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10 years of Public Health Genomics at CDC
1997-2007

2.0 Projects of the National Public Health Genomics

EGAPP™ | Annex 1 | Annex 2 | Annex 3 | Annex 4 | Annex 5 | Annex 6

Evaluation of Genomic Applications in Practice and Prevention (EGAPP™)


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Genetic tests for more than 1,200 diseases have been developed, with more than 1,000 currently available for clinical testing. Most are used for diagnosis of rare genetic disorders, but a growing number have population-based applications, including carrier identification, predictive testing for inherited risk of common diseases, and pharmacogenetic testing for variation in drug response. These tests and other anticipated applications of genomic technologies have the potential for broad public health impact.

In recent years, a number of issues have been raised about the current status of genetic testing implementation and oversight, including the need to develop evidence to establish efficacy and cost-effectiveness before tests are broadly commercialized. With the growing availability and promotion of genetic tests, clinicians need authoritative advice on their validity and utility. In fact, as new genomic technologies with potential applications in clinical practice continue to become available, there is an increasingly urgent need for timely and reliable information that will allow health care providers and payers, consumers, and policy makers to identify tests that are safe and effective. There has been a natural evolution of evidence-based processes (e.g., U.S. Preventative Services Task Force) that could be modified and applied to address these informational needs.

Validation gaps often exist within the translation continuum leading from gene discovery to clinical use of a genetic test in diagnosis, management or prevention. Often, data from clinical trials are limited or not available, leading to concerns about the safety and efficacy of emerging tests. Approval or clearance of genetic tests by the Food and Drug Administration (FDA) is required only for assay kits marketed to laboratories. However, the vast majority of genetic tests offered are laboratory-developed tests for which the FDA has authority, but currently does not regulate. Concerns continue to be raised about the adequacy of other regulatory (e.g., CMS/CLIA, New York Dept. of Health) and voluntary (e.g., College of American Pathologists) oversight mechanisms.

As with any new test or clinical intervention, the availability of practice guidelines can impact clinical practice and patient outcomes. Practice guidelines can be useful in supporting the introduction of new knowledge into clinical practice, translating complex research findings into recommendations, providing balanced information on benefits and limitations of tests and interventions, and improving medical decision making. Evidence-based approaches are critical for the generation of clinical practice guidelines, as they can promote credibility, reproducibility and transparency, while minimizing bias and identifying gaps in knowledge that can underscore where additional research is needed. It has been noted that genetic tests tend to fit less well within the framework of traditional "gold standard" processes of systematic evidence review. In addition to the limited number and quality of studies, many tests are aimed at interventions and outcomes that are not well defined. In addition, there is an overlay of advocacy from industry and patient interest groups surrounding genetic testing, and the ethical, legal, and social implications of genetic test implementation have been less amenable to a traditional evidence-based approach.
Recommendations on the development and implementation of safe and effective genetic tests have been produced by expert panels, professional organizations, and clinical experts, including the National Institutes of Health - Department of Energy Task Force on Genetic Testing2, the former Secretary's Advisory Committee on Genetic Testing,3 and the Secretary's Advisory Committee on Genetics, Health, and Society.4 The proposed components for evaluation of genetic tests that are generally accepted include analytic validity, clinical validity, clinical utility, as well as the ethical, legal and social implications associated with each evaluation component. However, a coordinated approach for effectively translating genomic applications into clinical practice and health policy is still needed.

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Evaluation of Genomic Applications in Practice and Prevention (EGAPP™)

In late 2004, OPHG initiated the pilot project Evaluation of Genomic Applications in Practice and Prevention (EGAPP™). The project's main goal is to establish and test a systematic, evidence-based process for evaluating genetic tests and other applications of genomic technology that are in transition from research to clinical and public health practice. The project aims to integrate existing recommendations and guidance on the implementation of genetic tests from professional organizations and advisory committees, as well as knowledge and experience gained from existing processes for evaluation and appraisal (e.g., U.S. Preventive Services Task Force, CDC's Task Force on Community Preventive Services), previous CDC initiatives (e.g., ACCE process; see Annex 1)1, and the international health technology assessment experience.

