Rapid advances in technology have lowered the cost of sequencing an individual’s genome from the several billion dollars that it cost a decade ago to just a few thousand dollars today and have correspondingly greatly expanded the use of genomic information in medicine (Hayden, 2014). This trend is anticipated to continue as technologies advance and as research increases the understanding of the basis of human disease.
The clinical use of DNA sequence information relies on the identification of linkages between diseases and genetic variants or groups of variants. Depending on the clinical setting, large-scale DNA sequencing may be used to identify germline/inherited or somatic/acquired mutations. More than 140,000 germline mutation entries have been submitted to the Human Gene Mutation Database, a collection of mutations in genes that have been linked with inherited human disease (Stenson et al., 2003, 2014). ClinVar2 is another resource which contains information about genetic variants and related phenotypes (Landrum et al., 2014). Additionally, almost 12,000 single-nucleotide polymorphisms3 have been associated with various diseases, including Alzheimer’s and type 2 diabetes, but the majority of associations have not been rigorously confirmed and may play only a minor role in disease (Cruchaga et al., 2014).
1The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and are not necessarily endorsed or verified by the Institute of Medicine, and they should not be construed as reflecting any group consensus.
Because of the lack of evidence available for assessing variants, evaluation bodies have made only a few recommendations for the use of genetic tests in health care. For example, organizations, such as the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) working group, have sought to set standards for the kinds of evaluations needed to make population-level health decisions (EGAPP, 2014a).4 However, due to insufficient evidence, it has been challenging to recommend the use of a genetic test (EGAPP, 2009, 2010, 2014b).
An additional challenge to using large-scale sequencing in the clinic is that it may uncover “secondary,” or “incidental,” findings5—genetic variants that have been associated with a disease but that are not necessarily related to the conditions that led to the decision to use genomic testing (Berg et al., 2013; Kohane et al., 2006). Furthermore, as more genetic variants are associated with diseases, new information becomes available about genomic tests performed previously, which raises issues about how and whether to return this information to physicians and patients and also about who is responsible for the information.
The value of genetic sequence information will depend on how it is used in the clinic, said David Veenstra, professor in the pharmaceutical outcomes research and policy program in the Department of Pharmacy at the University of Washington and chair of the workshop. Evidence is a driver of key health care decisions, and it is used to determine whether a treatment or procedure is reimbursed. “The focus of this meeting is to understand the processes that are being used to evaluate evidence” and to suggest pragmatic approaches that would address the challenges encountered during this process, Veenstra emphasized, but “not to identify a single process as the best [or] to try to establish what level of evidence is needed or what specific recommendations should be made.”
Until better evidence becomes available, best practices could allow for making genomic-based clinical decisions in the context of abundant information but limited evidence. Exploring these best practices requires an understanding of how stakeholders gather and evaluate existing genomic evidence to make clinical decisions, to develop practice guidelines, and to decide whether to cover and reimburse the generation and use of genomic information. To help develop a better understanding of
5Presidential Commission for the Study of Bioethical Issues. Anticipate and Communicate. http://bioethics.gov/sites/default/files/FINALAnticipateCommunicate_PCSBI_0.pdf. See Table 1.2 (accessed June 25, 2014).
how genomic information is used for health care decision making, the Roundtable on Translating Genomic-Based Research for Health of the Institute of Medicine (IOM) held a workshop in Washington, DC, on February 3, 2014.6 Stakeholders, including clinicians, researchers, patients, and government officials, discussed the issues related to the use of genomic information in medical practice. The objectives for the workshop are outlined in Box 1-1.
Chapter 2 summarizes the presentations of several representatives of research and clinical organizations who described how they gather evidence and how that evidence is assessed, graded, and evaluated for both inherited and acquired diseases. A particular focus of these presenters was the “actionability” of specific genetic variants—that is, whether these variants warrant clinical action—and how it is determined whether a specific genetic variant is actionable. In short, this chapter examines the foundations upon which clinical decisions involving genomic evidence are made; the details of how these decisions are made are discussed in the three chapters that follow Chapter 2.
- Provide a forum for diverse stakeholders to present approaches for assessing genome sequencing information for clinical use.
- Compare and contrast evidence evaluation processes for different clinical indications and across stakeholders.
- Discuss key challenges in the evidence evaluation process.
- Elicit pragmatic approaches to facilitate the effective translation of genomics into the clinic by improving evidence-based policy development.
6The workshop agenda, speaker biographical sketches, full statement of task, and registered attendees can be found in Appendixes A–D. For more information about the workshop, see http://www.iom.edu/Activities/Research/GenomicBasedResearch/2014-FEB03.aspx (accessed July 11, 2014).
The use of genomic information to make patient care and health decisions is examined in Chapter 3. The specific issues covered in this chapter include what evidence is used to make the decision whether to use large-scale sequencing or a more targeted (e.g., gene panel) approach, the role of patient preferences in deciding on testing, and what information is disclosed to the patient.
Chapter 4 focuses on the process of developing clinical guidelines. In addition to describing how the guidelines process is being applied to next-generation sequencing, the chapter also covers challenges to developing guidelines and the use of recommendations for developing practice guidelines.
Decisions made about the coverage and reimbursement of genomic tests are examined in Chapter 5. Private and government payers explained their perspectives on the process used to evaluate genomic or multi-panel sequencing for reimbursement as well as on the criteria used for deciding on coverage.
The final chapter of this workshop summary reviews the major themes that developed over the course of the workshop, as identified by individual speakers. These themes include consistency of gathering, analyzing, grading, and reimbursing the collection of genomic data; developing collaborations for generating and applying genomic data; and considering patient preferences when using genomic information in the clinic. Other topics were also addressed by a panel of discussants, including the challenges for genomic medicine; two such challenges that individual workshop participants identified are a lack of evidence and a lack of sequencing standards.