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Introduction

Advances in genetics and genomics¹—fueled by the rapid development of enabling technologies, such as DNA and RNA sequencing, proteomics, metabolomics, computational biology, and related data-sharing platforms—are transforming medical practice. Correspondingly, there has been a dramatic growth of genetic testing in the health care system and rapid development of publicly available genetic testing services outside the health care system, for example, through direct-to-consumer testing.

Advances in genetics and genomics, however, have also brought challenges, including the need for rigorous evaluation of the validity and utility of genetic tests and questions as to the best ways to incorporate them into medical practice and to weigh their cost against potential short- and long-term benefits. As the fraction of the economy consumed by health care expands, there is increasing concern about costs, about the value of achieving measurable improvement in clinical outcomes, and about the possibility of increasing inequality in health care (Rogowski et al., 2010). Moreover, like other medical tests, genetic testing can produce information that has ethical, legal, or social implications for the person tested and for family members and society at large.

The costs associated with genetic testing are difficult to evaluate because the costs are changing rapidly (generally decreasing), and the economic benefits of genetic testing, including those resulting from the obviation of the diagnostic odyssey (the pursuit of potentially expensive and invasive diagnostic tests) and those resulting from more rapid and targeted treatment, have not been well studied. Other challenges are associated with judging the medical and economic benefits and consequences of genetic testing beyond traditional health outcomes, such as information that might affect patient anxiety, motivate patient behavior, and inform personal planning. The economic issues are dynamic and continue to influence decision making regarding both clinical use and insurance coverage of genetic testing.

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¹ Genetic tests focus on a single or a limited number of genes, whereas genomic tests focus on studying large sections of an individual’s genome.

GENETICS AND MEDICINE: A BRIEF HISTORICAL PERSPECTIVE

Our understanding of genetics began with Gregor Mendel’s 1865 study aimed at identifying the rules for generational transmission of factors that determine simple phenotypic features of pea plants (Mendel, 1866). Initially unappreciated, because its generalizability was not apparent, Mendel’s work was rediscovered in 1900 by deVries, Correns, and von Tschermak and aggressively promoted by Bateson (Dunn, 1965; Carlson, 2004). Mendel’s laws were quickly extended to other plants and to animals and, in a seminal paper by Archibald Garrod, to humans (Garrod, 1996). The terms gene, genotype, and phenotype were soon defined (Johannsen, 1909), and that set the stage for the groundbreaking studies of TH Morgan and his students at Columbia in 1910–1927 (Kohler, 1994). Those investigators used phenotype-based studies of the fruit fly (Drosophila melanogaster) to develop a scientific context that set the foundations of modern genetics. Simultaneously, R. A. Fischer, J. B. S. Haldane, Sewall Wright, Theodosius Dobzhansky, and Ernst Mayr established the principles of how different forms of genes (alleles) are distributed in populations (population genetics) and catalyzed the union of modern genetics with evolutionary biology (the “modern synthesis”) (Dunn, 1965).

In the early 1940s, a major step toward solving the mystery of how information in genes determined cellular development and function was taken by Beadle and Tatum with their assertion of “one gene, one polypeptide” (Beadle and Tatum, 1941). Avery and his colleagues later showed that DNA was heritable material (Avery et al., 1944), which set the stage for the discovery of the antiparallel double helical structure of DNA in 1953 by James Watson and Francis Crick (Watson and Crick, 1953). That discovery gave rise to molecular biology, elucidation of the genetic code, protein synthesis, and the development of powerful new scientific techniques, such as recombinant-DNA, genetic engineering, and DNA sequencing (NLM, n.d.). Another key step toward understanding how genes encode organisms came in 1961, when Jacob and Monod discovered the lac operon and used it to show that proteins encoded by genes could control the functioning of other genes (Jacob and Monod, 1961). The development of techniques to sequence DNA by Frederick Sanger in the 1970s and the automation of DNA sequencing in the 1980s led to the idea of analyzing the human genome, that is, the complete complement of DNA, including all its genes, in the cells of an individual (NRC, 1988).

