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October 02, 2018 Feature

What Will “All of Us” Mean for Each of Us?

BY ELLEN W. CLAYTON, MD, JD

Genetic Variation Is One of Many Factors Contributing to Health and Disease

The first human genome sequence was “completed” eighteen years ago to great fanfare,1 but even then, it was clear that that was the first step on a very long journey. Although thousands of “single gene disorders”—those in which variations in a single gene play a major role in causing disease—are known, most common diseases such as hypertension and diabetes are affected by variants in dozens to hundreds of different genes. In part because humans are a young species and in part due to the impact of history and selection, genetic variation is not distributed evenly around the world. Rather, the frequency of some variants differs depending on an individual’s ancestral origin.

To make matters even more complicated, almost all human traits are the product of complex interactions among our human genome, the microbiome (the genomes of the many organisms that live in and on us), the environment, intercurrent illnesses, and our personal behaviors. The impact of all of these elements changes over the life course, as suggested in the figure below. For example, different genes are expressed during childhood than after puberty or after menopause/andropause. Exposures may be more or less toxic depending on whether they occur to children, young adults, or the elderly. Lead is worse for fetuses and young children. Influenza is usually worse for the young and the very old.2

Understanding how all these factors interact to affect human health and disease requires the collection and analysis of enormous amounts of well-characterized data about individuals. The rapidly decreasing cost of DNA sequencing and data storage as well as new methods to analyze large amounts of data converge to make examination of these relationships possible, creating exciting new opportunities to continue our millennia-old quest to improve human health and well-being. The many collections of data that already exist, including in many countries around the world, 3 and the studies that have been conducted to date, while useful, have a number of limitations. They rarely contain complete information about people, typically collecting data about a limited number of variables.

Focusing on genomics specifically, one of the most important “lacunae” is the lack of diversity among the populations that have been studied. A recent report by Popejoy and Fullerton4 revealed that as of 2016, 81% of participants in genome-wide association studies were of European ancestry and 14% were of Asian ancestry, while less than 4% were of African, Hispanic, or Native ancestry. While this distribution is more equitable than existed previously, it is still the case that much less is known about how genetic variation contributes to the health of members of the latter groups.

Why Are We Doing the Precision Medicine Initiative?

The Precision Medicine Initiative5 was created by Congress as part of the 21st Century Cures Act6 late in the Obama administration. Many of the features of this project reflect a desire to fill earlier gaps in existing data. The organizers hope to recruit more than a million participants who will provide genomic, medical, behavioral, and exposure information over many years to provide the rich data required to understand these complex interactions. Traditional questionnaires and surveys will be supplemented by access to information in electronic medical records; individual devices to monitor behavior, activity, and exposure; and, of course, genomic information.

One of the major goals of this project is to recruit and retain underrepresented minorities. To this end, the project is undertaking an unprecedented array of engagement activities. The decision to rename this initiative “All of Us”7 reflects this commitment to including everyone in order to ensure that all stand to benefit from this bold project.

The Vision of Precision Medicine

Ideally, when the clinician applies her medical knowledge, she takes into account her personal knowledge of her patients and their circumstances. A major goal of research on precision medicine is to assist the clinician who cares for the whole patient by providing a more scientific understanding of how the patient and his characteristics and circumstances interact to cause health or disease.8 A common mantra for precision medicine is making the right diagnosis and delivering the right medicine or treatment at the right time. Precision medicine already can point to two areas of progress that rely on greater understanding of genomics. One is pharmacogenomics, in which genetic variants can help explain why some patients respond to particular medications, while others do not.9 The other, which overlaps with the first, is cancer diagnosis and treatment.11 Cancer is increasingly understood as a genetic disorder, characterized by acquired or somatic genetic changes and at times spurred by inherited or germ-line changes. Understanding which genes are involved in a particular patient’s cancer not only may lead to a more accurate diagnosis but, in some cases, may permit prediction of which drug may be effective as treatment. The pace of this research is extremely rapid, with new articles appearing in major medical journals almost weekly. The FDA approved sixteen genomically targeted drugs last year, many of which were directed to the treatment of cancer.12

Yet the promise of precision medicine is and likely will be beyond the reach of many for the foreseeable future. Even where biological pathways are understood and directed therapies have been developed, many barriers exist.13 Most clinicians are ill-prepared to use this knowledge. It has been known for decades that most physicians have inadequate knowledge of genetics,14 a situation that in some ways has gotten even worse given the dramatic advances in this area of science.15 There are not enough genetics-informed personnel available to meet patients’ needs.16 Clinical decision support is often lacking17 and, when available, is of uneven quality and beyond the regulatory reach of the FDA.18

