Mapping the Ethics of Translational Genomics: Situating Return of Results and Navigating the Research-Clinical Divide

See Wolf S. M. , “Managing Incidental Findings in Human Subjects Research: Analysis and Recommendations,” Journal of Law, Medicine & Ethics 36, no. 2 (2008): 219–248.

Green R. C. , “ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing,” Genetics in Medicine 15, no. 7 (2013): 565–574; American College of Medical Genetics and Genomics (ACMG), “Incidental Findings in Clinical Genomics: A Clarification,” Genetics in Medicine 15, no. 8 (2013): 664–666.

See, e.g., Burke W. , “Recommendations for Returning Genomic Incidental Findings? We Need to Talk!,” Genetics in Medicine 15, no. 11 (2013): 854–859; McGuire A. L. , “Ethics and Genomic Incidental Findings,” Science 340, no. 6136 (2013): 1047–1048; Wolf S. M. Annas G. J. Elias S. , “Patient Autonomy and Incidental Findings in Clinical Genomics,” Science 340, no. 6136 (2013): 1049–1050.

ACMG Board of Directors, “ACMG Policy Statement: Updated Recommendations Regarding Analysis and Reporting of Secondary Findings in Clinical Genome-Scale Sequencing,” Genetics in Medicine 17, no. 1 (2015): 68–69.

Presidential Commission for the Study of Bioethical Issues, Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts (Washington, D.C.: Presidential Commission for the Study of Bioethical Issues, 2013), available at <http://bioethics.gov/node/3169> (last visited August 21, 2015).

See Wolf S. M. , “Return of Individual Research Results and Incidental Findings: Facing the Challenges of Translational Science,” Annual Review of Genomics and Human Genetics 14 (2013): 557–577; Wolf S. M. , “The Role of Law in the Debate over Return of Research Results and Incidental Findings: The Challenge of Developing Law for Translational Science,” Minnesota Journal of Law, Science & Technology 13, no. 2 (2012): 435–448; Wolf S. M. , “Incidental Findings in Neuroscience Research: A Fundamental Challenge to the Structure of Bioethics and Health Law,” in Illes J. Sahakian B. J. , eds., The Oxford Handbook of Neuroethics (New York: Oxford University Press, 2011): At 623–634.

For the Common Rule, see Department of Health and Human Services (DHHS), “Protection of Human Subjects,” 45 C.F.R. Part 46, available at <http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html> (last visited August 21, 2015); DHHS, “Federal Policy for the Protection of Human Subjects (‘Common Rule’),” available at <http://www.hhs.gov/ohrp/humansubjects/commonrule/index.html> (last visited August 21, 2015).

See references cited in note 6, supra.

See, e.g., Wolf S. M. , “Managing Incidental Findings and Research Results in Genomic Research Involving Biobanks & Archived Datasets,” Genetics in Medicine 14, no. 4 (2012): 361–384; Fabsitz R. R. , “Ethical and Practical Guidelines for Reporting Genetic Research Results to Study Participants: Updated Guidelines from a National Heart, Lung and Blood Institute Working Group,” Circulation: Cardiovascular Genetics 3, no. 6 (2010): 574–580; Wolf (2008), supra note 1.

See, e.g., Bledsoe M. J. , “Return of Research Results from Genomic Biobanks: Cost Matters,” Genetics in Medicine 15, no. 2 (2013): 159–160; Clayton E. W. McGuire A. L. , “The Legal Risks of Returning Results of Genomic Research,” Genetics in Medicine 14, no. 4 (2012): 473–477.

Jarvik G. P. , “Return of Results to Research Participants: The Floor, the Ceiling, and the Choices In Between,” American Journal of Human Genetics 94, no. 6 (2014): 818–826.

Presidential Commission, supra note 5.

Hall A. , PHG Foundation, “Genomics and the Boundary Between Research and Clinical Care and Treatment,” April 2014, available at <http://www.phgfoundation.org/briefing_notes/303/> (last visited January 4, 2015).

For an influential argument that researchers bear obligations of ancillary care, see Richardson H. S. , Moral Entanglements: The Ancillary-Care Obligations of Medical Researchers (New York: Oxford University Press, 2013).

