating institutions in a clinical trial. (2) Methods: The CDS committee, made up of clinical content and CDS experts, developed a framework and contributed to the creation of the CDS using the following guiding principles: 1. medical algorithm consensus; 2. actionability; 3. context-sensitive triggers; 4. workflow integration; 5. feasibility; 6. interpretability; 7. portability; and 8. discrete reporting of lab results. (3) Results: Utilizing the principle of discrete patient laboratory and vital information, a novel CDS for APOL1 , NAT2 , and YEATS4 was created for use in a multi-institutional trial based on a medical algorithm consensus. The alerts are actionable and easily interpretable, clearly displaying the purpose and recommendations with pertinent laboratory results, vitals and links to ordersets with suggested antihypertensive dosages. Alerts were either triggered immediately once a provider starts to order relevant antihypertensive agents or strategically placed in workflow-appropriate general CDS sections in the electronic health record (EHR). Detailed implementation instructions were shared across institutions to achieve maximum portability. (4) Conclusions: Using sound principles, the created genetic algorithms were applied across multiple institutions. The framework outlined in this study should apply to other disease-gene and pharmacogenomic projects employing CDS.
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- 2021
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30. Expanding evidence leads to new pharmacogenomics payer coverage.
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Empey PE, Pratt VM, Hoffman JM, Caudle KE, and Klein TE
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- Humans, Pharmacogenetics
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- 2021
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31. Ending the pharmacogenomic gag rule: the imperative to report all results.
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Halverson CM, Pratt VM, Skaar TC, and Schwartz PH
- Subjects
- Adverse Drug Reaction Reporting Systems, Humans, Negative Results, Pharmacogenomic Testing, Precision Medicine, Publishing, Pharmacogenetics ethics
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- 2021
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32. Tracheal Aspirate as an Alternative Biologic Sample for Pharmacogenomics Testing in Mechanically Ventilated Pediatric Patients.
- Author
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Hargreaves KA, Pratt VM, Medeiros EB, Lynnes TC, Granfield CA, Skaar TC, Iwata-Otsubo A, and Tillman EM
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- Adolescent, Child, DNA analysis, Drug-Related Side Effects and Adverse Reactions genetics, Feasibility Studies, Female, Humans, Infant, Intensive Care Units, Pediatric, Male, Pharmacogenomic Variants, Pilot Projects, Respiration, Artificial, Bodily Secretions chemistry, Drug-Related Side Effects and Adverse Reactions prevention & control, Genotyping Techniques methods, Pharmacogenomic Testing methods, Trachea metabolism
- Abstract
Patients in the pediatric intensive care unit are exposed to multiple medications and are at high risk for adverse drug reactions. Pharmacogenomic (PGx) testing could help decrease their risk of adverse reactions. Although whole blood is preferred for PGx testing, blood volume in this population is often limited. However, for patients on mechanical ventilation, tracheal secretions are abundant, frequently suctioned, and discarded. Thus, the aim of this pilot study was to determine if tracheal aspirates could be used as a source of human genomic DNA for PGx testing. We successfully extracted DNA from tracheal secretions of all 23 patients in the study. The samples were successfully genotyped for 10 clinically actionable single nucleotide variants across 3 cytochrome P450 genes (CYP2D6, CYP2C19, and CYP3A5). Using DNA from whole blood samples in 11 of the patients, we confirmed the accuracy of the genotyping with 100% concordance. Therefore, our results support the use of tracheal aspirates from mechanically ventilated children as an adequate biospecimen for clinical genetic testing., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
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- 2021
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33. PharmVar GeneFocus: CYP2C19.
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Botton MR, Whirl-Carrillo M, Del Tredici AL, Sangkuhl K, Cavallari LH, Agúndez JAG, Duconge J, Lee MTM, Woodahl EL, Claudio-Campos K, Daly AK, Klein TE, Pratt VM, Scott SA, and Gaedigk A
- Subjects
- Alleles, Genetic Variation genetics, Genotype, Haplotypes genetics, Humans, Knowledge Bases, Pharmacogenetics methods, Cytochrome P-450 CYP2C19 genetics
- Abstract
The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C19 gene. CYP2C19 genetic variation impacts the metabolism of many drugs and has been associated with both efficacy and safety issues for several commonly prescribed medications. This GeneFocus provides a comprehensive overview and summary of CYP2C19 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase and the Clinical Pharmacogenetics Implementation Consortium (CPIC)., (© 2020 The Author. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2021
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34. Characterization of Reference Materials for Spinal Muscular Atrophy Genetic Testing: A Genetic Testing Reference Materials Coordination Program Collaborative Project.
