Preemptive Testing Research Articles

Estimating the potential impact of implementing pre-emptive pharmacogenetic testing in primary care across the UK.

Pharmacogenetics (PGx) in the UK is currently implemented in secondary care for a small group of high-risk medicines. However, most prescribing takes place in primary care, with a large group of medicines influenced by commonly occurring genetic variations. The goal of this study is to quantitatively estimate the volumes of medicines impacted by implementation of a population-level, pre-emptive pharmacogenetic screening programme for nine genes related to medicines frequently dispensed in primary care in 2019. A large community pharmacy database was analysed to estimate the national incidence of first prescriptions for 56 PGx drugs used in the UK for the period 1 January-31 December 2019. These estimated prescription volumes were combined with phenotype frequency data to estimate the occurrence of actionable drug-gene interactions (DGI) in daily practice in community pharmacies. In between 19.1 and 21.1% (n=5 233 353-5 780 595) of all new prescriptions for 56 drugs (n=27 411 288 new prescriptions/year), an actionable drug-gene interaction (DGI) was present according to the guidelines of the Dutch Pharmacogenetics Working Group and/or the Clinical Pharmacogenetics Implementation Consortium. In these cases, the DGI would result in either increased monitoring, guarding against a maximum ceiling dose or an optional or immediate drug/dose change. An immediate dose adjustment or change in drug regimen accounted for 8.6-9.1% (n=2 354 058-2 500 283) of these prescriptions. Actionable drug-gene interactions frequently occur in UK primary care, with a large opportunity to optimise prescribing.

Impact and applicability of pharmacogenomics in rheumatology: an integrated analysis.

Rheumatology medications are often associated with adverse drug reactions (ADRs) or inadequate response (IR). Pharmacogenomics may be a solution, but there is limited knowledge of its potential utility within rheumatology. We analysed medication changes and pharmacogenomically actionable prescriptions for all adult rheumatology outpatient encounters at our medical centre between 10/2012-12/2018. Three sources defined pharmacogenomic actionability: FDA labels, Clinical Pharmacogenetics Implementation Consortium guidelines, and our institutionally-deliverable pharmacogenomic clinical decision support (CDS) summaries. A subset of patients (validation cohort) had previously undergone broad, preemptive pharmacogenomic testing within other clinics but results were unavailable within rheumatology. We assessed the occurrence of specific pharmacogenomic ADRs/IRs in this group. From 174,834 prescribing events, 6300/7761 patients (81%) had clinically actionable pharmacogenomic drug prescriptions (i.e. institutional CDS summaries would have been deployable if testing had been done). Using more conservative standards (pharmacogenomically actionable by ≥2 guidance bodies), 4158/7761 (54%) patient prescriptions could have been impacted. The greatest proportions of potentially impacted rheumatologic prescriptions were for tramadol (47%), allopurinol (21%), azathioprine (17%) and celecoxib (8%). Among our validation cohort (94 previously-genotyped patients), 29 (31%) patients had a pharmacogenomic genotype that would have cautioned possible ADRs/IRs for ≥1 medication. Four patients actually suffered ADRs/IRs that would have been predicted by preemptive genotyping. Pharmacogenomic genotyping could inform prescribing for the majority of rheumatology patients and may prevent a subset of ADRs/IRs. These findings justify prospective evaluation of pharmacogenomic testing including assessment of cost-effectiveness in selected rheumatology populations to further understand impact on therapy-related toxicities and treatment outcomes.

An Updated Review of the Diagnostic Methods in Delayed Drug Hypersensitivity.

