Empowering personalized pharmacogenomics with generative AI solutions.

OBJECTIVE: This study evaluates an AI assistant developed using OpenAI's GPT-4 for interpreting pharmacogenomic (PGx) testing results, aiming to improve decision-making and knowledge sharing in clinical genetics and to enhance patient care with equitable access. MATERIALS AND METHODS: The AI assistant employs retrieval-augmented generation (RAG), which combines retrieval and generative techniques, by harnessing a knowledge base (KB) that comprises data from the Clinical Pharmacogenetics Implementation Consortium (CPIC). It uses context-aware GPT-4 to generate tailored responses to user queries from this KB, further refined through prompt engineering and guardrails. RESULTS: Evaluated against a specialized PGx question catalog, the AI assistant showed high efficacy in addressing user queries. Compared with OpenAI's ChatGPT 3.5, it demonstrated better performance, especially in provider-specific queries requiring specialized data and citations. Key areas for improvement include enhancing accuracy, relevancy, and representative language in responses. DISCUSSION: The integration of context-aware GPT-4 with RAG significantly enhanced the AI assistant's utility. RAG's ability to incorporate domain-specific CPIC data, including recent literature, proved beneficial. Challenges persist, such as the need for specialized genetic/PGx models to improve accuracy and relevancy and addressing ethical, regulatory, and safety concerns. CONCLUSION: This study underscores generative AI's potential for transforming healthcare provider support and patient accessibility to complex pharmacogenomic information. While careful implementation of large language models like GPT-4 is necessary, it is clear that they can substantially improve understanding of pharmacogenomic data. With further development, these tools could augment healthcare expertise, provider productivity, and the delivery of equitable, patient-centered healthcare services.

The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities.

Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in the All of Us cohort. The European ancestry subgroup showed the highest overall rate of pathogenic variation, with 2.26% of participants having a pathogenic variant. Other ancestry groups had lower rates of pathogenic variation, including 1.62% for the African ancestry group and 1.32% in the Latino/Admixed American ancestry group. Pathogenic variants were most frequently observed in genes related to Breast/Ovarian Cancer or Hypercholesterolemia. Variant frequencies in many genes were consistent with the data from the public gnomAD database, with some notable exceptions resolved using gnomAD subsets. Differences in pathogenic variant frequency observed between ancestral groups generally indicate biases of ascertainment of knowledge about those variants, but some deviations may be indicative of differences in disease prevalence. This work will allow targeted precision medicine efforts at revealed disparities.

Updated DPYD HapB3 haplotype structure and implications for pharmacogenomic testing.

The DPYD gene encodes dihydropyrimidine dehydrogenase, the rate-limiting enzyme for the metabolism of fluoropyrimidines 5-fluorouracil and capecitabine. Genetic variants in DPYD have been associated with altered enzyme activity, therefore accurate detection and interpretation is critical to predict metabolizer status for individualized fluoropyrimidine therapy. The most commonly observed deleterious variation is the causal variant linked to the previously described HapB3 haplotype, c.1129-5923C>G (rs75017182) in intron 10, which introduces a cryptic splice site. A benign synonymous variant in exon 11, c.1236G>A (rs56038477) is also linked to HapB3 and is commonly used for testing. Previously, these single-nucleotide polymorphisms (SNPs) have been reported to be in perfect linkage disequilibrium (LD); therefore, c.1236G>A is often utilized as a proxy for the function-altering intronic variant. Clinical genotyping of DPYD identified a patient who had c.1236G>A, but not c.1129-5923C>G, suggesting that these two SNPs may not be in perfect LD, as previously assumed. Additional individuals with c.1236G>A, but not c.1129-5923C>G, were identified in the Children's Mercy Data Warehouse and the All of Us Research Program version 7 cohort substantiating incomplete SNP linkage. Consequently, testing only c.1236G>A can generate false-positive results in some cases and lead to suboptimal dosing that may negatively impact patient therapy and prospect of survival. Our data show that DPYD genotyping should include the functional variant c.1129-5923C>G, and not the c.1236G>A proxy, to accurately predict DPD activity.

