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Abstract

Massively parallel sequencing is emerging from research settings into clinical practice, helping the vision of precision medicine to become a reality. The most successful applications are using the tools of implementation science within the framework of the learning health-care system. This article examines the application of massively parallel sequencing to four clinical scenarios: pharmacogenomics, diagnostic testing, somatic testing for molecular tumor characterization, and population screening. For each application, it highlights an exemplar program to illustrate the enablers and challenges of implementation. International examples are also presented. These early lessons will allow other programs to account for these factors, helping to accelerate the implementation of precision medicine and health.

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2019-08-31
2024-03-28
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Literature Cited

  1. 1.
    AACR Proj. GENIE Consort 2017. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discov 7:818–31
    [Google Scholar]
  2. 2.
    Alver M, Palover M, Saar A, Läll K, Zekavat SM et al. 2019. Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia. Genet. Med. 21:1173–80
    [Google Scholar]
  3. 3.
    Atik T, Bademci G, Diaz-Horta O, Blanton SH, Tekin M 2015. Whole-exome sequencing and its impact in hereditary hearing loss. Genet. Res. 97:e4
    [Google Scholar]
  4. 4.
    Barwell JG, O'Sullivan RBG, Mansbridge LK, Lowry JM, Dorkins HR 2018. Challenges in implementing genomic medicine: the 100,000 Genomes Project. J. Transl. Genet. Genom. 2:13
    [Google Scholar]
  5. 5.
    Berg JS, Agrawal PB, Bailey DB Jr, Beggs AH, Brenner SE et al. 2017. Newborn sequencing in genomic medicine and public health. Pediatrics 139:e20162252
    [Google Scholar]
  6. 6.
    Blagec K, Koopmann R, Crommentuijn-van Rhenen M, Holsappel I, van der Wouden CH et al. 2018. Implementing pharmacogenomics decision support across seven European countries: the Ubiquitous Pharmacogenomics (U-PGx) project. J. Am. Med. Inform. Assoc. 25:893–98
    [Google Scholar]
  7. 7.
    Caraballo PJ, Hodge LS, Bielinski SJ, Stewart AK, Farrugia G et al. 2017. Multidisciplinary model to implement pharmacogenomics at the point of care. Genet. Med. 19:421–29
    [Google Scholar]
  8. 8.
    Carey DJ, Fetterolf SN, Davis FD, Faucett WA, Kirchner HL et al. 2016. The Geisinger MyCode community health initiative: an electronic health record-linked biobank for precision medicine research. Genet. Med. 18:906–13
    [Google Scholar]
  9. 9.
    Caudle KE, Dunnenberger HM, Freimuth RR, Peterson JF, Burlison JD et al. 2017. Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet. Med. 19:215–23
    [Google Scholar]
  10. 10.
    Cavallari LH, Lee CR, Beitelshees AL, Cooper-DeHoff RM, Duarte JD et al. 2018. Multisite investigation of outcomes with implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention. JACC Cardiovasc. Interv. 11:181–91
    [Google Scholar]
  11. 11.
    Cecchin E, Roncato R, Guchelaar HJ, Toffoli G (Ubiquitous Pharmacogenom. Consort.). 2017. Ubiquitous Pharmacogenomics (U-PGx): the time for implementation is now. An Horizon2020 program to drive pharmacogenomics into clinical practice. Curr. Pharm. Biotechnol. 18:204–9
    [Google Scholar]
  12. 12.
    Cent. Dis. Control Prev 2014. Tier 1 genomics applications and their importance to public health. Centers for Disease Control and Prevention Mar. 6. https://www.cdc.gov/genomics/implementation/toolkit/tier1.htm
    [Google Scholar]
  13. 13.
    Christensen CM, Grossman JH, Hwang J 2009. The Innovator's Prescription: A Disruptive Solution for Health Care New York: McGraw-Hill
  14. 14.
    Clin. Pharmacogenet. Implement. Consort. (CPIC) 2018. Guidelines. Clinical Pharmacogenetics Implementation Consortium Nov. 30. https://cpicpgx.org/guidelines
    [Google Scholar]
  15. 15.
    Collins FS, Varmus H. 2015. A new initiative on precision medicine. N. Engl. J. Med. 372:793–95
    [Google Scholar]
  16. 16.