Structure

EGAPP™ is a non-regulatory process focused around an independent, non-federal Working Group established in April, 2005. The Working Group is currently composed of 13 multidisciplinary experts in areas such as evidence-based review, clinical practice, public health, laboratory practice, genomics, epidemiology, economics, ethics, policy, and health technology assessment (Annex 2). Working Group members were selected from a pool of nominated individuals by a Department of Health and Human Services interagency Steering Committee (Annex 3). Nominations were solicited from a wide range of organizations and individuals.


Roles of the Working Group include:

  • establishment/adaptation of methods and processes for evidence review,
  • identification, prioritization and selection of topics for evidence review,
  • participation on technical expert panels for commissioned evidence reviews,
  • development of recommendations based on the evidence, and
  • publication of methods and experience.

  1. Haddow JE, Palomaki GE: ACCE: A Model Process for Evaluating Data on Emerging Genetic Tests. In: Human Genome Epidemiology: A Scientific Foundation for Using Genetic Information to Improve Health and Prevent Disease. Khoury M, Little J, Burke W (eds.), Oxford University Press, pp. 217-233, 2003.
  2. Task Force on Genetic Testing. Joint NIH-DOE Ethical, Legal and Social Implications Working Group of the Human Genome Project. April 1995. http://www.genome.gov/10001808; accessed July 11, 2007.
  3. Secretary's Advisory Committee on Genetic Testing. http://oba.od.nih.gov/SACGHS/sacghs_home.html; accessed November 20, 2008.
  4. Secretary's Advisory Committee on Genetics, Health, and Society. http://oba.od.nih.gov/sacghs/sacghs_home.html; accessed November 20, 2008.

EGAPP™ Milestones At A Glance


October, 2004:
  • OPHG established EGAPP™ Pilot Project
  • EGAPP™ Steering Committee (SC) formed; two SC meetings held
2005:
  • Methodology meeting, in-person SC Meeting
  • EGAPP™ Working Group formed
  • Three Working Group and four Steering Committee meetings held
  • Four evidence reports commissioned (three of which were from AHRQ)
2006:
  • Two evidence reports released by the AHRQ Evidence-based Practice Center
  • One Steering Committee and three Working Group meetings held
2007:
  • In-person SC meeting held
  • Two evidence reports finalized (one AHRQ); Draft report in final review
  • Three Working Group meetings held
  • EGAPP™reviews.org Web site established
  • EGAPP™ Stakeholders Group (ESG) established
  • First EGAPP™ Working Group recommendation statement published

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Key procedural objectives of the Working Group are a transparent process and the provision of clear linkage between the scientific evidence developed and the conclusions, recommendations and information subsequently disseminated. Primary products of the EGAPP™ include evidence reports and Working Group recommendation statements.

OPHG-based EGAPP™ staff provides support to the Working Group and coordinates EGAPP™ activities. EGAPP™-supported expert consultants provide subject matter expertise in the preparation of methods, evidence reports and recommendation statements.

Process

EGAPP™ methods have incorporated many aspects of the ACCE process including: formal assessment of analytic validity and relevant ethical, legal and social implications, use of questions to organize collection of information, knowledge synthesis, and identification of gaps in knowledge. EGAPP™ also integrates knowledge and experience from existing evaluative processes, such as: commissioning comprehensive reviews through Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Centers (EPCs), development of analytic frameworks with key questions, explicit search strategies, assessment of quality of individual studies and strength of evidence, formulating recommendations with clear linkage to the evidence, and identification of research agendas. The EGAPP™ approach also adds value to existing processes in several areas. For example, EGAPP™ maintains a focus on "hard" medical outcomes (morbidity/mortality), but considers a range of specific family or societal outcomes when appropriate. EGAPP™ is developing systematic approaches for collecting and grading evidence on analytic validity, optimizing existing methods for handling data on clinical validity and utility of genetic tests, assessing the usefulness of modeling, and addressing cost effectiveness and cost-utility. EGAPP™ is currently investigating methods to generate targeted, practical reviews within a shorter time-frame.