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Prior TW, Bayrak-Toydemir P, Lynnes TC, Mao R, Metcalf JD, Muralidharan K, Iwata-Otsubo A, Pham HT, Pratt VM, Qureshi S, Requesens D, Shen J, Vetrini F, and Kalman L
- Subjects
- Alleles, Cell Line, DNA Copy Number Variations, Gene Dosage, Genetic Counseling methods, Genotyping Techniques methods, Humans, Infant, Newborn, Neonatal Screening methods, Phenotype, Real-Time Polymerase Chain Reaction methods, Survival of Motor Neuron 2 Protein genetics, Genetic Carrier Screening methods, Muscular Atrophy, Spinal diagnosis, Muscular Atrophy, Spinal genetics, Survival of Motor Neuron 1 Protein genetics
- Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive disorder predominately caused by bi-allelic loss of the SMN1 gene. Increased copies of SMN2, a low functioning nearly identical paralog, are associated with a less severe phenotype. SMA was recently recommended for inclusion in newborn screening. Clinical laboratories must accurately measure SMN1 and SMN2 copy number to identify SMA patients and carriers, and to identify individuals likely to benefit from therapeutic interventions. Having publicly available and appropriately characterized reference materials with various combinations of SMN1 and SMN2 copy number variants is critical to assure accurate SMA clinical testing. To address this need, the CDC-based Genetic Testing Reference Materials Coordination Program, in collaboration with members of the genetic testing community and the Coriell Institute for Medical Research, has characterized 15 SMA reference materials derived from publicly available cell lines. DNA samples were distributed to four volunteer testing laboratories for genotyping using three different methods. The characterized samples had zero to four copies of SMN1 and zero to five copies SMN2. The samples also contained clinically important allele combinations (eg, zero copies SMN1, three copies SMN2), and several had markers indicative of an SMA carrier. These and other reference materials characterized by the Genetic Testing Reference Materials Coordination Program are available from the Coriell Institute and are proposed to support the quality of clinical laboratory testing., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2021
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35. BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms.
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Barish S, Barakat TS, Michel BC, Mashtalir N, Phillips JB, Valencia AM, Ugur B, Wegner J, Scott TM, Bostwick B, Murdock DR, Dai H, Perenthaler E, Nikoncuk A, van Slegtenhorst M, Brooks AS, Keren B, Nava C, Mignot C, Douglas J, Rodan L, Nowak C, Ellard S, Stals K, Lynch SA, Faoucher M, Lesca G, Edery P, Engleman KL, Zhou D, Thiffault I, Herriges J, Gass J, Louie RJ, Stolerman E, Washington C, Vetrini F, Otsubo A, Pratt VM, Conboy E, Treat K, Shannon N, Camacho J, Wakeling E, Yuan B, Chen CA, Rosenfeld JA, Westerfield M, Wangler M, Yamamoto S, Kadoch C, Scott DA, and Bellen HJ
- Subjects
- Adolescent, Animals, Child, Child, Preschool, Drosophila Proteins genetics, Drosophila melanogaster, Female, Genes, Dominant, Genetic Variation, Haploinsufficiency, Humans, Infant, Male, Microscopy, Confocal, Neuroglia metabolism, Neurons metabolism, Protein Binding, Zebrafish, Zebrafish Proteins genetics, Chromosomal Proteins, Non-Histone genetics, Developmental Disabilities genetics, Mutation, Missense, Phenotype, Tumor Suppressor Proteins genetics
- Abstract
SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported., (Copyright © 2020 American Society of Human Genetics. All rights reserved.)
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- 2020
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36. EVEN-PLUS syndrome: A case report with novel variants in HSPA9 and evidence of HSPA9 gene dysfunction.