See, e.g., Angrist M. Jamal L. , “Living Laboratory: Whole-Genome Sequencing as a Learning Healthcare Enterprise,” Clinical Genetics 87, no. 4 (2015): 311–318; Berkman B. E. Hull S. Eckstein L. G. , “The Unintended Implications of Blurring the Line between Research and Clinical Care in a Genomic Age,” Personalized Medicine 11, no. 3 (2014): 1–18; Brody H. Miller F. G. , “The Research-Clinical Practice Distinction, Learning Health Systems, and Relationships,” Hastings Center Report 43, no. 5 (2013): 41–47, at 45 (discussing “reasons to hang onto the distinction, even in the face of examples like learning health systems that seem at first to challenge its utility”); Faden R. R. , “An Ethics Framework for a Learning Health Care System: A Departure from Traditional Research Ethics and Clinical Ethics,” Hastings Center Report 43, no. 1 (2013): S16–S27; Lyon G. J. Segal J. P. , “Practical, Ethical and Regulatory Considerations for the Evolving Medical and Research Genomics Landscape,” Applied & Translational Genomics 2, no. 1 (2013): 34–40; Phimister E. G. Feero W. G. Guttmacher A. E. , “Realizing Genomic Medicine,” New England Journal of Medicine 366, no. 8 (2012): 757–759, at 757 (“The potential consequences of blurring clinical and research infrastructures are considerable, and such a merger should not be undertaken without extensive public debate.”); Largent E. A. Joffe S. Miller F. G. , “Can Research and Care Be Ethically Integrated?” Hastings Center Report 41, no. 4 (2011): 37–46, at 38 (“Thirty years after Belmont, the sharp distinction between research and care is becoming increasingly blurred.”).

CSER: Clinical Sequencing Exploratory Research, available at <https://cser-consortium.org/> (last visited August 21, 2015); National Human Genome Research Institute (NHGRI), Clinical Sequencing Exploratory Research (CSER), available at <http://www.genome.gov/27546194> (last visited August 21, 2015).

eMERGE Network: Electronic Medical Records & Genomics, available at <http://emerge.mc.vanderbilt.edu/> (last visited August 21, 2015); NIH, Electronic Medical Records and Genomics (eMERGE) Network, available at <http://www.genome.gov/27540473> (last visited August 21, 2015).

Pharmacogenomics Research Network (PGRN), available at <http://pgrn.org/display/pgrnwebsite/PGRN+Home> (last visited August 21, 2015); NIH, National Institute of General Medical Sciences (NIGMS), NIH Pharmacogenomics Research Network, available at <http://www.nigms.nih.gov/Research/SpecificAreas/PGRN/Pages/default.aspx> (last visited August 21, 2015); NIH, National Heart, Lung and Blood Institute (NHLBI), PGRN: Pharmacogenomics Research Network, available at <http://www.nhlbi.nih.gov/research/resources/genetics-genomics/pgrn> (last visited August 21, 2015).

See Zerhouni E. A. , “Translational and Clinical Science: Time for a New Vision,” New England Journal of Medicine 353, no. 15 (2005): 1621–1623. See also Zerhouni E. A. , “Clinical Research at a Crossroads: The NIH Roadmap,” Journal of Investigative Medicine 54, no. 4 (2006): 171–173. For prior NIH history, see NIH, Intramural Research Program, Advancing Translational Science, available at <http://irp.nih.gov/nihclinical-center/advancing-translational-science> (last visited August 21, 2015).

See Woolf S. H. , “The Meaning of Translational Research and Why It Matters,” JAMA 299, no. 2 (2008): 211–213; NIH, National Center for Advancing Translational Sciences (NCATS), available at <http://www.ncats.nih.gov/> (last visited January 18, 2015); NIH, NCATS, Clinical and Translational Science Awards, available at <http://www.ncats.nih.gov/research/cts/ctsa/ctsa.html> (last visited August 21, 2015). See also Institute of Medicine A. I. Leshner , eds., The CTSA Program at NIH: Opportunities for Advancing Clinical and Translational Research (Washington, D.C.: National Academies Press, 2013), available at <http://www.iom.edu/Reports/2013/The-CTSA-Program-at-NIH-Opportunities-for-Advancing-Clinical-and-Translational-Research.aspx> (last visited August 21, 2015).

