Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.
Aniwaa Owusu Obeng, Kezhen Fei, Kenneth D. Levy, Amanda R. Elsey, Toni I. Pollin, Andrea H. Ramirez, Kristin W. Weitzel and Carol R. Horowitz
Genet Med. 2018 Jul 12.
Physician-Reported Benefits and Barriers to Clinical Implementation of Genomic Medicine: A Multi-Site IGNITE-Network Survey
Aniwaa Owusu Obeng, Kezhen Fei, Kenneth D. Levy, Amanda R. Elsey, Toni I. Pollin, Andrea H. Ramirez, Kristin W. Weitzel and Carol R. Horowitz
J. Pers. Med. 2018, 8(3), 24
Implementation, adoption, and utility of family health history risk assessment in diverse care settings: evaluating implementation processes and impact with an implementation framework.
Wu RR, Myers RA, Sperber N, Voils CI, Neuner J, McCarty CA, Haller IV, Harry M, Fulda KG, Cross D, Dimmock D, Rakhra-Burris T, Buchanan AH, Ginsburg GS, Orlando LA
Genet Med. 2018 Jun 6
Ginsburg GS & Phillips KA.
Health Aff (Millwood). 2018 May;37(5):694-701
Clinical Outcomes and Sustainability of Using CYP2C19 Genotype–Guided Antiplatelet Therapy After Percutaneous Coronary Intervention
Craig R. Lee, Vindhya B. Sriramoju, Alexandra Cervantes, Lucius A. Howell, Nicholas Varunok, Shivanshu Madan, Kasey Hamrick, Melissa J. Polasek, John Andrew Lee, Megan Clarke, Jonathan D. Cicci, Karen E. Weck and George A. Stouffer.
Circ Genom Precis Med. 2018;11:e002069.
Clinical Implementation of Rapid CYP2C19 Genotyping to Guide Antiplatelet Therapy after Percutaneous Coronary Intervention
Cavallari LH, Franchi F, Rollini F, Been L, Rivas A, Agarwal M, Smith DM, Newsom K, Gong Y, Elsey AR, Starostik P, Johnson JA, Angiolillo D
J Transl Med 2018;16:92.
Research Directions in the Clinical Implementation of Pharmacogenomics: An Overview of US Programs and Projects
Volpi S1, Bult CJ2, Chisholm RL3, Deverka PA4, Ginsburg GS5, Jacob HJ6, Kasapi M1, McLeod HL7, Roden DM8, Williams MS9, Green ED1, Rodriguez LL1, Aronson S10, Cavallari LH11, Denny JC12, Dressler LG13, Johnson JA11, Klein TE14, Leeder JS15, Piquette-Miller M16, Perera M17, Rasmussen-Torvik LJ18, Rehm HL19, Ritchie MD20, Skaar TC21, Wagle N22, Weinshilboum R23, Weitzel KW24, Wildin R25, Wilson J26, Manolio TA1, Relling MV27
Clin Pharmacol Ther. 2018 May;103(5):778-786
Design and rational for the precision medicine guided treatment for cancer pain pragmatic clinical trial. Contemp Clin Trials
Authors: Mosley SA, Kevin Hicks J, Portman DG, Donovan KA, Gopalan P, Schmit J, Starr J, Silver N, Gong Y, Langaee T, Clare-Salzler M, Starostik P, Chang YD, Rajasekhara S, Smith JE, Soares HP, George TJ Jr, McLeod HL, Cavallari LH
2018 Mar 10. pii: S1551-7144(17)30626-2
Authors: Numanagić I1,2,3, Malikić S1, Ford M1, Qin X4, Toji L5, Radovich M6, Skaar TC6, Pratt VM6, Berger B2,3, Scherer S4, Sahinalp SC7
Nat Commun. 2018 Feb 26;9(1):828
Authors: Skaar TC, Desta Z.
Clin Pharmacol Ther. 2018 Feb 23. doi: 10.1002/cpt.1039.[Epub ahead of print]
Recommendations for Clinical CYP2C19 Genotyping Allele Selection: A Report of the Association for Molecular Pathology
Authors: Pratt VM, Del Tredici AL, Hachad H, Ji Y, Kalman LV, Scott SA, Weck KE.
J Mol Diagn. 2018 Feb 21. pii: S1525-1578(17)30519-6.
Authors: Smith DM, Weitzel KW, Cavallari LH, Elsey AR, Schmidt SO
Personalized MedicineVol. 15, No. 2
Implementation of Standardized Clinical Processes for TPMT Testing in a Diverse Multidisciplinary Population: Challenges and Lessons Learned.
Authors: Weitzel KW, Smith DM, Elsey AR, Duong BQ, Burkley B, Clare-Salzler M, Gong Y, Higgins TA, Kong B, Langaee T, McDonough CW, Staley BJ, Vo TT, Wake DT, Cavallari LH, Johnson JA
Clin Transl Sci. 2018 Jan 19.
Authors: Mangal N, Hamadeh I, Arwood MJ, Cavallari LH, Samant TS, Klinker KP, Bulitta J, Schmidt S
Clin Pharmacol Ther. 2018 Jan 9
Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy
Authors: Empey PE, Stevenson JM, Tuteja S, Weitzel KW, Angiolillo DJ, Beitelshees AL, Coons JC, Duarte JD, Franchi F, Jeng LJB, Johnson JA, Kreutz RP, Limdi NA, Maloney KA, Owusu Obeng A, Peterson JF, Petry N, Pratt VM, Rollini F, Scott SA, Skaar TC, Vesely MR, Stouffer GA, Wilke RA, Cavallari LH, Lee CR; IGNITE Network
Clin Pharmacol Ther. 2017 Dec 26.
Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention
Authors: Cavallari LH, Lee CR, Beitelshees AL, Cooper-DeHoff RM, Duarte JD, Voora D, Kimmel SE, McDonough CW, Gong Y, Dave CV, Pratt VM, Alestock TD, Anderson RD, Alsip J, Ardati AK, Brott BC, Brown L, Chumnumwat S, Clare-Salzler MJ, Coons JC, Denny JC, Dillon C, Elsey AR, Hamadeh I, Harada S, Hillegass WB, Hines L, Horenstein RB, Howell LA, Jeng LJB, Kelemen MD, Lee YM, Magvanjav O, Montasser M, Nelson DR, Nutescu EA, Nwaba DC, Pakyz RE, Palmer K, Peterson JF, Pollin TI, Quinn AH, Robinson SW, Schub J, Skaar TC, Smith DM, Sriramoju VB, Starostik P, Stys TP, Stevenson JM, Varunok N, Vesely MR, Wake DT, Weck KE, Weitzel KW, Wilke RA, Willig J, Zhao RY, Kreutz RP, Stouffer GA, Empey PE, Limdi NA, Shuldiner AR, Winterstein AG, Johnson JA.
CC Cardiovasc Interv. 2017 Oct 25. pii: S1936-8798(17)31499-1. [Epub ahead of print]
Association of the HLA-B alleles with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in the Javanese and Sundanese population of Indonesia: the important role of the HLA-B75 serotype
Authors: Yuliwulandari R, Kristin E, Prayuni K, Sachrowardi Q, Suyatna FD, Menaldi SL, Wichukchinda N, Mahasirimongkol S, Cavallari LH.
Pharmacogenomics. 2017 Dec;18(18):1643-1648
Author: Cavallari LH
(Invited Editorial) Future Cardiol. 2017 Oct 2. [Epub ahead of print].
Evaluation of the Informational Content, Readability and Comprehensibility of Online Health Information on Monogenic Diabetes
Authors: Guan Y, Maloney KA, Roter DL, Pollin TI
The purpose of this study was to assess the informational content, readability, suitability and comprehensibility of websites offering educational information about monogenic diabetes available to patients. The top 20 results from 15 queries in four search engines were screened. Content analysis was performed by two independent coders. Readability was determined using Flesch-Kincaid grade level (FKGL) and Simplified Measure of Goobledygook (SMOG). The Comprehensibility Assessment of Materials (SAM + CAM) scale was utilized to evaluate website suitability and comprehensibility. Only 2% (N = 29) of 1200 screened websites met inclusion criteria. Content analysis showed that 16 websites presented information on at least the most common forms of MODY (1, 2 and 3), four addressed the utility of genetic counseling, and none included support resources for patients. All websites exceeded the consensus readability level (6th grade) as assessed by FKGL (10.1 grade) and SMOG (12.8 ± 1.5 grades). Although the majority (N = 20) of websites had an overall “adequate” to “superior” quality score (SAM + CAM score > = 40%), more than one-third scored “not suitable” in categories of content, literacy demand, graphics, and learning motivation. The online educational resources for monogenic diabetes have a high readability level and require improvement in ease of use and comprehensibility for patients with diabetes.
J Genet Couns. 2017 Sep 26. [Epub ahead of print]
Developing a common framework for evaluating the implementation of genomic medicine interventions in clinical care: the IGNITE Network’s Common Measures Working Group
Authors: Orlando LA, Sperber NR, Voils CI, Nichols M, Myers RA, Wu RR, Rakhra-Burris T, Levy KD, Levy M, Pollin TI, Guan Y, Horowitz CR, Ramox M, Kimmel SE, Caitrin WM, Madden EB, Damschroder LJ
Implementation research provides a structure for evaluating the clinical integration of genomic medicine interventions. This paper describes the Implementing Genomics in Practice (IGNITE) Network’s efforts to promote (i) a broader understanding of genomic medicine implementation research and (ii) the sharing of knowledge generated in the network.
Genet Med. 2017 Sep 14. doi: 10.1038/gim.2017.144
Authors: Xie C, Wilke WA
S D Med. 2017 Aug;70(8):342-344.
Authors: Kaplan B, Caddle-Steele C, Chisholm G, Esmond WA, Ferryman K, Gertner M, Goytia C, Hauser D, Richardson LD, Robinson M, Horowitz CR
There has been limited community engagement in the burgeoning field of genomics research. In the wake of a new discovery of genetic variants that increase the risk of kidney failure and are almost unique to people of African ancestry, community and clinical leaders in Harlem, New York, formed a community board to inform the direction of related research. The board advised all aspects of a study to assess the impact of testing for these genetic variants at primary care sites that serve diverse populations, including explaining genetic risk to participants. By reflecting on the board’s experiences, we found that community voices can have tangible impact on research that navigates the controversial intersection of race, ancestry, and genomics by heightening vigilance, fostering clear communication between researchers and the community, and encouraging researchers to cede some control. Our reflections and work provide a strong justification for longitudinal community partnerships in genomics research.
Prog Community Health Partnersh. 2017;11(2):161-165.
Personalizing antiplatelet prescribing using genetics for patients undergoing percutaneous coronary intervention
Author: Cavallari LH
Clopidogrel is commonly prescribed with aspirin to reduce the risk for adverse cardiovascular events after percutaneous coronary intervention (PCI). However, there is significant inter-patient variability in clopidogrel response. The CYP2C19 enzyme is involved in the biotransformation of clopidogrel to its pharmacologically active form, and variation in the CYP2C19 gene contributes to clopidogrel response variability. Areas covered. This article describes the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics, and effectiveness. Examples of clinical implementation of CYP2C19 genotyping-guided antiplatelet therapy for patients undergoing PCI are also described as are emerging outcomes data with this treatment approach. Expert commentary. A large clinical trial evaluating outcomes with CYP2C19 genotype-guided antiplatelet therapy after PCI is on-going. In the meantime, data from pragmatic and observational studies and smaller trials support improved outcomes with genotyping after PCI and use of alternative antiplatelet therapy in patients with a CYP2C19 genotype associated with reduced clopidogrel effectiveness.
Expert Rev Cardiovasc Ther. 2017 Jul 12. [Epub ahead of print]
Authors: Moon JY, Franchi F, Rollini F, Rivas Rios JR, Kureti M, Cavallari LH, Angiolillo DJ
Variability in individual response profiles to antiplatelet therapy, in particular clopidogrel, is a well-established phenomenon. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been associated with clopidogrel response profiles. Moreover, the presence of a CYP2C19 loss-of-function allele is associated with an increased risk of atherothrombotic events among clopidogrel-treated patients undergoing percutaneous coronary interventions (PCI), prompting studies evaluating the use of genetic tests to identify patients who may be potential candidates for alternative platelet P2Y12 receptor inhibiting therapies (prasugrel or ticagrelor). Areas covered: The present manuscript provides an overview of genetic factors associated with response profiles to platelet P2Y12 receptor inhibitors and their clinical implications, as well as the most recent developments and future considerations on the role of genetic testing in patients undergoing PCI. Expert Commentary: The availability of more user-friendly genetic tests has contributed towards the development of many ongoing clinical trials and personalized medicine programs for patients undergoing PCI. Results of pilot investigations have shown promising results, which however need to be confirmed in larger-scale studies to support the routine use of genetic testing as a strategy to personalize antiplatelet therapy and improve clinical outcomes.
Expert Rev Clin Pharmacol. 2017 Jul 10. [Epub ahead of print]
Authors: Ermer D, Vik T
S D Med. 2017 Jul;70(7):294-296.
Authors: Pierson RC, Gufford BT, Desta Z, Eadon MT
Pharmacogenomic testing has become increasingly widespread. However, there remains a need to bridge the gap between test results and providers lacking the expertise required to interpret these results. The Indiana Genomics Implementation trial is underway at our institution to examine total healthcare cost and patient outcomes after genotyping in a safety-net healthcare system. As part of the study, trial investigators and clinical pharmacology fellows interpret genotype results, review patient histories and medication lists and evaluate potential drug-drug interactions. We present a case series of patients in whom pharmacogenomic consultations aided providers in appropriately applying pharmacogenomic results within the clinical context. Formal consultations not only provide valuable patient care information but educational opportunities for the fellows to cement pharmacogenomic concepts.
Pharmacogenomics. 2017 Jun;18(9):835-841. Epub 2017 Jun 8.
Authors: Petry N, Hines LJ
S D Med. 2017 Jun;70(6):246-248.
Challenges and Strategies for Implementing Genomic Services in Diverse Settings: Experiences from the Implementing GeNomics In PracTicE (IGNITE) Network
Authors: Sperber NR, Carpenter JS, Cavallari LH, Damschroder L, Cooper-DeHoff RM, Denny JC, Ginsburg GS, Guan Y, Horowitz CR, Levy KD, Levy MA, Madden EB, Matheny ME, Pollin TI, Pratt VM, Rosenman M, Voils CI, Weitzel K, Wilke RA, Wu RR, Orlando LA
To realize potential public health benefits from genetic and genomic innovations, understanding how best to implement the innovations into clinical care is important. The objective of this study was to synthesize data on challenges identified by six diverse projects that are part of a National Human Genome Research Institute (NHGRI)-funded network focused on implementing genomics into practice and strategies to overcome these challenges.