N-Acetylcysteine and Probenecid Adjuvant Therapy for Traumatic Brain Injury.

N-Acetylcysteine (NAC) has shown promise as a putative neurotherapeutic for traumatic brain injury (TBI). Yet, many such promising compounds have limited ability to cross the blood-brain barrier (BBB), achieve therapeutic concentrations in brain, demonstrate target engagement, among other things, that have hampered successful translation. A pharmacologic strategy for overcoming poor BBB permeability and/or efflux out of the brain of organic acid-based, small molecule therapeutics such as NAC is co-administration with a targeted or nonselective membrane transporter inhibitor. Probenecid is a classic ATP-binding cassette and solute carrier inhibitor that blocks transport of organic acids, including NAC. Accordingly, combination therapy using probenecid as an adjuvant with NAC represents a logical neurotherapeutic strategy for treatment of TBI (and other CNS diseases). We have completed a proof-of-concept pilot study using this drug combination in children with severe TBI-the Pro-NAC Trial (ClinicalTrials.gov NCT01322009). In this review, we will discuss the background and rationale for combination therapy with probenecid and NAC in TBI, providing justification for further clinical investigation.

Pharmacogenomics in the Management of Pulmonary Arterial Hypertension: Current Perspectives.

Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include CYP2C8, CYP2C9, CAMK2D, and PFAS. CYP2C8 and CYP2C9 are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with CYP2C9 were associated with lower treatment persistence. Additionally, a higher CYP2C9 activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include CAMK2D, which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, PFAS is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include GNG2 and CYP2C9. A genetic variant in GNG2 (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with CYP2C9 (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.

Development of Competency-based Online Genomic Medicine Training (COGENT).

The fields of genetics and genomics have greatly expanded across medicine through the development of new technologies that have revealed genetic contributions to a wide array of traits and diseases. Thus, the development of widely available educational resources for all healthcare providers is essential to ensure the timely and appropriate utilization of genetics and genomics patient care. In 2020, the National Human Genome Research Institute released a call for new proposals to develop accessible, sustainable online education for health providers. This paper describes the efforts of the six teams awarded to reach the goal of providing genetic and genomic training modules that are broadly available for busy clinicians.

Evaluation of Potential Racial Disparities in CYP2C19-Guided P2Y12 Inhibitor Prescribing After Percutaneous Coronary Intervention.

Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y12 inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI. Patients from 9 sites that performed clinical CYP2C19 genotyping after PCI were included. Alternative therapy (e.g., prasugrel or ticagrelor) was recommended for CYP2C19 no-function allele carriers, in whom clopidogrel is predicted to be less effective. The primary outcome was choice of P2Y12 inhibitor (clopidogrel vs. alternative therapy) based on genotype. Of 3,342 patients included, 2,448 (73%) were White, and 659 (20%) were Black. More Black than White patients had a no-function allele (34.3% vs. 29.7%, P = 0.024). At hospital discharge following PCI, 44.2% of Black and 44.0% of White no-function allele carriers were prescribed alternative therapy. At the time of the last follow-up within 12 months, numerically fewer Black (51.8%) than White (56.7%) no-function allele carriers were prescribed alternative therapy (P = 0.190). However, the difference was not significant after accounting for other factors associated with P2Y12 inhibitor selection (odds ratio 0.79, 95% confidence interval 0.58-1.08). Alternative therapy use did not differ between Black (14.3%) and White (16.7%) patients without a no-function allele (P = 0.232). Among real-world patients who received CYP2C19 testing after PCI, P2Y12 inhibitor prescribing rates did not differ between Black and White patients. Our data suggest an absence of racial disparity in genotype-guided antiplatelet prescribing among patients receiving CYP2C19 testing.

PharmVar GeneFocus: SLCO1B1.

