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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 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.)

The DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), which is involved in the catalysis of uracil and thymine, as well as 5-fluorouracil (5-FU), which is used to treat solid tumors. Patients with decreased DPD activity are at risk of serious, sometimes fatal, adverse drug reactions to this important cancer drug. Pharmacogenetic testing for DPYD is increasingly provided by clinical and research laboratories; however, only a limited number of quality control and reference materials are currently available for clinical DPYD testing. To address this need, the Division of Laboratory Systems, Centers for Disease Control and Prevention-based Genetic Testing Reference Materials Coordination Program, in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Institute for Medical Research, has characterized 33 DNA samples derived from Coriell cell lines for DPYD. Samples were distributed to four volunteer laboratories for genetic testing using a variety of commercially available and laboratory-developed tests. Sanger sequencing was used by one laboratory and publicly available whole-genome sequence data from the 1000 Genomes Project were used by another to inform genotype. Thirty-three distinct DPYD variants were identified among the 33 samples characterized. 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., Competing Interests: Disclosure Statement RPRD Diagnostics LLC is a fee-for-service laboratory that offers clinical pharmacogenetic testing. A.J.T. was supported in part by, and holds equity in, RPRD Diagnostics. U.B. is the CEO of RPRD Diagnostics and holds equity. A.G. is the Director of PharmVar. A.J.T., E.C.B., A.M.M., W.Y.W., and P.Z. are members of PharmVar., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. All rights reserved.)

Purpose: Pharmacogenetic testing can identify patients who may benefit from personalized drug treatment. However, clinical uptake of pharmacogenetic testing has been limited. Clinical practice guidelines recommend biomarker tests that the guideline authors deem to have demonstrated clinical utility, meaning that testing improves treatment outcomes. The objective of this narrative review is to describe the current status of pharmacogenetic testing recommendations within clinical practice guidelines in the US., Summary: Guidelines were reviewed for pharmacogenetic testing recommendations for 21 gene-drug pairs that have well-established drug response associations and all of which are categorized as clinically actionable by the Clinical Pharmacogenetics Implementation Consortium. The degree of consistency within and between organizations in pharmacogenetic testing recommendations was assessed. Relatively few clinical practice guidelines that provide a pharmacogenetic testing recommendation were identified. Testing recommendations for HLA-B*57:01 before initiation of abacavir and G6PD before initiation of rasburicase, both of which are included in drug labeling, were mostly consistent across guidelines. Gene-drug pairs with at least one clinical practice guideline recommending testing or stating that testing could be considered included CYP2C19-clopidogrel, CYP2D6-codeine, CYP2D6-tramadol, CYP2B6-efavirenz, TPMT-thiopurines, and NUDT15-thiopurines. Testing recommendations for the same gene-drug pair were often inconsistent between organizations and sometimes inconsistent between different guidelines from the same organization., Conclusion: A standardized approach to evaluating the evidence of clinical utility for pharmacogenetic testing may increase the inclusion and consistency of pharmacogenetic testing recommendations in clinical practice guidelines, which could benefit patients and society by increasing clinical use of pharmacogenetic testing., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Pharmacogenomics (PGx) investigates the influence of genetics on drug responses, enabling tailored treatments for personalized healthcare. This study assessed the accuracy of genotyping six genes using whole genome sequencing with four different computational tools and various sequencing depths. The effects of using different reference genomes (GRCh38 and GRCh37) and sequence aligners (BWA-MEM and Bowtie2) were also explored. The results showed generally minor variations in tool performance across most genes; however, more notable discrepancies were observed in the analysis of the complex CYP2D6 gene. Cyrius, a CYP2D6-specific tool, demonstrated the most robust performance, achieving the highest concordance rates for CYP2D6 in all instances, comparable to the consensus approach in most cases. There were rather small differences between the samples with 20× coverage depth and those with higher depth, but the decreased performance was more evident at lower depths, particularly at 5×. Additionally, variations in CYP2D6 results were observed when samples were aligned to different reference genomes using the same method, or to the same genome using different aligners, which led to reporting incorrect rare star alleles in several cases. These findings inform the selection of optimal PGx tools and methodologies as well as suggest that employing a consensus approach with two or more tools might be preferable for certain genes and tool combinations, especially at lower sequencing depths, to ensure accurate results. Additionally, we show how the upstream alignment can affect the performance of tools, an important factor to take into account., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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.)

The application of pharmacogenomics could meaningfully contribute toward medicines optimization within primary care. This review identified 13 studies describing eight implementation models utilizing a multi-gene pharmacogenomic panel within a primary care or community setting. These were small feasibility studies (n <200). They demonstrated importance and feasibility of pre-test counseling, the role of the pharmacist, data integration into the electronic medical record and point-of-care clinical decision support systems (CDSS). Findings were considered alongside existing primary care prescribing practices and implementation frameworks to demonstrate how issues may be addressed by existing nationalized healthcare and primary care infrastructure. Development of point-of-care CDSS should be prioritized; establishing clinical leadership, education programs, defining practitioner roles and responsibilities and addressing commissioning issues will also be crucial.