Delayed drug hypersensitivity reactions are clinically diverse reactions that vary from isolated benign skin conditions that remit quickly with no or symptomatic treatment, drug discontinuation or even continued drug treatment, to the other extreme of severe cutaneous adverse reactions (SCARs) that are associated with presumed life-long memory T-cell responses, significant acute and long-term morbidity and mortality. Diagnostic “in clinic” approaches to delayed hypersensitivity reactions have included patch testing (PT), delayed intradermal testing (IDT) and drug challenges for milder reactions. Patch and IDT are, in general, performed no sooner than 4–6 weeks after resolution of the acute reaction at the maximum non-irritating concentrations. Functional in vitro and ex vivo assays have largely remained the province of research laboratories and include lymphocyte transformation test (LTT) and cytokine release enzyme linked ImmunoSpot (ELISpot) assay, an emerging diagnostic tool which uses cytokine release, typically IFN-γ, after the patient’s peripheral blood mononuclear cells are stimulated with the suspected drug(s). Genetic markers such as human leukocyte antigen have shown recent promise for both pre-prescription screening as well as pre-emptive and diagnostic testing strategies.

Review on Databases and Bioinformatic Approaches on Pharmacogenomics of Adverse Drug Reactions.

Pharmacogenomics has been used effectively in studying adverse drug reactions by determining the person-specific genetic factors associated with individual response to a drug. Current approaches have revealed the significant importance of sequencing technologies and sequence analysis strategies for interpreting the contribution of genetic variation in developing adverse reactions. Advance in next generation sequencing and platform brings new opportunities in validating the genetic candidates in certain reactions, and could be used to develop the preemptive tests to predict the outcome of the variation in a personal response to a drug. With the highly accumulated available data recently, the in silico approach with data analysis and modeling plays as other important alternatives which significantly support the final decisions in the transformation from research to clinical applications such as diagnosis and treatments for various types of adverse responses.

436. Assessing SARS-CoV-2 Infection among Persons Experiencing Homelessness — Atlanta, GA, 2020

BackgroundPersons experiencing homelessness (PEH) often do not have sufficient resources to practice public health interventions. PEH may reside at overcrowded shelters, have poor access to health care, and often suffer from significant co-morbid conditions. In this study, we describe prevalence of COVID-19 amongst PEH and homeless service staff in Atlanta, Georgia, as well as demographic data, underlying conditions, and symptoms.MethodsIn response to the COVID-19 pandemic in Atlanta, PEH and homeless service providers were offered PCR testing for SARS-CoV-2 via nasopharyngeal, nasal mid-turbinate, and oropharyngeal swabs. Shelters identified as having a higher number of COVID-19 infections underwent re-testing 3–4 weeks after initial testing. Demographic information was collected, and individuals were screened for symptoms and underlying conditions.ResultsA total of 2,294 PEH and 544 staff underwent SARS-CoV-2 PCR testing from April 8 - May 6, 2020. 24 homeless shelters were included in this study. The majority of individuals were male (66.3% sheltered, 85.5% unsheltered, 55.3% staff), and 2,192 of 2,838 (78.3%) persons identified as black. Approximately half of individuals had no known underlying conditions (51.5% sheltered, 47.7% unsheltered, 55.5% staff). Cardiovascular disease was the most frequently reported condition (32.0%), followed by chronic lung disease (14.8%). In total, 45 of 2,823 (1.6%) individuals had detectable PCR results for SARS-CoV-2, including 35 of 1,666 (2.1%) sheltered clients, 3 of 614 (0.5%) unsheltered clients, and 7 of 543 (1.3%) staff. Among individuals with detectable SARS-CoV-2, 5 of 20 (25%) reported at least one symptom in the last week. Most shelters (16 of 24) had at least one individual with detectable SARS-CoV-2. The prevalence of SARS-CoV-2 in the majority of shelters (19 of 24) was < 3%, with a median prevalence of 0.2% across all shelters. Upon retesting 4 shelters with a higher number of COVID-19 infections, only 3 individuals from 2 shelters tested positive out of 357 total retested (0.8%). ConclusionWe identified a low prevalence of SARS-CoV-2 infection among PEH in Atlanta, which was influenced by a pre-emptive testing strategy. Continued vigilance is necessary to limit spread in this vulnerable population.Disclosures All Authors: No reported disclosures

Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy.