The Human Genome Project²—conceived in the 1980s, began in 1990, and completed by 2003—provided a nearly complete draft of the sequence of the human genome (Lander et al., 2001; Venter et al., 2001). The sequence has been refined and, with enumeration of its common variations, is a freely available resource for a broad array of biomedical studies, including studies that identify genetic variations associated with disease risk. Coincidental with this growth in biologic data have been tremendous technologic advances in DNA sequencing (often referred to as next-generation sequencing, NGS). The result is that an entire human genome can now be sequenced in a few hours at a cost that is less by several orders of magnitude than the cost of the original effort (Mardis, 2008; Behjati and Tarpey, 2013; van Dijk et al., 2014; Miller et al., 2015). Simultaneously, there has been an increase in the understanding of how genetic variation and environmental experience work in concert to affect health and disease. DNA sequencing is increasingly used to determine the sequence of individual alleles (variant³ forms of a particular

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² In 1990, Congress established funding for the Human Genome Project; it was led by the National Institutes of Health.

³ The neutral term variant is used instead of mutation or polymorphism to avoid confusion about pathogenicity (Richards et al., 2015).

gene) that are known to be responsible for particular genetic diseases (“disease genes”); of panels of disease genes any one of which can cause a particular clinical condition; of the entire protein-coding region of the genome (the exome, which is about 1.5% of the total genome); or of entire genomes.

Advances in understanding of the molecular basis of rare and common disorders, the proliferation of genetic information in easily accessible databases, and bioinformatics tools for analyzing DNA sequences computationally are making precise molecular diagnosis possible and thereby enabling prevention and treatment strategies that promise to improve and individualize medicine. Thousands of disease genes and their variants are now known, and the number continues to increase (Chong et al., 2015). Those discoveries are curated in continuously updated, publicly accessible databases (e.g., OMIM at omim.org and ClinVar at www.ncbi.nlm.nih.gov/clinvar [both accessed January 31, 2017]). As a result of those advances, a large number of genetic tests that identify variants associated with disease have been developed since the completion of the Human Genome Project. In fact, the National Institutes of Health (NIH) Genetic Testing Registry (GTR)⁴ notes that 48,916 tests for 16,210 genes associated with 10,683 conditions have been entered into the database, and more than 486 laboratories are performing the tests as of November 2016 (Rubenstein et al., 2013). Such proliferation provides increasing opportunities for genetic diagnosis but challenges the ability to validate the tests (Chong et al., 2015).

STATEMENT OF TASK

It was in the environment of rapid development of genetic tests, both laboratory-developed tests and those marketed directly to the consumer, and the lack of federal regulation governing genetic tests that the Department of Defense (DoD) Office of Health Affairs asked the National Academies of Sciences, Engineering, and Medicine to

The DoD Office of Health Affairs assists in the development of strategies and priorities to achieve the health mission of the Military Health System (MHS) and participates in formulating, developing, overseeing, and advocating the policies of the secretary of defense. The office is responsible for providing a cost-effective, high-quality health benefit to about 9.6 million active-duty uniformed-services members, retirees, survivors, and their families. The MHS has a $50 billion annual budget and consists of a worldwide network of 59 military hospitals, 360 health clinics, private-sector health-business partners, and the Uniformed Services University of the Health Sciences (MHS, n.d.). TRICARE is a major part of the MHS that

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⁴ The GTR provides a central location for voluntary submission of genetic test information by providers. It includes a test’s purpose, its method, its validity, evidence of its usefulness, and laboratory contacts and credentials. The overarching goal of the GTR is to advance public health and research in the genetic basis of health and disease (Rubenstein et al., 2013; available at: www.ncbi.nlm.nih.gov/gtr (accessed January 31, 2017).