See, e.g., Clinical and Translational Science, available at <http://onlinelibrary.wiley.com/journal/10.1111/%28ISSN%291752–8062> (last visited August 21, 2015); Applied & Translational Genomics, available at <http://www.journals.elsevier.com/applied-and-translational-genomics/> (last visited August 21, 2015).

Woolf, supra note 20, at 211.

Green E. D. Guyer M. S. , “National Human Genome Research Institute: Charting a Course for Genomic Medicine from Base Pairs to Bedside,” Nature 470, no. 7333 (2011): 204–213, at 204.

Khoury M. J. , “The Continuum of Translational Research in Genomic Medicine: How Can We Accelerate the Appropriate Integration of Human Genome Discoveries into Health Care and Disease Prevention?” Genetics in Medicine 9, no. 10 (2007): 665–674, at 666.

Khoury M. J. , “Beyond Base Pairs to Bedside: A Population Perspective on How Genomics Can Improve Health,” American Journal of Public Health 102, no. 1 (2012): 34–37; Khoury M. J. , “Knowledge Integration at the Center of Genomic Medicine,” Genetics in Medicine 14, no. 7 (2012): 643–647.

On the multiple models proposed, see Trochim W. , “Evaluating Translational Research: A Process Marker Model,” Clinical and Translational Science 4, no. 3 (2011): 153–162.

See, e.g., Evans J. P. Khoury M. J. , “The Arrival of Genomic Medicine to the Clinic Is Only the Beginning of the Journey,” Genetics in Medicine 15, no. 4 (2013): 268–269; Manolio T. A. , “Implementing Genomic Medicine in the Clinic: The Future Is Here,” Genetics in Medicine 15, no. 4 (2013): 258–267.

See Goering S. Holland S. Edwards K. , “Making Good on the Promise of Genetics: Justice in Translational Science,” in Burke W. , eds., Achieving Justice in Genomic Translation: Rethinking the Pathway to Benefit (New York: Oxford University Press, 2011): At 3–21; Kelley M. “Values in Translation: How Asking the Right Questions Can Move Translational Science toward Greater Health Impact,” Clinical and Translational Science 5, no. 6 (2012): 445–451.

Goering , supra note 28, at 7.

Henderson G. E. , “The Challenge of Informed Consent and Return of Results in Translational Genomics: Empirical Analysis and Recommendations,” Journal of Law, Medicine & Ethics 42, no. 3 (2014): 344–355.

CSER: Clinical Sequencing Exploratory Research, supra note 16 (emphasis added).

National Human Genome Research Institute (NHGRI), Clinical Sequencing Exploratory Research (CSER), supra note 16 (emphasis added).

Maienschein J. , “The Ethos and Ethics of Translational Research,” AJOB 8, no. 3 (2008): 43–51, at 43.

Sofaer N. Eyal N. , “The Diverse Ethics of Translational Research,” AJOB 10, no. 8 (2010): 19–30, at 20. Kimmelman and London respond to the concerns over translational research by offering a model of the drug pipeline that envisions information about the safe and effective use of products as the main output, rather than the products themselves. Kimmelman J. London A. J. , “The Stucture of Clinical Translation: Efficiency, Information, and Ethics,” Hastings Center Report 45, no. 2 (2015): 27–39.

Kelley , supra note 28; Shapiro R. S. Layde P. M. , “Integrating Bioethics into Clinical and Translational Science Research: A Roadmap,” Clinical and Translational Science 1, no. 1 (2008): 67–70.

Burke W. , “Translational Genomics: Seeking a Shared Vision of Benefit,” AJOB 8, no. 3 (2008): 54–56.

Lin J. S. , “Evaluating Genomic Tests from Bench to Bedside: A Practical Framework,” BMC Medical Informatics and Decision Making 12, no. 1 (2012): 117–125.

Id., at 123.