Fluoropyrimidines (FPs), mainly 5-fluorouracil (5-FU) and its oral prodrug capecitabine (Cap), remain the backbone of the treatment of many different solid tumors. Despite their broad use in clinical routine, 10&ndash;40% of patients experience severe, and in rare cases (0.2&ndash;0.5%) even lethal, FP-related toxicity in early chemotherapy cycles. Today, there is a plethora of evidence that genetic variants in the gene encoding for the 5-FU catabolising enzyme dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) are predictive of severe FP-related toxicities, and international clinical practice recommendations for DPYD genotype-guided FP dosing and therapeutic drug monitoring (TDM) are available. In spite of this strong evidence and DPYD genotyping becoming standard practice in other countries, it is has not been widely adopted in Switzerland to date. Here, we discuss current guidelines on genotype-guided FP dosing and TDM, and propose recommendations tailored to the situation in Switzerland to facilitate their clinical uptake for the further individualisation of FP chemotherapy. We recommend preemptive testing of four DPYD variants (c.1905+1G&gt;A (rs3918290), c.1679T&gt;G (rs55886062), c.2846A&gt;T (rs67376798) and c.1129-5923C&gt;G (rs75017182, c.1236G&gt;A/HapB3)) in patients with an indication for FP-based chemotherapy, with the costs reimbursed through the compulsory health insurance in Switzerland. Carriers of these variants (6.5% in the Swiss population) have a 40&ndash;50% risk of developing severe early-onset toxicity when treated with standard FP doses. In these patients, we therefore recommend the use of a reduced starting dose, based on a dose adjustment scheme provided herein. Furthermore, we recommend the use of infusional 5-FU in patients with a DPYD risk genotype in order to enable TDM-based dose escalation. Only if the use of an infusional 5-FU regimen is not feasible should a slow titration of Cap, starting with the recommended reduced dose and basing further doses on monitoring of toxicity, be considered. Given that several studies have shown that TDM in 5-FU treatment improves not only the therapy&rsquo;s safety, but potentially also its efficacy, we also include detailed TDM-based dosing guidelines and discuss the pre-analytical aspects of 5-FU TDM.

Risk stratification through implementation and evaluation of aCOVID-19 score : Aretrospective diagnostic study

HintergrundDie COVID-19-Erkrankung (Coronavirus Disease 2019) ist in ihrer klinischen Manifestation unspezifisch und sehr variabel, wodurch die Diskriminationsfähigkeit zu anderen (Virus‑)Infekten erschwert ist. Weder Einzelbefunde noch Befundkombinationen sind spezifisch genug, um eine COVID-19-Erkrankung mit hoher Sicherheit diagnostizieren zu können. Ziel war es, in der Notaufnahme durch Anwendung eines Scores frühzeitig Patienten identifizieren zu können, die ein Risiko für eine COVID-19-Erkrankung haben und somit präemptiv isoliert werden müssen.MethodeEntwicklung und Implementierung eines symptombasierten COVID-19-Scores anhand einer multizentrischen retrospektiven Diagnostikstudie in 3 deutschen Notaufnahmen vom 09.03. bis 30.04.2020 an Patienten mit Verdacht auf COVID-19 und anschließender SARS-CoV-2-PCR-Diagnostik.ErgebnisseDas Studienkollektiv umfasste 697 Patienten, bei 9,4 % dieser Patienten wurde eine COVID-19-Infektion diagnostiziert. Ein COVID-19-Score ≥5 Punkte ging mit einer deutlich erhöhten Erkrankungswahrscheinlichkeit einher. Die Sensitivität des Scores lag bei 98,4 % bei einer allerdings mäßigen Spezifität von 48,3 %.SchlussfolgerungDer während der Ersteinschätzung einfach zu erhebende Score unterstützt im Rahmen der Risikostratifizierung die Beurteilung der Vortestwahrscheinlichkeit für eine COVID-19-Infektion und kann frühzeitig den Behandlungspfad bezüglich präemptiver Isolation, PCR-Testung und weiterer Behandlungsoptionen beeinflussen. Aufgrund der unspezifischen Symptomatik der Erkrankung muss allerdings in Kauf genommen werden, dass für das Ziel einer hohen Sensitivität eine relativ geringe Spezifität des Scores resultiert.