BMC Med Genomics. 2017 May 22;10(1):35.
Authors: Weitzel KW, Cavallari LH, Lesko LJ
While recent discoveries have paved the way for the use of genotype-guided prescribing in some clinical environments, significant debate persists among clinicians and researchers about the optimal approach to pharmacogenetic testing in clinical practice. One crucial factor in this debate surrounds the timing and methodology of genotyping, specifically whether genotyping should be performed reactively for targeted genes when a single drug is prescribed, or preemptively using a panel-based approach prior to drug prescribing. While early clinical models that employed a preemptive approach were largely developed in academic health centers through multidisciplinary efforts, increasing examples of pharmacogenetic testing are emerging in community-based and primary care practice environments. However, educational and practice-based resources for these clinicians remain largely nonexistent. As such, there is a need for the health care system to shift its focus from debating about preemptive genotyping to developing and disseminating needed resources to equip frontline clinicians for clinical implementation of pharmacogenetics. Providing tools and guidance to support these emerging models of care will be essential to support the thoughtful, evidence-based use of pharmacogenetic information in diverse clinical practice environments. Specifically, the creation of efficient and accurate point-of-care resources, practice-based tools, and clinical models is needed, along with identification and dissemination of sustainable avenues for pharmacogenetic test reimbursement.
Pharm Res. 2017 Aug;34(8):1551-1555.
Authors: Lu WJ, Chavour S
S D Med. 2017 May;70(5):199-201.
Authors: Hamadeh IS, Klinker KP, Borgert SJ, Richards AI, Li W, Mangal N, Hiemenz JW, Schmidt S, Langaee TY, Peloquin CA, Johnson JA, Cavallari LH
Voriconazole, a first-line agent for the treatment of invasive fungal infections (IFIs), is metabolized by CYP2C19. A significant proportion of patients fail to achieve therapeutic trough concentrations with standard weight-based voriconazole dosing, placing them at increased risk for treatment failure, which can be life threatening. We sought to test the association between the CYP2C19 genotype and subtherapeutic voriconazole concentrations in adults with IFIs.
Pharmacogenet Genomics. 2017 May;27(5):190-196.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update
Authors: Johnson JA, Caudle KE, Gong L3, Whirl-Carrillo M, Stein CM, Scott SA, Lee MT, Gage BF, Kimmel SE, Perera MA, Anderson JL, Pirmohamed M, Klein TE, Limdi NA, Cavallari LH, Wadelius M
This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.
Clin Pharmacol Ther. 2017 Sep;102(3):397-404. doi: 10.1002/cpt.668. Epub 2017 Apr 4.
Authors: Jensen CH, Fanciullo J
S D Med. 2017 Apr;70(4):151-152.
Authors: Cavallari LH, Weitzel KW, Elsey AR, Liu X, Mosley SA, Smith DM, Staley BJ, Winterstein AG, Mathews CA, Franchi F, Rollini F, Angiolillo DJ, Starostik P, Clare-Salzler MJ, Nelson DR, Johnson JA
The University of Florida (UF) Health Personalized Medicine Program launched in 2012 with CYP2C19 genotyping for clopidogrel response at UF Health Shands Hospital. We have since expanded CYP2C19 genotyping to UF Health Jacksonville and established the infrastructure at UF Health to support clinical implementation for five additional gene-drug pairs: TPMT-thiopurines, IFNL3 (IL28B)-PEG IFN-α-based regimens, CYP2D6-opioids, CYP2D6/CYP2C19-antidepressants and CYP2C19-proton pump inhibitors. We are contributing to the evidence based on outcomes with genotype-guided therapy through pragmatic studies of our clinical implementations. In addition, we have developed a broad array of educational programs for providers, trainees and students that incorporate personal genotype evaluation to enhance participant learning.
Pharmacogenomics. 2017 Apr;18(5):421-426.
Is Universal HLA-B*15:02 Screening a Cost-Effective Option in an Ethnically-Diverse Population? A Case Study of Malaysia
Authors: Chong HY, Mohamed Z, Tan LL, Wu DB, Shabaruddin FH, Dahlui M, Apalasamy YD, Snyder SR, Williams MS, Hao J, Cavallari LH, Chaiyakunapruk N
Strong association was documented between human leukocyte antigen (HLA)-B*15:02 and carbamazepine-induced severe cutaneous adverse reactions (SCARs) in Asians. Beyond Asia, the HLA testing is potentially valuable in many countries with increasingly diverse communities of Asian ancestry, to facilitate an early recognition of patient susceptibility to SCARs.
Br J Dermatol. 2017 Mar 27.
The IGNITE Pharmacogenetics Working Group: An Opportunity for Building Evidence with Pharmacogenetic Implementation in a Real-World Setting
Authors: Cavallari LH, Beitelshees AL, Blake KV, Dressler LG, Duarte JD, Elsey A, Eichmeyer JN, Empey PE, Franciosi JP, Hicks JK, Holmes AM, Jeng L, Lee CR, Lima JJ, Limdi NA, Modlin J, Obeng AO,Petry N, Pratt VM, Skaar TC, Tuteja S, Voora D, Wagner M, Weitzel KW, Wilke RA, Peterson JF,Johnson JA
Clin Transl Sci. 2017 May;10(3):143-146.
Genotype is increasingly recognized as an important factor influencing the likelihood for drug effectiveness or risk for adverse events. Genetic information is now included in US Food and Drug Administration‐approved labeling for over 130 drugs, and in some cases, the information is in the form of a boxed warning given the potentially serious implications of genotype on drug response. Based on the growing body of evidence supporting genetic contributions to drug response, the Clinical Pharmacogenetics Implementation Consortium (CPIC) was formed to provide consensus guidelines on interpretation and translation of genotype results into actionable prescribing decisions. Guidelines have been published for 18 drugs or drug classes as of late 2016. The Precision Medicine Initiative is expected to further drive discoveries in genomic medicine and their translation to patient care. In 2013, the National Institutes of Health (NIH)‐funded Implementing GeNomics In praTticE (IGNITE) network was established to support the development and investigation of genomic medicine practice models to enhance its implementation into routine clinical practice.
Authors: Wilke RA, Fanciullo J
S D Med. 2017 Mar;70(3):102-104.
Authors: Horowitz CR, Shameer K, Gabrilove J, Atreja A, Shepard P, Goytia CN, Smith GW, Dudley J, Manning R, Bickell NA, Galvez MP
Development and implementation of effective, sustainable, and scalable interventions that advance equity could be propelled by innovative and inclusive partnerships. Readied catalytic frameworks that foster communication, collaboration, a shared vision, and transformative translational research across scientific and non-scientific divides are needed to foster rapid generation of novel solutions to address and ultimately eliminate disparities. To achieve this, we transformed and expanded a community-academic board into a translational science board with members from public, academic and private sectors. Rooted in team science, diverse board experts formed topic-specific “accelerators”, tasked with collaborating to rapidly generate new ideas, questions, approaches, and projects comprising patients, advocates, clinicians, researchers, funders, public health and industry leaders. We began with four accelerators-digital health, big data, genomics and environmental health-and were rapidly able to respond to funding opportunities, transform new ideas into clinical and community programs, generate new, accessible, actionable data, and more efficiently and effectively conduct research. This innovative model has the power to maximize research quality and efficiency, improve patient care and engagement, optimize data democratization and dissemination among target populations, contribute to policy, and lead to systems changes needed to address the root causes of disparities.
Int J Environ Res Public Health. 2017 Feb 23;14(3). pii: E225.
High-Throughput Assays to Assess the Functional Impact of Genetic Variants: A Road Towards Genomic-Driven Medicine
Authors: Ipe J, Swart M, Burgess KS, Skaar TC
Genome‐wide genotyping and DNA sequencing has led to the identification of large numbers of genetic variants that are associated with many clinical phenotypes. The functional impacts of most of the variants are unknown. In this article, we review high‐throughput assays that have been developed to assess a variety of the functional impacts of the variants. A better understanding of their functions should facilitate the implementation of many more variants in genomic‐driven medicine.
Clin Transl Sci. 2017 Mar;10(2):67-77.
Authors: Lu WJ, Miller NJ
S D Med. 2017 Feb;70(2):54-56.
Authors: Horowitz CR, Ferryman K, Negron R, Sabin T, Rodriguez M, Zinberg RF, Bottinger E, Robinson M
Variants of the APOL1 gene increase risk for kidney failure 10-fold, and are nearly exclusively found in people with African ancestry. To translate genomic discoveries into practice, we gathered information about effects and challenges incorporating genetic risk in clinical care.
J Health Care Poor Underserved. 2017;28(1):248-260.
The Pharmacogenomics Research Network Translational Pharmacogenetics Program: outcomes and metrics of pharmacogenetics implementation across diverse healthcare systems
Authors: Luzum JA, Pakyz RE, Elsey AR, Haidar CE, Peterson JF, Whirl-Carrillo M, Handelman SK, Palmer K, Pulley JM, Beller M, Schildcrout JS, Field JR, Weitzel KW, Cooper-DeHoff RM, Cavallari LH, O’Donnell PH, Altman RB, Pereira N, Ratain MJ, Roden DM, Embi PJ, Sadee W, Klein TE, Johnson JA, Relling MV, Wang L, Weinshilboum RM, Shuldiner AR, Freimuth RR
Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.
Clin Pharmacol Ther 2017 Jan 16.
Authors: Carpenter JS, Rosenman MB, Knisely MR, Decker BS, Levy KD, Flockhart DA
Objective: Prior to implementing a trial to evaluate the economic costs and clinical outcomes of pharmacogenetic testing in a large safety net health care system, we determined the number of patients taking targeted medications and their clinical care encounter sites. Methods: Using 1-year electronic medical record data, we evaluated the number of patients who had started one or more of 30 known pharmacogenomically actionable medications and the number of care encounter sites the patients had visited. Results: Results showed 7039 unique patients who started one or more of the target medications within a 12-month period with visits to 73 care sites within the system. Conclusion: Findings suggest that the type of large-scale, multi-drug, multi-gene approach to pharmacogenetic testing we are planning is widely relevant, and successful implementation will require wide-scale education of prescribers and other personnel involved in medication dispensing and handling.
SAGE Open Med. 2016 Jan 7;4:2050312115624333.
Authors: Cavallari LH, Obeng AO
There is significant interpatient variability in clopidogrel effectiveness, which is due in part to cytochrome P450 (CYP) 2C19 genotype. Approximately 30% of individuals carry CYP2C19 loss-of-function alleles, which have been consistently shown to reduce clopidogrel effectiveness after an acute coronary syndrome and percutaneous coronary intervention. Guidelines recommend consideration of prasugrel or ticagrelor in these patients. A clinical trial examining outcomes with CYP2C19 genotype-guided antiplatelet therapy is ongoing. In the meantime, based on the evidence available to date, several institutions have started clinically implementing CYP2C19 genotyping to assist with antiplatelet selection after percutaneous coronary intervention.
Interv Cardiol Clin. 2017 Jan;6(1):141-149.
Authors: Weitzel KW, Aquilante CL, Johnson S, Kisor DF, Empey PE
Consensus-based pharmacist competencies and guidelines have been published to guide pharmacogenomics knowledge attainment and application in clinical practice. Pharmacogenomics education is integrated into various pharmacy school courses and, increasingly, into Pharm.D. curricula in the form of required standalone courses. Continuing-education programs and a limited number of postgraduate training opportunities are available to practicing pharmacists. For colleges and schools of pharmacy, identifying the optimal structure and content of pharmacogenomics education remains a challenge; insufficient numbers of faculty members with pharmacogenomics expertise and the inadequate availability of practice settings for experiential education are other limiting factors. Strategies for overcoming those challenges include providing early exposure to pharmacogenomics through foundational courses and incorporating pharmacogenomics into practice-based therapeutics courses and introductory and advanced pharmacy practice experiences. For practitioner education, online resources, clinical decision support-based tools, and certificate programs can be used to supplement structured postgraduate training in pharmacogenomics. Recently published data indicate successful use of “shared curricula” and participatory education models involving opportunities for learners to undergo personal genomic testing.
Am J Health Syst Pharm. 2016 Dec 1;73(23):1986-1998.
Authors: Cavallari LH, Lee CR, Duarte JD, Nutescu EA, Weitzel KW, Stouffer GA, Johnson JA
Pharmacists are well positioned to assume important roles in facilitating the clinical use of genetic information to optimize drug therapy given their expertise in clinical pharmacology and therapeutics. Pharmacists have assumed important roles in implementing inpatient pharmacogenetics programs. This includes programs designed to incorporate genetic test results to optimize antiplatelet drug selection after percutaneous coronary intervention and personalize warfarin dosing. Pharmacist involvement occurs on many levels, including championing and leading pharmacogenetics implementation efforts, establishing clinical processes to support genotype-guided therapy, assisting the clinical staff with interpreting genetic test results and applying them to prescribing decisions, and educating other healthcare providers and patients on genomic medicine. The three inpatient pharmacogenetics programs described use reactive versus preemptive genotyping, the most feasible approach under the current third-party payment structure. All three sites also follow Clinical Pharmacogenetics Implementation Consortium guidelines for drug therapy recommendations based on genetic test results.
Am J Health Syst Pharm. 2016 Dec 1;73(23):1944-1954.
Author: Johnson, JA
Am J Health Syst Pharm. 2016 Dec 1;73(23):2013-2016.
Authors: Roederer MW, Kuo GM, Kisor DF, Frye RF, Hoffman JM, Jenkins J, Weitzel KW
The emerging use of genomic data to inform medication therapy populates the medical literature and provides evidence for guidelines in the prescribing information for many medications. Despite the availability of pharmacogenomic studies, few pharmacists feel competent to use these new data in patient care. The first pharmacogenomics competency statement for pharmacists was published in 2002. In 2011, the Pharmacogenomics Special Interest Group of the American Association of Colleges of Pharmacy led a process to update this competency statement with the use of a consensus-based method that incorporated input from multiple key professional pharmacy organizations to reflect growth in genomic science as well as the need for pharmacist application of genomic data. Given the rapidly evolving science, educational needs, and practice models in this area, a standardized competency-based approach to pharmacist education and training in pharmacogenomics is needed to equip pharmacists for leadership roles as essential members of health care teams that implement clinical utilization strategies for genomic data.