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Younger G, Vetrini F, Weaver DD, Lynnes TC, Treat K, Pratt VM, and Torres-Martinez W
- Subjects
- Clubfoot complications, Cryptorchidism complications, Exome, Genetic Association Studies, Genetic Variation, Humans, Hydronephrosis complications, Imaging, Three-Dimensional, Infant, Karyotyping, Male, Muscle Hypotonia complications, Mutation, Phenotype, RNA, Messenger metabolism, Ribs abnormalities, Septum Pellucidum abnormalities, Sternum abnormalities, Syndrome, Exome Sequencing, HSP70 Heat-Shock Proteins genetics, Mitochondrial Proteins genetics, Musculoskeletal Abnormalities genetics, Mutation, Missense, Septum Pellucidum pathology
- Abstract
EVEN-PLUS syndrome is a rare condition characterized by its involvement of the Epiphyses, Vertebrae, Ears, and Nose, PLUS other associated findings. We report here the fifth case of EVEN-PLUS syndrome with novel variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in the HSPA9 gene identified through whole-exome sequencing. The patient is the first male known to be affected and presented with additional features not previously described with EVEN-PLUS syndrome. These features include agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia. qPCR analysis provides supporting evidence for a nonsense-mediated decay mechanism for the HSPA9 truncating variant. In silico 3D modeling supports the pathogenicity of the c.955C > T (p.L319F) missense variant. The study presented here further describes the syndrome and broadens its mutational and phenotypic spectrum. Our study also lends support to HSPA9 variants as the underlying etiology of EVEN-PLUS syndrome and ultimately provides a better understanding of the molecular basis of the condition., (© 2020 Wiley Periodicals LLC.)
- Published
- 2020
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37. Identifying End Users' Preferences about Structuring Pharmacogenetic Test Orders in an Electronic Health Record System.
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Hull LE, Vassy JL, Stone A, Chanfreau-Coffinier CC, Heise CW, Pratt VM, Przygodzki R, Voils CI, Voora D, Wang-Rodriguez J, Schichman SA, and Scheuner MT
- Subjects
- Humans, Surveys and Questionnaires, Choice Behavior, Electronic Health Records, Pharmacogenomic Testing
- Abstract
Pharmacogenetics (PGx) testing can be used for detecting genetic variations that may affect an individual's anticipated metabolism of, or response to, medications. Although several studies have focused on developing tools for delivering results from PGx testing, there is a relative dearth of information about how to design provider-friendly electronic order-entry systems for PGx. The U.S. Department of Veterans Affairs (VA) is preparing to implement a new electronic health records system. In this study, VA PGx test end users were surveyed about their preferences for how electronic test orders for PGx should be structured, including the nomenclature that should be used to search for and identify PGx-test orders, whether to offer single- versus multigene tests, and whether information about test methodology should be included in the order name. Responses were analyzed systematically to identify areas of agreement and disagreement with the survey options, and areas where respondents' opinions diverged. End users endorsed preferences for flexible ways to identify and order PGx tests and multigene panel tests; opinions on whether test methodology should be included in the test name were divergent. The results could be used for both informing the VA's new electronic health records implementation (including how PGx tests are searched for and ordered) and for providing insights for other health systems implementing PGx-testing programs., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2020
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38. Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.
- Author
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Levy KD, Blake K, Fletcher-Hoppe C, Franciosi J, Goto D, Hicks JK, Holmes AM, Kanuri SH, Madden EB, Musty MD, Orlando L, Pratt VM, Ramos M, Wu R, and Ginsburg GS
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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39. Recommendations for Clinical Warfarin Genotyping Allele Selection: A Report of the Association for Molecular Pathology and the College of American Pathologists.
- Author
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Pratt VM, Cavallari LH, Del Tredici AL, Hachad H, Ji Y, Kalman LV, Ly RC, Moyer AM, Scott SA, Whirl-Carrillo M, and Weck KE
- Subjects
- Dose-Response Relationship, Drug, Drug Resistance genetics, Gene Frequency, Genetic Testing methods, Humans, Polymorphism, Single Nucleotide, Precision Medicine methods, Research Report, Alleles, Anticoagulants administration & dosage, Cytochrome P-450 CYP2C9 genetics, Genotype, Genotyping Techniques methods, Vitamin K Epoxide Reductases genetics, Warfarin administration & dosage
- Abstract
The goal of the Association for Molecular Pathology (AMP) Clinical Practice Committee's AMP Pharmacogenomics (PGx) Working Group is to define the key attributes of PGx alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum panel of variant alleles (tier 1) and an extended panel of variant alleles (tier 2) that will aid clinical laboratories when designing assays for PGx testing. The AMP PGx Working Group considered functional impact of the variants, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. The ultimate goal is to promote standardization of PGx gene/allele testing across clinical laboratories. These recommendations are not to be interpreted as prescriptive but to provide a reference guide. Of note, a separate article with recommendations for CYP2C9 allele selection was previously developed by the PGx Working Group that can be applied broadly to CYP2C9-related medications. The warfarin allele recommendations in this report incorporate the previous CYP2C9 allele recommendations and additional genes and alleles that are specific to warfarin testing., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2020
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40. Severe Capecitabine Toxicity Associated With a Rare DPYD Variant Identified Through Whole-Genome Sequencing.
