lunes, 17 de septiembre de 2012

Improving the efficiency and relevance of evidence-based recommendations in the era of whole-genome sequencing: an EGAPP methods update : Genetics in Medicine : Nature Publishing Group

Improving the efficiency and relevance of evidence-based recommendations in the era of whole-genome sequencing: an EGAPP methods update : Genetics in Medicine : Nature Publishing Group

Improving the efficiency and relevance of evidence-based recommendations in the era of whole-genome sequencing: an EGAPP methods update

Genetics in Medicine
Published online


To provide an update on recent revisions to Evaluation of Genomic Applications in Practice and Prevention (EGAPP) methods designed to improve efficiency, and an assessment of the implications of whole genome sequencing for evidence-based recommendation development. Improvements to the EGAPP approach include automated searches for horizon scanning, a quantitative ranking process for topic prioritization, and the development of a staged evidence review and evaluation process. The staged process entails (i) triaging tests with minimal evidence of clinical validity, (ii) using and updating existing reviews, (iii) evaluating clinical validity prior to analytic validity or clinical utility, (iv) using decision modeling to assess potential clinical utility when direct evidence is not available. EGAPP experience to date suggests the following approaches will be critical for the development of evidence based recommendations in the whole genome sequencing era: (i) use of triage approaches and frameworks to improve efficiency, (ii) development of evidence thresholds that consider the value of further research, (iii) incorporation of patient preferences, and (iv) engagement of diverse stakeholders. The rapid advances in genomics present a significant challenge to traditional evidence based medicine, but also an opportunity for innovative approaches to recommendation development.
Genet Med advance online publication 6 September 2012.


evidence-based medicine/methods; evidence-based medicine/standards; genetics; genomics/methods; genomics/standards; medical/methods


In 2004, the Office of Public Health Genomics (OPHG) of the Centers for Disease Control and Prevention (CDC) recognized a critical need for providing guidance to health-care providers and patients on the appropriate use of the genomic tests that were rapidly being introduced in clinical practice and marketed directly to consumers. In response to this need, the OPHG launched Evaluation of Genomic Applications in Practice and Prevention (EGAPP), the first federal, evidence-based initiative to specifically address genomic testing. The independent EGAPP Working Group was established for the purpose of adapting existing evidence review methods to the systematic evaluation of genomic tests and to link scientific evidence to recommendations for the clinical use of genomic tests, thereby addressing the challenges posed by complex and rapidly emerging genomic applications.
The significant challenges in developing evidence-based reviews and recommendations for genomic tests include: (i) uncertainty and difficulty in establishing clinical validity, (ii) lack of direct evidence of clinical utility (i.e., lack of evidence directly connecting the use of a test to the clinical outcome), (iii) the rapid development and marketing of a large number of tests, and (iv) the lack of a robust regulatory infrastructure for genetic testing, hampering the dissemination of such testing into clinical practice. Further, systematic reviews of tests are complex because there are many steps between the ordering of the test and the outcome with respect to the patient’s health.1 In addition, reviews of genomic tests require that many outcomes be considered, given that the results often have implications for family members and society as well. Lastly, there is limited consensus among stakeholders about the types of evidence needed, outcomes to be assessed, and thresholds to be set before recommending genomic tests.2
In order to address some of these challenges, EGAPP developed a set of methods based on the evaluation of analytical validity, clinical validity, clinical utility, and, to some extent, the ethical, legal, and social implications (ELSI) of each test (the “ACCE” framework).3,4 This approach uses systematic, transparent, and evidence-based methods for identifying and evaluating evidence and developing recommendations, and is based, to a large extent, on the approach of the United States Preventive Services Task Force (USPSTF).5 To date, EGAPP has commissioned 10 reviews and developed recommendations for 8 genomic tests (two tests had “recommendations for” routine use, one had a “recommendation against,” and for five tests there was “insufficient evidence” to make a recommendation).
Despite the successful development of these recommendations, EGAPP has encountered several challenges in the process: (i) significant time and resources were dedicated to evaluating tests that proved to have no clinical validity or implausible clinical utility, (ii) there was no formal framework for evaluating indirect evidence of clinical utility, and (iii) the overall process was time-consuming in the context of the paucity of direct evidence of clinical utility and the growing number of tests being made available. These challenges almost certainly will be exacerbated by the recent significant increases in genome sequencing capabilities.
The objective of this report is to provide an update on the EGAPP methodological procedures that were developed using an iterative consensus development process with the primary goal of improving efficiency without sacrificing quality. We also assess the implications of the era of whole-genome sequencing for developing evidence-based guidelines. These findings will facilitate the use of pragmatic, evidence-based processes by various organizations that evaluate genomic tests or develop genomic testing procedures.

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