The Pharmacogene Variation Consortium (PharmVar) is now providing star (*) allele nomenclature for the highly polymorphic human SLCO1B1 gene encoding the organic anion transporting polypeptide 1B1 (OATP1B1) drug transporter. Genetic variation within the SLCO1B1 gene locus impacts drug transport, which can lead to altered pharmacokinetic profiles of several commonly prescribed drugs. Variable OATP1B1 function is of particular importance regarding hepatic uptake of statins and the risk of statin-associated musculoskeletal symptoms. To introduce this important drug transporter gene into the PharmVar database and serve as a unified reference of haplotype variation moving forward, an international group of gene experts has performed an extensive review of all published SLCO1B1 star alleles. Previously published star alleles were self-assigned by authors and only loosely followed the star nomenclature system that was first developed for cytochrome P450 genes. This nomenclature system has been standardized by PharmVar and is now applied to other important pharmacogenes such as SLCO1B1. In addition, data from the 1000 Genomes Project and investigator-submitted data were utilized to confirm existing haplotypes, fill knowledge gaps, and/or define novel star alleles. The PharmVar-developed SLCO1B1 nomenclature has been incorporated by the Clinical Pharmacogenetics Implementation Consortium (CPIC) 2022 guideline on statin-associated musculoskeletal symptoms.

Antiplatelet Therapy and Bleeding Outcomes With CYP2C19 Genotyping.

PURPOSE: The impact of antiplatelet therapy with availability of CYP2C19 genotyping on bleeding in a real-world setting has not been extensively studied. METHODS: Prospective, single-center, cohort study conducted between December 2015 and October 2019 with 1-year follow-up. Patients underwent percutaneous coronary intervention (PCI), CYP2C19 genotyping, and received P2Y12 inhibitor therapy. The primary outcome was time to first bleed of any severity using Bleeding Academic Research Consortium criteria. Secondary outcomes included time to first major bleed and rates of antiplatelet switching. RESULTS: The primary outcome occurred in 697 of 2091 (33%) participants at a median of 15 days. Major bleeding occurred in 176 (8%) of patients. Compared to clopidogrel, treatment with ticagrelor or prasugrel was associated with increased risk of any bleeding (adjusted HR [aHR] 2.04, 95% CI 1.69-2.46). For patients without CYP2C19 no function alleles, treatment with prasugrel or ticagrelor was associated with increased risk of any bleeding (aHR 2.31, 95% CI 1.83-2.90). Similar associations were observed for major bleeding. No difference in ischemic events was observed. Among patients discharged on ticagrelor or prasugrel, 199 (36%) were de-escalated to clopidogrel within 1 year. De-escalation was more likely after a bleed if patients did not have a no function allele (35.9% vs 19.1%; P = .02). CONCLUSION: Bleeding is common in post-PCI patients on antiplatelet therapy. Patients on high potency agents had higher bleeding risk in the population at-large and in non-carriers of CYP2C19 no function alleles. Genotype-guided antiplatelet de-escalation should be further explored in prospective studies.

Transport and Permeation Properties of Dapivirine: Understanding Potential Drug-Drug Interactions.

The dapivirine (DPV) vaginal ring was developed by the nonprofit International Partnership for Microbicides (IPM) for reducing the risk of HIV infection. A clinical study (IPM 028) showed that concomitant use of the DPV ring and miconazole (MIC) altered DPV pharmacokinetic profile. In this work, we investigated whether or not DPV transport and permeation contributed to the observed DPV-MIC interaction. Our study evaluated the interaction between DPV and several transporters that are highly expressed in the human female reproductive tract, including MRP1, MRP4, P-gp, BCRP, and ENT1, using vesicular and cellular systems. We also evaluated the impact of DPV/MIC on cellular tight junctions by monitoring transepithelial electrical resistance with the Ussing chamber. Lastly, we evaluated the effect of MIC on DPV permeability across human cervical tissue. Our findings showed that DPV was not a substrate of MRP1, MRP4, P-gp, BCRP, or ENT1 transporters. Additionally, DPV did not inhibit the activity of these transporters. DPV, MIC, and their combination also did not disrupt cellular tight junctions. MIC did not affect DPV tissue permeability but significantly reduced DPV tissue levels. Therefore, our results suggest that the DPV-MIC interaction is not due to these five transporters, altered tight junction integrity, or altered tissue permeability.

Fetal pharmacogenomics: A promising addition to complex neonatal care.