Given the expansion of genetics in medicine, there is a growing need to develop approaches to engage patients in understanding how genetics affects their health. Various qualitative methods have been applied to gain a deeper understanding of patient perspectives in topics related to genetics. Community dialogues (CD) are a bi-directional research method that invites community members to discuss a pertinent, challenging topic over the course of a multi-week period and the community members openly discuss their positions on the topic. Authors discuss the first application of the CD method to the topic of pharmacogenetics testing. Additional CD are needed to engage diverse participant populations on this topic to improve genetics literacy, enhance physician engagement and drive policy change.

Consensus guidelines exist for genotype-guided fluoropyrimidine dosing based on variation in the gene dihydropyrimidine dehydrogenase (DPYD). However, these guidelines have not been widely implemented in North America and most studies of pretreatment DPYD screening have been conducted in Europe. Given regional differences in treatment practices and rates of adverse events (AEs), we investigated the impact of pretreatment DPYD genotyping on AEs in a Canadian context. Patients referred for DPYD genotyping prior to fluoropyrimidine treatment were enrolled from December 2013 through November 2019 and followed until completion of fluoropyrimidine treatment. Patients were genotyped for DPYD c.1905+1G>A, c.2846A>T, c.1679T>G, and c.1236G>A. Genotype-guided dosing recommendations were informed by Clinical Pharmacogenetics Implementation Consortium guidelines. The primary outcome was the proportion of patients who experienced a severe fluoropyrimidine-related AE (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Secondary outcomes included early severe AEs, severe AEs by toxicity category, discontinuation of fluoropyrimidine treatment due to AEs, and fluoropyrimidine-related death. Among 1394 patients, mean (SD) age was 64 (12) years, 764 (54.8%) were men, and 47 (3.4%) were DPYD variant carriers treated with dose reduction. Eleven variant carriers (23%) and 418 (31.0%) noncarriers experienced a severe fluoropyrimidine-related AE (p = 0.265). Six carriers (15%) and 284 noncarriers (21.1%) experienced early severe fluoropyrimidine-related AEs (p = 0.167). DPYD variant carriers treated with genotype-guided dosing did not experience an increased risk for severe AEs. Our data support a role for DPYD genotyping in the use of fluoropyrimidines in North America., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Predictive biomarkers play an important role in our efforts to individualize pharmacotherapy, and within recent years, a number of different types of assays have been introduced. These biomarkers may potentially support the selection and dosage of specific drugs in order to maximize efficacy and minimize adverse reactions in the individual patient. However, in many instances, the scientific and clinical evidence is insufficient to support the prescribing decision. When predictive biomarkers are used to guide pharmacotherapy, it is important to secure that decisions are based on solid clinical evidence. Here, the regulatory authorities, especially the FDA, have been at the forefront in relation to regulate this type of biomarker assay in order to secure patient safety. The approval process for companion diagnostics is an example of this effort, where the scientific validity of the biomarker and assay is in focus. With the approaching implementation of the new IVD Regulation, greater attention will also be paid to analytical and clinical validity of biomarker assays in the EU. For any type of predictive biomarker assay, including pharmacogenetic and tumour profiling tests, the clinical evidence needs to be in place before they are used routinely in the clinic., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Aim: To assess providers' knowledge, attitudes, perceptions, and experiences related to pharmacogenomic (PGx) testing in pediatric patients. Materials & methods: An electronic survey was sent to multidisciplinary healthcare providers at a pediatric hospital. Results: Of 261 respondents, 71.3% were slightly or not at all familiar with PGx, despite 50.2% reporting prior PGx education or training. Most providers, apart from psychiatry, perceived PGx to be at least moderately useful to inform clinical decisions. However, only 26.4% of providers had recent PGx testing experience. Unfamiliarity with PGx and uncertainty about the clinical value of testing were common perceived challenges. Conclusion: Low PGx familiarity among pediatric providers suggests additional education and electronic resources are needed for PGx examples in which data support testing in children.

The accessibility of pharmacogenomic (PGx) testing has grown substantially over the last decade and with it has arisen a demand for patients to be counseled on the use of these tests. While guidelines exist for the use of PGx results; objective determinants for who should receive PGx testing remain incomplete. PGx clinical services have been created to meet these screening and education needs and significant variability exists between these programs. This article describes the practices of four PGx clinics during pretest counseling sessions. A description of the major tenets of the benefits, limitations and risks of testing are compiled. Additional tools are provided to serve as a foundation for those wishing to begin or expand their own counseling service.