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EGAPP™ Subcommittees

At the first EGAPP™ Working Group meeting, three subcommittees were established to address Topics, Methods, and Outcomes; in early 2006, a Products Subcommittee was added. Two-day EGAPP™ Working Group meetings are held three times per year, and the work of the subcommittees continues between meetings through teleconferencing. Based on the agenda and specific tests under consideration or review, members are asked to declare any potential conflicts of interest prior to each meeting.

The Topics Subcommittee develops the processes for review, prioritization, and topic selection, and leads the review and selection of topics for the full Working Group.

The Methods Subcommittee addresses a range of methodological issues, including formulation of key questions and analytic frameworks for specific reviews, development of EGAPP™ evidence review protocols (e.g., grading quality of studies or strength of evidence), and translation of evidence to recommendations.

The Outcomes Subcommittee completed a lexicon of medical, family and population outcomes from which the outcomes of interest for specific reviews can be selected in early 2006.

The Products Subcommittee considers content, format and timelines for EGAPP™ products (e.g., publications, abstracts/presentations, Web postings, recommendations), overseas development, and implementation of processes for internal and peer review and dissemination of EGAPP™ written and Web products, and clears products to go to the full Working Group for approval.

EGAPP™ Working Group members also serve on Technical Expert Panels (TEPs) established to advise the investigators conducting each specific evidence review.

EGAPP™ Basics: Identification, Review, and Selection of Topics for Evidence Review

Scope of Topics - Because EGAPP™ is a pilot project with a public health focus, it was decided not to attempt to address the broad range of genetic tests in this first phase, but rather to focus on tests recognized as having wider population application (e.g., higher disorder prevalence, higher frequency of test use), and those with a higher potential to impact clinical and public health practice. Tests could include those used in a specific clinical scenario to guide intervention (e.g., diagnostic workup, treatment, or prevention) or tests used for risk prediction or population screening. However, it is intended that the methods and approaches developed during the pilot phase of EGAPP™ will have application to other types of testing in the future. In addition to limiting the scope of the pilot project, this early decision also recognized that, in some cases, other translation and evaluation processes are underway. The EGAPP™ project is not currently focusing on certain large categories of tests, including newborn screening, most testing for rare single gene disorders, or reproductive genetic testing.

 

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Identifying Topics - Potential topics through periodic horizon scanning by EGAPP™ project staff (e.g., internet and publications searching) and through suggestions from stakeholders, the EGAPP™ Steering Committee, and EGAPP™ Working Group members. Individuals, professional organizations, and members of the scientific and general public are encouraged to submit topics for future consideration through the www.egappreviews.org Web site comments page.

Review, Prioritization, and Formal Selection of Topics - Under the direction of the EGAPP™ Topics Subcommittee, EGAPP™ project staff maintains a list of topics suggested for consideration. The EGAPP™ Working Group considers selection for evidence review based on defining the disorder/effect to be tested for, the specific test to be used, and the clinical scenario(s) in which the test will be used (e.g., diagnosis or screening, population to be tested). All topics submitted are first reviewed to determine if they fall within the current stated project scope. Topics are then considered for review by the EGAPP™ Working Group based on specific criteria and other considerations related to the research objectives of the pilot project, as shown in Table 1.

Table 1. Selected Criteria and Considerations for Prioritization and Selection of Topics for Evidence Reviews

Criteria Related to Health Burden Prevalence of disorder Severity/burden of disorder Strength of genotype/phenotype association Availability of effective intervention Relevance to practice
Criteria Related to Practice Issues Clinical availability of test Likelihood of inappropriate use Potential impact of evidence
Other Considerations Pilot project objectives/portfolio of tests Availability of evidence Other practical issues (e.g., avoiding duplication of effort) Ensuring diversity of test categories and types in reviews

The focus of topics will be those which are more common (i.e., higher prevalence of disease/disorder or prevalence of test use), and tests used to guide clinical interventions and used for risk prediction or population screening. Tests that do not meet eligibility criteria are listed for future consideration but not developed further. After listing a topic, EGAPP™ staff develops a short summary, which is a limited review of the published (focused on review articles) and grey literature designed to provide basic descriptive information (disorder, test, proposed clinical scenario) to the Working Group.