    Dewey FE, Murray MF, Overton JD, Habegger L, Leader JB et al. 2016. Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. Science 354:aaf6814
    [Google Scholar]
  17. 17.
    Di Martino S, Rainone A, Troise A, De Paolo M, Pugliese S et al. 2015. Overview of FDA-approved anti cancer drugs used for targeted therapy. World Cancer Res. J. 2:e553
    [Google Scholar]
  18. 18.
    Dunnenberger HM, Crews KR, Hoffman JM, Caudle KE, Broeckel U et al. 2015. Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers. Annu. Rev. Pharmacol. Toxicol. 55:89–106
    [Google Scholar]
  19. 19.
    Empey PE, Stevenson JM, Tuteja S, Weitzel KW, Angiolillo DJ et al. 2018. Multisite investigation of strategies for the implementation of CYP2C19 genotype-guided antiplatelet therapy. Clin. Pharmacol. Ther. 104:664–74
    [Google Scholar]
  20. 20.
    Farnaes L, Hildreth A, Sweeney NM, Clark MM, Chowdhury S et al. 2018. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. NPJ Genom. Med. 3:10
    [Google Scholar]
  21. 21.
    Faucett WA, Davis FD. 2016. How Geisinger made the case for an institutional duty to return genomic results to biobank participants. Appl. Transl. Genom. 8:33–35
    [Google Scholar]
  22. 22.
    Fogarty Int. Cent 2018. Toolkit part 1: implementation science methodologies and frameworks. Fogarty International Center https://www.fic.nih.gov/About/center-global-health-studies/neuroscience-implementation-toolkit/Pages/methodologies-frameworks.aspx
    [Google Scholar]
  23. 23.
    Fogel BL, Satya-Murti S, Cohen BH 2016. Clinical exome sequencing in neurologic disease. Neurol. Clin. Pract 6:164–76 Erratum. 2016. Neurol.Clin.Pract. 6:368
    [Google Scholar]
  24. 24.
    Gahl WA, Boerkoel CF, Boehm M 2012. The NIH Undiagnosed Diseases Program: bonding scientists and clinicians. Dis. Model. Mech. 5:3–5
    [Google Scholar]
  25. 25.
    Gahl WA, Markello TC, Toro C, Fajardo KF, Sincan M et al. 2012. The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases. Genet. Med. 14:51–59
    [Google Scholar]
  26. 26.
    Geisinger 2018. MyCode® results reported. Geisinger Dec. 1. https://www.geisinger.org/MyCode-results
    [Google Scholar]
  27. 27.
    Genet. Test. Regist 2018. Search results for “Human genome[TESTTARGET] OR Whole exome[TESTTARGET]”. Genetic Testing Registry https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=Human+genome%5BTESTTARGET%5D+OR+Whole+exome%5BTESTTARGET%5D
    [Google Scholar]
  28. 28.
    Genom. Engl 2018. The 100,000 Genomes Project. Genomics England https://www.genomicsengland.co.uk/the-100000-genomes-project
    [Google Scholar]
  29. 29.
    Gordon AS, Fulton RS, Qin X, Mardis ER, Nickerson DA, Scherer S 2016. PGRNseq: a targeted capture sequencing panel for pharmacogenetic research and implementation. Pharmacogenet. Genom. 26:161–68
    [Google Scholar]
  30. 30.
    Gupta S, Chatterjee S, Mukherjee A, Mutsuddi M 2017. Whole exome sequencing: uncovering causal genetic variants for ocular diseases. Exp. Eye Res. 164:139–50
    [Google Scholar]
  31. 31.
    Haghighi A, Krier JB, Toth-Petroczy A, Cassa CA, Frank NY et al. 2018. An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery. NPJ Genom. Med. 3:21
    [Google Scholar]
  32. 32.
    Hamermesh RG, Giusti KE, Huckman RS, Kelley J 2017. Intermountain Healthcare: pursuing precision medicine Case 818-018, Harv. Bus. School Boston, MA:
  33. 33.
    Hamilton JG, Abdiwahab E, Edwards HM, Fang ML, Jdayani A, Breslau ES 2017. Primary care providers’ cancer genetic testing-related knowledge, attitudes, and communication behaviors: a systematic review and research agenda. J. Gen. Intern. Med. 32:315–24
    [Google Scholar]
  34. 34.