OBJECTIVE: Pharmacogenomics (PGx) characterizes genetic variation in medication response. 85-95% of the population carries actionable PGx variants. No prior studies have demonstrated the application and feasibility of PGx in prenatal testing. We assessed parental desire for PGx findings from fetal exome sequencing (ES), evaluated PGx variants, and reviewed implications for medically complex neonates. METHODS: A prospective cohort undergoing ES for nonimmune hydrops fetalis were offered PGx results as a secondary finding. Seven pharmacogenes with Level A evidence, defined by Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, were tested and reported to patients and referring providers. Medication administration records were reviewed. RESULTS: Most participants (36/40, 90%) desired PGx testing. 32/36 (89%) had potentially actionable PGx diplotypes in six genes: CYP2C19 (20/36, 56%), CYP2C9 (16/36, 44%), CYP2D6 (10/36, 28%), SLCO1B1 (13/36, 36%), TPMT (6/36, 17%), UGT1A1 (4/36, 11%). 12/13 (92%) live births had PGx variants. Neonatal chart review indicated that three medications with CPIC Level A evidence were administered to four neonates. None of the patients received a medication that aligned with an actionable pharmacogenetic variant as defined by Level A CPIC guidance. CONCLUSION: Most participants opted to receive PGx results. 89% had actionable variants, consistent with population estimates. Obtaining fetal PGx data is feasible for medically complex neonates. Further studies are needed for broad clinical application of PGx in fetuses with major congenital abnormalities. Our study demonstrates the potential of PGx as useful preemptive clinical information that could be obtained at the time of fetal exome sequencing for other indications. CLINICALTRIALS: gov Registration: NCT03911531.

Simultaneous detection of a panel of nine sedatives and metabolites in plasma from critically ill pediatric patients via UPLC-MS/MS.

Sedative use can result in adverse drug reactions. Intensive care unit patients are especially at risk and pharmacokinetic modeling of drug concentrations is an approach to develop precision dosing strategies. However, limited blood sampling availability in critically ill children and need for multiple assays to quantify a variety of commonly used sedatives creates logistical challenges. The goal of this project was to develop a sensitive and selective assay for the simultaneous quantification of a panel of sedatives comprised of midazolam (MDZ), alpha hydroxymidazolam (1- OH MDZ), dexmedetomidine (DEX), morphine (MOR), morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), fentanyl (FEN), norfentanyl (NF), and hydromorphone (HM) in small volume pediatric plasma samples. A sensitive and efficient ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method was developed following FDA guidance for bioanalytical validation. Minimal sample preparation consisting of simple protein precipitation extraction using acetonitrile with internal standards was utilized. Analyte separation was achieved using a gradient mixture of (A: 0.15% formic acid in water and B: Acetonitrile) and a Waters Acquity C18, 1.7 µm (2.1 × 100 mm) column. Assays were linear over the clinical concentration ranges: MDZ, MOR, HM: 0.5-125 ng/mL; 1-OH MDZ, M3G, M6G: 5-500 ng/mL; and DEX, FEN, NF: 0.05-7.5 ng/mL (R2 > 0.99 for all). Assay run time was 10 min and required only 100 µL of plasma. Initial testing of samples from pediatric patients demonstrates adequacy of assay to measure sedatives and metabolites at clinical concentrations confidently in low volumes of plasma. This novel highly-sensitive and specific method to measure a total of nine different analytes (five sedatives, four metabolites) simultaneously enables comprehensive analysis of a panel of sedatives in small volumes such as in pediatric ICU patients.

Best-worst scaling methodology to evaluate constructs of the Consolidated Framework for Implementation Research: application to the implementation of pharmacogenetic testing for antidepressant therapy.

