Celebrating a Decade of Evidence-Based Evaluation of Genomic Tests

Posted on by W. David Dotson and Muin J Khoury, Office of Public Health Genomics, Centers for Disease Control and Prevention
Ira Lubin, Doris Zallen, Dave Dotson, Sheri Schully, Marc Williams, Ned Calonge, Roger Klein, Muin Khoury and Cecile Janssens at the EGAPP meeting
Ira Lubin, Doris Zallen, Dave Dotson, Sheri Schully, Marc Williams, Ned Calonge, Roger Klein, Muin Khoury and Cecile Janssens at the EGAPP meeting

CDC’s Office of Public Health Genomics (OPHG) launched the Evaluation of Genomic Applications in Practice and Prevention Initiative (EGAPP) in 2004. The independent EGAPP Working Group (EWG) celebrated a decade of achievements and accomplishments at their meeting in Atlanta on October 27-28, 2014. The EWG is comprised entirely of volunteers, encompassing multiples areas of expertise who are committed to developing and applying evidence-based methods for evaluation of genomic tests for use in practice. The EWG has published four methods papers, as well as nine recommendation statements addressing genomic testing topics in oncology, psychiatry, cardiovascular disease, and diabetes. A few additional statements are in preparation.

During the past decade, the number of laboratories that offer genetic testing remained relatively flat, however, the number of diseases for which testing is available increased consistently and dramatically. As of November, 2014, there are more than 42,000 tests available for just over 4,000 disorders. In terms of raw numbers, the recommendations from a decade of EGAPP fall drastically short of covering the field. Nevertheless, EGAPP, dubbed by CDC as a pilot initiative, has been enormously influential in prioritizing tests for evaluation, determining what questions need to be asked and answered, and identifying where key crosscutting weaknesses in research must be addressed in genomics.

Muin Khoury presenting the certificate of recognition to Ned Calonge
Muin Khoury presenting a certificate of recognition to Ned Calonge

We have heard both high praise and harsh criticism of the EGAPP initiative over the past decade. Commendations often center upon the assertion that nobody else is doing what EGAPP does, and that the general approach EGAPP uses, of assessing the analytic and clinical validity, and especially the clinical utility of genomic tests, is critically needed. Criticisms, on the other hand, generally fall into three categories: 1) that the process is too slow, 2) that the evidentiary “bar” espoused by EGAPP (which relies on demonstration of clinical utility) is too high, and as a result, 3) guidelines with insufficient evidence to recommend for or against testing will proliferate, thus, in essence offering no clinically actionable guidance whatsoever. While we gratefully accept the kudos, we have seen the increased use of EGAPP-inspired concepts and frameworks in genomic evaluations. More and more, we see groups such as ACMG, ASCO, and NCCN producing guidelines that involve assessment of clinical utility. It can no longer be said, if it ever could, that EGAPP reviews and recommendations are unique in addressing this critical area in genomics. We acknowledge that high quality systematic reviews require significant investments in time and resources. Whether requiring demonstration of clinical utility is too stringent a criterion for implementation of tests in clinical practice may largely be a decision for individual practitioners, patients, and health payers. For implementation of genomic testing applications in public health programs, however, we argue that establishment of clinical utility is a necessary prerequisite. Finally, we acknowledge that 2/3 of the published EGAPP recommendations have concluded that insufficient evidence was available to recommend for or against testing. In these instances, we are still quite pleased that the process has led to the identification of key gaps in knowledge that should help to set productive future research agendas. Needless to say, we are very pleased that EGAPP has been able to produce two recommendations for (cascade screening for Lynch syndrome, pharmacogenomic KRAS testing with anti-EGFR therapy), and one recommendation against (factor V Leiden testing for idiopathic venous thromboembolism) use of genomic applications in specific clinical scenarios. In addition we appreciate the nuances available in EGAPP methods, which allow encouragement or discouragement (e.g., CYP450 testing for patients with major depression before treatment with specific SSRI drugs) of use in those instances where evidence is insufficient for a formal up or down recommendation.

Roger Klein, Muin Khoury, Michael Iademarco, Cecile Janssens, Ned Calonge, Dave Dotson, Sheri Schully, Doris Zallen and Marc Williams at dinner
Roger Klein, Muin Khoury, Michael Iademarco, Cecile Janssens, Ned Calonge, Dave Dotson, Sheri Schully, Doris Zallen and Marc Williams at dinner

As we celebrate a decade of the EGAPP initiative, the immediate priority for OPHG is to move more downstream along the translation continuum with a new initiative that benefits from the lessons learned by the EWG. As implied above, we believe that EGAPP has had a tremendously positive impact, primarily through influence on the methods of other groups evaluating genomic testing in the T2 phase of translation. In addition, the emerging ClinGen Resource appears poised to address expansive tracts in the genomics T2 space, with assessment of clinical utility in mind. Our new initiative will facilitate the development and application of stakeholder-centered methods, approaches, and best practices for reviewing the evidence on implementation and impact of public health genomic technologies in the real world. While guidelines may be developed as needed through the initiative, they will not be the central focus. Instead, emphasis will be placed on accelerating the implementation of genomic applications that hold particular promise in public health, with stakeholder input, through a variety of means and methods. An expansive group of stakeholders will be recruited to inform the initiative, with CDC programs and state health departments comprising the core stakeholder group. Beyond this, representatives from a broad array of federal agencies will be included, as will professional and patient organizations. One or more methods development groups will be assembled from the stakeholders, to review and address challenges in implementation identified by the stakeholders themselves. Methods groups will not be standing committees, but will be formed to address specific projects before dissolving back into the larger pool of stakeholders. Current and former EWG members will be invited to join the stakeholder group, as will members of the EGAPP steering committee.

Full details on the new initiative are still being hammered out, and you can expect to read more about it in the coming months here on the OPHG blog. In the meantime, the current EWG expressed strong interest in maintaining its independent status and will continue to develop and apply methods for genomic tests evaluation. As we close out this chapter of public health genomics, we want to thank each and every member of the EWG for their amazing work and service. The field of genomics owes EGAPP a tremendous debt of gratitude for developing a strong evidentiary foundation for genomic medicine. We look forward to working with members of the EWG under the aegis of the new public health genomics initiative.

Posted on by W. David Dotson and Muin J Khoury, Office of Public Health Genomics, Centers for Disease Control and PreventionTags , , ,

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Page last reviewed: April 26, 2021
Page last updated: April 26, 2021