    Haslem DS, Chakravarty I, Fulde G, Gilbert H, Tudor BP et al. 2018. Precision oncology in advanced cancer patients improves overall survival with lower weekly healthcare costs. Oncotarget 9:12316–22
    [Google Scholar]
  35. 35.
    Haslem DS, Van Norman SB, Fulde G, Knighton AJ, Belnap T et al. 2017. A retrospective analysis of precision medicine outcomes in patients with advanced cancer reveals improved progression-free survival without increased health care costs. J. Oncol. Pract. 13:e108–19
    [Google Scholar]
  36. 36.
    Hill S. 2018. Introducing genomics into cancer care. Br. J. Surg. 105:e14–15
    [Google Scholar]
  37. 37.
    Inst. Med 2007. The Learning Healthcare System: Workshop Summary. Ed. LA Olsen, D Aisner, JM McGinnis Washington, DC: Natl. Acad. Press https://www.ncbi.nlm.nih.gov/books/NBK53494
  38. 38.
    Inst. Med 2015. Genomics-Enabled Learning Health Care Systems: Gathering and Using Genomic Information to Improve Patient Care and Research: Workshop Summary Washington, DC: Natl. Acad. Press
  39. 39.
    Inst. Med 2015. The Learning Health System Series: continuous improvement and innovation in health and health care Broch., Inst. Med Washington, DC: http://www.nationalacademies.org/hmd/∼/media/Files/Activity%20Files/Quality/VSRT/Core%20Documents/LearningHealthSystem.pdf
  40. 40.
    Katlic MR, Facktor MA, Berry SA, McKinley KE, Bothe A Jr, Steele GD Jr 2011. ProvenCare lung cancer: a multi-institutional improvement collaborative. CA Cancer J. Clin 61:382–96
    [Google Scholar]
  41. 41.
    Kohane IS. 2009. The twin questions of personalized medicine: Who are you and whom do you most resemble?. Genome Med 1:4
    [Google Scholar]
  42. 42.
    Leitsalu L, Haller T, Esko T, Tammesoo ML, Alavere H et al. 2015. Cohort profile: Estonian Biobank of the Estonian Genome Center, University of Tartu. Int. J. Epidemiol. 44:1137–47
    [Google Scholar]
  43. 43.
    Luzum JA, Pakyz RE, Elsey AR, Haidar CE, Peterson JF et al. 2017. The Pharmacogenomics Research Network Translational Pharmacogenetics Program: outcomes and metrics of pharmacogenetic implementations across diverse healthcare systems. Clin. Pharmacol. Ther. 102:502–10
    [Google Scholar]
  44. 44.
    Manickam K, Buchanan AH, Schwartz MLB, Hallquist MLG, Williams JL et al. 2018. Exome sequencing–based screening for BRCA1/2 expected pathogenic variants among adult biobank participants. JAMA Netw. Open 1:e182140
    [Google Scholar]
  45. 45.
    Metspalu A. 2004. The Estonian Genome Project. Drug Dev. Res. 62:97–101
    [Google Scholar]
  46. 46.
    Morash M, Mitchell H, Beltran H, Elemento O, Pathak J 2018. The role of next-generation sequencing in precision medicine: a review of outcomes in oncology. J. Pers. Med. 8:e30
    [Google Scholar]
  47. 47.
    Morris ZS, Wooding S, Grant J 2011. The answer is 17 years, what is the question: understanding time lags in translational research. J. R. Soc. Med. 104:510–20
    [Google Scholar]
  48. 48.
    Nadauld LD, Ford JM, Pritchard D, Brown T 2018. Strategies for clinical implementation: precision oncology at three distinct institutions. Health Aff 37:751–56
    [Google Scholar]
  49. 49.
    Nakagawa H, Fujita M. 2018. Whole genome sequencing analysis for cancer genomics and precision medicine. Cancer Sci 109:513–22
    [Google Scholar]
  50. 50.
    Natl. Cancer Inst 2017. Precision medicine in cancer treatment. National Cancer Institute Oct. 3. https://www.cancer.gov/about-cancer/treatment/types/precision-medicine
    [Google Scholar]
  51. 51.