We evaluated the clinical validity of a combinatorial pharmacogenomic test and single-gene Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines against patient outcomes and medication blood levels to assess their ability to inform prescribing in major depressive disorder (MDD). This is a secondary analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) randomized-controlled trial, which included patients with a diagnosis of MDD, and ≥1 prior medication failure. The ability to predict increased/decreased medication metabolism was validated against blood levels at screening (adjusted for age, sex, smoking status). The ability of predicted gene-drug interactions (pharmacogenomic test) or therapeutic recommendations (single-gene guidelines) to predict patient outcomes was validated against week 8 outcomes (17-item Hamilton Depression Rating Scale; symptom improvement, response, remission). Analyses were performed for patients taking any eligible medication (outcomes N=1,022, blood levels N=1,034) and the subset taking medications with single-gene guidelines (outcomes N=584, blood levels N=372). The combinatorial pharmacogenomic test was the only significant predictor of patient outcomes. Both the combinatorial pharmacogenomic test and single-gene guidelines were significant predictors of blood levels for all medications when evaluated separately; however, only the combinatorial pharmacogenomic test remained significant when both were included in the multivariate model. There were no substantial differences when all medications were evaluated or for the subset with single-gene guidelines. Overall, this evaluation of clinical validity demonstrates that the combinatorial pharmacogenomic test was a superior predictor of patient outcomes and medication blood levels when compared with guidelines based on individual genes., (Copyright © 2020. Published by Elsevier B.V.)

The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes ( CYP2D6, CYP2C19 ). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine ( HLA-A and HLA-B ), oxcarbazepine ( HLA-B ), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes ( POLG, OTC, CSP1 ) is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry., Competing Interests: Dr. Bousman reports a grant from Alberta Innovates Strategic Research Project G2018000868, during the conduct of the study; and he has received in-kind testing kits from Myriad Neuroscience, CNSDose, Genomind, and AB-Biotics for research purposes but has not received payments or received any equity, stocks, or options in these companies or any other pharmacogenetic companies. Dr. Bengesser has nothing to disclose. Dr. Aitchison reports grants from Alberta Innovates Strategic Research Project G2018000868, other from Neuroscience and Mental Health Institute, other from Department of Psychiatry, during the conduct of the study; non-financial support from HLS Therapeutics, grants from Janssen Inc., Canada, outside the submitted work; and Member, Pharmacogene Variation Consortium (PharmVar); Coauthor, Haplotype Translators for CYP2D6 and CYP2C19; Member, Alberta Cannabis Research and Innovation Network; Member, Schizophrenia Society of Alberta; Board Member, Canadian Consortium for Early Intervention in Psychosis. Dr. Amare has nothing to disclose. Dr. Aschauer has nothing to disclose. Dr. Baune has nothing to disclose. Ms. Behroozi Asl reports grants from Alberta Innovates, during the conduct of the study. Dr. Bishop reports personal fees from OptumRx, outside the submitted work; and he is a member of the Clinical Pharmacogenetics Implementation Consortium. Dr. Burmeister reports personal fees from Chinese University of Hong Kong (Shen Zhen), personal fees from Research Grants Council (RGC) of Hong Kong, personal fees from Alexander von Humboldt Foundation, outside the submitted work. Dr. Chaumette reports personal fees from Janssen-Cilag, grants from Fondation Bettencourt-Schueller, outside the submitted work. Dr. Chen has nothing to disclose. Dr. Cordner has nothing to disclose. Dr. Deckert reports grants from DFG, grants from BMBF, grants from Vogel-Foundation, grants from EU, grants from Bavarian Secretary of Commerce, outside the submitted work. Dr. Degenhardt has nothing to disclose. Dr. DeLisi has nothing to disclose. Dr. Folkersen has nothing to disclose. Dr. Kennedy has a patent 'PGx of Antipsychotic Response'; and 'PGx of Wt Gain' both pending. No licensees. Dr. Kennedy's affiliated hospital, (which is not his employer) the Centre for Addiction and Mental Health, is a part owner of the Canadian subsidiary of Myriad Neuroscience, USA. Dr. Klein reports grants from NIH/NHGRI, during the conduct of the study. Dr. McClay has nothing to disclose. Dr. McMahon has nothing to disclose. Dr. Musil reports personal fees from Otsuka/Lundbeck, outside the submitted work. Dr. Saccone reports that her spouse is listed as an inventor on Issued U.S. Patent 8,080,371, “Markers for Addiction” covering the use of certain single nucleotide polymorphisms in determining the diagnosis, prognosis, and treatment of addiction. Dr. Sangkuhl reports grants from NIH/NHGRI, during the conduct of the study. Dr. Stowe has nothing to disclose. Dr. Tan has nothing to disclose. Dr. Tiwari reports that he is a co-investigator on two pharmacogenetic studies where genetic test kits were provided as in-kind contribution by Assurex Health (Myriad Neuroscience) but he did not receive any payments or any equity, stocks, or options from this company or any other pharmacogenetic companies. Dr. Tiwari is also a co-inventor on a patent assessing risk for antipsychotic-induced weight gain. Dr. C. Zai has a patent for suicide markers issued, and a patent for antipsychotic-induced weight gain markers pending. Dr. G. Zai has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Gaedigk has nothing to disclose. Dr. Müller reports to be a co-investigator on two pharmacogenetic studies where genetic test kits were provided as in-kind contribution by Myriad Neuroscience. He did not receive any payments or any equity, stocks, or options from any pharmacogenetic companies. Dr. Müller is also a co-inventor on two patent assessing risk for antipsychotic-induced weight gain (pending)., (Thieme. All rights reserved.)

