Kurt D. Christensen, PhD; J. Scott Roberts, PhD; Peter J. Whitehouse, MD, PhD; Charmaine D.M. Royal, PhD; Thomas O. Obisesan, MD, MPH; L. Adrienne Cupples, PhD; Jacqueline A. Vernarelli, PhD; Deepak L. Bhatt, MD, MPH; Erin Linnenbringer, PhD; Melissa B. Butson, ScM, PhD; Grace-Ann Fasaye, ScM, CGC; Wendy R. Uhlmann, MS, MPH; Susan Hiraki, MS, MPH; Na Wang, MA; Robert Cook-Deegan, MD; Robert C. Green, MD, MPH, (*); for the REVEAL Study Group*
Grant Support: By grants HG002213, HG006500, HD077671, HG006993, AG013846, RR000533, RR010284, and TR001102 from the National Institutes of Health.
Disclosures: Dr. Christensen reports grants from the National Human Genome Research Institute during the conduct of the study. Dr. Bhatt reports grants from Amarin Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company, Roche, Pfizer, Forest Laboratories, and Ischemix; other from Flowco Solutions, PLx Pharma, Takeda Pharmaceuticals, Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, Clinical Cardiology, Department of Veterans Affairs, St. Jude Medical, Biotronik, and Cardax Pharmaceuticals; personal fees from Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, American College of Cardiology, Belvoir Publications, Slack Publications, WebMD, Elsevier, HMP Communications, Harvard Clinical Research Institute, and Journal of the American College of Cardiology; and nonfinancial support from American College of Cardiology, Society of Cardiovascular Patient Care, and American Heart Association outside the submitted work. Ms. Uhlmann reports grants from the National Institutes of Health during the conduct of the study and book royalties from Wiley-Blackwell outside the submitted work. Ms. Hiraki reports employment with GeneDx outside the submitted work. Dr. Green reports personal fees from Invitae and Illumina and research funding from Illumina outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/Conflict OfInterestForms.do?msNum=M15-0187.
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.
Reproducible Research Statement:Study protocol, statistical code, and data set: Available from Dr. Green (e-mail, email@example.com).
Requests for Single Reprints: Robert C. Green, MD, MPH, Brigham and Women's Hospital and Harvard Medical School, Partners Personalized Medicine, EC Alumnae Building, Suite 301, 41 Avenue Louis Pasteur, Boston, MA 02115; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Christensen and Green: Brigham and Women's Hospital, EC Alumnae Building, Suite 301, 41 Avenue Louis Pasteur, Boston, MA 02115.
Dr. Roberts: University of Michigan School of Public Health, 3854 SPH I, 1415 Washington Heights, Ann Arbor, MI 48109.
Drs. Whitehouse and Butson: Case Western Reserve University, University Foley Elderhealth Center, 12200 Fairhill Road, Cleveland, OH 44120.
Dr. Royal: Duke University, Office of Undergraduate Scholars and Fellows, Smith Warehouse, Room B209, 114 South Buchanan Street, Box 90756, Durham, NC 27701.
Dr. Obisesan: Howard University Hospital, 2041 Georgia Avenue NW, Towers Building 5000, Washington, DC 20060.
Dr. Cupples: Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA 02118.
Dr. Vernarelli: Fairfield University, 1073 North Benson Road, Fairfield, CT 06824.
Dr. Bhatt: Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
Dr. Linnenbringer: Washington University School of Medicine, Division of Public Health Sciences, Department of Surgery, 660 South Euclid Avenue, Campus Box 8100, St. Louis, MO 63110.
Ms. Fasaye: Walter Reed National Military Medical Center, 8901 Rockville Pike, Bethesda, MD 20889.
Ms. Uhlmann: University of Michigan Medical School, Department of Human Genetics, 300 North Ingalls Building, NI3 A03, SPC 5419, Ann Arbor, MI 48109.
Ms. Hiraki: GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877.
Ms. Wang: Boston University School of Public Health, 801 Massachusetts Avenue, CT340C, Boston, MA 02118.
Dr. Cook-Deegan: Sanford School of Public Policy, Duke Box 90239, Durham, NC 27708.
Author Contributions: Conception and design: K.D. Christensen, J.S. Roberts, P.J. Whitehouse, T.O. Obisesan, L.A. Cupples, D.L. Bhatt, M.B. Butson, W.R. Uhlmann, R. Cook-Deegan, R.C. Green.
