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.

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.

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.

The clinical utility of polygenic risk scores in genomic medicine practices: a systematic review

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Judit Kumuthini, Brittany Zick, Angeliki Balasopoulou, Constantina Chalikiopoulou, Collet Dandara, Ghada El-Kamah, Laura Findley, Theodora Katsila, Rongling Li, Ebner Bon Maceda, Henrietta Monye, Gabriel Rada, Meow-Keong Thong, Thilina Wanigasekera, Hannah Kennel, Veeramani Marimuthu, G2MC Evidence investigators; Marc S Williams, Fahd Al-Mulla, Marc Abramowicz

Abstract
Genomic medicine aims to improve health using the individual genomic data of people to inform care. While clinical utility of genomic medicine in many monogenic, Mendelian disorders is amply demonstrated, clinical utility is less evident in polygenic traits, e.g., coronary artery disease or breast cancer. Polygenic risk scores (PRS) are subsets of individual genotypes designed to capture heritability of common traits, and hence to allow the stratification of risk of the trait in a population. We systematically reviewed the PubMed database for unequivocal evidence of clinical utility of polygenic risk scores, using stringent inclusion and exclusion criteria. While we identified studies demonstrating clinical validity in conditions where medical intervention based on a PRS is likely to benefit patient outcome, we did not identify a single study demonstrating unequivocally such a benefit, i.e. clinical utility. We conclude that while the routine use of PRSs hold great promise, translational research is still needed before they should enter mainstream clinical practice.

Development and Validation of the Minnesota Assessment of Pharmacogenomic Literacy (MAPL)

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Josiah D Allen, Lusi Zhang, Alyssa N K Johnson, Pamala A Jacobson, Catherine A McCarty, Amy L Pittenger, Jeffrey R Bishop

Abstract
Ensuring that patients have an adequate understanding of pharmacogenomic (PGx) test results is a critical component of implementing precision medicine into clinical care. However, no PGx-specific validated literacy assessment has yet been developed. To address this need, we developed and validated the Minnesota Assessment of Pharmacogenomic Literacy (MAPLTM). Foundational work included a scoping review of patient and general public attitudes and experiences with pharmacogenomic testing, three focus groups, readability assessments, and review by experts and members of the general public. This resulted in a 15-item assessment designed to assess knowledge in four domains: underlying concepts, limitations, benefits, and privacy. For validation, 646 participants completed the MAPL as a part of a larger survey about pharmacogenomic research and statewide PGx implementation. Two items were deemed to be “too easy” and dropped. The remaining 13 items were retained in the final MAPL with good internal reliability (Cronbach’s alpha = 0.75). Confirmatory factor analysis validated the four-domain construct of MAPL and suggested good model performance and high internal validity. The estimated coefficient loadings across 13 questions on the corresponding domains are all positive and statistically significant (p < 0.05). The MAPL covers multiple knowledge domains of specific relevance to PGx and is a useful tool for clinical and research settings where quantitative assessment of PGx literacy is of value.

Keywords: genetic counseling; genomic literacy; literacy assessment; pharmacogenomics; psychometric validation.