Pharmacogenomics is rapidly assuming an integral part in modern health care. Still, its broad applicability relies on the feasibility of performing pharmacogenomic testing in all clinical settings, including in remote areas or resource-limited settings with budget restrictions. In this study, we describe the development and feasibility of rapid and reliable pharmacogenomics assays using a portable molecular biology laboratory, namely the 2MoBiL (Mobile Molecular Biology Laboratory). More precisely, we demonstrate that the genotyping of rs4149056, located within SLCO1B1 , can be efficiently and reliably performed using the 2MoBiL portable laboratory and conventional benchtop laboratory equipment and a gold standard genotyping method (KASP assay) as directly comparable methodologies. Taking into account the compact size of 2MoBiL, which directly and positively impacts on its portability, and the high accuracy achieved, we conclude that the 2MoBiL-based genotyping method is warranted for further studies in clinical practices at remote areas and resource-limited as well as time-constrained planetary health settings. To contextualize the broader and potential future applications of 2MoBiL, we emphasize that genotyping of a limited set of clinically relevant single-nucleotide polymorphisms is often a common endpoint of genomics and pharmacogenomics discovery and translational research pipeline. Hence, rapid genotyping by 2MoBiL can be an essential catalyst for global implementation of pharmacogenomics and personalized medicine in the clinic. The Clinical Trial Registration number is NCT03093818.

Background: Large sample sizes are often required to detect statistically significant associations between pharmacogenetic markers and treatment response. Meta-analysis may be performed to synthesize data from several studies, increasing sample size and, consequently, power to detect significant genetic effects. However, performing robust synthesis of data from pharmacogenetic studies is often challenging because of poor reporting of key data in study reports. There is currently no guideline for the reporting of pharmacogenetic studies that has been developed using a widely accepted robust methodology. The objective of this project was to develop the STrengthening the Reporting Of Pharmacogenetic Studies (STROPS) guideline., Methods and Findings: We established a preliminary checklist of reporting items to be considered for inclusion in the guideline. We invited representatives of key stakeholder groups to participate in a 2-round Delphi survey. A total of 52 individuals participated in both rounds of the survey, scoring items with regards to their importance for inclusion in the STROPS guideline. We then held a consensus meeting, at which 8 individuals considered the results of the Delphi survey and voted on whether each item ought to be included in the final guideline. The STROPS guideline consists of 54 items and is accompanied by an explanation and elaboration document. The guideline contains items that are particularly important in the field of pharmacogenetics, such as the drug regimen of interest and whether adherence to treatment was accounted for in the conducted analyses. The guideline also requires that outcomes be clearly defined and justified, because in pharmacogenetic studies, there may be a greater number of possible outcomes than in other types of study (for example, disease-gene association studies). A limitation of this project is that our consensus meeting involved a small number of individuals, the majority of whom are based in the United Kingdom., Conclusions: Our aim is for the STROPS guideline to improve the transparency of reporting of pharmacogenetic studies and also to facilitate the conduct of high-quality systematic reviews and meta-analyses. We encourage authors to adhere to the STROPS guideline when publishing pharmacogenetic studies., Competing Interests: The authors have declared that no competing interests exist.