Clyne M. , “Horizon Scanning for Translational Genomic Research Beyond Bench to Bedside,” Genetics in Medicine 16, no. 7 (2014): 535–538; Schully S. D. Khoury M. J. , “What Is Translational Genomics? An Expanded Research Agenda for Improving Individual and Population Health,” Applied & Translational Genomics 3, no. 4 (2014): 82–83; Puggal M. A. , “Translation of Genetics Research to Clinical Medicine: The National Heart, Lung and Blood Institute Perspective,” Circulation: Cardiovascular Genetics 6, no. 6 (2013): 634–639; Schully S. D. Benedicto C. B. Khoury M. J. , “How Can We Stimulate Translational Research in Cancer Genomics Beyond Bench to Bedside?” Genetics in Medicine 14, no. 1 (2012): 169–170; Schully S. D. , “Translational Research in Cancer Genetics: The Road Less Traveled,” Public Health Genomics 14, no. 1 (2011): 1–8.

Compare, e.g., Berg J. S. Khoury M. J. Evans J. P. , “Deploying Whole Genome Sequencing in Clinical Practice and Public Health: Meeting the Challenge One Bin at a Time,” Genetics in Medicine 13, no. 6 (2011): 499–504, at 500 (arguing for “[t]he imperative to ignore variants of unknown significance”); McGuire A. L. Lupski J. R. , “Personal Genome Research: What Should the Participant Be Told?” Trends in Genetics 26, no. 5 (2010): 199–201, at 200 (“At this early stage of WGS research there should not be a moral or legal obligation to return results of unproven significance.”); Richards C. S. , “ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations: Revision 2007,” Genetics in Medicine 10, no. 4 (2008): 294–300, at 296 (“Because this information may be used for medical decisions, such as surgery or pregnancy termination, the recommended conservative approach is to avoid speculation and simply classify the variant as one of unknown clinical significance, even if potentially more frustrating for the patient.”). See also Institute of Medicine Beachy S. H. , Assessing Genomic Sequencing Information for Health Care Decision Making: Workshop Summary (Washington, D.C.: National Academies Press, 2014), at 17, available at <http://www.iom.edu/reports/2014/assessing-genomic-sequencing-information-for-health-care-decision-making.aspx> (last visited August 21, 2015) (“The vast majority of genetic variants have no known clinical relevance. The challenge, Berg said, is therefore to parse through variants to determine which ones can be used to inform clinical decisions. This process requires setting a high bar for which variants from a genome-scale test to report; otherwise, reporting variants with unknown clinical validity…or unknown implications for the asymptomatic patient's health could potentially have negative impacts, such as patient concern…or unnecessary medical costs for testing….”). For the experience of an informed patient dealing with variants of unknown significance (VUSs), see Couzin-Frankel J. , “Unknown Significance,” Science 346, no. 6214 (2014): 1167–1170. For data on participants' interest in receiving VUSs, see, e.g., Facio F. M. , “Intentions To Receive Individual Results from Whole-Genome Sequencing Among Participants in the ClinSeq Study,” European Journal of Human Genetics 21, no. 3 (2013): 261–265.

See Goering Kelley , supra note 28.

See discussion in Wolf (2012), supra note 9, at 364.

Brothers K. B. , “Biobanking in Pediatrics: The Human Non-subjects Approach,” Personalized Medicine 8, no. 1 (2011): 79; Brothers K. B. Clayton E. W. , “‘Human Non-Subjects Research’: Privacy and Compliance,” AJOB 10, no. 9 (2010): 15–17.

U.S. Department of Health and Human Services (DHHS), “Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators,” Federal Register 76 (2011): 44,512–44,531, available at <http://www.gpo.gov/fdsys/pkg/FR-2011-07-26/html/2011–18792.htm> (last visited August 21, 2015). A 2014 statute called for taking the next step – issuance of a notice of proposed rule-making (NPRM) – by June 2015 and promulgation of the final rules by December 2016. See Newborn Screening Saves Lives Reauthorization Act of 2014, H. R. 1281, 113th Congress, Pub. L. 113–240, Section 12, available at <https://www.govtrack.us/congress/bills/113/hr1281> (last visited August 21, 2015). The NPRM was issued in September 2015. Department of Homeland Security et al., “Federal Policy for the Protection of Human Subjects,” Federal Register 80 (2015): 53,933–64,061, available at <https://www.federalregister.gov/articles/2015/09/08/2015–21756/federal-policy-for-the-protection-of-human-subjects> (last visited September 8, 2015). Note that the NIH Genomic Data Sharing Policy that applied beginning Jan. 25, 2015, states that “For studies proposing to use genomic data from cell lines or clinical specimens that were created or collected after the effective date of the Policy, NIH expects that informed consent for future research use and broad data sharing will have been obtained even if the cell lines or clinical specimens are deidentified.” National Institutes of Health Genomic Data Sharing Policy, August 27, 2014, at 5, available at <http://gds.nih.gov/PDF/NIH_GDS_Policy.pdf> (last visited March 30, 2015) (citation omitted).

