Jason L. Vassy, MD, MPH, SM; Kurt D. Christensen, PhD, MPH; Erica F. Schonman, MPH; Carrie L. Blout, MS, CGC; Jill O. Robinson, MA; Joel B. Krier, MD; Pamela M. Diamond, PhD; Matthew Lebo, PhD; Kalotina Machini, PhD; Danielle R. Azzariti, MS, CGC; Dmitry Dukhovny, MD, MPH; David W. Bates, MD, MSc; Calum A. MacRae, MD, PhD; Michael F. Murray, MD; Heidi L. Rehm, PhD; Amy L. McGuire, JD, PhD; Robert C. Green, MD, MPH,; for the MedSeq Project (*)
Disclaimer: The contents do not necessarily represent the views of the U.S. Department of Veterans Affairs (VA), the U.S. government, Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health (NIH).
Acknowledgment: The authors thank 5AM Solutions (Rockville, Maryland) for their help in customizing the workflow of the My Family Health Portrait Web tool for this study. The authors thank the patient participants, physician participants, and genetics panelists of the MedSeq Project. Dr. Vassy affirms that he has listed everyone who contributed significantly to this work.
Financial Support: By grant U01-HG006500 from the National Human Genome Research Institute of the NIH. Dr. Vassy is an employee of the VA Boston Healthcare System and received support from NIH grant KL2-TR001100 and Career Development Award IK2-CX001262 from the VA Clinical Sciences Research and Development Service. Drs. Green and Rehm are also supported by NIH grants U19-HD077671, U01-HG008685, and U41-HG006834 and by funding from the Broad Institute of MIT and Harvard. Dr. Christensen is supported by NIH grant K01-HG009173. Dr. MacRae's work in this area is supported by NIH grant U01-HG007690 and by the Burroughs Wellcome Fund. This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and National Center for Advancing Translational Sciences, NIH grant UL1-TR001102) and financial contributions from Harvard University and its affiliated academic health care centers.
Disclosures: Ms. Blout reports grants from the NIH during the conduct of the study. Dr. Lebo reports grants from the National Human Genome Research Institute during the conduct of the study. Dr. Machini reports grants from the NIH during the conduct of the study. Ms. Azzariti reports grant support from the National Human Genome Research Institute of the NIH during the conduct of the study. Dr. Dukhovny reports consulting for Vermont Oxford Network, Gerson Lehrman Group, and ClearView Healthcare Partners and being faculty for Vermont Oxford Network outside the submitted work. Dr. Bates reports grants from EarlySense; personal fees from S.E.A. Medical Systems, EarlySense, QPID Health, Center for Digital Innovation (Negev), Enelgy, Valera Health, Intensix, and MDClone; and equity from S.E.A. Medical Systems, QPID Health, Enelgy, Valera Health, Intensix, and MDClone outside the submitted work. In addition, Dr. Bates has a patent for Medicalis with royalties paid to Brigham and Women's Hospital. Dr. Bates chaired the FDASIA workgroup, which has advised the U.S. Food and Drug Administration, the Federal Communications Commission, and the Office of the National Coordinator on the regulation of health care information technology including mobile technology, and also served as a member of the Health Information Technology Policy Committee. Dr. MacRae reports grants from the NIH during the conduct of the study. In addition, Dr. MacRae has a patent for gene testing in cardiomyopathies with royalties paid to Partners HealthCare. Dr. Murray reports personal fees from InVitae and Merck and grants from Regeneron outside the submitted work. Dr. Rehm reports grants from the NIH during the conduct of the study, payment for advisory board services from Genome Medical outside the submitted work, and employment at Partners HealthCare Laboratory for Molecular Medicine and The Broad Institute of MIT and Harvard (fee-based services) outside the submitted work. Dr. McGuire reports grants from MedSeq during the conduct of the study. Dr. McGuire is a consultant for Human Longevity outside the submitted work. Dr. Green reports personal fees from Illumina, Invitae, Helix, GenePeeks, Veritas, and Ohana and is a cofounder with equity in Genome Medical. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-0188.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol, statistical code, and data set: Available from Dr. Vassy (e-mail, email@example.com).
Requests for Single Reprints: Jason L. Vassy, MD, MPH, SM, VA Boston Healthcare System, 150 South Huntington Avenue, 152-G, Boston, MA 02115; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Vassy: 150 South Huntington Avenue, 152-G, Boston, MA 02130.
Drs. Christensen, Krier, and Green; Ms. Schonman; and Ms. Blout: 41 Avenue Louis Pasteur, Suite 301, Boston, MA 02115.
Ms. Robinson and Dr. McGuire: 1 Baylor Plaza, Suite 310D, Houston, TX 77030.
Dr. Diamond: 7000 Fannin, UCT Suite 2614, Houston, TX 77030.
Drs. Lebo, Machini, and Rehm and Ms. Azzariti: 65 Landsdowne Street, Suite 350, Cambridge, MA 02139.
Dr. Dukhovny: 707 SW Gaines Street, Mail Code-CDRC-P, Portland, OR 97239.
Dr. Bates: 1620 Tremont Street, 3rd Floor, BC3-2M, Boston, MA 02120.