Another major challenge is the lack of third-party coverage. Payers often refuse to reimburse for genetic tests, especially those that cover large parts of the genome, which often are performed for the evaluation of children with complex medical problems of uncertain etiology.19 Even more troubling are the high prices of some of the genotype-driven drugs, which can exceed $500,000 per year.20 Many patients face geographic barriers to access because efforts at implementation of precision medicine are typically limited to major medical centers, far away from many parts of the country. Telemedicine efforts, while promising, are in their early stages.21

At the same time, it is increasingly likely that genomic tests, if they are performed, will provide more results than are needed to answer the clinical or research question for many patients. There is growing pressure to move away from testing for single or a limited number of variants in so-called panels, and instead to use whole-genome technologies, including whole-genome sequencing, on the ground that this approach to obtaining the actual data may be less expensive. But while some propose that laboratories examine only the particular sequence data needed to answer the clinical or research question, it has become increasingly common, and some would say ethically permissible or required, to examine part or all of the rest of the genomic data to look for variation in other genes.22 These additional findings may be particularly challenging for clinicians to address given the lack of scientific evidence about the impact of many variants in individuals who do not have a pertinent family history or who are not currently symptomatic. Counseling and following up these participants will likely divert resources from other uses. What the impact of returning these so-called secondary findings will be on patients, families, clinicians, and health care systems is currently the subject of intense study in several NIH-funded studies.23

Another critical barrier to access is that the current knowledge base is incomplete. Not enough is known about how genomic variations and other factors interact to cause health and disease, particularly in underrepresented minorities and other groups who have not previously been included in this type of research. The All of Us project laudably is committed to inclusion to fill this crucial gap, but this goal will be difficult to achieve in light of a longstanding history of mistrust.24 In the meantime, people will vary in how many benefits they can receive from precision medicine.

The expectations for precision medicine are enormous. Our knowledge base, while rapidly growing, however, is incomplete, particularly in regard to some populations and disorders. Implementing what is known about precision medicine is complicated in our fragmented health care system, where personnel often are unprepared, coverage often is limited, and regulatory frameworks are not yet in place. Inevitably, some hopes and needs will not be met. As a result, legal issues will arise at various points in the process but will be challenging to address in this rapidly evolving, complex environment.

*This project was funded in part by grant number 1RM1 HG009034. u

Endnotes

1. Office of the Press Secretary The White House, Remarks Made by the President, Prime Minister Tony Blair of England (via satellite), Dr. Francis Collins, Director of the National Human Genome Research Institute, and Dr. Craig Venter, President and Chief Scientific Officer, Celera Genomics Corporation, on the Completion of the First Survey of the Entire Human Genome Project (2000), available at https://www.genome.gov/10001356/june-2000-white-house-event/; Int’l Human Genome Sequencing Consortium, Initial Sequencing and Analysis of the Human Henome, 409 Nature 860 (2001); J. Craig Venter et al., The Sequence of the Human Genome, 291 Science 1304 (2001).

2. The Spanish flu was a notable exception, in that it affected young adults as well. Jeffery K. Taubenberger & David M. Morens, 1918 Influenza: The Mother of All Pandemics, 12 Emerging Infectious Diseases 15 (2006).

3. A number of other countries have established population-based biobanks for genomics research, including Iceland in 1996, deCODE Genetics (2018), https://www.decode.com/; Estonia in 2004, Estonian Genome Center, Inst. of Genomics, Univ. of Tartu (2018), https://www.geenivaramu.ee/en; and the United Kingdom in 2006, Biobank UK (2018), http://www.ukbiobank.ac.uk. Other large databases exist as well.

4. A. B. Popejoy & S. M. Fullerton, Genomics Is Failing on Diversity, 538 Nature 161 (2016).

5. NIH Precision Med. Initiative (PMI) Working Grp. Report to the Advisory Committee to the Director, The Precision Medicine Initiative Cohort—Building a Research Foundation for 21st Century Medicine (2015), available at http://acd.od.nih.gov/reports/DRAFT-PMI-WG-Report-9-11-2015-508.pdf.

6. 21st Century Cures Act, Pub. L. No. 114-255, 130 Stat. 1033 (2016).

7. All of Us: The Future of Health Begins with You, Nat’l Inst. of Health (2018), https://allofus.nih.gov/; see also Lucia A. Hindorff et al., Prioritizing Diversity in Human Genomics Research, 19 NATURE REVIEWS GENETICS 175 (2018).

8. What Is Precision Medicine?, Genetics Home Reference, U.S. Nat’l Libr. Med. (2018), https://ghr.nlm.nih.gov/primer/precisionmedicine/definition. Earlier, it was common to refer to this practice as personalized medicine, but many physicians objected to that terminology on the ground that they had already been providing personalized care.

9. A. Lavertu et al., Pharmacogenomics and Big Genomic Data: From Lab to Clinic and Back Again, 27 Hum. Molecular Genetics R72 (2018).

