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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.)

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.)

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.)

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.)

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.

High-throughput sequencing provides the means to determine the allelic decomposition for any gene of interest-the number of copies and the exact sequence content of each copy of a gene. Although many clinically and functionally important genes are highly polymorphic and have undergone structural alterations, no high-throughput sequencing data analysis tool has yet been designed to effectively solve the full allelic decomposition problem. Here we introduce a combinatorial optimization framework that successfully resolves this challenging problem, including for genes with structural alterations. We provide an associated computational tool Aldy that performs allelic decomposition of highly polymorphic, multi-copy genes through using whole or targeted genome sequencing data. For a large diverse sequencing data set, Aldy identifies multiple rare and novel alleles for several important pharmacogenes, significantly improving upon the accuracy and utility of current genotyping assays. As more data sets become available, we expect Aldy to become an essential component of genotyping toolkits.

Motivation: CYP2D6 is highly polymorphic gene which encodes the (CYP2D6) enzyme, involved in the metabolism of 20-25% of all clinically prescribed drugs and other xenobiotics in the human body. CYP2D6 genotyping is recommended prior to treatment decisions involving one or more of the numerous drugs sensitive to CYP2D6 allelic composition. In this context, high-throughput sequencing (HTS) technologies provide a promising time-efficient and cost-effective alternative to currently used genotyping techniques. To achieve accurate interpretation of HTS data, however, one needs to overcome several obstacles such as high sequence similarity and genetic recombinations between CYP2D6 and evolutionarily related pseudogenes CYP2D7 and CYP2D8, high copy number variation among individuals and short read lengths generated by HTS technologies., Results: In this work, we present the first algorithm to computationally infer CYP2D6 genotype at basepair resolution from HTS data. Our algorithm is able to resolve complex genotypes, including alleles that are the products of duplication, deletion and fusion events involving CYP2D6 and its evolutionarily related cousin CYP2D7. Through extensive experiments using simulated and real datasets, we show that our algorithm accurately solves this important problem with potential clinical implications., Availability and Implementation: Cypiripi is available at http://sfu-compbio.github.io/cypiripi., (© The Author 2015. Published by Oxford University Press.)

Tamoxifen, a widely prescribed drug for the treatment and prevention of breast cancer, is metabolized to more potent metabolites by the cytochrome P450 2D6 (CYP2D6) enzyme. Variants in the CYP2D6 gene can cause patients to be either intermediate or poor metabolizers, thereby rendering tamoxifen treatment less effective. Testing for CYP2D6 gene variants is available in Clinical Laboratory Improvement Amendments-certified clinical laboratories; however, the biological complexity of the variants makes result interpretation and phenotype prediction challenging. This article describes the clinical significance of variants as well as important analytical, interpretative, and reporting issues. It is designed to be a guideline for clinical laboratory professionals in performing tests and interpreting results with respect to CYP2D6 genetic variants.

Pharmacogenetic testing is becoming more common; however, very few quality control and other reference materials that cover alleles commonly included in such assays are currently available. To address these needs, the Centers for Disease Control and Prevention's Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing community and the Coriell Cell Repositories, have characterized a panel of 107 genomic DNA reference materials for five loci (CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1) that are commonly included in pharmacogenetic testing panels and proficiency testing surveys. Genomic DNA from publicly available cell lines was sent to volunteer laboratories for genotyping. Each sample was tested in three to six laboratories using a variety of commercially available or laboratory-developed platforms. The results were consistent among laboratories, with differences in allele assignments largely related to the manufacturer's assay design and variable nomenclature, especially for CYP2D6. The alleles included in the assay platforms varied, but most were identified in the set of 107 DNA samples. Nine additional pharmacogenetic loci (CYP4F2, EPHX1, ABCB1, HLAB, KIF6, CYP3A4, CYP3A5, TPMT, and DPD) were also tested. These samples are publicly available from Coriell and will be useful for quality assurance, proficiency testing, test development, and research.

PurposeThe Veterans Health Administration (VHA) Clinical Pharmacogenetics Subcommittee is charged with making recommendations about whether specific pharmacogenetic tests should be used in healthcare at VHA facilities. We describe a process to inform VHA pharmacogenetic testing policy.MethodsAfter developing consensus definitions of clinical validity and utility, the Subcommittee identified salient drug-gene pairs with potential clinical application in VHA. Members met monthly to discuss each drug-gene pair, the evidence of clinical utility for the associated pharmacogenetic test, and any VHA-specific testing considerations. The Subcommittee classified each test as strongly recommended, recommended, or not routinely recommended before drug initiation.ResultsOf 30 drug-gene pair tests reviewed, the Subcommittee classified 4 (13%) as strongly recommended, including HLA-B*15:02 for carbamazepine-associated Stevens-Johnston syndrome and G6PD for rasburicase-associated hemolytic anemia; 12 (40%) as recommended, including CYP2D6 for codeine toxicity; and 14 (47%) as not routinely recommended, such as CYP2C19 for clopidogrel dosing.ConclusionOnly half of drug-gene pairs with high clinical validity received Subcommittee support for policy promoting their widespread use across VHA. The Subcommittee generally found insufficient evidence of clinical utility or available, effective alternative strategies for the remainders. Continual evidence review and rigorous outcomes research will help promote the translation of pharmacogenetic discovery to healthcare.

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. [ABSTRACT FROM AUTHOR]