J Am Pharm Assoc (2003). 2017 Jan – Feb;57(1):120-125.
Authors: Rosenman MB, Decker B, Levy KD, Holmes AM, Pratt VM, Eadon MT
Implementing new programs to support precision medicine in clinical settings is a complex endeavor. We describe challenges and potential solutions based on the Indiana GENomics Implementation: an Opportunity for the Underserved (INGenious) program at Eskenazi Health-one of six sites supported by the Implementing GeNomics In pracTicE network grant of the National Institutes of Health/National Human Genome Research Institute. INGenious is an implementation of a panel of genomic tests.
Value Health. 2017 Jan;20(1):54-59.
Authors: Parsa A, Kanetsky PA, Xiao R, Gupta J, Mitra N, Limou S, Xie D, Xu H, Anderson AH, Ojo A, Kusek JW, Lora CM, Hamm LL, He J, Sandholm N, Jeff J, Raj DE, Böger CA, Bottinger E, Salimi S, Parekh RS, Adler SG, Langefeld CD, Bowden DW; FIND Consortium, Groop PH, Forsblom C, Freedman BI, Lipkowitz M, Fox CS, Winkler CA, Feldman HI; and the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators
The rate of decline of renal function varies significantly among individuals with CKD. To understand better the contribution of genetics to CKD progression, we performed a genome-wide association study among participants in the Chronic Renal Insufficiency Cohort Study. Our outcome of interest was CKD progression measured as change in eGFR over time among 1331 blacks and 1476 whites with CKD. We stratified all analyses by race and subsequently, diabetes status. Single-nucleotide polymorphisms (SNPs) that surpassed a significance threshold of P<1×10-6 for association with eGFR slope were selected as candidates for follow-up and secondarily tested for association with proteinuria and time to ESRD. We identified 12 such SNPs among black patients and six such SNPs among white patients. We were able to conduct follow-up analyses of three candidate SNPs in similar (replication) cohorts and eight candidate SNPs in phenotype-related (validation) cohorts. Among blacks without diabetes, rs653747 in LINC00923 replicated in the African American Study of Kidney Disease and Hypertension cohort (discovery P=5.42×10-7; replication P=0.039; combined P=7.42×10-9). This SNP also associated with ESRD (hazard ratio, 2.0 (95% confidence interval, 1.5 to 2.7); P=4.90×10-6). Similarly, rs931891 in LINC00923 associated with eGFR decline (P=1.44×10-4) in white patients without diabetes. In summary, SNPs in LINC00923, an RNA gene expressed in the kidney, significantly associated with CKD progression in individuals with nondiabetic CKD. However, the lack of equivalent cohorts hampered replication for most discovery loci. Further replication of our findings in comparable study populations is warranted.
J Am Soc Nephrol. 2017 Mar;28(3):923-934.
Effects of Using Personal Genotype Data on Student Learning and Attitudes in a Pharmacogenomics Course
Authors: Weitzel KW, McDonough CW, Elsey AR, Burkley B, Cavallari LH, Johnson JA
Two online elective courses (pharmacogenomics and genomic medicine) were offered to student pharmacists at the University of Florida using a flipped-classroom, patient-centered teaching approach. In the pharmacogenomics course, students could be genotyped and apply results to patient cases.
Am J Pharm Educ. 2016 Sep 25;80(7):122.
Family health history: An essential starting point for personalized risk assessment and disease prevention
Authors: Henrich VC, Orlando LA
Family health history (FHH) information is well established as a basis for assessing a patient’s personal disease risk, but is underutilized for diagnosis and making medical recommendations. Epidemiological and genetic information have heightened the value of FHH to an individual’s health. This has motivated the development of new FHH collection tools and strategies for family members, but will require greater awareness and knowledge by both patients and practitioners. FHH will be increasingly important as genomic data become a mainstay of medical diagnostics, since in many cases, a medically important FHH results from lineage-specific genetic variants. The impact of complementary FHH and genomic information will drive the pursuit of personalized and precise targeting of treatments and interventions aimed at maintaining patient health.
Pers Med. 2016;13(5):499-510 doi: 10.2217/pme-2016-0007
Authors: Kleinberger JW, Maloney KA, Pollin TI
The genetic architecture of diabetes mellitus in general and in pregnancy is complex, owing to the multiple types of diabetes that comprise both complex/polygenic forms and monogenic (largely caused by a mutation in a single gene) forms such as maturity-onset diabetes of the young (MODY). Type 1 diabetes (T1D) and type 2 diabetes (T2D) have complex genetic etiologies, with over 40 and 90 genes/loci, respectively, implicated that interact with environmental/lifestyle factors. The genetic etiology of gestational diabetes mellitus has largely been found to overlap that of T2D. Genetic testing for complex forms of diabetes is not currently useful clinically, but genetic testing for monogenic forms, particularly MODY, has important utility for determining treatment, managing risk in family members, and pregnancy management. In particular, diagnosing MODY2, caused by GCK mutations, indicates that insulin should not be used, including during pregnancy, with the possible exception of an unaffected pregnancy during the third trimester to prevent macrosomia. A relatively simple method for identifying women with MODY2 has been piloted. MODY1, caused by HNF4A mutations, can paradoxically cause neonatal hyperinsulinemic hypoglycemia and macrosomia, indicating that detecting these cases is also clinically important. Diagnosing all MODY types provides opportunities for diagnosing other family members.
Am J Perinatol. 2016 Nov;33(13):1319-1326.
Authors: Cavallari LH, Duarte JD
Clopidogrel is an ideal target for pharmacogenetic intervention for several reasons. First, there is a strong association between genotype, in this case CYP2C19 genotype, and clopidogrel effectiveness. Second, the consequences of reduced clopidogrel effectiveness, namely adverse cardiovascular events, can be life threatening and costly. Third, there are effective alternatives to clopidogrel that are not affected by CYP2C19 genotype. Fourth, there are guidelines to assist with translating genotype results into prescribing decisions. Finally, CYP2C19 genotyping to determine clopidogrel effectiveness is reimbursed by many third party payers, including Medicare. Because of these reasons, an increasing number of institutions have implemented CYP2C19 genotyping to predict clopidogrel response into clinical practice.
Future Cardiol. 2016 Sep;12(5):511-4.
Implementing Algorithm-Guided Warfarin Dosing in an Ethnically Diverse Patient Population Using Electronic Health Records and Preemptive CYP2C9 and VKORC1 Genetic Testing
Authors: Obeng AO, Kaszemacher T, Abul-Husn NS, Gottesman O, Vega A, Waite E, Myers K, Cho J, Bottinger EP, Ellis SB, Scott SA
Implementation of pharmacogenetic-guided warfarin dosing has been hindered by inconsistent results from reported clinical trials and a lack of available algorithms that include alleles prevalent in non-white populations. However, current evidence indicates that algorithm-guided dosing is more accurate than empirical dosing. To facilitate multiethnic algorithm-guided warfarin dosing using preemptive genetic testing, we developed a strategy that accounts for the complexity of race and leverages electronic health records for algorithm variables and deploying point-of-care dose recommendations.
Clin Pharmacol Ther. 2016 Nov;100(5):427-430.
The Spectrum of Clinical Utilities in Molecular Pathology Testing Procedures for Inherited Conditions and Cancer: A Report of the Association for Molecular Pathology
Authors: Joseph L, Cankovic M, Caughron S, Chandra P, Emmadi R, Hagenkord J, Hallam S, Jewell KE, Klein RD, Pratt VM, Rothberg PG, Temple-Smolkin RL, Lyon E
Clinical utility describes the benefits of each laboratory test for that patient. Many stakeholders have adopted narrow definitions for the clinical utility of molecular testing as applied to targeted pharmacotherapy in oncology, regardless of the population tested or the purpose of the testing. This definition does not address all of the important applications of molecular diagnostic testing. Definitions consistent with a patient-centered approach emphasize and recognize that a clinical test result’s utility depends on the context in which it is used and are particularly relevant to molecular diagnostic testing because of the nature of the information they provide. Debates surrounding levels and types of evidence needed to properly evaluate the clinical value of molecular diagnostics are increasingly important because the growing body of knowledge, stemming from the increase of genomic medicine, provides many new opportunities for molecular testing to improve health care. We address the challenges in defining the clinical utility of molecular diagnostics for inherited diseases or cancer and provide assessment recommendations. Starting with a modified analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications model for addressing clinical utility of molecular diagnostics with a variety of testing purposes, we recommend promotion of patient-centered definitions of clinical utility that appropriately recognize the valuable contribution of molecular diagnostic testing to improve patient care.
J Mol Diagn. 2016 Sep;18(5):605-19.
Impact of Genetic Testing and Family Health History Based Risk Counseling on Behavior Change and Cognitive Precursors for Type 2 Diabetes
Authors: Wu RR, Meyers RA, Hauser ER, Vorderstrasse A, Cho A, Ginsburg GS, Orlando LA
Family health history (FHH) in the context of risk assessment has been shown to positively impact risk perception and behavior change. The added value of genetic risk testing is less certain. The aim of this study was to determine the impact of Type 2 Diabetes (T2D) FHH and genetic risk counseling on behavior and its cognitive precursors. Subjects were non-diabetic patients randomized to counseling that included FHH +/- T2D genetic testing. Measurements included weight, BMI, fasting glucose at baseline and 12 months and behavioral and cognitive precursor (T2D risk perception and control over disease development) surveys at baseline, 3, and 12 months. 391 subjects enrolled of which 312 completed the study. Behavioral and clinical outcomes did not differ across FHH or genetic risk but cognitive precursors did. Higher FHH risk was associated with a stronger perceived T2D risk (pKendall < 0.001) and with a perception of “serious” risk (pKendall < 0.001). Genetic risk did not influence risk perception, but was correlated with an increase in perception of “serious” risk for moderate (pKendall = 0.04) and average FHH risk subjects (pKendall = 0.01), though not for the high FHH risk group. Perceived control over T2D risk was high and not affected by FHH or genetic risk. FHH appears to have a strong impact on cognitive precursors of behavior change, suggesting it could be leveraged to enhance risk counseling, particularly when lifestyle change is desirable. Genetic risk was able to alter perceptions about the seriousness of T2D risk in those with moderate and average FHH risk, suggesting that FHH could be used to selectively identify individuals who may benefit from genetic risk testing.
J Genet Couns 2017 Feb;26(1):133-140.
Implementing Pharmacogenomics at Your Institution: Establishment and Overcoming Implementation Challenges
Authors: Arwood MJ, Chumnumwat S, Cavallari LH, Nutescu EA, Duarte JD
With advancements in pharmacogenomics research and genotyping technology, implementation of pharmacogenomics into clinical practice is now feasible. The aim of this publication is to serve as a tutorial for institutions interested in developing pharmacogenomics services. Topics covered include resources needed, clinical decision support establishment, choosing a genotyping platform, and challenges faced with pharmacogenomics service implementation. This tutorial provides practical advice, drawing upon experience of two established clinical pharmacogenomics services.
Clin Transl Sci. 2016 May 23.
Authors: Ben S, Cooper-DeHoff RM, Flaten HK, Evero O, Ferrara TM, Spritz RA, Monte AA
Reliable, inexpensive, high-throughput genotyping methods are required for clinical trials. Traditional assays require numerous enzyme digestions or are too expensive for large sample volumes. Our objective was to develop an inexpensive, efficient, and reliable assay for CYP2D6 and ADRB1 accounting for numerous polymorphisms including gene duplications.
Hum Genomics. 2016 Apr 23;10:11.
The Path(way) Less Traveled: A Pathway-Oriented Approach to Providing Information about Precision Cancer Medicine on My Cancer Genome
Authors: Taylor AD, Micheel CM, Anderson IA, Levy MA, Lovly CM
This perspective describes the motivation, development, and implementation of pathway-based content for My Cancer Genome, an online precision medicine knowledge resource describing clinical implications of genetic alterations in cancer. As researchers uncover more about cancer pathogenesis, we are learning more not only about the specific genes and proteins involved but also about how those genes and proteins interact with others along cell signaling pathways. This knowledge has led researchers and clinicians to begin to think about cancer therapy using a pathway-based approach. To facilitate this approach, My Cancer Genome used a list of more than 800 cancer-related genes to identify 20 cancer-relevant pathways and then created content focused on demonstrating the therapeutic relevance of these pathways.
Transl Oncol. 2016 Apr;9(2):163-5.
Authors: Giuse NB, Kusnoor SV, Koonce TY, Naylor HM, Chen SC, Blasingame MN, Anderson IA, Micheel CM, Levy MA, Ye F, Lovly CM
As the role of genomics in health care grows, patients increasingly require adequate genetic literacy to fully engage in their care. This study investigated a model for delivering consumer-friendly genetic information to improve understanding of precision medicine using health literacy and learning style principles. My Cancer Genome (MCG), a freely available cancer decision support tool, was used as a testbed. MCG content on a melanoma tumor mutation, BRAF V600E, was translated to a 6th-grade reading level, incorporating multiple learning modalities. A total of 90 patients and caregivers were recruited from a melanoma clinic at an academic medical center and randomized to 3 groups. Group A (control) received an exact copy of text from MCG. Group B was given the same content with hyperlinks to videos explaining key genetic concepts, identified and labeled by the team as knowledge pearls. Group C received the translated content with the knowledge pearls embedded. Changes in knowledge were measured through pre and post questionnaires. Group C showed the greatest improvement in knowledge. The study results demonstrate that providing information based on health literacy and learning style principles can improve patients’ understanding of genetic concepts, thus increasing their likelihood of taking an active role in any decision making concerning their health.
J Health Commun. 2016;21 Suppl 1:5-17.
Authors: Eadon MT, Desta Z, Levy KD, Decker BS, Pierson RC, Pratt VM, Callaghan JT, Rosenman MB, Carpenter JS, Holmes AM, McDonald CA, Benson EA, Patil AS, Vuppalanchi R, Gufford BT, Dave N, Robarge JD, Hyder MA, Haas DM, Kreutz RP, Dexter PR, Skaar TC, Flockhart DA
Hospital systems increasingly utilize pharmacogenomic testing to inform clinical prescribing. Successful implementation efforts have been modeled at many academic centers. In contrast, this report provides insights into the formation of a pharmacogenomics consultation service at a safety-net hospital, which predominantly serves low-income, uninsured, and vulnerable populations. The report describes the INdiana GENomics Implementation: an Opportunity for the UnderServed (INGENIOUS) trial and addresses concerns of adjudication, credentialing, and funding.