    Natl. Hum. Genome Res. Inst 2014. CLINSEQ®: a large-scale medical sequencing clinical research pilot study. National Human Genome Research Institute June 13. https://www.genome.gov/20519355/clinseq-a-largescale-medical-sequencing-clinical-research-pilot-study
    [Google Scholar]
  52. 52.
    Natl. Hum. Genome Res. Inst 2016. Genomic medicine and health care. National Human Genome Research Institute July 21. https://www.genome.gov/27527652/genomic-medicine-and-health-care
    [Google Scholar]
  53. 53.
    NHS Engl 2014. Five Year Forward View Rep., NHS Engl Redditch, UK: https://www.england.nhs.uk/publication/nhs-five-year-forward-view
  54. 54.
    NHS Engl 2016. Improving outcomes through personalised medicine Rep., NHS Engl Redditch, UK: https://www.england.nhs.uk/wp-content/uploads/2016/09/improving-outcomes-personalised-medicine.pdf
  55. 55.
    Osheroff JA, Teich JM, Middleton B, Steen EB, Wright A, Detmer DE 2007. A roadmap for national action on clinical decision support. J. Am. Med. Inform. Assoc. 14:141–45
    [Google Scholar]
  56. 56.
    Pauker SG, Kassirer JP. 1987. Decision analysis. N. Engl. J. Med. 316:250–58
    [Google Scholar]
  57. 57.
    Richards S, Aziz N, Bale S, Bick D, Das S et al. 2015. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17:405–24
    [Google Scholar]
  58. 58.
    Schwarze K, Buchanan J, Taylor JC, Wordsworth S 2018. Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature. Genet. Med. 20:1122–30
    [Google Scholar]
  59. 59.
    Sholl L. 2017. Molecular diagnostics of lung cancer in the clinic. Transl. Lung Cancer Res. 6:560–69
    [Google Scholar]
  60. 60.
    Smith LD, Willig LK, Kingsmore SF 2015. Whole-exome sequencing and whole-genome sequencing in critically ill neonates suspected to have single-gene disorders. Cold Spring Harb. Perspect. Med. 6:a023168
    [Google Scholar]
  61. 61.
    Soden SE, Saunders CJ, Willig LK, Farrow EG, Smith LD et al. 2014. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci. Transl. Med. 6:265ra168
    [Google Scholar]
  62. 62.
    Splinter K, Adams DR, Bacino CA, Bellen HJ, Bernstein JA et al. 2018. Effect of genetic diagnosis on patients with previously undiagnosed disease. N. Engl. J. Med. 379:2131–39
    [Google Scholar]
  63. 63.
    Stark Z, Schofield D, Martyn M, Rynehart L, Shrestha R et al. 2019. Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness. Genet. Med 21:173–80 Erratum. 2019. Genet. Med 21:516
    [Google Scholar]
  64. 64.
    Steele GD, Feinberg DT. 2017. ProvenCare: How to Deliver Value-Based Healthcare the Geisinger Way New York: McGraw-Hill Educ.
  65. 65.
    Turnbull C, Scott RH, Thomas E, Jones L, Murugaesu N et al. 2018. The 100000 Genomes Project: bringing whole genome sequencing to the NHS. BMJ 361:k1687
    [Google Scholar]
  66. 66.
    UK Dep. Health 2017. Annual report of the Chief Medical Officer 2016: generation genome Rep., UK Dep. Health London: https://www.gov.uk/government/publications/chief-medical-officer-annual-report-2016-generation-genome
  67. 67.
    Wagner JK, Peltz-Rauchman C, Rahm AK, Johnson CC 2016. Precision engagement: the PMI's success will depend on more than genomes and big data. Genet. Med. 19:620–24
    [Google Scholar]
  68. 68.
    White House 2016. The Precision Medicine Initiative. The White House: President Barack Obama https://obamawhitehouse.archives.gov/precision-medicine
    [Google Scholar]
  69. 69.
    Williams JL, Chung WK, Fedotov A, Kiryluk K, Weng C et al. 2018. Harmonizing outcomes for genomic medicine: comparison of eMERGE outcomes to ClinGen outcome/intervention pairs. Healthcare 6:83
    [Google Scholar]
  70. 70.
    Williams MS, Buchanan AH, Davis FD, Faucett WA, Hallquist MLG et al. 2018. Patient-centered precision health in a learning health care system: Geisinger's genomic medicine experience. Health Aff 37:757–64
    [Google Scholar]
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