Why clinicians overtest: development of a thematic framework

BackgroundMedical tests provide important information to guide clinical management. Overtesting, however, may cause harm to patients and the healthcare system, including through misdiagnosis, false positives, false negatives and overdiagnosis. Clinicians are ultimately responsible for test requests, and are therefore ideally positioned to prevent overtesting and its unintended consequences. Through this narrative literature review and workshop discussion with experts at the Preventing Overdiagnosis Conference (Sydney, 2019), we aimed to identify and establish a thematic framework of factors that influence clinicians to request non-recommended and unnecessary tests.MethodsArticles exploring factors affecting clinician test ordering behaviour were identified through a systematic search of MedLine in April 2019, forward and backward citation searches and content experts. Two authors screened abstract titles and abstracts, and two authors screened full text for inclusion. Identified factors were categorised into a preliminary framework which was subsequently presented at the PODC for iterative development.ResultsThe MedLine search yielded 542 articles; 55 were included. Another 10 articles identified by forward-backward citation and content experts were included, resulting in 65 articles in total. Following small group discussion with workshop participants, a revised thematic framework of factors was developed:“Intrapersonal” – fear of malpractice and litigation; clinician knowledge and understanding; intolerance of uncertainty and risk aversion; cognitive biases and experiences; sense of medical obligation“Interpersonal” – pressure from patients and doctor-patient relationship; pressure from colleagues and medical culture;“Environment/context” – guidelines, protocols and policies; financial incentives and ownership of tests; time constraints, physical vulnerabilities and language barriers; availability and ease of access to tests; pre-emptive testing to facilitate subsequent care; contemporary medical practice and new technologyConclusionThis thematic framework may raise awareness of overtesting and prompt clinicians to change their test request behaviour. The development of a scale to assess clinician knowledge, attitudes and practices is planned to allow evaluation of clinician-targeted interventions to reduce overtesting.

Pharmacogenetic testing in the management of patients with prosthetic heart valves

Abstract Background This study examined clinical, demographic, anthropometric, and inheritance factors that influence individual sensitivity to warfarin therapy after heart valve surgery. The clinical significance of the pharmacogenetic approach was assessed using the individual time frame and time spent in the INR therapeutic range. Purpose To study the influence of the preemptive panel-based pharmacogenetic testing on the effectiveness and safety of anticoagulant therapy in patients with prosthetic heart valves. Materials and methods The study included 928 patients (519 men and 409 female) (mean age 56±10 years) living in Western Siberia, Russia. Mainly there were patients with rheumatic heart disease, heart failure III NYHA and atrial fibrillation in 35% of cases. Mechanical heart valve prostheses were used in 70% of cardiac surgery cases. Real-time polymerase chain reaction was used for molecular genetic testing for polymorphisms VKORC, CYP2C9*2, CYP2C9*3, and CYP4F2. Results The frequencies of alleles and genotypes of CYP2C9 and VKORC1 in the study population of patients with heart valves prosthetic correspond to the distribution in Caucasian populations. Correlation between the calculated and actual therapeutic doses of warfarin was found according to the B.F Gage algorithm. In analyzing the dependence of the actual therapeutic dose of warfarin on polymorphic variants of the CYP2C9 and VKORC1 genes, it was shown that all the studied variants were associated with a therapeutic dose of warfarin, which was significantly different in carriers of different genotypes. Genotypes A/A CYP2C9*3 and G/G VKORC1 were associated with the largest deviations of the actual therapeutic dose from the calculated one. The clinical effectiveness of the pharmacogenetic approach was assessed according to the prevalence of the studied polymorphic variants of the CYP2C9 and VKORC1 genes in patients with prosthetic heart valves in the Kemerovo region. As a result, two groups of patients were formed using the “copy pair” method, without statistically significant differences in genetic, clinical, demographic, and anthropometric data. Usage of the pharmacogenetic testing at the beginning of warfarin therapy twice reduced time required to select a therapeutic dose of the anticoagulant, while the time within therapeutic INR range was increased by 20.2%. Conclusion The use of the panel-based pharmacogenetic approach at the beginning of warfarin therapy in patients with prosthetic heart valves increases the effectiveness and safety of anticoagulant therapy in the early postoperative period. Funding Acknowledgement Type of funding source: None