BACKGROUND: Despite the increased demand for pharmacogenetic (PGx) testing to guide antidepressant use, little is known about how to implement testing in clinical practice. Best-worst scaling (BWS) is a stated preferences technique for determining the relative importance of alternative scenarios and is increasingly being used as a healthcare assessment tool, with potential applications in implementation research. We conducted a BWS experiment to evaluate the relative importance of implementation factors for PGx testing to guide antidepressant use. METHODS: We surveyed 17 healthcare organizations that either had implemented or were in the process of implementing PGx testing for antidepressants. The survey included a BWS experiment to evaluate the relative importance of Consolidated Framework for Implementation Research (CFIR) constructs from the perspective of implementing sites. RESULTS: Participating sites varied on their PGx testing platform and methods for returning recommendations to providers and patients, but they were consistent in ranking several CFIR constructs as most important for implementation: patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and identification of champions. CONCLUSIONS: This study demonstrates the feasibility of using choice experiments to systematically evaluate the relative importance of implementation determinants from the perspective of implementing organizations. BWS findings can inform other organizations interested in implementing PGx testing for mental health. Further, this study demonstrates the application of BWS to PGx, the findings of which may be used by other organizations to inform implementation of PGx testing for mental health disorders.

CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention in Diverse Clinical Settings.

Background Studies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss-of-function (LOF) variant carriers versus non-carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real-world outcomes with the clinical implementation of CYP2C19-guided antiplatelet therapy after PCI. Methods and Results Data from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a CYP2C19 LOF variant. The primary outcome was the composite of major atherothrombotic events (all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life-threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39-0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71-1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele. Conclusions Real-world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.

Multisite evaluation of institutional processes and implementation determinants for pharmacogenetic testing to guide antidepressant therapy.

There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best-worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx-guided pharmacotherapy for antidepressant management.

Pharmacists Leading the Way to Precision Medicine: Updates to the Core Pharmacist Competencies in Genomics.

Genomics is becoming an increasingly important part of health care, and pharmacists are well-positioned to be practice-based leaders in pharmacogenomics and precision medicine. Competencies available through the Genetics/Genomics Competency Center provide a framework for pharmacogenomics instruction in both pharmacy school curricula and continuing education programs. Given the significant advancements in pharmacogenomics over the past decade, the 2019-2020 American Association of Colleges of Pharmacy Pharmacogenomics Special Interest Group updated the pharmacist competencies. The process used a systematic approach which included mapping pharmacogenomics-specific competencies to the entrustable professional activities for pharmacists and seeking consensus from key stakeholders. The result is an expansion to 30 competencies that reflect the contemporary roles pharmacists play in the application of pharmacogenomics in clinical practice. When implemented into curricula, these competencies will ensure that learners are "practice ready" to integrate pharmacogenomics into patient care. Additional postgraduate training is needed for advanced roles in pharmacogenomics implementation, education, and research.

Documenting Pharmacogenomic Test Results in Electronic Health Records: Practical Considerations for Primary Care Teams.

With increasing patient interest in and access to pharmacogenomic testing, clinicians practicing in primary care are more likely than ever to encounter a patient seeking or presenting with pharmacogenomic test results. Gene-based prescribing recommendations are available to healthcare providers through Food and Drug Administration-approved drug labeling and Clinical Pharmacogenetics Implementation Consortium guidelines. Given the lifelong utility of pharmacogenomic test results to optimize pharmacotherapy for commonly prescribed medications, appropriate documentation of these results in a patient's electronic health record (EHR) is essential. The current "gold standard" for pharmacogenomics implementation includes entering pharmacogenomic test results into EHRs as discrete results with associated clinical decision support (CDS) alerts that will fire at the point of prescribing, similar to drug allergy alerts. However, such infrastructure is limited to the few institutions that have invested in the resources and personnel to develop and maintain it. For the majority of clinicians who do not practice at an institution with a dedicated clinical pharmacogenomics team and integrated pharmacogenomics CDS in the EHR, this report provides practical tips for documenting pharmacogenomic test results in the problem list and allergy field to maximize the visibility and utility of results over time, especially when such results could prevent the occurrence of serious adverse drug reactions or predict therapeutic failure.

Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing.

PURPOSE: The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear. METHODS: In this report, we compare and contrast implementation strategies for pre-emptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates. RESULTS: We found that while pre-emptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Finally, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for pre-emptive PGx testing remain low. CONCLUSION: These findings should inform the establishment of future implementation efforts at institutions considering a pre-emptive PGx testing program.