Newborn Screening Saves Lives Reauthorization Act of 2014, supra note 44.

Hudson K. L. Collins F. S. , “Biospecimen Policy: Family Matters,” Nature 500, no. 7461 (2013): 141–142; National Institutes of Health (NIH), Advisory Committee to the Director, HeLa Genome Data Access Working Group, Background, last reviewed August 7, 2013, available at <http://acd.od.nih.gov/hlgda.htm> (last visited August 21, 2015).

See, e.g., Wolf (2012), supra note 9, at 377; National Cancer Institute (NCI), Office of Biorepositories and Biospecimen Research, NCI Best Practices for Biospecimen Resources (2011), available at <http://biospecimens.cancer.gov/bestpractices/2011-NCIBestPractices.pdf> (last visited January 9, 2015).

Trochim , supra note 26.

Khoury , “Beyond Base Pairs,” supra note 25; Trochim , supra note 26; Khoury , “The Continuum,” supra note 24.

See Goering Kelley , supra note 28.

On organizational ethics, see, e.g., Boyle P. J. , Organizational Ethics in Health Care: Principles, Cases, and Practical Solutions (San Francisco: John Wiley & Sons, 2001); literature cited and analyzed in Bishop L. J. Cherry M. N. Darragh M. , National Reference Center for Bioethics Literature, “Organizational Ethics and Health Care: Expanding Bioethics to the Institutional Arena,” Kennedy Institute of Ethics, Scope Note 36, available at <http://220.227.128.112/downloads/ProfessionalEthics/sn36.pdf> (last visited August 21, 2015).

Institute of Medicine, Committee on the Learning Health Care System in America, Smith M. , eds., Best Care at Lower Cost: The Path to Continuously Learning Health Care in America (Washington, D.C.: National Academies Press, 2012); Grossmann C. for the Institute of Medicine, Committee on the Learning Health Care Systems in America, Engineering a Learning Healthcare System: A Look at the Future, Workshop Summary (Washington, D.C.: National Academies Press, 2011); Institute of Medicine, IOM Roundtable on Evidence-Based Medicine, Olsen L. Aisner D. McGinnis J.M. , eds., The Learning Healthcare System: Workshop Summary (Washington, D.C.: National Academies Press, 2007).

Faden , supra note 15, at S22.

See Green , supra note 2 (advocating opportunistic screening in individual sequencing); Burke , supra note 3 (arguing that the evidence base for such screening is not yet in place).

See, e.g., Knoppers B. M. , “Whole-Genome Sequencing in Newborn Screening Programs,” Science Translational Medicine 6, no. 229 (2014): cm2–cm5, posted online at <http://stm.sciencemag.org/content/6/229/229cm2.full.pdf> (last visited August 21, 2015). For controversy over genomic sequencing in newborn screening, see also Goldenberg A. J. Sharp R. R. , “The Ethical Hazards and Programmatic Challenges of Genomic Newborn Screening,” JAMA 307, no. 5 (2012): 461–462; Tarini B. A. Goldenberg A. J. , “Ethical Issues with Newborn Screening in the Genomics Era,” Annual Review of Genomics and Human Genetics 13 (2012): 381–393; Clayton E. W. , “State Run Newborn Screening in the Genomic Era, or How To Avoid Drowning When Drinking from a Fire Hose,” Journal of Law, Medicine & Ethics 38, no. 3 (2010): 697–700.

Wilson J. M. G. Jungner Y. G. , Principles and Practice of Screening for Disease (Geneva: World Health Organization, 1968), available at <http://www.who.int/bulletin/volumes/86/4/07–050112bp.pdf> (last visited August 21, 2015).

Burke W. , “Extending the Reach of Public Health Genomics: What Should Be the Agenda for Public Health in an Era of Genome-Based and ‘Personalized’ Medicine?” Genetics in Medicine 12, no. 12 (2010): 785–791, at 789.