The Topics Subcommittee categorizes and ranks topics based on preset criteria, and makes recommendations on topics to be developed further. After discussion with the Working Group, full summaries are requested to selected topics. Full summaries are more in-depth (but not comprehensive) reviews of recent literature, review articles and the grey literature. Completed full summaries go to the Topics Subcommittee and the full EGAPP™ Working Group for review. After review and discussion of background information, the EGAPP™ Working Group votes to formally select topics.

Topics currently under review are shown in Table 2. A schematic representation of the process for review, prioritization and selection of topics for evidence review is provided in Annex 4. Topics under consideration are listed in Annex 5.

Table 2. Topics Currently Under Review or Completed

Disorder/Effect Test to be Assessed* Clinical Scenario
Target Population Intended Use
Breast Cancer Gene expression profile Women diagnosed with breast cancer Treatment and recurrence risk
Cardiovascular Disease Multigene panels General population Risk prediction or nutritional/lifestyle management
Colorectal Cancer (CRC) UGT1A1 Individuals diagnosed with CRC Treatment with irinotecan
Depression CYP450 Individuals diagnosed with depression Treatment with SSRI drugs
Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Mismatch repair gene mutations Individuals diagnosed with CRC and their family members Management of individuals and early detection/prevention for family members
Ovarian Cancer Genomic Tests 1) General population of women and;
2) women at increased risk for ovarian cancer
1) and 2) Detection and management
Venous Thromboembolism (VTE) Factor V Leiden and Prothrombin 1) Personal and/or family history of venous thromboembolism, or
2) family history of Factor V Leiden mutation
Diagnosis and management for individuals; prevention for family members

Initiating an Evidence Report

Evidence reports are detailed, systematic, objective assessments of the available evidence on a specific topic. As such, they represent the first step in the EGAPP™ evaluation process, and do not include recommendations based on the evidence. Following the identification of scope and outcomes of interest for an evidence report, key questions and an analytic framework are developed by the Working Group and refined where appropriate by the reviewers with guidance from a Technical Expert Panel (TEP). An example of an analytic framework and key questions are provided in Annex 6. Through an interagency agreement, AHRQ Evidence-based Practice Centers (EPCs) conduct some evidence-based reviews for the EGAPP™ Working Group. Other contracted evidence review centers/groups may also be commissioned to conduct evidence-based reviews.


External Expert Review of Evidence Reports

Draft evidence reports are distributed by the EPC or other contractor for expert peer-review, generally to the TEP (includes EGAPP™ Working Group members) and selected experts. Objectives for peer review of draft evidence reports are to: 1) ensure accuracy, completeness, clarity, and organization of the document; 2) assess modeling, if present, for parameters/assumptions and clinical relevance; and 3) identify scientific or contextual issues that need to be addressed or clarified in the final evidence report. In general, the selection of reviewers is based on expertise, with consideration given to potential conflicts of interest.


Development and Peer Review of Recommendation Statements

Final evidence reports are reviewed and discussed by the Working Group. Based on their deliberations, selected members develop recommendation statements. These documents are intended to summarize current knowledge on the validity and utility of an intended use of a genetic test (what we know and don't know), consider contextual issues related to implementation, provide guidance on appropriate use, and suggest key gaps and research that is needed.

Proposed external peer reviewers for draft recommendation statements are selected by the Working Group from individuals and organizations that are expected to be impacted by the recommendation, from the TEP and EGAPP™ Steering Committee members, and from key project target audiences (e.g., health care providers and payers, policy makers, targeted consumer organizations).