- Author
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Ly RC, Schmidt RE, Kiel PJ, Pratt VM, Schneider BP, Radovich M, Offer SM, Diasio RB, and Skaar TC
- Abstract
Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Patrick J. KielEmployment: Amgen Speakers' Bureau: Takeda, Celgene, GenentechVictoria M. PrattStock and Other Ownership Interests: Quest Diagnostics, LabCorp Other Relationship: Avalon Healthcare Uncompensated Relationships: Veritas GeneticsMilan RadovichStock and Other Ownership Interests: LifeOmic, Macrogenics, Immunomedics, ArQule, Tyme Technologies Travel, Accommodations, Expenses: LifeOmicTodd C. SkaarHonoraria: Tabula Rasa Healthcare Travel, Accommodations, Expenses: Tabula Rasa Healthcare Other Relationship: National Institutes of Health No other potential conflicts of interest were reported.
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- 2020
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41. Implementation of a Renal Precision Medicine Program: Clinician Attitudes and Acceptance.
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Spiech KM, Tripathy PR, Woodcock AM, Sheth NA, Collins KS, Kannegolla K, Sinha AD, Sharfuddin AA, Pratt VM, Khalid M, Hains DS, Moe SM, Skaar TC, Moorthi RN, and Eadon MT
- Abstract
A precision health initiative was implemented across a multi-hospital health system, wherein a panel of genetic variants was tested and utilized in the clinical care of chronic kidney disease (CKD) patients. Pharmacogenomic predictors of antihypertensive response and genomic predictors of CKD were provided to clinicians caring for nephrology patients. To assess clinician knowledge, attitudes, and willingness to act on genetic testing results, a Likert-scale survey was sent to and self-administered by these nephrology providers (N = 76). Most respondents agreed that utilizing pharmacogenomic-guided antihypertensive prescribing is valuable (4.0 ± 0.7 on a scale of 1 to 5, where 5 indicates strong agreement). However, the respondents also expressed reluctance to use genetic testing for CKD risk stratification due to a perceived lack of supporting evidence (3.2 ± 0.9). Exploratory sub-group analyses associated this reluctance with negative responses to both knowledge and attitude discipline questions, thus suggesting reduced exposure to and comfort with genetic information. Given the evolving nature of genomic implementation in clinical care, further education is warranted to help overcome these perception barriers., Competing Interests: The authors declare that they have no relevant financial interests.
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- 2020
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42. Influence of Uridine Diphosphate Glucuronosyltransferase Family 1 Member A1 and Solute Carrier Organic Anion Transporter Family 1 Member B1 Polymorphisms and Efavirenz on Bilirubin Disposition in Healthy Volunteers.
- Author
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Collins KS, Metzger IF, Gufford BT, Lu JB, Medeiros EB, Pratt VM, Skaar TC, and Desta Z
- Subjects
- Adolescent, Adult, Female, Genotype, Healthy Volunteers, Humans, Male, Middle Aged, Multidrug Resistance-Associated Protein 2, Multidrug Resistance-Associated Proteins genetics, Phenotype, Young Adult, Alkynes pharmacology, Benzoxazines pharmacology, Bilirubin metabolism, Cyclopropanes pharmacology, Glucuronosyltransferase genetics, Liver-Specific Organic Anion Transporter 1 genetics, Polymorphism, Single Nucleotide genetics
- Abstract
Chronic administration of efavirenz is associated with decreased serum bilirubin levels, probably through induction of UGT1A1 We assessed the impact of efavirenz monotherapy and UGT1A1 phenotypes on total, conjugated, and unconjugated serum bilirubin levels in healthy volunteers. Healthy volunteers were enrolled into a clinical study designed to address efavirenz pharmacokinetics, drug interactions, and pharmacogenetics. Volunteers received multiple oral doses (600 mg/day for 17 days) of efavirenz. Serum bilirubin levels were obtained at study entry and 1 week after completion of the study. DNA genotyping was performed for UGT1A1 [ *80 (C>T), *6 (G>A), *28 (TA
7 ), *36 (TA5 ), and *37 (TA8 )] and for SLCO1B1 [ *5 (521T>C) and *1b (388A>G] variants. Diplotype predicted phenotypes were classified as normal, intermediate, and slow metabolizers. Compared with bilirubin levels at screening, treatment with efavirenz significantly reduced total, conjugated, and unconjugated bilirubin. After stratification by UGT1A1 phenotypes, there was a significant decrease in total bilirubin among all phenotypes, conjugated bilirubin among intermediate metabolizers, and unconjugated bilirubin among normal and intermediate metabolizers. The data also show that UGT1A1 genotype predicts serum bilirubin levels at baseline, but this relationship is lost after efavirenz treatment. SLCO1B1 genotypes did not predict bilirubin levels at baseline or after efavirenz treatment. Our data suggest that efavirenz may alter bilirubin disposition mainly through induction of UGT1A1 metabolism and efflux through multidrug resistance-associated protein 2. SIGNIFICANCE STATEMENT: Efavirenz likely alters the pharmacokinetics of coadministered drugs, potentially causing lack of efficacy or increased adverse effects, as well as the disposition of endogenous compounds relevant in homeostasis through upregulation of UGT1A1 and multidrug resistance-associated protein 2. Measurement of unconjugated and conjugated bilirubin during new drug development may provide mechanistic understanding regarding enzyme and transporters modulated by the new drug., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2020