Goddard K. A. B. , “Description and Pilot Results from a Novel Method for Evaluation Return of Incidental Findings from Next-Generation Sequencing Technologies,” Genetics in Medicine 15, no. 9 (2013): 721–728; Howard H. C. , “The Ethical Introduction of Genome-Based Information and Technologies into Public Health,” Public Health Genomics 16, no. 3 (2013): 100–109; Khoury , “Beyond Base Pairs,” supra note 25; Berg , supra note 38; Burke (2010), supra note 54, at 789 (“Developments in public health genomics require that attention is focused on managing multiple ethical issues…. Where ethically informed practices do not already exist, they should be developed.”).

Khoury , “The Continuum,” supra note 24, at 671, quoting from Lipscomb J. Donaldson M. S. Hiatt R. A. , “Cancer Outcomes Research and the Arenas of Application,” Journal of the National Cancer Institute Monographs no. 33 (2004): 1–7.

On the ethical issues raised by outcomes assessment and comparative effectiveness research, see, e.g., Frank L. , “Conceptual and Practical Foundations of Patient Engagement in Research at the Patient-Centered Outcomes Research Institute,” Quality of Life Research 24, no. 5 (2015): 1033–1041; Gray E. A. Thorpe J. H. , “Comparative Effectiveness Research and Big Data: Balancing Potential with Legal and Ethical Considerations,” Journal of Comparative Effectiveness Research 4, no. 1 (2015): 61–74; Lantos J. D. Feudtner C. , “SUPPORT and the Ethics of Study Implementation: Lessons for Comparative Effectiveness Research from the Trial of Oxygen Therapy for Premature Babies,” Hastings Center Report 45, no. 1 (2015): 30–40; Frank L. Basch E. Selby J. , “The PCORI Perspective on Patient-Centered Outcomes Research,” JAMA 312, no. 15 (2014): 1513–1514; Lantos J. D. Spertus J. A. , “The Concept of Risk in Comparative-Effectiveness Research,” New England Journal of Medicine 371, no. 22 (2014): 2129–2130; Platt R. Kass N. E. McGraw D. , “Ethics, Regulation, and Comparative Effectiveness Research: Time for a Change,” JAMA 311, no. 15 (2014): 1497–1498; Kass N. Faden R. Tunis S. , “Addressing Low-Risk Comparative Effectiveness Research in Proposed Changes to US Federal Regulations Governing Research,” JAMA 307, no. 15 (2012): 1589–1590. See also Faden , supra note 15.

Faden , supra note 15, at S16.

See, e.g., IOM, Assessing Genomic Sequencing, supra note 37, at 25 (“more data need to be generated from different racial and ethnic groups”); Lynch J. , “Race and Genomics in the Veterans Health Administration,” American Journal of Public Health 104, supp. 4 (2014): S522–S524 (“There are multiple barriers to genomic medicine for minorities…. Most large scale genome wide association studies have been conducted on populations of European ancestry.”) (reference omitted); Kohane I. S. Hsing M. Kong S. W. , “Taxonomizing, Sizing, and Overcoming the Incidentalome,” Genetics in Medicine 14, no. 4 (2012): 399–404, at 401–403 (“Fundamentally, the utility of the clinical annotation of a genomic variant is only as useful as its applicability to a patient. That is, if a variant were found to track with a disease in a specified group of patients, that annotation may in fact serve well if one belongs to that specific group of patients but serve rather poorly if one does not.”). On a cautionary note, see Sankar P. “Genetic Research and Health Disparities,” JAMA 291, no. 24 (2004): 2985–2989, at 2985 (“overemphasis on genetics as a major explanatory factor in health disparities could lead researchers to miss factors that contribute to disparities more substantially”). On disparities in health care more broadly, see IOM, Smedley B. D. Stith A. Y. Nelson A. R. , eds., Committee on Understanding and Eliminating Racial and Ethnic Disparities in Health Care, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care (Washington, D.C.: National Academies Press, 2003), available at <iom.nationalacademies.org/Reports/2002/Unequal-Treatment-Confronting-Racial-and-Ethnic-Disparities-in-Health-Care.aspx> (last visited September 11, 2015).

Compare, e.g., Green , supra note 2 (urging opportunistic genomic screening) with the critique by Burke , supra note 3 (arguing that the evidence base is not in place to justify such screening).