Clin Pharmacol Ther. 2016 Jul;100(1):63-6.
Authors: Warner JL, Wang L, Pao W, Sosman JA, Atreya RV, Carney P, Levy MA
As targeted cancer therapies and molecular profiling become widespread, the era of “precision oncology” is at hand. However, cancer genomes are complex, making mutation-specific outcomes difficult to track. We created a proof-of-principle, CUSTOM-SEQ: Continuously Updating System for Tracking Outcome by Mutation, to Support Evidence-based Querying, to automatically calculate and display mutation-specific survival statistics from electronic health record data.
J Am Med Inform Assoc. 2016 Jul;23(4):692-700.
An openly available online tool for implementing the ACMG/AMP standards and guidelines for the interpretation of sequence variants
Authors: Kleinberger J, Maloney KA, Pollin TI, Jeng LJ
To the Editor: The joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) on standards and guidelines for the interpretation of sequence variants, published in the May 2015 issue of Genetics in Medicine, is an excellent resource and reference for interpreting the clinical significance of next-generation sequencing variants using multiple categories and degrees of evidence.1 In our activities concerned with variant interpretation, we use the directives in the article extensively. To facilitate the process, we created an interactive tool based on the article that has been a valuable addition to our process, and we believe it would be useful for others performing variant interpretation.
Genet Med. 2016 Nov;18(11):1165.
Authors: Kisor DF, Smith HE, Grace E, Johnson SG, Weitzel KW, Farrell CL 2015. AACP Special Interest Group CAPE Paper.
Pharmacogenomics (PGx) is a rapidly evolving area of precision (i.e., personalized) medicine in which a patient’s genomic information is used to identify the safest and most effective treatment. While basic pharmacogenomic concepts have developed over the past 50 years, the pace of genomic research accelerated with the completion of the Human Genome Project in 2003. Using the genomic “roadmap” developed by this initiative, researchers and clinicians were able to speed up the process of identifying millions of genetic variants/polymorphisms along the DNA template. Pharmacogenetic studies use these genetic variants/polymorphisms to identify their potential effects on individual patient drug response, disposition, and/or toxicity.
Authors: Cavallari LH, Mason DL
CKD is an independent risk factor for cardiovascular disease (CVD). Thus, patients with CKD often require treatment with cardiovascular drugs, such as antiplatelet, antihypertensive, anticoagulant, and lipid-lowering agents. There is significant interpatient variability in response to cardiovascular therapies, which contributes to risk for treatment failure or adverse drug effects. Pharmacogenomics offers the potential to optimize cardiovascular pharmacotherapy and improve outcomes in patients with CVD, although data in patients with concomitant CKD are limited. The drugs with the most pharmacogenomic evidence are warfarin, clopidogrel, and statins. There are also accumulating data for genetic contributions to β-blocker response. Guidelines are now available to assist with applying pharmacogenetic test results to optimize warfarin dosing, selection of antiplatelet therapy after percutaneous coronary intervention, and prediction of risk for statin-induced myopathy. Clinical data, such as age, body size, and kidney function have long been used to optimize drug prescribing. An increasing number of institutions are also implementing genetic testing to be considered in the context of important clinical factors to further personalize drug therapy for patients with CVD.
Adv Chronic Kidney Dis. 2016 Mar;23(2):82-90.
Authors: Nadkarni GN, Horowitz CR
Recent advances in genomics and sequencing technology have led to a better understanding of genetic risk in CKD. Genetics could account in part for racial differences in treatment response for medications including antihypertensives and immunosuppressive medications due to its correlation with ancestry. However, there is still a substantial lag between generation of this knowledge and its adoption in routine clinical care. This review summarizes the recent advances in genomics and CKD, discusses potential reasons for its underutilization, and highlights potential avenues for application of genomic information to improve clinical care and outcomes in this particularly vulnerable population.
Adv Chronic Kidney Dis. 2016 Mar;23(2):120-4.
Authors: Orlando LA, Wu RR, Myers RA, Buchanan AH, Henrich VC, Hauser ER, Ginsburg GS
Purpose: Risk-stratified guidelines can improve quality of care and cost-effectiveness, but their uptake in primary care has been limited. MeTree, a Web-based, patient-facing risk-assessment and clinical decision support tool, is designed to facilitate uptake of risk-stratified guidelines. Methods: A hybrid implementation-effectiveness trial of three clinics (two intervention, one control). PARTICIPANTS: consentable nonadopted adults with upcoming appointments. Primary Outcome: agreement between patient risk level and risk management for those meeting evidence-based criteria for increased-risk risk-management strategies (increased risk) and those who do not (average risk) before MeTree and after. MEASURES: chart abstraction was used to identify risk management related to colon, breast, and ovarian cancer, hereditary cancer, and thrombosis. Results: Participants = 488, female = 284 (58.2%), white = 411 (85.7%), mean age = 58.7 (SD = 12.3). Agreement between risk management and risk level for all conditions for each participant, except for colon cancer, which was limited to those <50 years of age, was (i) 1.1% (N = 2/174) for the increased-risk group before MeTree and 16.1% (N = 28/174) after and (ii) 99.2% (N = 2,125/2,142) for the average-risk group before MeTree and 99.5% (N = 2,131/2,142) after. Of those receiving increased-risk risk-management strategies at baseline, 10.5% (N = 2/19) met criteria for increased risk. After MeTree, 80.7% (N = 46/57) met criteria. Conclusion: MeTree integration into primary care can improve uptake of risk-stratified guidelines and potentially reduce “overuse” and “underuse” of increased-risk services.
Genet Med. 2016 2016 Oct;18(10):1020-8.
Medical student preparedness for an era of personalized medicine: findings from one US medical school
Authors: Eden C, Johnson KW, Gottesman O, Bottinger EP, Abul-Husn NS
Aim: The objective of this research was to assess medical student preparedness for the use of personalized medicine. Materials & Methods: A survey instrument measuring attitude toward personalized medicine, perceived knowledge of genomic testing concepts and perceived ability to apply genomics to clinical care was distributed to students in medical school (MS) years 1-4. Results: Of 212 participants, 79% felt that it was important to learn about personalized medicine, but only 6% thought that their medical education had adequately prepared them to practice personalized medicine. Attitude did not vary across years; knowledge and ability increased after MS1, but not after MS2. Conclusion: While medical students support the use of personalized medicine, they do not feel prepared to apply genomics to clinical care.
Per Med. 2016 Mar;13(2):129-141.
Authors: Peterson JF, Field JR, Unertl KM, Schildcrout JS, Johnson DC, Shi Y, Danciu I, Cleator JH, Pulley JM, McPherson JA, Denny JC, Laposata M, Roden DM, Johnson KB
Physician responses to genomic information are vital to the success of precision medicine initiatives. We prospectively studied a pharmacogenomics implementation program for the propensity of clinicians to select antiplatelet therapy based on CYP2C19 loss-of-function variants in stented patients. Among 2,676 patients, 514 (19.2%) were found to have a CYP2C19 variant affecting clopidogrel metabolism. For the majority (93.6%) of the cohort, cardiologists received active and direct notification of CYP2C19 status. Over 12 months, 57.6% of poor metabolizers and 33.2% of intermediate metabolizers received alternatives to clopidogrel. CYP2C19 variant status was the most influential factor impacting the prescribing decision (hazard ratio [HR] in poor metabolizers 8.1, 95% confidence interval [CI] [5.4, 12.2] and HR 5.0, 95% CI [4.0, 6.3] in intermediate metabolizers), followed by patient age and type of stent implanted. We conclude that cardiologists tailored antiplatelet therapy for a minority of patients with a CYP2C19 variant and considered both genomic and nongenomic risks in their clinical decision-making.
Clin Pharmacol Ther. 2016 Jul;100(1):67-74.
Toward rapid learning in cancer treatment selection: An analytical engine for practice-based clinical data
Authors: Finlayson SG, Levy M, Reddy S, Rubin DL
J Biomed Inform. 2016 Apr;60:104-13. Wide-scale adoption of electronic medical records (EMRs) has created an unprecedented opportunity for the implementation of Rapid Learning Systems (RLSs) that leverage primary clinical data for real-time decision support. In cancer, where large variations among patient features leave gaps in traditional forms of medical evidence, the potential impact of a RLS is particularly promising. We developed the Melanoma Rapid Learning Utility (MRLU), a component of the RLS, providing an analytical engine and user interface that enables physicians to gain clinical insights by rapidly identifying and analyzing cohorts of patients similar to their own.
Authors: Rioth MJ, Staggs DB, Hackett L, Haberman E, Tod M, Levy M, Warner J
Oncology practice increasingly requires the use of molecular profiling of tumors to inform the use of targeted therapeutics. However, many oncologists use third-party laboratories to perform tumor genomic testing, and these laboratories may not have electronic interfaces with the provider’s electronic medical record (EMR) system. The resultant reporting mechanisms, such as plain-paper faxing, can reduce report fidelity, slow down reporting procedures for a physician’s practice, and make reports less accessible. Vanderbilt University Medical Center and its genomic laboratory testing partner have collaborated to create an automated electronic reporting system that incorporates genetic testing results directly into the clinical EMR. This system was iteratively tested, and causes of failure were discovered and addressed. Most errors were attributable to data entry or typographical errors that made reports unable to be linked to the correct patient in the EMR. By providing direct feedback to providers, we were able to significantly decrease the rate of transmission errors (from 6.29% to 3.84%; P < .001). The results and lessons of 1 year of using the system and transmitting 832 tumor genomic testing reports are reported.
J Oncol Pract. 2016 Mar;12(3):e332-7.
Authors: Roden DM, Denny JC
The Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009 mandates the development and implementation of electronic health record (EHR) systems across the country. While a primary goal is to improve the care of individual patients, EHRs are also key enabling resources for a vision of individualized (or personalized or precision) medicine: the aggregation of multiple EHRs within or across healthcare systems should allow discovery of patient subsets that have unusual and definable clinical trajectories that deviate importantly from the expected response in a “typical” patient. The spectrum of such personalized care can then extend from prevention to choice of medication to intensity or nature of follow-up.
Clin Pharmacol Ther. 2016 Mar;99(3):298-305.
Impact of GGCX, STX1B, and FPGS Polymorphisms on Warfarin Dose Requirements in European Americans and Egyptians
Authors: Hamadeh IS, Shahin MH, Lima SM, Oliveira F, Wilson L, Khalifa SI, Langaee TY, Cooper-DeHoff RM, Cavallari LH, Johnson JA
Genotype-based algorithms that include VKORC1 and CYP2C9 genotypes are less predictive of warfarin dose variability in Africans as opposed to Europeans. Polymorphisms in GGCX, FPGS, or STX1B are associated with warfarin dose requirements in African-Americans. We sought to determine if they influenced warfarin dose in European-Americans, and another African population, specifically Egyptians. We genotyped 529 adults (n = 325 European-Americans, 204 Egyptians) on a stable warfarin dose for GGCX rs12714145 and rs10654848, FPGS rs7856096, and STX1B rs4889606. Rs12714145, rs10654848, and rs7856096 were not associated with warfarin dose, whereas STX1B rs4889606 was a significant determinant in univariate analysis (P < 0.0001) in both cohorts. However, STX1B rs4889606 was in high linkage disequilibrium with VKORC1-1639 G>A, and was no longer significant after including VKORC1-1639 G>A in the regression model. Based on these data, the polymorphisms do not appear to influence, in a clinically important way, warfarin dose requirements in European-Americans and Egyptians.
Clin Transl Sci. 2016 Feb;9(1):36-42.
Authors: Khalil BM, Shahin MH, Solayman MH, Langaee T, Schaalan MF, Gong Y, Hammad LN, Al-Mesallamy HO, Hamdy NM, El-Hammady WA, Johnson JA
Aspirin and clopidogrel are the mainstay oral antiplatelet regimens, yet a substantial number of major adverse cardiac events (MACE) still occur. Herein, we investigated genetic and nongenetic factors associated with clopidogrel response in Egyptians. In all, 190 Egyptians with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI), treated with clopidogrel (75 mg/day) for at least a month, were genotyped for CYP2C19 *2, *3, *6, *8, *10, and *17, CES1 G143E and ABCB1*6 and *8. These variants along with nongenetic factors were tested for association with the risk of having MACE in clopidogrel-treated patients. CYP2C19 loss-of-function (LOF) alleles carriers had increased risk of MACE vs. noncarriers (odds ratio 2.52; 95% confidence interval 1.23-5.15, P = 0.011). In a logistic regression, CYP2C19 LOF variants (P = 0.011), age (P = 0.032), and body mass index (BMI, P = 0.039) were significantly associated with the incidence of MACE in patients taking clopidogrel. CYP2C19 genetic variants, age, and BMI are potential predictors associated with variability to clopidogrel response in Egyptians.
Clin Transl Sci. 2016 Feb;9(1):23-8.
Analytical Validation of a Personalized Medicine APOL1 Genotyping Assay for Nondiabetic Chronic Kidney Disease Risk Assessment
Authors: Zhang J, Fedick A, Wasserman S, Zhao G, Edelmann L, Bottinger EP, Kornreich R, Scott SA
The incidence of chronic kidney disease (CKD) varies by ancestry, with African Americans (AA) having a threefold to fourfold higher rate than whites. Notably, two APOL1 alleles, termed G1 [c.(1072A>G; 1200T>G)] and G2 (c.1212_1217del6), are strongly associated with higher rates of nondiabetic CKD and an increased risk for hypertensive end-stage renal disease. This has prompted the opportunity to implement APOL1 testing to identify at-risk patients and modify other risk factors to reduce the progression of CKD to end-stage renal disease. We developed an APOL1 genotyping assay using multiplex allele-specific primer extension, and validated using 58 positive and negative controls. Genotyping results were completely concordant with Sanger sequencing, and both triplicate interrun and intrarun genotyping results were completely concordant. Multiethnic APOL1 allele frequencies were also determined by genotyping 7059 AA, Hispanic, and Asian individuals from the New York City metropolitan area. The AA, Hispanic, and Asian APOL1 G1 and G2 allele frequencies were 0.22 and 0.13, 0.037 and 0.025, and 0.013 and 0.004, respectively. Notably, approximately 14% of the AA population carried two risk alleles and are at increased risk for CKD, compared with <1% of the Hispanic and Asian populations. This novel APOL1 genotyping assay is robust and highly accurate, and represents one of the first personalized medicine clinical genetic tests for disease risk prediction.