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43. PharmVar and the Landscape of Pharmacogenetic Resources.
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Gaedigk A, Whirl-Carrillo M, Pratt VM, Miller NA, and Klein TE
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- Algorithms, Alleles, Computational Biology, Humans, Pharmacogenomic Testing, Databases, Factual, Pharmacogenetics
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- 2020
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44. An unusual cause for Coffin-Lowry syndrome: Three brothers with a novel microduplication in RPS6KA3.
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Castelluccio VJ, Vetrini F, Lynnes T, Jones J, Holloway L, Belonis A, Breman AM, Graham BH, Sapp K, Wilson T, Schwartz CE, Pratt VM, and Weaver DD
- Subjects
- Child, Facies, Genetic Association Studies, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation, Pedigree, Phenotype, Chromosome Duplication, Coffin-Lowry Syndrome diagnosis, Coffin-Lowry Syndrome genetics, Ribosomal Protein S6 Kinases, 90-kDa genetics, Siblings
- Abstract
Coffin-Lowry syndrome (CLS) is a rare X-linked disorder characterized by moderate to severe intellectual disability, hypotonia, craniofacial features, tapering digits, short stature, and skeletal deformities. Using whole exome sequencing and high-resolution targeted comparative genomic hybridization array analysis, we identified a novel microduplication encompassing exons five through nine of RPS6KA3 in three full brothers. Each brother presented with intellectual disability and clinical and radiographic features consistent with CLS. qRT-PCR analyses performed on mRNA from the peripheral blood of the three siblings revealed a marked reduction of RPS6KA3 levels suggesting a loss-of-function mechanism. PCR analysis of the patients' cDNA detected a band greater than expected for an exon 4-10 amplicon, suggesting this was likely a direct duplication that lies between exons 4 through 10, which was later confirmed by Sanger sequencing. This microduplication is only the third intragenic duplication of RPS6KA3, and the second and smallest reported to date thought to cause CLS. Our study further supports the clinical utility of methods such as next-generation sequencing and high-resolution genomic arrays to detect small intragenic duplications. These methods, coupled with expression studies and cDNA structural analysis have the capacity to confirm the diagnosis of CLS in these rare cases., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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45. Characterization of Reference Materials for Genetic Testing of CYP2D6 Alleles: A GeT-RM Collaborative Project.
- Author
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Gaedigk A, Turner A, Everts RE, Scott SA, Aggarwal P, Broeckel U, McMillin GA, Melis R, Boone EC, Pratt VM, and Kalman LV
- Subjects
- Genetic Variation, Haplotypes genetics, High-Throughput Nucleotide Sequencing, Humans, Intersectoral Collaboration, Multiplex Polymerase Chain Reaction, Real-Time Polymerase Chain Reaction, Reference Standards, Alleles, Cytochrome P-450 CYP2D6 genetics, Genotyping Techniques standards
- Abstract
Pharmacogenetic testing increasingly is available from clinical and research laboratories. However, only a limited number of quality control and other reference materials currently are available for the complex rearrangements and rare variants that occur in the CYP2D6 gene. To address this need, the Division of Laboratory Systems, CDC-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Cell Repositories (Camden, NJ), has characterized 179 DNA samples derived from Coriell cell lines. Testing included the recharacterization of 137 genomic DNAs that were genotyped in previous Genetic Testing Reference Material Coordination Program studies and 42 additional samples that had not been characterized previously. DNA samples were distributed to volunteer testing laboratories for genotyping using a variety of commercially available and laboratory-developed tests. These publicly available samples will support the quality-assurance and quality-control programs of clinical laboratories performing CYP2D6 testing., (Copyright © 2019 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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46. Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing.