Malignant hyperthermia susceptibility: utilization of genetic results in an electronic medical record to increase safety.

Aim: This manuscript describes implementation of clinical decision supportfor providers concerned with perioperative complications of malignant hyperthermia susceptibility. Materials & methods: Clinical decision support for malignant hyperthermia susceptibility was implemented in 2018 based around our pre-emptive genotyping platform. We completed a brief descriptive review of patients who underwent pre-emptive testing, focused particularly on RYR1 and CACNA1S genes. Results: To date, we have completed pre-emptive genetic testing on more than 10,000 patients; 13 patients having been identified as a carrier of a pathogenic or likely pathogenic variant of RYR1 or CACNA1S. Conclusion: An alert system for malignant hyperthermia susceptibility - as an extension of our pre-emptive genomics platform - was implemented successfully. Implementation strategies and lessons learned are discussed herein.

Response to the Coronavirus Disease 2019 Pandemic Among People Experiencing Homelessness in Congregant Living Settings in San Diego, California

During April-August 2020, a preemptive testing strategy combined with accessible isolation and symptom screening among people experiencing homelessness in congregant living settings in San Diego contributed to a low incidence proportion of COVID-19: 0.9%. Proactively addressing challenges specific to a vulnerable population may significantly prevent spread and community outbreaks.

Preventing COVID-19 Outbreaks in Long-Term Care Facilities Through Preemptive Testing of Residents and Staff Members - Fulton County, Georgia, March-May 2020.

Long-term care facility (LTCF) residents are at particularly high risk for morbidity and mortality associated with infection with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), given their age and high prevalence of chronic medical conditions, combined with functional impairment that often requires frequent, close contact with health care providers, who might inadvertently spread the virus to residents (1,2). During March-May 2020 in Fulton County, Georgia, >50% of COVID-19-associated deaths occurred among LTCF residents, although these persons represented <1% of the population (3,4). Mass testing for SARS-CoV-2 has been an effective strategy for identifying asymptomatic and presymptomatic infections in LTCFs (5). This analysis sought to evaluate the timing at which mass testing took place in relation to the known presence of a COVID-19 infection and the resulting number of infections that occurred. In 15 LTCFs that performed facility-wide testing in response to an identified case, high prevalences of additional cases in residents and staff members were found at initial testing (28.0% and 7.4%, respectively), suggesting spread of infection had already occurred by the time the first case was identified. Prevalence was also high during follow-up, with a total of 42.4% of residents and 11.8% of staff members infected overall in the response facilities. In comparison, 13 LTCFs conducted testing as a preventive strategy before a case was identified. Although the majority of these LTCFs identified at least one COVID-19 case, the prevalence was significantly lower at initial testing in both residents and staff members (0.5% and 1.0%, respectively) and overall after follow-up (1.5% and 1.7%, respectively). These findings indicate that early awareness of infections might help facilities prevent potential outbreaks by prioritizing and adhering more strictly to infection prevention and control (IPC) recommendations, resulting in fewer infections than would occur when relying on symptom-based screening (6,7).

Pharmacogenetics in Psychiatry: An Update on Clinical Usability.