J Mol Diagn. 2016 Mar;18(2):260-6.
Authors: Weitzel KW, Alexander M, Bernhardt BA, Calman N, Carey DJ, Cavallari LH, Field JR, Hauser D, Junkins HA, Levin PA, Levy K, Madden EB, Manolio TA, Odgis J, Orlando LA, Pyeritz R, Wu RR, Shuldiner AR, Bottinger EP, Denny JC, Dexter PR, Flockhart DA, Horowitz CR, Johnson JA, Kimmel SE, Levy MA, Pollin TI, Ginsburg GS, IGNITE Network
Background: Patients, clinicians, researchers and payers are seeking to understand the value of using genomic information (as reflected by genotyping, sequencing, family history or other data) to inform clinical decision-making. However, challenges exist to widespread clinical implementation of genomic medicine, a prerequisite for developing evidence of its real-world utility. Methods: To address these challenges, the National Institutes of Health-funded IGNITE (Implementing GeNomics In pracTicE; www.ignite-genomics.org ) Network, comprised of six projects and a coordinating center, was established in 2013 to support the development, investigation and dissemination of genomic medicine practice models that seamlessly integrate genomic data into the electronic health record and that deploy tools for point of care decision making. IGNITE site projects are aligned in their purpose of testing these models, but individual projects vary in scope and design, including exploring genetic markers for disease risk prediction and prevention, developing tools for using family history data, incorporating pharmacogenomic data into clinical care, refining disease diagnosis using sequence-based mutation discovery, and creating novel educational approaches. Results: This paper describes the IGNITE Network and member projects, including network structure, collaborative initiatives, clinical decision support strategies, methods for return of genomic test results, and educational initiatives for patients and providers. Clinical and outcomes data from individual sites and network-wide projects are anticipated to begin being published over the next few years. Conclusions: The IGNITE Network is an innovative series of projects and pilot demonstrations aiming to enhance translation of validated actionable genomic information into clinical settings and develop and use measures of outcome in response to genome-based clinical interventions using a pragmatic framework to provide early data and proofs of concept on the utility of these interventions. Through these efforts and collaboration with other stakeholders, IGNITE is poised to have a significant impact on the acceleration of genomic information into medical practice.
BMC Med Genomics. 2016 Jan 5;9:1.
Determining the effects and challenges of incorporating genetic testing into primary care management of hypertensive patients with African ancestry
Authors: Horowitz CR, Abul-Husn NS, Ellis S, Ramos MA, Negron R, Suprun M, Zinberg RE, Sabin T, Hauser D, Calman N, Bagiella E, Bottinger EP
People of African ancestry (Blacks) have increased risk of kidney failure due to numerous socioeconomic, environmental, and clinical factors. Two variants in the APOL1 gene are now thought to account for much of the racial disparity associated with hypertensive kidney failure in Blacks. However, this knowledge has not been translated into clinical care to help improve patient outcomes and address disparities. GUARDD is a randomized trial to evaluate the effects and challenges of incorporating genetic risk information into primary care. Hypertensive, non-diabetic, adults with self-reported African ancestry, without kidney dysfunction, are recruited from diverse clinical settings and randomized to undergo APOL1 genetic testing at baseline (intervention) or at one year (waitlist control). Providers are educated about genomics and APOL1. Guided by a genetic counselor, trained staff return APOL1 results to patients and provide low-literacy educational materials. Real-time clinical decision support tools alert clinicians of their patients’ APOL1 results and associated risk status at the point of care. Our academic-community-clinical partnership designed a study to generate information about the impact of genetic risk information on patient care (blood pressure and renal surveillance) and on patient and provider knowledge, attitudes, beliefs, and behaviors. GUARDD will help establish the effective implementation of APOL1 risk-informed management of hypertensive patients at high risk of CKD, and will provide a robust framework for future endeavors to implement genomic medicine in diverse clinical practices. It will also add to the important dialog about factors that contribute to and may help eliminate racial disparities in kidney disease.
Contemp Clin Trials. 2016 Mar;47:101-8.
A prognostic model based on readily available clinical data enriched a pre-emptive pharmacogenetic testing program
Authors: Schildcrout JS, Shi Y, Danciu I, Bowton E, Field JR, Pulley JM, Basford MA, Gregg W, Cowan JD, Harrell FE, Roden DM, Peterson JF, Denny JC
Using deidentified electronic health records, we derived a prognostic model for the prescription of statins, warfarin, or clopidogrel. The model was implemented into a clinical decision support (CDS) tool to recommend pre-emptive genotyping for patients exceeding a prescription risk threshold. We evaluated the rule on an independent validation cohort and on an implementation cohort, representing the population in which the CDS tool was deployed.
J Clin Epidemiol. 2016 Apr;72:107-15.
Characterization of 137 Genomic DNA Reference Materials for 28 Pharmacogenetic Genes: A GeT-RM Collaborative Project
Authors: Pratt VM, Everts RE, Aggarwal P, Beyer BN, Broeckel U, Epstein-Baak R, Hujsak P, Kornreich R, Liao J, Lorier R, Scott SA, Smith CH, Toji LH, Turner A, Kalman LV
Pharmacogenetic testing is increasingly available from clinical laboratories. However, only a limited number of quality control and other reference materials are currently available to support clinical testing. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing community and the Coriell Cell Repositories, has characterized 137 genomic DNA samples for 28 genes commonly genotyped by pharmacogenetic testing assays (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP4F2, DPYD, GSTM1, GSTP1, GSTT1, NAT1, NAT2, SLC15A2, SLC22A2, SLCO1B1, SLCO2B1, TPMT, UGT1A1, UGT2B7, UGT2B15, UGT2B17, and VKORC1). One hundred thirty-seven Coriell cell lines were selected based on ethnic diversity and partial genotype characterization from earlier testing. DNA samples were coded and distributed to volunteer testing laboratories for targeted genotyping using a number of commercially available and laboratory developed tests. Through consensus verification, we confirmed the presence of at least 108 variant pharmacogenetic alleles. These samples are also being characterized by other pharmacogenetic assays, including next-generation sequencing, which will be reported separately. Genotyping results were consistent among laboratories, with most differences in allele assignments attributed to assay design and variability in reported allele nomenclature, particularly for CYP2D6, UGT1A1, and VKORC1.
J Mol Diagn. 2016 Jan;18(1):109-23.
Protocol for the “Implementation, adoption, and utility of family history in diverse care settings” study
Authors: Wu RR, Myers RA, McCarty CA, Dimmock D, Farrell M, Cross D, Chinevere TD, Ginsburg GS, Orlando LA, Family Health History Network
Background: Risk assessment with a thorough family health history is recommended by numerous organizations and is now a required component of the annual physical for Medicare beneficiaries under the Affordable Care Act. However, there are several barriers to incorporating robust risk assessments into routine care. MeTree, a web-based patient-facing health risk assessment tool, was developed with the aim of overcoming these barriers. In order to better understand what factors will be instrumental for broader adoption of risk assessment programs like MeTree in clinical settings, we obtained funding to perform a type III hybrid implementation-effectiveness study in primary care clinics at five diverse healthcare systems. Here, we describe the study’s protocol. Methods/Design: MeTree collects personal medical information and a three-generation family health history from patients on 98 conditions. Using algorithms built entirely from current clinical guidelines, it provides clinical decision support to providers and patients on 30 conditions. All adult patients with an upcoming well-visit appointment at one of the 20 intervention clinics are eligible to participate. Patient-oriented risk reports are provided in real time. Provider-oriented risk reports are uploaded to the electronic medical record for review at the time of the appointment. Implementation outcomes are enrollment rate of clinics, providers, and patients (enrolled vs approached) and their representativeness compared to the underlying population. Primary effectiveness outcomes are the percent of participants newly identified as being at increased risk for one of the clinical decision support conditions and the percent with appropriate risk-based screening. Secondary outcomes include percent change in those meeting goals for a healthy lifestyle (diet, exercise, and smoking). Outcomes are measured through electronic medical record data Abstract:ion, patient surveys, and surveys/qualitative interviews of clinical staff. Discussion: This study evaluates factors that are critical to successful implementation of a web-based risk assessment tool into routine clinical care in a variety of healthcare settings. The result will identify resource needs and potential barriers and solutions to implementation in each setting as well as an understanding potential effectiveness.
Implement Sci. 2015 Nov 24;10:163.
Authors: Cooper-DeHoff RM, Johnson JA
Cardiovascular and renal diseases are associated with many risk factors, of which hypertension is one of the most prevalent. Worldwide, blood pressure control is only achieved in ∼50% of those treated for hypertension, despite the availability of a considerable number of antihypertensive drugs from different pharmacological classes. Although many reasons exist for poor blood pressure control, a likely contributor is the inability to predict to which antihypertensive drug an individual is most likely to respond. Hypertension pharmacogenomics and other ‘omics’ technologies have the potential to identify genetic signals that are predictive of response or adverse outcome to particular drugs, and guide selection of hypertension treatment for a given individual. Continued research in this field will enhance our understanding of how to maximally deploy the various antihypertensive drug classes to optimize blood pressure response at the individual level. This Review summarizes the available literature on the most convincing genetic signals associated with antihypertensive drug responses and adverse cardiovascular outcomes. Future research in this area will be facilitated by enhancing collaboration between research groups through consortia such as the International Consortium for Antihypertensives Pharmacogenomics Studies, with the goal of translating replicated findings into clinical implementation.
Nat Rev Nephrol. 2016 Feb;12(2):110-22.
CYP2C19 and CES1 Polymorphisms and Efficacy of Clopidogrel and Aspirin Dual Antiplatelet Therapy in Patients with Symptomatic Intracranial Atherosclerotic Disease
Authors: Hoh BL, Gong Y, McDonough CW, Waters MF, Royster AJ, Sheehan TO, Burkley B, Langaee TY, Mocco J, Zuckerman SL, Mummareddy N, Stephens ML II, Ingram C, Shaffer CM, Denny JC, Brilliant MH, Kitchner TE, Linneman JG, Roden DM, Johnson JA
Symptomatic intracranial atherosclerotic disease (ICAD) has a high risk of recurrent stroke. Genetic polymorphisms in CYP2C19 and CES1 are associated with adverse outcomes in cardiovascular patients, but have not been studied in ICAD. The authors studied CYP2C19 and CES1 single-nucleotide polymorphisms (SNPs) in symptomatic ICAD patients.
J Neurosurg. 2016 Jun;124(6):1746-51.
Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting
Authors: Kalman LV, Agúndez J, Appell ML, Black JL, Bell GC, Boukouvala S, Bruckner C, Bruford E, Caudle K, Coulthard SA, Daly AK, Tredici AD, den Dunnen JT, Drozda K, Everts RE, Flockhart D, Freimuth RR, Gaedigk A, Hachad H, Hartshorne T, Ingelman-Sundberg M, Klein TE, Lauschke VM, Maglott DR, McLeod HL, McMillin GA, Meyer UA, Müller DJ, Nickerson DA, Oetting WS, Pacanowski M, Pratt VM, Relling MV, Roberts A, Rubinstein WS, Sangkuhl K, Schwab M, Scott SA, Sim SC, Thirumaran RK, Toji LH, Tyndale RF, van Schaik R, Whirl-Carrillo M, Yeo K, Zanger UM
This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.
Clin Pharmacol Ther. 2016 Feb;99(2):172-85.
Authors: Johnson JA, Weitzel KW
Pharmacogenomics is an important element of precision medicine. Advances in pharmacogenomics implementation have been made but significant barriers remain, including evidence, reimbursement, and clinician knowledge, among others. Widespread adoption of pharmacogenomics requires overcoming these barriers, a clinician champion group, which we propose will be pharmacists, and an easily accessible setting, which may be the community pharmacy. Whatever the path, it must be evidence-driven and pharmacogenomics must improve drug-related outcomes to become a standard of care.
Clin Pharmacol Ther. 2016 Feb;99(2):154-6.
Authors: Brothers KB, Holm IA, Childerhose JE, Antommaria AH, Bernhardt BA, Clayton EW, Gelb BD, Joffe S, Lynch JA, McCormick JB, McCullough LB, Parsons DW, Sundaresan AS, Wolf WA, Yu JH, Wilfond BS, Pediatrics Workgroup of the Clinical Sequencing Exploratory Research (CSER) Consortium, Pediatrics Workgroup of the Clinical Sequencing Exploratory Research CSER Consortium
The landscape of pediatric research is becoming more complex. Contemporary research studies, and genome studies in particular, frequently involve a range of research activities. For example, the Clinical Sequencing Exploratory Research Consortium studies evaluate whether genomic testing can be useful in clinical settings.1 These studies include the storage of biosamples for future research, observations about the way providers interact with results reported in electronic health records, and the contribution of data to national databases like ClinVar and the Database of Genotypes and Phenotypes (dbGaP).
J Pediatr. 2016 Jan;168:226-31.e1.
Authors: Henrich VC, Orlando LA
The successful practice of personalized medicine in primary care depends upon understanding a patient’s individual disease risk and anticipating the best course of treatment with the goal of maintaining good health. A personalized disease risk assessment leads to recommendations for evidence-based interventions that can delay/prevent disease onset or reduce the severity of disease. As the sophistication of medical diagnoses develops and new interventions become available, the value of collecting and analyzing family health history (FHH) for maintaining patient wellness by determining ‘the right treatment, at the right time, for the right patient’ is more apparent than ever. FHH remains underutilized in primary care, however, because of numerous barriers. Ironically, the introduction of genetic tests and genomic methods that identify carriers who might be vulnerable to a variety of medical conditions and diseases has simply raised the importance of collecting and utilizing FHH to guide patient management in primary care.
Fam Med Med Sci Res. 2015 Oct 15;4:185.
Authors: Kleinberger JW, Pollin TI
Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes that accounts for at least 1 % of all cases of diabetes mellitus. MODY classically presents as non-insulin-requiring diabetes in lean individuals typically younger than 25 with evidence of autosomal dominant inheritance, but these criteria do not capture all cases and can also overlap with other diabetes types. Genetic diagnosis of MODY is important for selecting the right treatment, yet ~95 % of MODY cases in the USA are misdiagnosed. MODY prevalence and characteristics have been well-studied in some populations, such as the UK and Norway, while other ethnicities, like African and Latino, need much more study. Emerging next-generation sequencing methods are making more widespread study and clinical diagnosis increasingly feasible; at the same time, they are detecting other mutations in the same genes of unknown clinical significance. This review will cover the current epidemiological studies of MODY and barriers and opportunities for moving toward a goal of access to an appropriate diagnosis for all affected individuals.