Analysis and interpretation of the data: K.D. Christensen, P.J. Whitehouse, T.O. Obisesan, L.A. Cupples, J.A. Vernarelli, D.L. Bhatt, W.R. Uhlmann, N. Wang, R.C. Green.
Drafting of the article: K.D. Christensen, J.S. Roberts, T.O. Obisesan, L.A. Cupples, W.R. Uhlmann, R.C. Green.
Critical revision of the article for important intellectual content: K.D. Christensen, J.S. Roberts, T.O. Obisesan, L.A. Cupples, D.L. Bhatt, W.R. Uhlmann.
Final approval of the article: K.D. Christensen, J.S. Roberts, P.J. Whitehouse, C.D.M. Royal, T.O. Obisesan, L.A. Cupples, J.A. Vernarelli, D.L. Bhatt, E. Linnenbringer, M.B. Butson, G.A. Fasaye, W.R. Uhlmann, S. Hiraki, N. Wang, R. Cook-Deegan, R.C. Green.
Provision of study materials or patients: P.J. Whitehouse, C.D.M. Royal, T.O. Obisesan, G.A. Fasaye, R.C. Green.
Statistical expertise: K.D. Christensen, L.A. Cupples, N. Wang.
Obtaining of funding: J.S. Roberts, P.J. Whitehouse, C.D.M. Royal, R.C. Green.
Administrative, technical, or logistic support: K.D. Christensen, P.J. Whitehouse, T.O. Obisesan, E. Linnenbringer, M.B. Butson, G.A. Fasaye, S. Hiraki.
Collection and assembly of data: K.D. Christensen, J.S. Roberts, P.J. Whitehouse, C.D.M. Royal, T.O. Obisesan, E. Linnenbringer, M.B. Butson, G.A. Fasaye, W.R. Uhlmann, S. Hiraki, R.C. Green.
Christensen KD, Roberts JS, Whitehouse PJ, Royal CD, Obisesan TO, Cupples LA, et al. Disclosing Pleiotropic Effects During Genetic Risk Assessment for Alzheimer Disease: A Randomized Trial. Ann Intern Med. 2016;164:155-163. doi: 10.7326/M15-0187
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Published: Ann Intern Med. 2016;164(3):155-163.
Published at www.annals.org on 26 January 2016
Increasing use of genetic testing raises questions about disclosing secondary findings, including pleiotropic information.
To determine the safety and behavioral effect of disclosing modest associations between apolipoprotein E (APOE) genotype and coronary artery disease (CAD) risk during APOE-based genetic risk assessments for Alzheimer disease (AD).
Randomized, multicenter equivalence clinical trial. (ClinicalTrials.gov: NCT00462917)
4 teaching hospitals.
257 asymptomatic adults were enrolled, 69% of whom had 1 AD-affected first-degree relative.
Disclosure of genetic risk information about AD and CAD (AD+CAD) or AD only (AD-only).
Primary outcomes were Beck Anxiety Inventory (BAI) and Center for Epidemiologic Studies Depression Scale (CES-D) scores at 12 months. Secondary outcomes were all measures at 6 weeks and 6 months and test-related distress and health behavior changes at 12 months.
At 12 months, mean BAI scores were 3.5 in both the AD-only and AD+CAD groups (difference, 0.0 [95% CI, −1.0 to 1.0]), and mean CES-D scores were 6.4 and 7.1 in the AD-only and AD+CAD groups, respectively (difference, 0.7 [CI, −1.0 to 2.4]). Both confidence bounds fell within the equivalence margin of ±5 points. Among carriers of the APOE ε4 allele, distress was lower in the AD+CAD groups (difference, −4.8 [CI, −8.6 to −1.0]) (P = 0.031 for the interaction between group and APOE genotype). Participants in the AD+CAD groups also reported more health behavior changes, regardless of APOE genotype.
Outcomes were self-reported by volunteers without severe anxiety, severe depression, or cognitive problems. Analyses omitted 33 randomly assigned participants.
Disclosure of pleiotropic information did not increase anxiety or depression and may have decreased distress among persons at increased risk for 2 conditions. Providing risk modification information about CAD improved health behaviors. Findings highlight the potential benefits of disclosure of secondary genetic findings when options exist for decreasing risk.
National Human Genome Research Institute.
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