Using pharmacogenetics in guiding drug therapy experiences a steady increase in uptake, although still leads to discussions as to its clinical use. Psychiatry constitutes a field where pharmacogenomic testing might help in guiding drug therapy. To address current challenges, this minireview provides an update regarding genotyping (SNP analysis/arrays/NGS), structural variant detection (star-alleles/CNVs/hybrid alleles), genotype-to-phenotype translations, cost-effectiveness, and actionability of results (FDA/CPIC/PharmGKB) regarding clinical importance of pre-emptive pharmacogenomic testing for prescription of antidepressants and antipsychotics.

PCV10 A MODEL-Based Cost-Effectiveness Analysis of Pharmacogenomic Panel Testing in Cardiovascular Disease Management: Preemptive, Reactive or NONE?

The field of pharmacogenomics (PGx) studies how inherited genetic variations in individuals affect drug absorption, distribution and metabolism in a patient body. PGx panel testing can potentially help improve efficiency and accuracy in individualizing therapy. However, the cost-effectiveness of PGx panel testing strategies regarding the timing of the tests has not been assessed. This study aims to compare the cost-effectiveness between preemptive PGx testing, reactive PGx testing and usual care (no PGx testing) in cardiovascular disease management. We developed a decision analytic model that composed of a short-term decision tree and life-time Markov model to compare the three testing strategies. The study sample included a hypothetical cohort of 10,000 patients that represents a target US population of age 45 years or older. The testing panel assumed to include tests for the following genes and corresponding drug choices: CYP2C19 (clopidogrel vs. ticagrelor), CYP2C9/VKORC1 (warfarin vs. novel oral anticoagulants), and SLCO1B1 (statins vs. PCSK9). Scenario and probabilistic sensitivity analyses were performed to assess the impact of age, sex, race, risk level, and time frame duration. The study reported incremental cost-effectiveness ratios (ICERs) as the main outcome while costs, quality-adjusted life years (QALYs), incremental costs, and incremental QALYs were also reported for the base-case and sensitivity analyses. The results suggested that preemptive testing was cost-effective compared to usual care (ICER $71,540/QALY) at the willingness-to-pay (WTP) of $100,000/QALY while reactive testing was not (ICER $155,870/QALY). Preemptive testing gained a patient an additional 0.74 QALYs compared to usual care, while reactive testing lead to a 0.12 QALYs increase. The cost-effectiveness was not sensitive to age, sex, race and risk-level, but was sensitive to longer time frame. This study concludes that preemptive PGx panel testing for CVD diseases management was cost-effective and should be implemented in a system wide manner for the target population.

Drug Use among Nursing Home Residents in Denmark for Drugs Having Pharmacogenomics Based (PGx) Dosing Guidelines: Potential for Preemptive PGx Testing.

Background: Polypharmacy is most prevalent among the elderly population and in particular among nursing home residents. The frequency of the use of drugs with pharmacogenomics (PGx)-based dosing guidelines for CYP2D6, CYP2C9, CYP2C19 and SLCO1B1 were measured among nursing home residents in the Capital Region of Denmark as well as drug–drug interactions. The aim was to evaluate the potential of applying PGx-test as a supportive tool in medication reviews. Methods: Drug use among nursing home residents during 2017–2018 in the Capital Region of Copenhagen, for drugs with PGx-based dosing guidelines available through the PharmGKB website, were measured. Drug–drug interactions were scored in severity by using drug interaction checkers. Results: The number of residents using drugs with PGx-based actionable dosing guidelines (AG) were 119 out of 141 residents (84.3%). Of these 119 residents, 87 residents used drugs with AG for CYP2C19, 47 residents for CYP2D6, and 42 residents for SLCO1B1. In addition, 30 residents used two drugs with an AG for CYP2C19, and for CYP2D6, it was only seven residents. The most used drugs with AG were clopidogrel (42), pantoprazole (32), simvastatin (30), metoprolol (25), and citalopram (24). The most frequent drug interactions found with warnings were combinations of proton pump inhibitors and clopidogrel underscoring the potential for phenoconversion. Conclusion: this study clearly showed that the majority of the nursing home residents were exposed to drugs or drug combinations for which there exist PGx-based AG. This indeed supports the notion of accessing and accounting for not only drug–gene but also drug–drug–gene interactions as a supplement to medication review.