Background: Acute coronary syndrome (ACS) is a highly thrombotic state, and a sustained antiplatelet effect is vital to the prevention of thrombotic complications. Clopidogrel, the most widely used oral P2Y12 receptor antagonist in ACS, has attracted considerable attention because of significant variability in antiplatelet effect depending on the presence of CYP2C19 allele. Other P2Y12 receptor antagonists offer sustained and more predictable antiplatelet effects than clopidogrel albeit at an increased cost. Several studies have demonstrated the promising application of pharmacogenetics in choosing personalized antiplatelet therapy using the point-of-care genotype assays., Areas of Uncertainty: Guidelines regarding the genotype-guided approach to the selection of antiplatelet therapy have been conflicting, and studies evaluating the effect of pharmacogenetic-guided selection of antiplatelet therapy on the outcomes have demonstrated mixed results., Data Sources: A literature search was conducted using MEDLINE and EMBASE for studies reporting the association of pharmacogenetic-guided selection of antiplatelet therapy and the outcomes in patients with ACS until December 2018., Results: Presence of specific CYP2C19 allele significantly influences clopidogrel metabolism and associated outcomes in patients with ACS. Thrombotic and bleeding complications are more common in patients with loss-of-function (LOF) and gain-of-function (GOF) alleles, respectively. Although the pharmacogenetic-guided approach to the selection of antiplatelet therapy appears promising in ACS, studies have shown conflicting results, and direct randomized evidence linking this approach with the better outcomes is lacking., Conclusions: Genotype-guided selection of antiplatelet therapy is expected to be useful in patients undergoing percutaneous coronary intervention (PCI) with a high risk of adverse outcomes. The patient-physician discussion should be an essential part of this decision-making process. Large-scale multicenter randomized controlled trials using the point-of-care genotype assay are needed to investigate this approach further before its use can be recommended in all comers.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used analgesics due to their lack of addictive potential. However, NSAIDs have the potential to cause serious gastrointestinal, renal, and cardiovascular adverse events. CYP2C9 polymorphisms influence metabolism and clearance of several drugs in this class, thereby affecting drug exposure and potentially safety. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for NSAIDs based on CYP2C9 genotype (updates at www.cpicpgx.org)., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Pharmacogenetics (PGx) aims to improve drug therapy using the individual patients' genetic make-up. Little is known about the potential impact of PGx on the population level, possibly hindering implementation of PGx in clinical care. Therefore, we investigated how many patients use actionable PGx drugs, have actionable genotypes or phenotypes and which patients could benefit the most of PGx testing. We included PGx recommendations from two international PGx consortia (Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG)). Using data from publically accessible sales information drawn from the Danish Register of Medicinal Product Statistics (MEDSTAT), we identified the number of users of actionable prescription PGx drugs among the total Danish population in 2017. We estimated actionable genotypes or phenotypes based on reported frequencies from literature. We identified 49 drug-gene interactions related to 41 unique prescription drugs. The estimated median frequency of actionable genotypes or phenotypes among prescription drug users was 25% (interquartile range 7-26%). Six of 41 drugs were used more than twice as much in women. Actionable PGx drugs were most frequently used by 45-79 year old patients (62%), followed by 25-44 year old patients (18%). Almost half of the actionable PGx drugs (19/41) were psychotropics (i.e., antidepressants, antipsychotics, or psychostimulants). PGx testing can have a substantial impact on the population, as one in four prescription drug users has an actionable genotype or phenotype and could thus benefit from PGx testing. We advocate for prospective panel-based PGx testing at the time of the first PGx drug prescription ("as needed"), with PGx results ready prior to start of the first, and all future, therapies., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

With the exception of a few medical specialties, the implementation of pharmacogenetic tests in daily practice has thus far been limited. The Royal Dutch Pharmacists Association (KNMP) has developed pharmacogenetics-based therapeutic doserecommendations for 80 medicinal product combinations on the basis of a systematic literature review. Genotyping of patients can take place on a reactive or pre-emptive basis; the advantage of pre-emptive genotyping is that it provides genetic information the moment a medicinal product is prescribed. Clinical decision support software is crucial to implement pharmacogenetics into daily practice.

Most literature describing pharmacogenetic implementations are within academic medical centers and use single-gene tests. Our objective was to describe the results and lessons learned from a multisite pharmacogenetic pilot that utilized panel-based testing in academic and nonacademic settings. This was a retrospective analysis of 667 patients from a pilot in 4 perioperative and 5 outpatient cardiology clinics. Recommendations related to 12 genes and 65 drugs were classified as actionable or not actionable. They were ascertained from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and US Food and Drug Administration (FDA) labeling. Patients displayed a high prevalence of actionable results (88%, 99%) and use of medications (28%, 46%) with FDA or CPIC recommendations, respectively. Sixteen percent of patients had an actionable result for a current medication per CPIC compared with 5% per FDA labeling. A systematic approach by a health system may be beneficial given the quantity and diversity of patients affected., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Informed consent forms (ICFs) in clinical trials are the only objective testimony whether the information provided to participants is comprehensive and presented in an accessible language. We evaluated the length of Hebrew ICFs and their English translations and evaluated the readability of the latter. In fifteen clinical trials (5 with pharmacogentic sub-study), the median number (IQR) of pages and words were: English clinical ICFs - 16 pages (13,18) and 7360 words (6959,8289); Hebrew clinical ICFs - 12 pages (10,14), 5807 words (5258,6403); English pharmacogenetics ICFs - 7 pages (4,11), 2930 words (2234,5100); Hebrew pharmacogenetics ICFs - 5 pages (4,8.5), 2273 words (1663,3889); the two English ICFs combined - 23 pages (18;29.5), 10,820 words (9515,15,600); and the two Hebrew ICFs combined - 19 pages (16,23), 8258 words (7340,10,515). Differences between the Hebrew clinical trial ICFs and their English translations were significant (p < 0.001). Median (IQR) Flesch Reading Ease scores for the clinical and the pharmacogenetics ICFs were 48.4 (42.7, 49.9) and 42.2 (41.7,42.65), respectively. Thirteen studies were multinational. Twelve were conducted simultaneously in the United States, where an assessment of readability scores is customary. In conclusion, the consent forms evaluated in this study were long, and readability scores were low.

