Clinician adherence to pharmacogenomics prescribing recommendations in clinical decision support alerts

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Jenny Q Nguyen, Kristine R Crews, Ben T Moore, Nancy M Kornegay, Donald K Baker, Murad Hasan, Patrick K Campbell, Shannon M Dean, Mary V Relling , James M Hoffman, Cyrine E Haidar

Abstract

Thoughtful integration of interruptive clinical decision support (CDS) alerts within the electronic health record is essential to guide clinicians on the application of pharmacogenomic results at point of care. St. Jude Children’s Research Hospital implemented a preemptive pharmacogenomic testing program in 2011 in a multidisciplinary effort involving extensive education to clinicians about pharmacogenomic implications. We conducted a retrospective analysis of clinicians’ adherence to 4783 pharmacogenomically guided CDS alerts that triggered for 12 genes and 60 drugs. Clinicians adhered to the therapeutic recommendations provided in 4392 alerts (92%). In our population of pediatric patients with catastrophic illnesses, the most frequently presented gene/drug CDS alerts were TPMT/NUDT15 and thiopurines (n = 3850), CYP2D6 and ondansetron (n = 667), CYP2D6 and oxycodone (n = 99), G6PD and G6PD high-risk medications (n = 51), and CYP2C19 and proton pump inhibitors (omeprazole and pantoprazole; n = 50). The high adherence rate was facilitated by our team approach to prescribing and our collaborative CDS design and delivery.

Keywords: clinical decision support; medication alert systems; pharmacogenetics; pharmacogenomics; precision medicine.

NASEM Report Says Researchers Need to Rethink and Justify How and Why Race, Ethnicity, and Ancestry Labels Are Used in Genetics and Genomics Research

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Researchers and scientists who utilize genetic and genomic data should rethink and justify how and why they use race, ethnicity, and ancestry labels in their work, says a new National Academies of Sciences, Engineering, and Medicine (NASEM) report.

The report says researchers should not use race as a proxy for describing human genetic variation. Race is a social concept, but it is often used in genomics and genetics research as a surrogate for describing human genetic differences, which is misleading, inaccurate, and harmful. To improve genomics research, the report presents a new framework and decision tree to help researchers choose descriptors and labels that are most appropriate for their study.

From the beginning of genetics and genomics research, researchers have used “population descriptors” as a shorthand for capturing the complex patterns of human genetic variation across the globe. For example, these descriptors can identify groups based on nationality, such as French; geography, such as North American; or ethnicity, such as Hispanic. But human genetic differences are distributed in complex ways that do not necessarily align with a single descriptor.

Read the full news release and report on the NASEM website.

 

Evidence Regarding Pharmacogenetics in Pain Management and Cancer

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D Max Smith, William D Figg

Abstract

Patients experience interindividual variation in response to analgesics, which may be partially explained by genetics. This commentary discusses a recently published trial on COMT genotype and opioid dose requirements and describes the potential role for COMT and other genes (eg, CYP2D6) on opioid therapy and the current evidence for germline pharmacogenetics and resources for opioid pharmacogenetics.

Keywords: cancer pain; opioids; pain; pharmacogenetics; pharmacogenomics. 

DPYD Testing: Time to Put Patient Safety First

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Sharyn D Baker, Susan E Bates, Gabriel A Brooks, William L Dahut, Robert B Diasio, Wafik S El-Deiry, William E Evans, William D Figg, Dan L Hertz, J Kevin Hicks, Suneel Kamath, Pashtoon Murtaza Kasi, Todd C Knepper, Howard L McLeod, Peter H O’Donnell, Mary V Relling, Michelle A Rudek, Tristan M Sissung, D Max Smith, Alex Sparreboom, Sandra M Swain, Christine M Walko

Pharmacogenetics of Antiplatelet Therapy

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Matteo Castrichini, Jasmine A Luzum, Naveen Pereira

Abstract

Antiplatelet therapy is used in the treatment of patients with acute coronary syndromes, stroke, and those undergoing percutaneous coronary intervention. Clopidogrel is the most widely used antiplatelet P2Y12 inhibitor in clinical practice. Genetic variation in CYP2C19 may influence its enzymatic activity, resulting in individuals who are carriers of loss-of-function CYP2C19 alleles and thus have reduced active clopidogrel metabolites, high on-treatment platelet reactivity, and increased ischemic risk. Prospective studies have examined the utility of CYP2C19 genetic testing to guide antiplatelet therapy, and more recently published meta-analyses suggest that pharmacogenetics represents a key treatment strategy to individualize antiplatelet therapy. Rapid genetic tests, including bedside genotyping platforms that are validated and have high reproducibility, are available to guide selection of P2Y12 inhibitors in clinical practice. The aim of this review is to provide an overview of the background and rationale for the role of a guided antiplatelet approach to enhance patient care.

Keywords: CYP2C19; dual antiplatelet therapy; guided antiplatelet therapy; pharmacogenetics; pharmacogenomics; precision medicine.