Global Frequencies of Clinically Important HLA Alleles and Their Implications For the Cost-Effectiveness of Preemptive Pharmacogenetic Testing.

Immune-mediated drug hypersensitivity reactions are an important source of iatrogenic morbidity and mortality. Human leukocyte antigen (HLA)-B*57:01, HLA-B*15:02, HLA-A*31:01, and HLA-B*58:01 constitute established risk factors and preemptive genotyping of these HLA alleles in patients prior to the initiation of abacavir, carbamazepine, and allopurinol-based therapies can prevent toxicity and improve patient outcomes. However, the cost-effectiveness of preemptive HLA testing has only been evaluated in the United States and few countries in Europe and Asia. In this study, we consolidated HLA genotypes from 3.5-6.4 million individuals across up to 74 countries and modeled the country-specific cost-effectiveness of genetic testing. We find major ethnogeographic differences in risk allele prevalence, which translated into pronounced differences in the number of patients needed to test to prevent one case of severe hypersensitivity reactions between countries and populations. At incremental cost-effectiveness ratio thresholds of $40,000, testing of HLA-B*57:01 in patients initiating abacavir was cost-effective in the majority of countries with potential exceptions of East Asia, Saudi Arabia, Ghana, and Zimbabwe. For carbamazepine, preemptive genotyping of HLA-B*15:02 is only cost-effective across most of East and South Asia, whereas HLA-A*31:01 testing is likely to be cost-effective globally. Testing of HLA-B*58:01 is more likely to be cost-effective throughout Africa and Asia compared with Europe and the Americas. We anticipate that this data set can serve as an important resource for clinicians and health economists to guide clinical decision making and inform public healthcare strategies.

CYP2C19 Allele Frequencies in Over 2.2 Million Direct-to-Consumer Genetics Research Participants and the Potential Implication for Prescriptions in a Large Health System.

Understanding the prevalence of clinically relevant pharmacogenetic variants using large unselected populations is critical for gauging the potential clinical impact of widespread preemptive pharmacogenetic testing. To this end, we assessed the frequencies and ethnic distribution of the three most common CYP2C19 alleles (*2, *3, and *17) in 2.29 million direct‐to‐consumer genetics research participants (23andMe, Sunnyvale, CA). The overall frequencies of *2, *3, and *17 were 15.2%, 0.3%, and 20.4%, respectively, but varied by ethnicity. The most common variant diplotypes were *1/*17 at 26% and *1/*2 at 19.4%. The less common *2/*17, *17/*17, and *2/*2 genotypes occurred at 6.0%, 4.4%, and 2.5%, respectively. Overall, 58.3% of participants had at least one increased‐function or no‐function CYP2C19 allele. To better understand how this high frequency might impact a real patient population, we examined the prescription rates (Rx) of high‐pharmacogenetic‐risk medications metabolized by CYP2C19 using the University of California at San Francisco (UCSF) health system’s anonymized database of over 1.25 million patients. Between 2012 and 2019, a total of 151,068 UCSF patients (15.8%) representing 5 self‐reported ethnicities were prescribed one or more high‐pharmacogenetic‐risk CYP2C19 medications: proton pump inhibitors (145,243 Rx), three selective serotonin reuptake inhibitor antidepressants (54,463 Rx), clopidogrel (14,376 Rx), and voriconazole (2,303 Rx).

How to Transition from Single-Gene Pharmacogenetic Testing to Preemptive Panel-Based Testing: A Tutorial.