The antiplatelet agent clopidogrel, a prodrug that requires bioactivation through the cytochrome P450 2C19 (CYP2C19) enzyme, is commonly prescribed post-percutaneous coronary intervention (PCI). Genetic variation in CYP2C19 contributes to individual variability in clopidogrel response, and can lead to adverse cardiovascular events. Incorporating CYP2C19 testing during routine clinical care helps identify high-risk patients, and provides the opportunity for pharmacotherapeutic interventions in the early post-PCI period. The Spartan RX CYP2C19 System has emerged as an optimal genotyping assay for use in clinical care due to ease of use, utilization of buccal swabs, and rapid turnaround time. However, workflow constraints related to sample collection and processing, storage, time, and personnel were encountered when integrating testing into clinical care. To improve clinical workflow and successfully implement CYP2C19 genotyping at our institution, we validated the Spartan RX System to return genotype utilizing blood samples. Our Molecular Diagnostic Laboratory tested 26 known reference materials and both blood and buccal swab samples from 23 patients and volunteers using the Spartan RX Assay. Genotype results were 100% concordant between DNA from blood and buccal swabs for all patients or volunteers, and consistent with expected results for the 26 reference materials. For reproducibility, three samples were tested in at least four separate runs, with all resulting genotypes in agreement between runs. Post-validation, the laboratory began offering CYP2C19 testing during clinical care. DNA extracted from blood can serve as a genomic DNA source for the Spartan RX Assay. Alteration of the methodology allowed for clinical implementation to support genotype-guided therapy., (© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Aim: To evaluate the clinical benefits of implementing pharmacogenomics testing for Chinese pediatric patients.  Materials &   methods : Based on the drug-gene interactions involved in the Clinical Pharmacogenetics Implementation Consortium guidelines, whole-genome sequencing data from the Chinese Academy of Sciences Precision Medicine Initiative project and the medication data of pediatric patients from a children's hospital, the prevalence of the Chinese population with actionable pharmacogenomic variants was calculated, the prescribing pattern for pediatric patients was analyzed. Results: 37.0% of the drugs involved in the Clinical Pharmacogenetics Implementation Consortium guidelines were used by Chinese pediatric patients, 8.91% inpatients and 0.89% outpatients received at least one pharmacogenomics medication, 1.24% (4803) inpatients and 0.16% (2940) outpatients were estimated to be at high risk of pharmacogenomic-related adverse therapeutic outcomes. Conclusion: Implementing pharmacogenomics testing can improve therapeutic outcomes for many Chinese pediatric patients.

Background: Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity., Summary: There is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. Key Messages: NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension., (© 2020 S. Karger AG, Basel.)

The cytochrome P450 2D6 (CYP2D6) gene locus is challenging to accurately genotype due to numerous single nucleotide variants and complex structural variation. Our goal was to determine whether the CYP2D6 genotype-phenotype correlation is improved when diplotype assignments incorporate structural variation, identified by the bioinformatics tool Stargazer, with next-generation sequencing data. Using CYP2D6 activity measured with substrates dextromethorphan and metoprolol, activity score explained 40% and 34% of variability in metabolite formation rates, respectively, when diplotype calls incorporated structural variation, increasing from 36% and 31%, respectively, when diplotypes did not incorporate structural variation. We also investigated whether the revised Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations for translating genotype to phenotype improve CYP2D6 activity predictions over the current system. Although the revised recommendations do not improve the correlation between activity score and CYP2D6 activity, perhaps because of low frequency of the CYP2D6*10 allele, the correlation with metabolizer phenotype group was significantly improved for both substrates. We also measured the function of seven rare coding variants: one (A449D) exhibited decreased (44%) and another (R474Q) increased (127%) activity compared with reference CYP2D6.1 protein. Allele-specific analysis found that A449D is part of a novel CYP2D6*4 suballele, CYP2D6*4.028. The novel haplotype containing R474Q was designated CYP2D6*138 by PharmVar; another novel haplotype containing R365H was designated CYP2D6*139. Accuracy of CYP2D6 phenotype prediction is improved when the CYP2D6 gene locus is interrogated using next-generation sequencing coupled with structural variation analysis. Additionally, revised CPIC genotype to phenotype translation recommendations provides an improvement in assigning CYP2D6 activity., (© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Translating CYP2D6 genotype to metabolizer phenotype is not standardized across clinical laboratories offering pharmacogenetic (PGx) testing and PGx clinical practice guidelines, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). The genotype to phenotype translation discordance between laboratories and guidelines can cause discordant cytochrome P450 2D6 (CYP2D6) phenotype assignments and, thus lead to inconsistent therapeutic recommendations and confusion among patients and clinicians. A modified-Delphi method was used to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts. Experts with diverse involvement in CYP2D6 interpretation (clinicians, researchers, genetic testing laboratorians, and PGx implementers; n = 37) participated in conference calls and surveys. After completion of 7 surveys, a consensus (> 70%) was reached with 82% of the CYP2D6 experts agreeing to the final CYP2D6 genotype to phenotype translation method. Broad adoption of the proposed CYP2D6 genotype to phenotype translation method by guideline developers, such as CPIC and DPWG, and clinical laboratories as well as researchers will result in more consistent interpretation of CYP2D6 genotype., (© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

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.)