See Hall , supra note 13.

See, e.g., IOM, Assessing Genomic Sequencing, supra note 38, at 26–27 (on unresolved challenges in establishing the reproducibility of genomic data, eliminating inaccurate published associations, and agreeing on standards to prove a genotype-phenotype association).

Khoury , “Beyond Base Pairs,” supra note 25.

See Goering Kelley , supra note 28.

Burke W. Evans B. J. Jarvik G. P. , “Return of Results: Ethical and Legal Distinctions between Research and Clinical Care,” American Journal of Medical Genetics Part C 166C (2014): 105–111. The Clinical Laboratory Improvement Amendments (CLIA) are explained at Centers for Medicare & Medicaid Services (CMS), Clinical Laboratory Improvement Amendments (CLIA), available at <http://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.html?redirect=/clia/> (last visited August 21, 2015). See also Centers for Disease Control and Prevention (CDC), “Clinical Laboratory Improvement Amendments (CLIA),” available at <http://wwwn.cdc.gov/clia/regulatory/default.aspx> (last visited August 21, 2015).

On research versus clinical standards for sequencing, see, e.g., Burke , supra note 68. FDA standards for sequencing are in transition. See, e.g., Lander E. S. , “Cutting the Gordian Helix – Regulating Genomic Testing in the Era of Precision Medicine,” New England Journal of Medicine 372, no. 13 (2015): 1185–1186; Food and Drug Administration (FDA), Optimizing FDA's Regulatory Oversight of Next Generation Sequencing Diagnostic Tests – Preliminary Discussion Paper (2015), available at <http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM427869.pdf> (last visited August 21, 2015). FDA announcement of a new approach to regulating laboratory-developed tests (LDTs), including in genomics, has met with considerable controversy. Compare, e.g., Sharfstein J. , “FDA Regulation of Laboratory-Developed Diagnostic Tests: Protect the Public, Advance the Science,” JAMA 313, no. 7 (2015): 667–668, with Evans J. P. Watson M. S. , “Genetic Testing and FDA Regulation: Overregulation Threatens the Emergence of Genomic Medicine,” JAMA 313, no. 7 (2015): 669–670.

Compare IOM, Assessing Genomic Sequencing, supra note 40, at 7 (“Exome sequencing can be used for either clinical or research purposes, though recently the boundaries between the two have been blurring. In Hegde's laboratory, exome data are divided according to why the sequencing is being done. For new disease presentations the diagnostic yield, or likelihood that the test will provide enough information to make an appropriate diagnosis, ranges roughly from 30 percent to 40 percent, depending on which laboratory is reporting and what kinds of cases are considered, Hegde said. When writing clinical reports, she said, it is critical to sorting the data into categories of what can be interpreted in the clinic and what is clinically actionable….”).

Author S. M. W. thanks Hank Greely for early conversation on this point.

See, e.g., Callahan D. Jennings B. , “Ethics and Public Health: Forging a Strong Relationship,” American Journal of Public Health 92, no. 2 (2002): 169–176; Kass N. E. , “An Ethics Framework for Public Health,” American Journal of Public Health 91, no. 11 (2001): 1776–1782.

See Trinidad S. B. , “Research Practice and Participant Preferences: The Growing Gulf,” Science 331, no. 6015 (2011): 287–288, at 288 (“We propose a shift from paternalistic protections to respectful engagement with individuals and groups whose conceptions of risk, benefit, and harm deserve consideration. Such an approach would treat participants as true stakeholders in research, who willingly take on risk because they see the potential benefits to society as outweighing potential harms.”); Kohane I. S. , “Reestablishing the Researcher-Patient Compact,” Science 316, no. 5826 (2007): 836–837, at 837 (arguing that it is “ethically superior” to treat “patients as partners in research rather than passive, disenfranchised purveyors of biomaterials and data”).

See Wolf (2012), supra note 9; Fabsitz , supra note 9.

Khoury , “Knowledge Integration,” supra note 25.

See references cited in note 6, supra.

Wolf S. M. , “Returning a Research Participant's Genomic Results to Relatives: Analysis and Recommendations,” Journal of Law, Medicine & Ethics 43, no. 3 (2015): 440–463.

See sources cited and discussed in id.