Curr Diab Rep. 2015 Dec;15(12):110.
Authors: Chang KL, Weitzel K, Schmidt S
Clinical pharmacogenetics, the use of genetic data to guide drug therapy decisions, is beginning to be used for medications commonly prescribed by family physicians. However, clinicians are largely unfamiliar with principles supporting clinical use of this type of data. For example, genetic variability in the cytochrome P450 2D6 drug metabolizing enzyme can alter the clinical effects of some opioid analgesics (e.g., codeine, tramadol), whereas variability in the CYP2C19 enzyme affects the antiplatelet agent clopidogrel. If testing is performed, patients who are ultrarapid or poor metabolizers of CYP2D6 should avoid codeine use (and possibly tramadol, hydrocodone, and oxycodone) because of the potential for increased toxicity or lack of effectiveness. Patients undergoing percutaneous coronary intervention for acute coronary syndromes who are known to be poor metabolizers of CYP2C19 should consider alternate antiplatelet therapy (e.g., ticagrelor, prasugrel). Some guidelines are available that address appropriate drug therapy changes, and others are in development. Additionally, a number of clinical resources are emerging to support family physicians in the use of pharmacogenetics. When used appropriately, pharmacogenetic testing can be a practical tool to optimize drug therapy and avoid medication adverse effects.
Am Fam Physician. 2015 Oct 1;92(7):588-94.
Development and preliminary evaluation of an online educational video about whole-genome sequencing for research participants, patients, and the general public
Authors: Sanderson SC, Suckiel SA, Zweig M, Bottinger EP, Jabs EW, Richardson LD
As whole-genome sequencing (WGS) increases in availability, WGS educational aids are needed for research participants, patients, and the general public. Our aim was therefore to develop an accessible and scalable WGS educational aid.
Genet Med. 2016 May;18(5):501-12.
Authors: Herr TM, Bielinski SJ, Bottinger E, Brautbar A, Brilliant M, Chute CG, Denny J, Freimuth RR, Hartzler A, Kannry J, Kohane IS, Kullo IJ, Lin S, Pathak J, Peissig P, Pulley J, Ralston J, Rasmussen L, Roden D, Tromp G, Williams MS, Starren J
Journal of pathology informatics. 2015 Aug 31;6:46.
Authors: Arwood MJ, Cavallari LH, Duarte JD
Heart disease is a leading cause of death in the United States, and hypertension is a predominant risk factor. Thus, effective blood pressure control is important to prevent adverse sequelae of hypertension, including heart failure, coronary artery disease, atrial fibrillation, and ischemic stroke. Over half of Americans have uncontrolled blood pressure, which may in part be explained by interpatient variability in drug response secondary to genetic polymorphism. As such, pharmacogenetic testing may be a supplementary tool to guide treatment. This review highlights the pharmacogenetics of antihypertensive response and response to drugs that treat adverse hypertension-related sequelae, particularly coronary artery disease and atrial fibrillation. While pharmacogenetic evidence may be more robust for the latter with respect to clinical implementation, there is increasing evidence of genetic variants that may help predict antihypertensive response. However, additional research and validation are needed before clinical implementation guidelines for antihypertensive therapy can become a reality.
Curr Hypertens Rep. 2015 Sep;17(9):586.
Authors: Peterson JF, Field JR, Shi Y, Schildcrout JS, Denny JC, McGregor TL, Van Driest SL, Pulley JM, Lubin IM, Laposata M, Roden DM, Clayton EW
Clinician attitudes toward multiplexed genomic testing may be vital to the success of translational programs. We surveyed clinicians at an academic medical center about their views on a large pharmacogenomics implementation, the PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment) program. Participants were asked about test ordering, major factors influencing use of results, expectations of efficacy and responsibility for applying results to patient care. Virtually all respondents (99%) agreed that pharmacogenomics variants influence patients’ response to drug therapy. The majority (92%) favored immediate, active notification when a clinically significant drug-genome interaction was present. However, clinicians were divided on which providers were responsible for acting on a result when a prescription change was indicated and whether patients should be directly notified of a significant result. We concluded genotype results were valued for tailoring prescriptions, but clinicians do not agree on how to appropriately assign clinical responsibility for actionable results from a multiplexed panel.
Pharmacogenomics J. 2016 Aug;16(4):393-8.
Authors: Unertl KM, Field JR, Price L, Peterson JF
AIM: To describe the knowledge and attitudes of clinicians participating in a large pharmacogenomics implementation program. MATERIALS & METHODS: Semi-structured interviews with 15 physicians and nurse practitioners were conducted. RESULTS: Three categories of themes were identified: preparation and knowledge, pharmacogenomics usage in practice, and future management of genomic variants. Providers expressed an inability to keep up with the rapid pace of evidence generation and indicated strong support for clinical decision support to assist with genotype-tailored therapies. Concerns raised by clinicians included effectively communicating results, long-term responsibility for actionable results and hand-offs with providers outside the implementation program. CONCLUSIONS: Clinicians identified their own knowledge deficits, workflow integration, and longitudinal responsibility as challenges to successful usage of pharmacogenomics in clinical practice.
Per Med. 2015 Aug;12(4):339-347.
Authors: El Rouby N, Cooper-DeHoff RM
Resistant hypertension (RHTN), defined as an uncontrolled blood pressure despite the use of multiple antihypertensive medications, is an increasing clinical problem associated with increased cardiovascular (CV) risk, including stroke and target organ damage. Genetic variability in blood pressure (BP)-regulating genes and pathways may, in part, account for the variability in BP response to antihypertensive agents, when taken alone or in combination, and may contribute to the RHTN phenotype. Pharmacogenomics focuses on the identification of genetic factors responsible for inter-individual variability in drug response. Expanding pharmacogenomics research to include patients with RHTN taking multiple BP-lowering medications may identify genetic markers associated with RHTN. To date, the available evidence surrounding pharmacogenomics in RHTN is limited and primarily focused on candidate genes. In this review, we summarize the most current data in RHTN pharmacogenomics and offer some recommendations on how to advance the field.
Curr Hypertens Rep. 2015 Sep;17(9):583.
Authors: Numanagić I, Malikić S, Pratt VM, Skaar TC, Flockhart DA, Sahinalp SC
Motivation: CYP2D6 is highly polymorphic gene which encodes the (CYP2D6) enzyme, involved in the metabolism of 20-25% of all clinically prescribed drugs and other xenobiotics in the human body. CYP2D6 genotyping is recommended prior to treatment decisions involving one or more of the numerous drugs sensitive to CYP2D6 allelic composition. In this context, high-throughput sequencing (HTS) technologies provide a promising time-efficient and cost-effective alternative to currently used genotyping techniques. To achieve accurate interpretation of HTS data, however, one needs to overcome several obstacles such as high sequence similarity and genetic recombinations between CYP2D6 and evolutionarily related pseudogenes CYP2D7 and CYP2D8, high copy number variation among individuals and short read lengths generated by HTS technologies. Results: In this work, we present the first algorithm to computationally infer CYP2D6 genotype at basepair resolution from HTS data. Our algorithm is able to resolve complex genotypes, including alleles that are the products of duplication, deletion and fusion events involving CYP2D6 and its evolutionarily related cousin CYP2D7. Through extensive experiments using simulated and real datasets, we show that our algorithm accurately solves this important problem with potential clinical implications.
Bioinformatics. 2015 Jun 15;31(12):i27-34.
FDA’s draft guidance on laboratory-developed tests increases clinical and economic risk to adoption of pharmacogenetic testing
Authors: Levy KD, Pratt VM, Skaar TC, Vance GH, Flockhart DA
The US Food and Drug Administration (FDA) notified Congress July 31, 2014, of its intent to regulate laboratory developed tests. These encompass thousands of clinical assays currently used in medical practice including most pharmacogenetic tests. This guidance has the potential to impact the innovation and sustainability of pharmacogenetic research and its clinical implementation.
J Clin Pharmacol. 2015 Jul;55(7):725-7.
Authors: Larson EA, and Wilke RA
Primary care is changing rapidly. The wide-scale expansion of electronic medical records is redefining the way we approach chronic disease management, and automated decision support is increasingly being leveraged to reduce risk and optimize quality. Many of these interventions are now beginning to integrate genomic data. We explore the convergence of these 2 forces (expansion of clinical informatics and integration of translational genomics), and we highlight several applications where these forces are helping our patients avoid potentially preventable events. Because gene-environment interactions are dynamic, the utility of gene-based decision support varies over time. Primary care providers will serve a key role as our patients navigate these changes.
Am J Med. 2015 Nov;128(11):1251.e1-5.
Authors: Cavallari LH, Weitzel K
Following completion of the Human Genome Project in 2003, Dr Francis Collins and others on behalf of the National Human Genome Research Institute announced their vision for the future of genomics research. A number of grand challenges were identified, and among these were developing strategies to identify genetic contributions to drug response, creating genome-based approaches to predict drug response, and applying discoveries to promote the use of genomic information into clinical practice. The NIH has invested significant resources in addressing these challenges, including funding the International HapMap and 1000 Genomes Projects, which have enabled genome-wide association studies (GWAS) of drug response. Through GWAS, investigators have identified genetic contributors to statin-induced myopathy, clopidogrel effectiveness and warfarin dose requirements. While most GWAS of drug response have been conducted in European populations, a recent GWAS in African–Americans revealed a novel association between the rs12777823 polymorphism and warfarin dose requirements in this population, demonstrating the importance of conducting pharmacogenomic studies in different ethnic groups.
Future Cardiol. 2015 May;11(3):281-6.
Authors: Wiley LK, Moretz JD, Denny JC, Peterson JF, Bush WS
It is unclear the extent to which best practices for phenotyping disease states from electronic medical records (EMRs) translate to phenotyping adverse drug events. Here we use statin-induced myotoxicity as a case study to identify best practices in this area. We compared multiple phenotyping algorithms using administrative codes, laboratory measurements, and full-text keyword matching to identify statin-related myopathy from EMRs. Manual review of 300 deidentified EMRs with exposure to at least one statin, created a gold standard set of 124 cases and 176 controls. We tested algorithms using ICD-9 billing codes, laboratory measurements of creatine kinase (CK) and keyword searches of clinical notes and allergy lists. The combined keyword algorithms produced were the most accurate (PPV=86%, NPV=91%). Unlike in most disease phenotyping algorithms, addition of ICD9 codes or laboratory data did not appreciably increase algorithm accuracy. We conclude that phenotype algorithms for adverse drug events should consider text based approaches.
AMIA Jt Summits Transl Sci Proc. 2015 Mar 25;2015:466-70.
Authors: Kleinberger JW, Pollin TI
Diabetes mellitus affects approximately 382 million individuals worldwide and is a leading cause of morbidity and mortality. Over 40 and nearly 80 genetic loci influencing susceptibility to type 1 and type 2 diabetes, respectively, have been identified. In addition, there is emerging evidence that some genetic variants help to predict response to treatment. Other variants confer apparent protection from diabetes or its complications and may lead to development of novel treatment approaches. Currently, there is clear clinical utility to genetic testing to find the at least 1% of diabetic individuals who have monogenic diabetes (e.g., maturity-onset diabetes of the young and KATP channel neonatal diabetes). Diagnosing many of these currently underdiagnosed types of diabetes enables personalized treatment, resulting in improved and less invasive glucose control, better prediction of prognosis, and enhanced familial risk assessment. Efforts to enhance the rate of detection, diagnosis, and personalized treatment of individuals with monogenic diabetes should set the stage for effective clinical translation of current genetic, pharmacogenetic, and pharmacogenomic research of more complex forms of diabetes.
Ann N Y Acad Sci. 2015 Jun;1346(1):45-56.
Loss of heterozygosity at the CYP2D6 locus in breast cancer: implications for tamoxifen pharmacogenetic studies
Authors: Johnson JA, Hamadeh IS, Langaee TY
Tamoxifen is a member of the Selective Estrogen Receptor Modulators (SERMs), and by virtue of its antiestrogenic properties, particularly in breast tissue, is considered an essential component in the armamentarium of drugs used for the prevention and treatment of hormone receptor–positive (HR+) breast cancer. Early studies evaluating the efficacy of tamoxifen demonstrated that its use in adjuvant settings resulted in an approximately 40% reduction in breast cancer recurrence rates and a 30% reduction in mortality rates. In light of such favorable patient outcomes, medical societies recommend that tamoxifen be offered for five years to all women with HR+ breast cancer and recent American Society of Clinical Oncology (ASCO) guidelines recommend 10 years of treatment in most women for prevention of recurrence. Additionally, guidelines recommend at least five years of tamoxifen therapy for primary prevention in women at risk for developing invasive HR+ breast cancer.
J Natl Cancer Inst. 2015 Jan 31;107(2).
A novel simple method for determining CYP2D6 gene copy number and identifying allele(s) with duplication/multiplication
Authors: Langaee T, Hamadeh I, Chapman AB, Gums JG, Johnson JA
Background: Cytochrome P450 2D6 (CYP2D6) gene duplication and multiplication can result in ultrarapid drug metabolism and therapeutic failure or excessive response in patients. Long range polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) and sequencing are usually used for genotyping CYP2D6 duplication/multiplications and identification, but are labor intensive, time consuming, and costly. Methods: We developed a simple allele quantification-based Pyrosequencing genotyping method that facilitates CYP2D6 copy number variation (CNV) genotyping while also identifying allele-specific CYP2D6 CNV in heterozygous samples. Most routine assays do not identify the allele containing a CNV. A total of 237 clinical and Coriell DNA samples with different known CYP2D6 gene copy numbers were genotyped for CYP2D6 *2, *3, *4, *6, *10, *17, *41 polymorphisms and CNV determination. Results: The CYP2D6 gene allele quantification/identification were determined simultaneously with CYP2D6*2, *3, *4, *6, *10, *17, *41 genotyping. We determined the exact CYP2D6 gene copy number, identified which allele had the duplication or multiplication, and assigned the correct phenotype and activity score for all samples. Conclusions: Our method can efficiently identify the duplicated CYP2D6 allele in heterozygous samples, determine its copy number in a fraction of time compared to conventional methods and prevent incorrect ultrarapid phenotype calls. It also greatly reduces the cost, effort and time associated with CYP2D6 CNV genotyping.
PLoS One. 2015 Jan 27;10(1):e0113808.