Dr. MacRae: Building for Transformative Medicine, 7016F, 60 Fenwood Road, Boston, MA 02115.
Dr. Murray: 190 Welles Street, Suite 128, Forty Fort, PA 18704.
Author Contributions: Conception and design: J.L. Vassy, K.D. Christensen, E.F. Schonman, J.B. Krier, D.W. Bates, M.F. Murray, H.L. Rehm, A.L. McGuire, R.C. Green.
Analysis and interpretation of the data: J.L. Vassy, K.D. Christensen, E.F. Schonman, J.O. Robinson, J.B. Krier, P.M. Diamond, M. Lebo, K. Machini, D.R. Azzariti, D. Dukhovny, D.W. Bates, C.A. MacRae, M.F. Murray, H.L. Rehm.
Drafting of the article: J.L. Vassy, K.D. Christensen, E.F. Schonman, J.O. Robinson, H.L. Rehm, R.C. Green.
Critical revision of the article for important intellectual content: J.L. Vassy, K.D. Christensen, E.F. Schonman, C.L. Blout, J.O. Robinson, J.B. Krier, K. Machini, D. Dukhovny, D.W. Bates, C.A. MacRae, M.F. Murray, H.L. Rehm, A.L. McGuire, R.C. Green.
Final approval of the article: J.L. Vassy, K.D. Christensen, E.F. Schonman, C.L. Blout, J.O. Robinson, J.B. Krier, P.M. Diamond, M. Lebo, K. Machini, D.R. Azzariti, D. Dukhovny, D.W. Bates, C.A. MacRae, M.F. Murray, H.L. Rehm, A.L. McGuire, R.C. Green.
Provision of study materials or patients: J.L. Vassy, C.L. Blout, C.A. MacRae, M.F. Murray.
Statistical expertise: J.L. Vassy, K.D. Christensen, P.M. Diamond.
Obtaining of funding: M.F. Murray, H.L. Rehm, A.L. McGuire, R.C. Green.
Administrative, technical, or logistic support: J.L. Vassy, E.F. Schonman, C.L. Blout, J.O. Robinson, J.B. Krier, D.R. Azzariti, H.L. Rehm.
Collection and assembly of data: J.L. Vassy, K.D. Christensen, E.F. Schonman, C.L. Blout, J.O. Robinson, J.B. Krier, M. Lebo, D.R. Azzariti, C.A. MacRae, M.F. Murray, H.L. Rehm, A.L. McGuire.
Whole-genome sequencing (WGS) in asymptomatic adults might prevent disease but increase health care use without clinical value.
To describe the effect on clinical care and outcomes of adding WGS to standardized family history assessment in primary care.
Pilot randomized trial. (ClinicalTrials.gov: NCT01736566)
Academic primary care practices.
9 primary care physicians (PCPs) and 100 generally healthy patients recruited at ages 40 to 65 years.
Patients were randomly assigned to receive a family history report alone (FH group) or in combination with an interpreted WGS report (FH + WGS group), which included monogenic disease risk (MDR) results (associated with Mendelian disorders), carrier variants, pharmacogenomic associations, and polygenic risk estimates for cardiometabolic traits. Each patient met with his or her PCP to discuss the report.
Clinical outcomes and health care use through 6 months were obtained from medical records and audio-recorded discussions between PCPs and patients. Patients' health behavior changes were surveyed 6 months after receiving results. A panel of clinician-geneticists rated the appropriateness of how PCPs managed MDR results.
Mean age was 55 years; 58% of patients were female. Eleven FH + WGS patients (22% [95% CI, 12% to 36%]) had new MDR results. Only 2 (4% [CI, 0.01% to 15%]) had evidence of the phenotypes predicted by an MDR result (fundus albipunctatus due to RDH5 and variegate porphyria due to PPOX). Primary care physicians recommended new clinical actions for 16% (CI, 8% to 30%) of FH patients and 34% (CI, 22% to 49%) of FH + WGS patients. Thirty percent (CI, 17% to 45%) and 41% (CI, 27% to 56%) of FH and FH + WGS patients, respectively, reported making a health behavior change after 6 months. Geneticists rated PCP management of 8 MDR results (73% [CI, 39% to 99%]) as appropriate and 2 results (18% [CI, 3% to 52%]) as inappropriate.
Limited sample size and ancestral and socioeconomic diversity.
Adding WGS to primary care reveals new molecular findings of uncertain clinical utility. Nongeneticist providers may be able to manage WGS results appropriately, but WGS may prompt additional clinical actions of unclear value.
National Institutes of Health.
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Vassy JL, Christensen KD, Schonman EF, Blout CL, Robinson JO, Krier JB, et al. The Impact of Whole-Genome Sequencing on the Primary Care and Outcomes of Healthy Adult Patients: A Pilot Randomized Trial. Ann Intern Med. 2017;167:159–169. doi: 10.7326/M17-0188
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Published: Ann Intern Med. 2017;167(3):159-169.
Published at www.annals.org on 27 June 2017
Cardiology, Gastroenterology/Hepatology, Healthcare Delivery and Policy, Liver Disease, Prevention/Screening.
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Print ISSN: 0003-4819 | Online ISSN: 1539-3704
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