- Author
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Cavallari LH, Van Driest SL, Prows CA, Bishop JR, Limdi NA, Pratt VM, Ramsey LB, Smith DM, Tuteja S, Duong BQ, Hicks JK, Lee JC, Obeng AO, Beitelshees AL, Bell GC, Blake K, Crona DJ, Dressler L, Gregg RA, Hines LJ, Scott SA, Shelton RC, Weitzel KW, Johnson JA, Peterson JF, Empey PE, and Skaar TC
- Subjects
- Cytochrome P-450 CYP2D6 pharmacology, Decision Support Systems, Clinical, Drug Prescriptions standards, Genotype, Humans, Pharmacogenomic Testing methods, Pharmacogenomic Testing trends, Phenotype, Cytochrome P-450 CYP2D6 genetics, Genetic Testing methods, Pharmacogenetics methods
- Abstract
Purpose: 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.
- Published
- 2019
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47. Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists.
- Author
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Pratt VM, Cavallari LH, Del Tredici AL, Hachad H, Ji Y, Moyer AM, Scott SA, Whirl-Carrillo M, and Weck KE
- Subjects
- Alleles, Anticoagulants administration & dosage, Humans, Pharmacogenomic Testing methods, Cytochrome P-450 CYP2C9 genetics, Guidelines as Topic, Pathology, Molecular, Pharmacogenomic Testing standards, Polymorphism, Genetic
- Abstract
The goals of the Association for Molecular Pathology Pharmacogenomics (PGx) Working Group of the Association for Molecular Pathology Clinical Practice Committee are to define the key attributes of PGx alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for CYP2C9 testing. The Working Group considered the functional impact of the variants, allele frequencies in different populations and ethnicities, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. Our goal is to promote standardization of testing PGx genes and alleles across clinical laboratories. These recommendations are not to be interpreted as restrictive but to provide a reference guide. The current document will focus on CYP2C9 testing that can be applied to all CYP2C9-related medications. A separate recommendation on warfarin PGx testing is being developed to include recommendations on CYP2C9 alleles and additional warfarin sensitivity-associated genes and alleles., (Copyright © 2019 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
48. Response to Gammal et al.
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Vassy JL, Stone A, Callaghan JT, Mendes M, Meyer LJ, Pratt VM, Przygodzki RM, Scheuner MT, Wang-Rodriguez J, and Schichman SA
- Subjects
- Humans, Pharmacogenetics, United States, United States Department of Veterans Affairs, Veterans Health, Pharmacogenomic Testing, Veterans
- Published
- 2019
- Full Text
- View/download PDF
49. Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.
- Author
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Levy KD, Blake K, Fletcher-Hoppe C, Franciosi J, Goto D, Hicks JK, Holmes AM, Kanuri SH, Madden EB, Musty MD, Orlando L, Pratt VM, Ramos M, Wu R, and Ginsburg GS
- Abstract
The original version of this Article contained an error in the spelling of the author Geoffrey S. Ginsburg, which was incorrectly given as Geoffrey Ginsburg. This has now been corrected in both the PDF and HTML versions of the Article.
- Published
- 2019
- Full Text
- View/download PDF
50. Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology.
- Author
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Swart M, Stansberry WM, Pratt VM, Medeiros EB, Kiel PJ, Shen F, Schneider BP, and Skaar TC
- Subjects
- Genotype, Germ-Line Mutation genetics, Humans, Sensitivity and Specificity, Genotyping Techniques methods, Mutation genetics, Neoplasms genetics, Neoplasms therapy
- Abstract
The Clinical Laboratory Improvement Amendments of 1988 require that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a Clinical Laboratory Improvement Amendments-accredited laboratory. Because no known reference materials were available, existing DNA samples were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other Clinical Laboratory Improvement Amendments-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays., (Copyright © 2019 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
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