Authors: Cavallari LH, Duarte JD
Genotypes for cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) contribute significantly to the inter-patient variability in warfarin dose requirements. These genotypes in addition to clinical factors explain approximately 50% of the dose variability in Europeans, but less in other populations. Thus, a large portion of the variability remains unexplained and has been the focus of on-going research. Trials evaluating the clinical utility of genotype-guided warfarin dosing have shown a benefit in Europeans, but not in an ethnically diverse cohort. Identifying and accounting for variants important in non-European populations will likely be necessary before a benefit with genotype-guided dosing will be realized in these populations.
J Clin Pharmacol. 2015 Mar;55(3):258-60. doi: 10.1002/jcph.425. Epub 2014 Dec 30.
Authors: Pratt VM, Beyer BN, Koller DL, Skaar TC, Flockhart DA, Levy KD, Vance GH
The ATP-binding cassette, subfamily C [CFTR/MRP], member 2 (ABCC2) gene is a member of the ATP-binding cassette transporters and is involved in the transport of molecules across cellular membranes. Substrates transported by ABCC2 include antiepileptics, statins, tenofovir, cisplatin, irinotecan, and carbamazepine. Because of the pharmacogenomics implications, we developed a clinical laboratory-developed assay to test for seven variants in the ABCC2 gene: c.3563T>A (p.V1188E, rs17222723), c.1249G>A (p.V417I, rs2273697), c.3972C>T (p.I1324I, rs3740066), c.2302C>T (p.R768W, rs56199535), c.2366C>T (p.S789F, rs56220353), c.-24C>T (5’UTR, rs717620), and c.4544G>A (p.C1515Y, rs8187710). During the validation process, we noted several DNA samples, obtained from the Coriell Cell Repository, that contained both c.3563T>A, c.4544G>A, and a third variant, suggesting that c.3563T>A and c.4544G>A are in cis on the chromosome in some individuals. We obtained DNA samples from a trio (father, mother, and child), tested their ABCC2 variants, and confirmed that c.3563T>A and c.4544G>A were in cis on the same chromosome. Here, we report a new haplotype in ABCC2.
J Mol Diagn. 2015 Mar;17(2):201-5.
Incorporating temporal EHR data in predictive models for risk stratification of renal function deterioration
Authors: Singh A, Nadkarni G, Gottesman O, Ellis SB, Bottinger EP, Guttag JV
Predictive models built using temporal data in electronic health records (EHRs) can potentially play a major role in improving management of chronic diseases. However, these data present a multitude of technical challenges, including irregular sampling of data and varying length of available patient history. In this paper, we describe and evaluate three different approaches that use machine learning to build predictive models using temporal EHR data of a patient. The first approach is a commonly used non-temporal approach that aggregates values of the predictors in the patient’s medical history. The other two approaches exploit the temporal dynamics of the data. The two temporal approaches vary in how they model temporal information and handle missing data. Using data from the EHR of Mount Sinai Medical Center, we learned and evaluated the models in the context of predicting loss of estimated glomerular filtration rate (eGFR), the most common assessment of kidney function. Our results show that incorporating temporal information in patient’s medical history can lead to better prediction of loss of kidney function. They also demonstrate that exactly how this information is incorporated is important. In particular, our results demonstrate that the relative importance of different predictors varies over time, and that using multi-task learning to account for this is an appropriate way to robustly capture the temporal dynamics in EHR data. Using a case study, we also demonstrate how the multi-task learning based model can yield predictive models with better performance for identifying patients at high risk of short-term loss of kidney function.
J Biomed Inform. 2015 Feb;53:220-8.
Authors: Udler MS, Nadkarni GN, Belbin G, Lotay V, Wyatt C, Gottesman O, Bottinger EP, Kenny EE, Peter I
Self-reported ancestry, genetically determined ancestry, and APOL1 polymorphisms are associated with variation in kidney function and related disease risk, but the relative importance of these factors remains unclear. We estimated the global proportion of African ancestry for 9048 individuals at Mount Sinai Medical Center in Manhattan (3189 African Americans, 1721 European Americans, and 4138 Hispanic/Latino Americans by self-report) using genome-wide genotype data. CKD-EPI eGFR and genotypes of three APOL1 coding variants were available. In admixed African Americans and Hispanic/Latino Americans, serum creatinine values increased as African ancestry increased (per 10% increase in African ancestry, creatinine values increased 1% in African Americans and 0.9% in Hispanic/Latino Americans; P≤1×10(-7)). eGFR was likewise significantly associated with African genetic ancestry in both populations. In contrast, APOL1 risk haplotypes were significantly associated with CKD, eGFR<45 ml/min per 1.73 m(2), and ESRD, with effects increasing with worsening disease states and the contribution of genetic African ancestry decreasing in parallel. Using genetic ancestry in the eGFR equation to reclassify patients as black on the basis of ≥50% African ancestry resulted in higher eGFR for 14.7% of Hispanic/Latino Americans and lower eGFR for 4.1% of African Americans, affecting CKD staging in 4.3% and 1% of participants, respectively. Reclassified individuals had electrolyte values consistent with their newly assigned CKD stage. In summary, proportion of African ancestry was significantly associated with normal-range creatinine and eGFR, whereas APOL1 risk haplotypes drove the associations with CKD. Recalculation of eGFR on the basis of genetic ancestry affected CKD staging and warrants additional investigation.
J Am Soc Nephrol. 2015 Jul;26(7):1682-92.
Authors: Owusu-Obeng A, Weitzel KW, Hatton RC, Staley BJ, Ashton J, Cooper-Dehoff RM, Johnson JA
Pharmacists are uniquely qualified to play essential roles in the clinical implementation of pharmacogenomics. However, specific responsibilities and resources needed for these roles have not been defined. We describe roles for pharmacists that emerged in the clinical implementation of genotype-guided clopidogrel therapy in the University of Florida Health Personalized Medicine Program, summarize preliminary program results, and discuss education, training, and resources needed to support such programs. Planning for University of Florida Health Personalized Medicine Program began in summer 2011 under leadership of a pharmacist, with clinical launch in June 2012 of a clopidogrel-CYP2C19 pilot project aimed at tailoring antiplatelet therapies for patients undergoing percutaneous coronary intervention and stent placement. More than 1000 patients were genotyped in the pilot project in year 1. Essential pharmacist roles and responsibilities that developed and/or emerged required expertise in pharmacy informatics (development of clinical decision support in the electronic medical record), medication safety, medication-use policies and processes, development of group and individual educational strategies, literature analysis, drug information, database management, patient care in targeted areas, logistical issues in genetic testing and follow-up, research and ethical issues, and clinical precepting. In the first 2 years of the program (1 year planning and 1 year postimplementation), a total of 14 different pharmacists were directly and indirectly involved, with effort levels ranging from a few hours per month, to 25-30% effort for the director and associate director, to nearly full-time for residents. Clinical pharmacists are well positioned to implement clinical pharmacogenomics programs, with expertise in pharmacokinetics, pharmacogenomics, informatics, and patient care. Education, training, and practice-based resources are needed to support these roles and to facilitate the development of financially sustainable pharmacist-led clinical pharmacogenomics practice models.
Pharmacotherapy. 2014 Oct;34(10):1102-12.
Authors: Johnson JA, Cavallari LH
The cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly and consistently associated with warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be predictive of stable warfarin dose. However, clinical trials evaluating genotype-guided warfarin dosing produced mixed results, calling into question the utility of this approach. Recent trials used surrogate markers as endpoints rather than clinical endpoints, further complicating translation of the data to clinical practice. The present data do not support genetic testing to guide warfarin dosing, but in the setting where genotype data are available, use of such data in those of European ancestry is reasonable. Outcomes data are expected from an on-going trial, observational studies continue, and more work is needed to define dosing algorithms that incorporate appropriate variants in minority populations; all these will further shape guidelines and recommendations on the clinical utility of genotype-guided warfarin dosing.
Trends Cardiovasc Med. 2015 Jan;25(1):33-41.
Use of a patient-centered family health history tool with decision support in primary care: impact of identification of increased risk patients on genetic counseling attendance
Authors: Buchanan A, Christianson CA, Himmel T, Powell KP, Agbaje A, Ginsburg GS, Henrich VC, Orlando LA
Several barriers inhibit collection and use of detailed family health history (FHH) in primary care. MeTree, a computer-based FHH intake and risk assessment tool with clinical decision support, was developed to overcome these barriers. Here, we describe the impact of MeTree on genetic counseling (GC) referrals and attendance. Non-adopted, English speaking adults scheduled for a well-visit in two community-based primary-care clinics were invited to participate in an Implementation-Effectiveness study of MeTree. Participants’ demographic characteristics and beliefs were assessed at baseline. Immediately after an appointment with a patient for whom GC was recommended, clinicians indicated whether they referred the patient and, if not, why. The study genetic counselor kept a database of patients with a GC recommendation and contacted those with a referral. Of 542 patients completing MeTree, 156 (29 %) received a GC recommendation. Of these, 46 % (n = 72) were referred and 21 % (n = 33) underwent counseling. Patient preferences, additional clinical information unavailable to MeTree, and an incomplete clinician evaluation of the FHH accounted for the 85 patients clinicians chose not to refer. Although MeTree identified a significant proportion of patients for whom GC was recommended, persistent barriers indicate the need for improved referral processes and patient and physician education about the benefits of GC.
J Genet Couns. 2015 Feb;24(1):179-88.
Authors: Ratain MJ, Johnson JA
There has been recent debate regarding the evidence required prior to routine implementation of pharmacogenetics. Although some might wish to see randomized clinical trials (RCTs) for every pharmacogenetic example, we argue that for many examples current evidence supports the implementation of preemptive genotyping to guide prescribing. We also argue that there is more evidence supporting genomic prescribing than many reimbursed services, including but not limited to repeated documentation of a family history, a meaningful-use criterion.
Clin Pharmacol Ther. 2014 Dec;96(6):650-2.
Authors: Abul-Husn NS, Owusu Obeng A, Sanderson SC, Gottesman O, Scott SA
Clinical genetic testing began over 30 years ago with the availability of mutation detection for sickle cell disease diagnosis. Since then, the field has dramatically transformed to include gene sequencing, high-throughput targeted genotyping, prenatal mutation detection, preimplantation genetic diagnosis, population-based carrier screening, and now genome-wide analyses using microarrays and next-generation sequencing. Despite these significant advances in molecular technologies and testing capabilities, clinical genetics laboratories historically have been centered on mutation detection for Mendelian disorders. However, the ongoing identification of deoxyribonucleic acid (DNA) sequence variants associated with common diseases prompted the availability of testing for personal disease risk estimation, and created commercial opportunities for direct-to-consumer genetic testing companies that assay these variants. This germline genetic risk, in conjunction with other clinical, family, and demographic variables, are the key components of the personalized medicine paradigm, which aims to apply personal genomic and other relevant data into a patient’s clinical assessment to more precisely guide medical management. However, genetic testing for disease risk estimation is an ongoing topic of debate, largely due to inconsistencies in the results, concerns over clinical validity and utility, and the variable mode of delivery when returning genetic results to patients in the absence of traditional counseling. A related class of genetic testing with analogous issues of clinical utility and acceptance is pharmacogenetic testing, which interrogates sequence variants implicated in interindividual drug response variability. Although clinical pharmacogenetic testing has not previously been widely adopted, advances in rapid turnaround time genetic testing technology and the recent implementation of preemptive genotyping programs at selected medical centers suggest that personalized medicine through pharmacogenetics is now a reality. This review aims to summarize the current state of implementing genetic testing for personalized medicine, with an emphasis on clinical pharmacogenetic testing.
Pharmgenomics Pers Med. 2014 Aug 13;7:227-40.
Authors: Langaee TY, Zhu HJ, Wang X, El Rouby N, Markowitz JS, Goldstein JA, Johnson JA
Background/Objectives: The polymorphic hepatic enzyme CYP2C19 catalyzes the metabolism of clinically important drugs such as clopidogrel, proton-pump inhibitors, and others and clinical pharmacogenetic testing for clopidogrel is increasingly common. The CYP2C19*10 single-nucleotide polymorphism (SNP) is located 1 bp upstream the CYP2C19*2 SNP. Despite the low frequency of the CYP2C19*10 allele, its impact on metabolism of CYP2C19 substrates and CYP2C19*2 genotyping makes it an important SNP to consider for pharmacogenetic testing of CYP2C19. However, the effect of the CYP2C19*10 allele on clopidogrel metabolism has not been explored to date. Methods: We measured the enzymatic activity of the CYP2C19.10 protein against clopidogrel. DNA samples from two clinical studies were genotyped for CYP2C19*2 and *10 by pyrosequencing genotyping method. Results: The catalytic activity of CYP2C19.10 in the biotransformation of clopidogrel and 2-oxo-clopidogrel was significantly decreased relative to the wild-type CYP2C19.1B. We also reported that the CYP2C19*10 SNP interferes with the CYP2C19*2 TaqMan genotyping assay, resulting in miscalling of CYP2C19*10/*2 as CYP2C19*2/*2. Conclusions: Our data provide evidence that CYP2C19.10 variant partially metabolizes clopidogrel and 2-oxo-clopidogrel, and the presence of CYP2C19*10 allele affects the CY2C19*2 TaqMan genotyping assay and results in misclassification of CYP2C19*10/*2 as CYP2C19*2/*2.
Pharmacogenet Genomics. 2014 Aug;24(8):381-6.
The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update
Authors: Ramsey LB, Johnson SG, Caudle KE, Haidar CE, Voora D, Wilke RA, Maxwell WD, McLeod HL, Krauss RM, Roden DM, Feng Q, Cooper-DeHoff RM, Gong L, Klein TE, Wadelius M, Niemi M
Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single-nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy.
Clin Pharmacol Ther. 2014 Oct;96(4):423-8.
Identifying Patients at Increased Disease Risk: Comparing Clinical Judgment and Clinical Risk Assessment Tool
Authors: Abhi S, Wu RR, Beadles C, Himmel T, Buchanan AH, Powell KP, Hauser ER, Ginsburg GS, Orlando LA
Introduction: There are several barriers to the appropriate use of Family Health History (FHH) for risk management within primary care. Among these is a lack of physician confidence in their ability to identify high risk individuals and determine guideline concordant care. In this study, we compared Primary Care Providers’ (PCP) clinical assessment of appropriate risk-management for patients to guideline based recommendations generated by an IT platform, MeTree. In addition, we compared MeTree with clinical assessments of Genetic Counselors (GC).
J Family Med Community Health 1 (2): 1010.