10. Adverse Effects of Vaccines. Evidence and Causality. (Nat’l Acads. Press 2012).

11. Heidi L Rehm, Evolving Health Care Through Personal Genomics, 18 Nature Reviews Genetics 259 (2017).

12. Ctr. for Drug Evaluation & Research, Food & Drug Admin., Advancing Health Through Innovation: 2017 New Drug Therapy Approvals (2018).

13. Lavertu et al., supra note 11.

14. K. J. Hofman et al., Physicians’ Knowledge of Genetics and Genetic Tests, 68 Acad. Med. 625 (1993).

15. Caryn Kseniya Rubanovich et al., Physician Preparedness for Big Genomic Data: A Review of Genomic Medicine Education Initiatives in the United States, Hum. Molecular Genetics (forthcoming 2018).

16. See, e.g., Todd Bookman, Genetic Counselors Struggle to Keep Up with Huge New Demand, Kaiser Health News (Apr. 18, 2016), https://khn.org/news/genetic-counselors-struggle-to-keep-up-with-huge-new-demand.

17. J. L. St. Sauver et al., Integrating Pharmacogenomics into Clinical Practice: Promise vs Reality, 129 Am. J. Med. 1093 (2016); B. M. Welch & K. Kawamoto, The Need for Clinical Decision Support Integrated with the Electronic Health Record for the Clinical Application of Whole Genome Sequencing Information, 3 J. Pers. Med. 306 (2013).

18. 21st Century Cures Act, Pub. L. No. 114-255, § 3060, 130 Stat. 1033, 1130–33 (2016); Food & Drug Admin., Clinical and Patient Decision Support Software: Draft Guidance for Industry and Food and Drug Administration Staff (Dec. 8, 2017).

19. J. D. Chambers et al., Examining Evidence in U.S. Payer Coverage Policies for Multi-gene Panels and Sequencing Tests, 33 Int’l J. Tech Assessment Health Care 534 (2017); Rebecca Eisenberg & Harold Varmus, Insurance for Broad Genomic Tests in Oncology, 358 Science 1133 (2017).

20. Walid F. Gellad & Aaron S. Kesselheim, Accelerated Approval and Expensive Drugs—a Challenging Combination, 376 New Eng. J. Med. 2001 (2017); Paul Workman et al., How Much Longer Will We Put Up with $100,000 Cancer Drugs?, 168 Cell 579 (2017). The prices of older drugs are rising as well. Vinay Prasad et al., The Rising Price of Cancer Drugs—a New Old Problem?, 3 JAMA Oncology 2374 (2017).

21. Grace M. Kuo et al., Telemedicine, Genomics and Personalized Medicine: Synergies and Challenges, 9 Current Pharmacogenomics & Personalized Med. 6 (2011); Erynn S Gordon et al., The Future Is Now: Technology’s Impact on the Practice of Genetic Counseling, 178 Am J. Med. Genetics Part C: Seminars in Med. Genetics 15 (2018).

22. S. Kalia et al., Recommendations for Reporting of Secondary Findings in Clinical Exome and Genome Sequencing, 2016 Update (ACMG SF v2.0): A Policy Statement of the American College of Medical Genetics and Genomics, 19 Genetics in Med. 249 (2017); S. M. Wolf et al., Managing Incidental Findings and Research Results in Genomic Research Involving Biobanks and Archived Data Sets, 14 Genetics in Med. 361 (2012).

23. Elec. Med. Records & Genomics (eMERGE), https://emerge.mc.vanderbilt.edu/; Integrating Genomics into Practice, https://ignite-genomics.org/about-ignite/; Clinical Sequencing Evidence-Generating Research, https://cser-consortium.org.

24. See, e.g., James H. Jones, Bad Blood: The Tuskegee Syphillis Experiment (Free Press 1992); Rebecca Skloot, The Immortal Life of Henrietta Lacks (Crown Publ’g Grp. 2010). See also Stephanie A. Kraft et al., Beyond Consent: Building Trusting Relationships with Diverse Populations in Precision Medicine Research, 18 AM. J. Bioethics 3 (2018); M. Smirnoff et al., A Paradigm for Understanding Trust and Mistrust in Medical Research: The Community VOICES Study, 9 AJOB Empirical Bioethics 39 (2018).

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BY ELLEN W. CLAYTON, MD, JD

Ellen Wright Clayton, MD, JD ([email protected]) is the Craig-Weaver Professor of Pediatrics and Professor of Health Policy at Vanderbilt University Medical Center, Professor of Law at Vanderbilt University School of Law, and co-PI of Center of Excellence in ELSI Research on genetic privacy and identity and LawSeqSM, devoted to understanding legal issues in genomics and making recommendations for the future. She is an investigator in eMERGE, studying the impact of returning results to participants.