Background: This project evaluated the clinical use of pharmacogenetic testing in an outpatient psychiatric practice, integrated a standardized measure for assessing depressive symptoms, and captured data regarding treatment efficacy., Local Problem: According to the Centers for Disease Control and Prevention (2016), more than 10% of all outpatient office visits include a depression-related diagnosis. Patients who require more medication trials to experience remission of depressive symptoms are more likely to relapse in the follow-up period than those who do not (National Institute of Mental Health, 2001)., Methods and Interventions: Baseline Patient Health Questionnaire-9 (PHQ-9) scores and medication regimens were recorded for 15 adults with major depressive disorder who completed pharmacogenetic testing. Repeat PHQ-9 scores and medication regimens were recorded at follow-up appointments within 6 weeks post-pharmacogenetic testing and compared with baseline data., Results: The PHQ-9 scores ranged from a 5-point reduction to a 2-point increase in depressive symptoms at follow-up appointment. The PHQ-9 scores were lower at follow-up screening for 14 participants. Six of the 15 participants were on a single medication, with significant drug-gene interactions. Medications with significant drug-gene interactions were eliminated from the regimen for three of the six patients. For the remaining three patients, providers deemed it to be reasonable to continue the medications with significant drug-gene interactions., Conclusions: Pharmacogenetic testing is a useful clinical tool for guiding medication selection but does not replace provider judgment. Drug-gene interaction testing results should be considered in addition to patient preference, medication cost, possible side effects, and immediate clinical needs.

Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y 12 receptor inhibitor is the standard treatment for patients undergoing percutaneous coronary intervention. The availability of different P2Y 12 receptor inhibitors (clopidogrel, prasugrel, ticagrelor) with varying levels of potency has enabled physicians to contemplate individualized treatment regimens, which may include escalation or de-escalation of P2Y 12 -inhibiting therapy. Indeed, individualized and alternative DAPT strategies may be chosen according to the clinical setting (stable coronary artery disease vs. acute coronary syndrome), the stage of the disease (early- vs. long-term treatment), and patient risk for ischemic and bleeding complications. A tailored DAPT approach may be potentially guided by platelet function testing (PFT) or genetic testing. Although the routine use of PFT or genetic testing in percutaneous coronary intervention-treated patients is not recommended, recent data have led to an update in guideline recommendations that allow considering selective use of PFT for DAPT de-escalation. However, guidelines do not expand on when to implement the selective use of such assays into decision making for personalized treatment approaches. Therefore, an international expert consensus group of key leaders from North America, Asia, and Europe with expertise in the field of antiplatelet treatment was convened. This document updates 2 prior consensus papers on this topic and summarizes the contemporary updated expert consensus recommendations for the selective use of PFT or genotyping in patients undergoing percutaneous coronary intervention., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The cost-effectiveness of testing for multiple genes implicated in adverse drug reactions requires the simultaneous assessment of all actionable information, including future prescribing decisions based on incidental findings. We developed methodology for determining the value of pharmacogenetic panel tests, illustrated with a multigene panel, including HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, HLA-B*58:01, HLA-B (158T), and HLA-DQB1 (126Q). If the findings for all alleles are acted upon, regardless of their individual cost-effectiveness, the HLA panel resulted in cost savings of £378 (US $491), and a quality-adjusted life year gain of 0.0069. Based on a stratified analysis and compared with no testing, initial use of the panel was cost-effective in patients eligible for abacavir (HLA-B*57:01), carbamazepine (HLA-A*31:01), and clozapine (HLA-B (158T) and HLA-DQB1 (126Q)), but not for carbamazepine (HLA-B*15:02) or allopurinol (HLA-B*58:01). The methods presented allow for the assessment of the cost-effectiveness of multiple-gene panels., (© 2018 The Authors Clinical Pharmacology & Therapeutics © 2018 American Society for Clinical Pharmacology and Therapeutics.)

Pharmacogenetic testing is increasingly implemented in routine diagnostics. However, quality control measures, in particular confirmation practices e.g. the use of two independent genotyping techniques, are subject of debate and there are no clear guidelines. The aim of the current paper is to discuss the current practice in confirmation testing in the field of pharmacogenetics and draw attention to this situation. DPYD genotyping is used as a case example to highlight the importance of assigning the correct genotype. Current confirmation practices in laboratories are explored through a survey. Substantial heterogeneity was observed with 54% of the laboratories applying different forms of confirmation practice. Finally, we evaluated over 10 years of genotyping results from two large genotyping facilities, which both use a second, independent genotyping technique. Discrepancies between tests were identified in 9 patients (0.01%), possibly due to allele dropout. We feel that a second, independent technique is useful for genetic tests with a high clinical impact, such as DPYD testing. Guidelines can help to align confirmatory laboratory practices for pharmacogenetics, which may need to be specified per gene and test., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Regulatory approval of next generation sequencing (NGS) by the FDA is advancing the use of genomic-based precision medicine for the therapeutic management of cancer as standard care. Recent FDA guidance for the classification of genomic variants based on clinical evidence to aid clinicians in understanding the actionability of identified variants provided by comprehensive NGS panels has also been set forth. In this retrospective analysis, we interpreted and applied the FDA variant classification guidance to comprehensive NGS testing performed for advanced cancer patients and assessed oncologist agreement with NGS test treatment recommendations., Methods: NGS comprehensive genomic profiling was performed in a CLIA certified lab (657 completed tests for 646 patients treated at Roswell Park Comprehensive Cancer Center) between June 2016 and June 2017. Physician treatment recommendations made within 120 days post-test were gathered from tested patients' medical records and classified as targeted therapy, precision medicine clinical trial, immunotherapy, hormonal therapy, chemotherapy/radiation, surgery, transplant, or non-therapeutic (hospice, surveillance, or palliative care). Agreement between NGS test report targeted therapy recommendations based on the FDA variant classification and physician targeted therapy treatment recommendations were evaluated., Results: Excluding variants contraindicating targeted therapy (i.e., KRAS or NRAS mutations), at least one variant with FDA level 1 companion diagnostic supporting evidence as the most actionable was identified in 14% of tests, with physicians most frequently recommending targeted therapy (48%) for patients with these results. This stands in contrast to physicians recommending targeted therapy based on test results with FDA level 2 (practice guideline) or FDA level 3 (clinical trial or off label) evidence as the most actionable result (11 and 4%, respectively)., Conclusions: We found an appropriate "dose-response" relationship between the strength of clinical evidence supporting biomarker-directed targeted therapy based on application of FDA guidance for NGS test variant classification, and subsequent treatment recommendations made by treating physicians. In view of recent changes at FDA, it is paramount to define regulatory grounds and medical policy coverage for NGS testing based on this guidance.

