Exome sequencing: value is in the eye of the beholder

Abstract

Recent studies have discussed the benefits of using exome sequencing (ES) as part of the genetics evaluation of early onset seizure disorders, neurodevelopmental disorders, and acute illness in newborns of suspected genetic origin, among others. However, barriers to the clinical use of ES include a widespread reluctance of insurers to pay for testing. This leaves researchers who develop and evaluate genetic tests and clinicians who must make the case for their patient’s need for genetic testing with questions regarding what evidence would be required to ensure coverage and patient access. Coverage of ES by US health-care payers has until recently been uncommon. An important source of information on payer coverage of genetic testing is the University of California–San Francisco (UCSF) Center for Translational and Policy Research on Personalized Medicine (TRANSPERS) Payer Coverage Policy Registry©. A 2015 survey found that a minority of plans covered multigene tests of any kind and none covered ES. During 2014–2017, multigene panels accounted for roughly 60% of private plan spending on genetic testing and <2% was spent on exome or genome sequencing. Two recent analyses from the UCSF Program in Prenatal and Pediatric Genomic Sequencing (P3EGS) have reported that growing numbers of health plans are now covering pediatric ES for at least some indications. One study reported that 8 of 15 payers surveyed in 2017 covered ES for children. In this issue, Trosman et al. report on qualitative research on factors underlying those evolving coverage decisions. What drives payers’ coverage decisions for genetic testing is not well understood. Payers often cite the lack of data on “clinical utility” as justification for noncoverage, but the understanding of what constitutes clinical utility varies. Does clinical utility refer specifically to improved health outcomes or does it also embrace the ability of a molecular genetic diagnosis to guide treatment options and to end diagnostic odysseys? Clinical utility has often been defined by researchers and health policy experts in terms of net health outcomes (death and serious disease or disability), whereas clinical geneticists, including the American College of Medical Genetics and Genomics (ACMG), have defined clinical utility more broadly to include effects on clinical management, prognostic implications, benefits of the information for patients and their family members, and the economic impact on health-care systems. Others have proposed that the personal utility of genomic information be considered independent of its use to alter clinical management or outcomes. Finally, interpretation of evidence differs; Douglas et al. reported that the same clinical utility studies were cited by some plans as reasons to cover pediatric ES and by other plans as grounds for negative decisions. TRANSPERS investigators have previously investigated reasons for coverage decisions for other types of genetic testing. For example, Dervan et al. reported that as of early 2016 just 8 of 19 payers covered cell-free fetal DNA testing for aneuploidies in average-risk pregnancies. Most (15/19) plans cited evidence of clinical validity in their decisionmaking process, and the majority (11/19) also cited clinical utility, which was defined in all policies as the expected change in net health outcomes. Three of the plans also considered change in patient management or clinical decision-making as part of the definition of clinical utility. Similarly, TRANSPERS surveys of representatives of payers regarding why multigene panels of tumor testing for hereditary cancers were not covered found that the primary reason offered was that such testing does not fit the standard coverage framework that requires evidence of clinical benefit to justify a treatment as “medically necessary.” That is, although there might be sufficient evidence of clinical benefit from identification of some gene variants, because other variants with unclear implications are also identified, the test as a whole would be classified as investigational. In addition, it is reported that payers rely on clinical guidelines in coverage decisions on genetic testing to a larger extent than for drugs. Also, it was reported that evidence of cost-effectiveness was rarely considered, and budget impact, i.e., net cost savings, was not cited in any of the coverage decisions reviewed. In this issue, Trosman et al. provide data to help understand payer coverage decisions for pediatric and prenatal ES. They