Review and Consensus on Pharmacogenomic Testing in Psychiatry.

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.

STrengthening the Reporting Of Pharmacogenetic Studies: Development of the STROPS guideline.

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.

Genotype-Guided Hydralazine Therapy.

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.

Advances in the Pharmacogenomics of Antiplatelet Therapy.

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.

Patient characteristics driving clinical utility in psychiatric pharmacogenetics: a reanalysis from the AB-GEN multicentric trial.

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.

Application of pharmacogenetics in clinical practice: problems and solutions.

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.

Clinical utility of pharmacogenetic testing in children and adolescents with severe mental disorders.

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.

Host genetic profiling to increase drug safety in colorectal cancer from discovery to implementation.

Adverse events affect the pharmacological treatment of approximately 90% of colorectal cancer (CRC) patients at any stage of the disease. Chemotherapy including fluoropyrimidines, irinotecan, and oxaliplatin is the cornerstone of the pharmacological treatment of CRC. The introduction of novel targeted agents, as anti-EGFR (i.e. cetuximab, panitumumab) and antiangiogenic (i.e. bevacizumab, ziv-aflibercept, regorafenib, and ramucirumab) molecules, into the oncologist's toolbox has led to significant improvements in the life expectancy of advanced CRC patients, but with a substantial increase in toxicity burden. In this respect, pharmacogenomics has largely been applied to the personalization of CRC chemotherapy, focusing mainly on the study of inhered polymorphisms in genes encoding phase I and II enzymes, ATP-binding cassette (ABC)/solute carrier (SLC) membrane transporters, proteins involved in DNA repair, folate pathway and immune response. These research efforts have led to the identification of some validated genetic markers of chemotherapy toxicity, for fluoropyrimidines and irinotecan. No validated genetic determinants of oxaliplatin-specific toxicity, as peripheral neuropathy, has thus far been established. The contribution of host genetic markers in predicting the toxicity associated with novel targeted agents' administration is still controversial due to the heterogeneity of published data. Pharmacogenomics guidelines have been published by some international scientific consortia such as the Clinical Pharmacogenomics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) strongly suggesting a pre-treatment dose adjustment of irinotecan based on UGT1A1*28 genotype and of fluoropyrimidines based on some DPYD genetic variants, to increase treatment safety. However, these recommendations are still poorly applied at the patient's bedside. Several ongoing projects in the U.S. and Europe are currently evaluating how pharmacogenomics can be implemented successfully in daily clinical practice. The majority of drug-related adverse events are still unexplained, and a great deal of ongoing research is aimed at improving knowledge of the role of pharmacogenomics in increasing treatment safety. In this review, the issue of pre-treatment identification of CRC patients at risk of toxicity via the analysis of patients' genetic profiles is addressed. Available pharmacogenomics guidelines with ongoing efforts to implement them in clinical practice and new exploratory markers for clinical validation are described.

Treatment recommendations to cancer patients in the context of FDA guidance for next generation sequencing.

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.

Pharmacogenetics: a general review on progress to date.

BACKGROUND: Pharmacogenetics is not a new subject area but its relevance to drug prescribing has become clearer in recent years due to developments in gene cloning and DNA genotyping and sequencing. SOURCES OF DATA: There is a very extensive published literature concerned with a variety of different genes and drugs. AREAS OF AGREEMENT: There is general agreement that pharmacogenetic testing is essential for the safe use of drugs such as the thiopurines and abacavir. AREAS OF CONTROVERSY: Whether pharmacogenetic testing should be applied more widely including to the prescription of certain drugs such as warfarin and clopidogrel where the overall benefit is less clear remains controversial. GROWING POINTS: Personal genotype information is increasingly being made available directly to the consumer. This is likely to increase demand for personalized prescription and mean that prescribers need to take pharmacogenetic information into account. Projects such as 100 000 genomes are providing complete genome sequences that can form part of a patient medical record. This information will be of great value in personalized prescribing. AREAS TIMELY FOR DEVELOPING RESEARCH: Development of new drugs targeting particular genetic risk factors for disease. These could be prescribed to those with an at risk genotype.

Quality control materials for pharmacogenomic testing in the clinic.

Pharmacogenomics has significantly added to our understanding of drug responses in clinical pharmacology, changing the paradigm of treatment decisions. Interrogations of both inherited and somatic variations for therapeutic purposes are increasingly being adopted in clinics, where quality control (QC) materials are required. However, for many pharmacogenomic tests, the acquisition of well-characterized QC materials is often difficult or impossible. In this review, several sources of appropriate QC materials for therapy-associated genetic testing are discussed. Among them, the novel methods for producing renewable controls that resemble patient samples are highlighted. Owing to technological complexity, more efforts are needed to develop proper controls for next-generation sequencing-based assay.

Integrating clinical decision support systems for pharmacogenomic testing into clinical routine - a scoping review of designs of user-system interactions in recent system development.

BACKGROUND: Pharmacogenomic clinical decision support systems (CDSS) have the potential to help overcome some of the barriers for translating pharmacogenomic knowledge into clinical routine. Before developing a prototype it is crucial for developers to know which pharmacogenomic CDSS features and user-system interactions have yet been developed, implemented and tested in previous pharmacogenomic CDSS efforts and if they have been successfully applied. We address this issue by providing an overview of the designs of user-system interactions of recently developed pharmacogenomic CDSS. METHODS: We searched PubMed for pharmacogenomic CDSS published between January 1, 2012 and November 15, 2016. Thirty-two out of 118 identified articles were summarized and included in the final analysis. We then compared the designs of user-system interactions of the 20 pharmacogenomic CDSS we had identified. RESULTS: Alerts are the most widespread tools for physician-system interactions, but need to be implemented carefully to prevent alert fatigue and avoid liabilities. Pharmacogenomic test results and override reasons stored in the local EHR might help communicate pharmacogenomic information to other internal care providers. Integrating patients into user-system interactions through patient letters and online portals might be crucial for transferring pharmacogenomic data to external health care providers. Inbox messages inform physicians about new pharmacogenomic test results and enable them to request pharmacogenomic consultations. Search engines enable physicians to compare medical treatment options based on a patient's genotype. CONCLUSIONS: Within the last 5 years, several pharmacogenomic CDSS have been developed. However, most of the included articles are solely describing prototypes of pharmacogenomic CDSS rather than evaluating them. To support the development of prototypes further evaluation efforts will be necessary. In the future, pharmacogenomic CDSS will likely include prediction models to identify patients who are suitable for preemptive genotyping.

Recommendations for pharmacogenetic testing in clinical practice guidelines in the US.

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.

Benchmarking pharmacogenomics genotyping tools: Performance analysis on short-read sequencing samples and depth-dependent evaluation.

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.

Application of the community dialogues method to identify ethical values and priorities related to pharmacogenomics.

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.

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.

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.

Synthesis of major pharmacogenomics pretest counseling themes: a multisite comparison.

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.

Providers' perspectives on the clinical utility of pharmacogenomic testing in pediatric patients.

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.

Pharmacogenomic testing to support prescribing in primary care: a structured review of implementation models.

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.