Clinical utility of commercial multi-gene pharmacogenetic tests in depression is starting to be studied with some promising results on efficacy and tolerability. Among the next steps is the definition of the patient profile that is most likely to benefit from testing. Here we present a reanalysis of data from the AB-GEN randomized clinical trial showing that clinical utility of pharmacogenetic testing can be markedly influenced by patient characteristics such as age, baseline severity and duration of current depressive episode.Trial registration ClinicalTrials.gov NCT02529462.

This is a retrospective cohort study of 20 children and adolescents to evaluate the clinical utility of a pharmacogenetic decision support tool. Twenty children and adolescents underwent pharmacogenetic testing between June 2014 and May 2017. All children and adolescents were evaluated at Puerta de Hierro University Hospital-Majadahonda (Madrid, Spain). We report the proportion of patients achieving clinical improvement, amelioration of side effects, and changes in number of drugs. Data normality was assessed with the Shapiro-Wilk test, and changes of pre- and post-pharmacogenetic testing were analyzed with the Wilcoxon test for paired samples. A two-sided p value threshold of 0.05 was considered for significance. Pharmacogenetic testing helped to improve the clinical outcome as measured by the Clinical Global Impressions (CGI) Scale in virtually all children (95%; 19 out of 20 children). The CGI improvement (CGI-I) was 2 (0.79) (range 1-4), 2.1 (0.56) (range 1-3), and 1.9 (0.99) (range 1-4) in foster and non-foster care children, respectively. Pharmacogenetic testing also helped to reduce the number of children using polypharmacy (from 65 to 45%), the mean number of drugs per children (from 3.3 to 2.4 drugs, p = 0.017), and self-reported relevant side effects (p = 0.006). Pharmacogenetic testing helped to improve the clinical outcome, and to reduce polypharmacy and the number of drugs used in children and adolescents with severe mental disorders. More evidence using robust (i.e., clinical trials) independent studies is required to properly determine the clinical utility and cost-effectiveness of pharmacogenetic testing tools in children and adolescents with mental disorders.

This paper discusses difficulties of pharmacogenomic data integration into clinical practice. It emphasizes the need for developing simple and easy to use bioinformatics tools to help prescribers to rapidly access and use genetic data in clinical decision-making at the point of encounter.

Late-life depression (LLD) is a major depressive disorder that affects someone after the age of 60 years. LLD is frequently associated with inadequate response and remission from antidepressants, in addition to polypharmacy. Pharmacogenetics offers a promising approach to improve clinical outcomes in LLD via new discoveries determining the genetic basis of response rates and side effects, as well as the development of tailored pharmacogenetic-based decision support tools. This invited review evaluates the LLD pharmacogenetic evidence base and the extent to which this was incorporated into existing commercial decision support tools and clinical pharmacogenetic guidelines.

Current guideline recommendations for pharmacogenetic testing for clopidogrel by the American Heart Association/American College of Cardiology (AHA/ACC) contradict the Clinical Pharmacogenetics Implementation Consortium and the US FDA. The AHA/ACC recommends against routine pharmacogenetic testing for clopidogrel because no randomized controlled trials have demonstrated that testing improves patients' outcomes. However the AHA/ACC and the National Comprehensive Cancer Network (NCCN) recommend other pharmacogenetic tests in the absence of randomized controlled trials evidence. Using clopidogrel as a case example, we compared the evidence for other pharmacogenetic tests recommended by the AHA/ACC and NCCN. In patients that received percutaneous coronary intervention, the evidence supporting pharmacogenetic testing for clopidogrel is stronger than other pharmacogenetic tests recommended by the AHA/ACC and NCCN.