combines the resources of military hospitals and clinics with civilian health care networks. TRICARE covers members of the uniformed services—active-duty and retired members of the US Army, Air Force, Navy, Marine Corps, Coast Guard; the Commissioned Corps of the US Public Health Service; and the Commissioned Corps of the National Oceanic and Atmospheric Association—and the National Guard and reserves. Family members, survivors, former spouses, and Medal of Honor recipients and their families are also eligible for TRICARE.⁵

APPROACH TO THE TASK

A 17-member committee was appointed to represent diverse fields of expertise in genetics, including basic science and molecular genetics; clinical practice in genetics, pediatrics, clinical medicine; bioethics; and health economics. The committee members met five times over the course of the study.

The committee began its deliberations by agreeing on definitions of key terms and discussing the similarities and differences between genetic and genomic tests and tests used in other medical contexts. It focused on the clinical application and clinical utility of genetic tests as directed by the statement of task. It examined how evidence is generated, evaluated, and summarized. And it reviewed approaches to and frameworks for decision making in the context of genetic tests.

In support of the committee’s discussions and deliberations, targeted literature searches were conducted, and information from relevant scientific, professional, and federal sources was gathered. It was quickly found that numerous ad hoc groups, regulatory agencies, organizations, and professional societies were developing approaches to various aspects of genetic testing and collecting and using evidence with various methods. None of the approaches was judged to be entirely satisfactory for DoD’s purposes, but generating an entirely new approach was judged both unnecessary—many aspects of the problem have been addressed well in one framework or another—and infeasible because of the constraints on time and resources. Thus, the committee reached consensus early in its deliberations to use a compilation of several sources judged to be the best of what was already available. The committee recognizes that as a consequence of the rapidity of development, a framework aimed only at current technologies might soon be outdated. With that in mind, it attempted to develop a framework that focuses on general principles of clinical usefulness that are relevant to any genetic technology. The committee makes suggestions about how the framework might be used in practice, but stops short of providing complete illustrative examples because it could not substitute its judgments for those that the DoD alone is in a position to make.

The committee decided to focus on germline DNA-based tests following publicly held conversations with DoD and its internal discussion and deliberations regarding the interpretation of the statement of task. The committee was concerned that too-broad a scope (e.g., to include RNA and other molecular-based tests) would expand the task to an unmanageable level. In the end, however, the committee believes that the recommended framework is broadly applicable to assessment of other molecular technologies. In fact, many of the approaches that the framework is based on include mention of other types of testing including the US Preventive Services Task Force, Fryback–Thornbury, Frueh and Quinn, and McMaster approaches (Fryback and Thornbury, 1991; Giacomini et al., 2003; Frueh and Quinn, 2014; USPSTF, 2015).

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⁵ Available at: http://www.tricare.mil/Plans/Eligibility (accessed January 31, 2016).

ORGANIZATION OF THE REPORT

The remainder of the report will cover the issues pertaining to genetic testing, evidence for genetic testing, and a framework for DoD as it evaluates genetic tests. Specifically, Chapter 2 provides a basic overview of some of the important concepts in genetics that explain genetic diseases and patterns of inheritance, offers a brief history of genetics, and reviews the different types of genetic tests. Chapter 3 provides background on several commonly used frameworks for assessing genetic tests and a comparative analysis of the methods for evaluating genetic tests. Chapter 4 discusses the different types of evidence for genetic tests while focusing on the concepts of analytic validity, clinical validity, and clinical utility. The committee provides conclusions and recommendations for advancing the evidence base on genetic testing. Finally, Chapter 5 describes the committee’s framework and presents the committee’s conclusions and recommendations regarding the elements of a framework for decision making.

There are three appendixes: Appendix A provides background on genetic variance and phenotype expression, Appendix B provides the detailed list of the Genetic testing Evidence Tracking Tool questions, and Appendix C discusses various organizations’ efforts in using evidence for genetic tests. The references cited throughout the report can be found after Appendix C, followed by a glossary of important terms used in the report.

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