Return of genomic results to research participants: the floor, the ceiling, and the choices in between
Authors: Jarvik GP, Amendola LM, Berg JS, Brothers K, Clayton EW, Chung W, Evans BJ, Evans JP, Fullerton SM, Gallego CJ, Garrison NA, Gray SW, Holm IA, Kullo IJ, Lehmann LS, McCarty C, Prows CA, Rehm HL, Sharp RR, Salama J, Sanderson S, Van Driest SL, Williams MS, Wolf SM, Wolf WA, eMERGE Act-ROR Committee and CERC Committee, CSER Act-ROR Working Group, Burke W
As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants’ health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles.
Am J Hum Genet. 2014 Jun 5;94(6):818-26.
Authors: Levy KD, Decker BS, Carpenter JS, Flockhart DA, Dexter PR, Desta Z, Skaar TC
Pharmacogenomics (PGx) technology is advancing rapidly; however, clinical adoption is lagging. The Indiana Institute of Personalized Medicine (IIPM) places a strong focus on translating PGx research into clinical practice. We describe what have been found to be the key requirements that must be delivered in order to ensure a successful and enduring PGx implementation within a large health-care system.
Clin Pharmacol Ther. 2014 Sep;96(3):307-9.
Authors: Weitzel KW, Elsey AR, Langaee TY, Burkley B, Nessl DR, Obeng AO, Staley BJ, Dong HJ, Allan RW, Liu JF, Cooper-Dehoff RM, Anderson RD, Conlon M, Clare-Salzler MJ, Nelson DR, Johnson JA
Current challenges exist to widespread clinical implementation of genomic medicine and pharmacogenetics. The University of Florida (UF) Health Personalized Medicine Program (PMP) is a pharmacist-led, multidisciplinary initiative created in 2011 within the UF Clinical Translational Science Institute. Initial efforts focused on pharmacogenetics, with long-term goals to include expansion to disease-risk prediction and disease stratification. Herein we describe the processes for development of the program, the challenges that were encountered and the clinical acceptance by clinicians of the genomic medicine implementation. The initial clinical implementation of the UF PMP began in June 2012 and targeted clopidogrel use and the CYP2C19 genotype in patients undergoing left heart catheterization and percutaneous-coronary intervention (PCI). After 1 year, 1,097 patients undergoing left heart catheterization were genotyped preemptively, and 291 of those underwent subsequent PCI. Genotype results were reported to the medical record for 100% of genotyped patients. Eighty patients who underwent PCI had an actionable genotype, with drug therapy changes implemented in 56 individuals. Average turnaround time from blood draw to genotype result entry in the medical record was 3.5 business days. Seven different third party payors, including Medicare, reimbursed for the test during the first month of billing, with an 85% reimbursement rate for outpatient claims that were submitted in the first month. These data highlight multiple levels of success in clinical implementation of genomic medicine.
Am J Med Genet C Semin Med Genet. 2014 Mar;166C(1):56-67.
Implementing family health history risk stratification in primary care: impact of guideline criteria on populations and resource demand
Authors: Orlando LA, Wu RR, Beadles C, Himmel T, Buchanan AH, Powell KP, Hauser ER, Henrich VC, Ginsburg GS
The Genomic Medicine Model aims to facilitate patient engagement, patient/provider education of genomics/personalized medicine, and uptake of risk-stratified evidence-based prevention guidelines using MeTree, a patient-facing family health history (FHH) collection and clinical decision support (CDS) program. Here we report the number of increased risk (above population-level risk) patients identified for breast/ovarian cancer, colon cancer, hereditary syndrome risk, and thrombosis; the prevalence of FHH elements triggering increased-risk status; and the resources needed to manage their risk.
Am J Med Genet C Semin Med Genet. 2014 Mar;166C(1):24-33.
Authors: Overby CL, Erwin AL, Abul-Husn NS, Ellis SB, Scott SA, Obeng AO, Kannry JL, Hripcsak G, Bottinger EP, Gottesman O
This study assessed physician attitudes toward adopting genome-guided prescribing through clinical decision support (CDS), prior to enlisting in the Clinical Implementation of Personalized Medicine through Electronic Health Records and Genomics pilot pharmacogenomics project (CLIPMERGE PGx). We developed a survey instrument that includes the Evidence Based Practice Attitude Scale, adapted to measure attitudes toward adopting genome-informed interventions (EBPAS-GII). The survey also includes items to measure physicians’ characteristics (awareness, experience, and perceived usefulness), attitudes about personal genome testing (PGT) services, and comfort using technology. We surveyed 101 General Internal Medicine physicians from the Icahn School of Medicine at Mount Sinai (ISMMS). The majority were residency program trainees (~88%). Prior to enlisting into CLIPMERGE PGx, most physicians were aware of and had used decision support aids. Few physicians, however, were aware of and had used genome-guided prescribing. The majority of physicians viewed decision support aids and genotype data as being useful for making prescribing decisions. Most physicians had not heard of, but were willing to use, PGT services and felt comfortable interpreting PGT results. Most physicians were comfortable with technology. Physicians who perceived genotype data to be useful in making prescribing decisions, had more positive attitudes toward adopting genome-guided prescribing through CDS. Our findings suggest that internal medicine physicians have a deficit in their familiarity and comfort interpreting and using genomic information. This has reinforced the importance of gathering feedback and guidance from our enrolled physicians when designing genome-guided CDS and the importance of prioritizing genomic medicine education at our institutions.
J Pers Med. 2014 Feb 27;4(1):35-49.
Authors: Wu RR, Himmel T, Buchanan A, Powell KP, Hauser E, Ginsburg GS, Henrich VC, Orlando LA
Studies have shown that the quality of family health history (FHH) collection in primary care is inadequate to assess disease risk. To use FHH for risk assessment, collected data must have adequate detail. To address this issue, we developed a patient facing FHH assessment tool, MeTree. In this paper we report the content and quality of the FHH collected using MeTree.
BMC Fam Pract 2014 Feb 13;15:31.
Authors: Beadles C, Wu RR, Himmel T, Buchanan A, Powell KP, Hauser E, Henrich VC, Ginsburg GS, Orlando LA
Family health history (FHH) is an underutilized tool in primary care to identify and risk-stratify individuals with increased cancer risk.
Fam Cancer. 2014 Jun;13(2):325-32.
CYP2C19 polymorphisms and therapeutic drug monitoring of voriconazole: are we ready for clinical implementation of pharmacogenomics?
Authors: Owusu Obeng A, Egelund EF, Alsultan A, Peloquin CA, Johnson JA
Since its approval by the U.S. Food and Drug Administration in 2002, voriconazole has become a key component in the successful treatment of many invasive fungal infections including the most common, aspergillosis and candidiasis. Despite voriconazole’s widespread use, optimizing its treatment in an individual can be challenging due to significant interpatient variability in plasma concentrations of the drug. Variability is due to nonlinear pharmacokinetics and the influence of patient characteristics such as age, sex, weight, liver disease, and genetic polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) encoding for the CYP2C19 enzyme, the primary enzyme responsible for metabolism of voriconazole. CYP2C19 polymorphisms account for the largest portion of variability in voriconazole exposure, posing significant difficulty to clinicians in targeting therapeutic concentrations. In this review, we discuss the role of CYP2C19 polymorphisms and their influence on voriconazole’s pharmacokinetics, adverse effects, and clinical efficacy. Given the association between CYP2C19 genotype and voriconazole concentrations, as well as the association between voriconazole concentrations and clinical outcomes, particularly efficacy, it seems reasonable to suggest a potential role for CYP2C19 genotype to guide initial voriconazole dose selection followed by therapeutic drug monitoring to increase the probability of achieving efficacy while avoiding toxicity.
Pharmacotherapy. 2014 Jul;34(7):703-18.
Authors: Perera MA, Cavallari LH, Johnson JA
Translation of pharmacogenetics to clinical practice is increasingly common. However, most data arise in people of European ancestry, so clinical translation in non-Europeans can be challenging. Depending on the population being assessed, a polymorphism’s effect can differ in magniture or be absent. Studies in minorities are therefore essential as they present opportunities for discovery that would be missed through European-only studies, and they ensure that all populations benefit from clinical pharmacogenetics.
Clin Pharmacol Ther. 2014 Mar;95(3):242-4.
Patient and primary care provider experience using a family health history collection, risk stratification, and clinical decision support tool: a type 2 hybrid controlled implementation-effectiveness tria
Authors: Wu Rebekah, Orlando LA, Himmel T, Buchanan A, Powell K, Hauser E, Agbaje A, Henrich VC, and Ginsburg GS
Family health history (FHH) is the single strongest predictor of disease risk and yet is significantly underutilized in primary care. We developed a patient facing FHH collection tool, MeTree, that uses risk stratification to generate clinical decision support for breast cancer, colorectal cancer, ovarian cancer, hereditary cancer syndromes, and thrombosis. Here we present data on the experience of patients and providers after integration of MeTree into 2 primary care practices.
BMC Fam Pract. 2013 Aug 6;14:111.
Willingness to participate in genomics research and desire for personal results among underrepresented minority patients: a structured interview study
Authors: Sanderson SC, Diefenbach MA, Zinberg R, Horowitz CR, Richardson LD
Patients from traditionally underrepresented communities need to be involved in discussions around genomics research including attitudes towards participation and receiving personal results. Structured interviews, including open-ended and closed-ended questions, were conducted with 205 patients in an inner-city hospital outpatient clinic: 48 % of participants self-identified as Black or African American, 29 % Hispanic, 10 % White; 49 % had an annual household income of <$20,000. When the potential for personal results to be returned was not mentioned, 82 % of participants were willing to participate in genomics research. Reasons for willingness fell into four themes: altruism; benefit to family members; personal health benefit; personal curiosity and improving understanding. Reasons for being unwilling fell into five themes: negative perception of research; not personally relevant; negative feelings about procedures (e.g., blood draws); practical barriers; and fear of results. Participants were more likely to report that they would participate in genomics research if personal results were offered than if they were not offered (89 vs. 62 % respectively, p < 0.001). Participants were more interested in receiving personal genomic risk results for cancer, heart disease and type 2 diabetes than obesity (89, 89, 91, 80 % respectively, all p < 0.001). The only characteristic consistently associated with interest in receiving personal results was disease-specific worry. There was considerable willingness to participate in and desire for personal results from genomics research in this sample of predominantly low-income, Hispanic and African American patients. When returning results is not practical, or even when it is, alternatively or additionally providing generic information about genomics and health may also be a valuable commodity to underrepresented minority and other populations considering participating in genomics research.
J Community Genet. 2013 Oct; 4(4): 469–482.
Authors: Powell KP, Christianson CA, Hahn SE, Dave G, Evans L, Blanton SH, Hauser E, Agbaje A, Orlando LA, Ginsburg GS, Henrich VC
Family health history can predict a patient’s risk for common complex diseases. This project assessed the completeness of family health history data in medical charts and evaluated the utility of these data for performing risk assessments in primary care.
N C Med J. 2013 Jul-Aug;74(4):279-86.
Development and validation of a primary care-based family health history and decision support program (MeTree)
Authors: Orlando LA, Buchanan AH, Hahn SE, Christianson CA, Powell KP, Skinner CS, Chesnut B, Blach C, Due B, Ginsburg GS, Henrich VC
Family health history is a strong predictor of disease risk. To reduce the morbidity and mortality of many chronic diseases, risk-stratified evidence-based guidelines strongly encourage the collection and synthesis of family health history to guide selection of primary prevention strategies. However, the collection and synthesis of such information is not well integrated into clinical practice. To address barriers to collection and use of family health histories, the Genomedical Connection developed and validated MeTree, a Web-based, patient-facing family health history collection and clinical decision support tool. MeTree is designed for integration into primary care practices as part of the genomic medicine model for primary care.
N C Med J. 2013 Jul-Aug;74(4):287-96.
The Genomic Medicine Model: An Integrated Approach to Implementation of Family Health History in Primary Care
Authors: Orlando LA, Henrich VC, Hauser E, Wilson C, Ginsburg GS
As an essential tool for risk stratification, family health history (FHH) is a central component of personalized medicine; yet, despite its widespread acceptance among professional societies and its established place in the medical interview, its widespread adoption is hindered by three major barriers: quality of FHH collection, risk stratification capabilities and interpretation of risk stratification for clinical care. To overcome these barriers and bring FHH to the forefront of the personalized medicine effort, we developed the genomic medicine model (GMM) for primary care. The GMM, founded upon the principles of the Health Belief Model, Adult Learning Theory and the implementation sciences, shifts responsibility for FHH onto the patient, uses information technology (MeTree©) for risk stratification and interpretation, and provides education across multiple levels for each stakeholder, freeing up the clinical encounter for discussion around personalized preventive healthcare plans. The GMM has been implemented and optimized as part of an implementation-effectiveness hybrid pilot study for breast/ovarian cancer, colon cancer and thrombosis, and risk for hereditary cancer syndromes in two primary care clinics in NC, USA. This paper describes the conceptual development of the model and key findings relevant for broader uptake and sustainability in the primary care community.
Pers Med. 2013. 10(3):295-306.
The CLIPMERGE PGx Program: clinical implementation of personalized medicine through electronic health records and genomics-pharmacogenomics
Authors: Gottesman O, Scott SA, Ellis SB, Overby CL, Ludtke A, Hulot JS, Hall J, Chatani K, Myers K, Kannry JL, Bottinger EP
The exponential rise in genomics research over the past decade has yielded a growing number of sequence variants associated with medication response that may have clinical utility. Despite existing barriers, attention is turning to strategies that integrate these data into clinical care. The CLIPMERGE PGx Program is establishing a best-practices infrastructure for implementation of genome-informed prescribing using a biobank-derived clinical cohort, pre-emptive genetic testing, and real-time clinical decision support deployed through the electronic health record.
Clin Pharmacol Ther. 2013 Aug;94(2):214-7.
Genetic and lifestyle causal beliefs about obesity and associated diseases among ethnically diverse patients: a structured interview study
Authors: Sanderson SC, Diefenbach MA, Streicher SA, Jabs EW, Smirnoff M, Horowitz CR, Zinberg R, Clesca C, Richardson LD
New genetic associations with obesity are rapidly being discovered. People’s causal beliefs about obesity may influence their obesity-related behaviors. Little is known about genetic compared to lifestyle causal beliefs regarding obesity, and obesity-related diseases, among minority populations. This study examined genetic and lifestyle causal beliefs about obesity and 3 obesity-related diseases among a low-income, ethnically diverse patient sample.
Public Health Genomics. 2013;16(3):83-93.