Eight pharmacokinetic genetic variants are not associated with the risk of bleeding from direct oral anticoagulants in non-valvular atrial fibrillation patients

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Alessandra M Campos-Staffico, Michael P Dorsch, Geoffrey D Barnes, Hao-Jie Zhu, Nita A Limdi, Jasmine A Luzum

Abstract

Background: Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing this risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy since they are as effective and overall safer than warfarin in preventing AF-related stroke. Although patients bleed less from DOACs compared to warfarin, bleeding remains the primary safety concern with this therapy. Hypothesis: Genetic variants known to modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs could increase the risk of bleeding. Aim: To assess the association of eight, functional PK-related single nucleotide variants (SNVs) in five genes (ABCB1, ABCG2, CYP2J2, CYP3A4, CYP3A5) with the risk of bleeding from DOACs in non-valvular AF patients. Methods: A retrospective cohort study was carried out with 2,364 self-identified white non-valvular AF patients treated with either rivaroxaban or apixaban. Genotyping was performed with Illumina Infinium CoreExome v12.1 bead arrays by the Michigan Genomics Initiative biobank. The primary endpoint was a composite of major and clinically relevant non-major bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of the eight PK-related SNVs with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. The pre-specified primary analysis was the covariate-adjusted, additive genetic models. Six tests were performed in the primary analysis as three SNVs are in the same haplotype, and thus p-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. Results: In the primary analysis, none of the SNVs met the Bonferroni-corrected level of statistical significance (all p > 0.1). In exploratory analyses with other genetic models, the ABCB1 (rs4148732) GG genotype tended to be associated with the risk of bleeding from rivaroxaban [HR: 1.391 (95%CI: 1.019-1.900); p = 0.038] but not from apixaban (p = 0.487). Conclusion: Eight functional PK-related genetic variants were not significantly associated with bleeding from either rivaroxaban or apixaban in more than 2,000 AF self-identified white outpatients.

Keywords: DOAC; anticoagulation; atrial fibrillation; bleeding; pharmacogenetics.

 

Patients’ Perspectives of Factors That Influence Pharmacogenetic Testing Uptake: Enhancing Patient Counseling and Results Dissemination

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Diliara Bagautdinova, Christelle Lteif, Elizabeth Eddy, Joshua Terrell, Carla L Fisher, Julio D Duarte

Abstract

Patient preferences for pharmacogenetic (PGx) counseling, testing and results dissemination are not well-established, especially in medically underserved Black and Latino populations. The aim of this study was to capture the preferences of Black and Latino patients who received PGx testing to ascertain: (1) factors enhancing their willingness to do testing and (2) preferences for the dissemination of results. Using the constant comparative method, we thematically analyzed interviews with 13 patients from medically underserved populations who had undergone PGx testing. The findings describe participants wanting better medication options, receiving a clear explanation about the testing, valuing or having an interest in science or medicine and having misconceptions about testing results as factors affecting one’s willingness to undergo PGx testing. Additionally, patients confirmed preferring receiving results of PGx testing in a sharable format and described the significance of discussing results in a clinical appointment. The findings provide insight into what Black and Latino patients may prefer in terms of clinical implementation of PGx testing. These results can be utilized for tailoring future implementation of PGx testing and informing best pre- and post-test patient counseling and education practices.

Keywords: medically underserved population; patient preferences; pharmacogenetic testing; qualitative research.

FAVOR: functional annotation of variants online resource and annotator for variation across the human genome

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Hufeng Zhou, Theodore Arapoglou, Xihao Li, Zilin Li, Xiuwen Zheng, Jill Moore, Abhijith Asok, Sushant Kumar, Elizabeth E Blue, Steven Buyske, Nancy Cox, Adam Felsenfeld, Mark Gerstein, Eimear Kenny, Bingshan Li, Tara Matise, Anthony Philippakis, Heidi L Rehm, Heidi J Sofia, Grace Snyder; NHGRI Genome Sequencing Program Variant Functional Annotation Working Group; Zhiping Weng, Benjamin Neale, Shamil R Sunyaev, Xihong Lin

Abstract
Large biobank-scale whole genome sequencing (WGS) studies are rapidly identifying a multitude of coding and non-coding variants. They provide an unprecedented resource for illuminating the genetic basis of human diseases. Variant functional annotations play a critical role in WGS analysis, result interpretation, and prioritization of disease- or trait-associated causal variants. Existing functional annotation databases have limited scope to perform online queries and functionally annotate the genotype data of large biobank-scale WGS studies. We develop the Functional Annotation of Variants Online Resources (FAVOR) to meet these pressing needs. FAVOR provides a comprehensive multi-faceted variant functional annotation online portal that summarizes and visualizes findings of all possible nine billion single nucleotide variants (SNVs) across the genome. It allows for rapid variant-, gene- and region-level queries of variant functional annotations. FAVOR integrates variant functional information from multiple sources to describe the functional characteristics of variants and facilitates prioritizing plausible causal variants influencing human phenotypes. Furthermore, we provide a scalable annotation tool, FAVORannotator, to functionally annotate large-scale WGS studies and efficiently store the genotype and their variant functional annotation data in a single file using the annotated Genomic Data Structure (aGDS) format, making downstream analysis more convenient. FAVOR and FAVORannotator are available at https://favor.genohub.org.

Implementation-effectiveness trial of systematic family health history based risk assessment and impact on clinical disease prevention and surveillance activities

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R Ryanne Wu, Rachel A Myers, Joan Neuner, Catherine McCarty, Irina V Haller, Melissa Harry, Kimberly G Fulda, David Dimmock, Tejinder Rakhra-Burris, Adam Buchanan, Geoffrey S Ginsburg, Lori A Orlando
Background: Systematically assessing disease risk can improve population health by identifying those eligible for enhanced prevention/screening strategies. This study aims to determine the clinical impact of a systematic risk assessment in diverse primary care populations.
Keywords: Clinical decision support; Family health history; Health belief model; Hybrid implementation-effectiveness; Precision medicine; Risk assessment.