There have been significant advancements in precision medicine and approaches to medication selection based on pharmacogenetic results. With the availability of direct-to-consumer genetic testing and growing awareness of genetic interindividual variability, patient demand for more precise, individually tailored drug regimens is increasing. The University of Florida (UF) Health Precision Medicine Program (PMP) was established in 2011 to improve integration of genomic data into clinical practice. In the ensuing years, the UF Health PMP has successfully implemented several single-gene tests to optimize the precision of medication prescribing across a variety of clinical settings. Most recently, the UF Health PMP launched a custom-designed pharmacogenetic panel, including pharmacogenes relevant to supportive care medications commonly prescribed to patients undergoing chemotherapy treatment, referred to as "GatorPGx." This tutorial provides guidance and information to institutions on how to transition from the implementation of single-gene pharmacogenetic testing to a preemptive panel-based testing approach. Here, we demonstrate application of the preemptive panel in the setting of an adult solid tumor oncology clinic. Importantly, the information included herein can be applied to other clinical practice settings.

Prescription patterns of outpatients and the potential of multiplexed pharmacogenomic testing.

Pre-emptive pharmacogenomic (PGx) testing is potentially an efficient approach to improve drug safety and efficacy but the target population to test is unclear. We aim to describe the prescription pattern of PGx drugs among adult medical outpatients. We estimated the 5-year cumulative incidence (CI) for receiving three groups of PGx drugs using competing risks analysis: (i) all PGx drugs, (ii) PGx drugs with guidelines and (iii) PGx drugs with serious clinical effects. Comparisons of CIs were also done by patient characteristics using Gray's test. The 5-year CIs of receiving any new PGx drug, PGx drug with guidelines and serious clinical effects were 42.6%, 37.3% and 13.7%, respectively. The 5-year CI of receiving any new PGx drug was higher for patients >40 years old (43.6% vs ≤40 years old 36.0%, P < 2.2 × 10-22 ), Malays and Indians (50.3% and 49.8% vs Chinese 31.1%, P < 2.2 × 10-22 ), those who attended one of the following four specialties at the index visit compared to other specialties (infectious diseases [46.2% vs 42.6%, P = 2.9 × 10-4 ], psychiatry [48.3% vs 42.3%, P = 7.4 × 10-13 ], renal [49.8% vs 40.9%, P < 2.2 × 10-22 ], and rheumatology and immunology [54.8% vs 41.7%, P < 2.2 × 10-22 ]) and those prescribed ≥5 drugs at index visit (51.7% vs 0-4 drugs 41.7%, P < 2.2 × 10-22 ). Medical outpatients have a substantial probability of benefiting from pre-emptive PGx testing and this is higher in certain subgroups of patients.

Pharmacogenomics of anticancer drugs: Personalising the choice and dose to manage drug response.

The field of pharmacogenomics has made great strides in oncology over the last 20 years and indeed a significant number of pre-emptive genetic tests are now routinely undertaken prior to anticancer drug administration. Many of these gene-drug interactions are the fruits of candidate gene and genome-wide association studies, which have largely focused on common genetic variants (allele frequency>1%). Examples where there is clinical utility include genotyping or phenotyping for G6PD to prevent rasburicase-induced RBC haemolysis, and TPMT to prevent thiopurine-induced bone marrow suppression. Other associations such as CYP2D6 status in determining the efficacy of tamoxifen are more controversial because of contradictory evidence from different sources, which has led to variability in the implementation of testing. As genomic technology becomes ever cheaper and more accessible, we must look to the additional data our genome can provide to explain interindividual variability in anticancer drug response. Clearly genes do not act on their own and it is therefore important to investigate genetic factors in conjunction with clinical factors, interacting concomitant drug therapies and other factors such as the microbiome, which can all affect drug disposition. Taking account of all of these factors, in conjunction with the somatic genome, is more likely to provide better predictive accuracy in determining anticancer drug response, both efficacy and safety. This review summarises the existing knowledge related to the pharmacogenomics of anticancer drugs and discusses areas of opportunity for further advances in personalisation of therapy in order to improve both drug safety and efficacy.