The objectives of the peer review process for EGAPP™ recommendation statements are to:

  • ensure the accuracy and completeness of the evidence summarized in the recommendation statement, and transparency of the linkage to the evidence report;
  • improve the clarity and organization of EGAPP™ work products;
  • solicit feedback from experts with different perspectives; and
  • identify contextual issues that need to be addressed or clarified in the final recommendation statement.

Appropriate written guidance is provided to reviewers regarding background issues and any particular areas they may be asked to focus upon. After review, discussion, and final approval by vote of the Working Group, the final recommendation statement is submitted to Genetics in Medicine, along with a list of reviewers that commented on the draft. The external peer review process does not involve public comment, but feedback from the public and other stakeholders is solicited later through evaluation surveys.


Evaluation of EGAPP™ Processes, Products and Impact

To assess the outcomes of the EGAPP™ pilot project, an outside evaluation consultant (contracted through McKing Consulting) is overseeing an evaluation plan. The objectives are to: 1) document project processes and timelines (e.g., infrastructure development, Working Group function, development of collaborations/partnerships); 2) collect feedback from stakeholders on the value and impact of EGAPP™ products developed (e.g., evidence reports, published evidence summaries, published Working Group recommendations, targeted informational messages); and 3) collect feedback on the effectiveness of dissemination. We plan to obtain feedback by surveying members from each of four key stakeholder groups designated for the EGAPP™ pilot project, including health care providers (e.g., physicians, genetic counselors, mid-level practitioners, nurses), health care payers/purchasers (e.g., health plans, insurers, companies), policy makers (e.g., professional and other public health organizations), and targeted consumer groups (e.g., members of advocacy organizations and persons with health concerns related to topics). Five web-based surveys have been developed, in order to ensure that the most relevant information is captured from each of the key stakeholder groups. CDC will use the knowledge generated from the surveys and the evaluation activities to inform the further development of the EGAPP™ project, refine products, and identify priorities for future evaluation of genetic tests.


Key Accomplishments

OPHG established the EGAPP™ Steering committee in October 2004. The Steering Committee directed development of the EGAPP™ Working Group, which was established in April 2005. To date, OPHG has provided logistical and organizational support for nine EGAPP™ Steering Committee meetings, two of which have been in-person, as well as nine Working Group meetings.

Since 2004, OPHG-based EGAPP™ staff and the Working Group have been successful in establishing and maintaining processes, and commissioning and overseeing seven evidence reviews. To date, four reports have been completed through an interagency agreement with AHRQ:

  • Genomic Tests for Ovarian Cancer Detection and Management (October 2006)
    (http://www.ahrq.gov/clinic/tp/genovctp.htm) which was conducted by Duke University AHRQ Evidence-based Practice Center
  • Testing for Cytochrome P450 Polymorphisms (CYP450) in Adults with Non-Psychotic Depression Prior to Treatment with Selective Serotonin Reuptake Inhibitors (SSRIs) (January 2007)
    (http://www.ahrq.gov/clinic/tp/cyp450tp.htm) conducted by Duke University AHRQ Evidence-based Practice Center
  • Hereditary Nonpolyposis Colorectal Cancer: Diagnostic Strategies and Their Implications (May 2007)
    (http://www.ahrq.gov/clinic/tp/genovctp.htm) conducted by the Tufts-New England Medical Center AHRQ Evidence-based Practice Center
  • Impact of Gene Expression Profiling Tests on Breast Cancer Outcomes (pending release)

EGAPP™ has established an agreement with Genetics in Medicine to publish EGAPP™ Working Group recommendation statements and summary evidence reports. The first recommendation statement was published in December 2007.

  • Recommendations from the EGAPP™ Working Group: Testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors. Gene Med. 2007:9(12):819-825.

EGAPP™ has recently launched an independent Web site – www.egappreviews.org – to provide access to the EGAPP™ Working Group's processes, methods, and products. This Web site was developed by Cadence Group contractors, with the support of OPHG.


Current Activities

The EGAPP™ Working Group is developing recommendation statements on:

  • UGT1A1 Mutation Analysis in Colorectal Cancer Patients Treated with Irinotecan (in review)
  • Genomic Tests for Ovarian Cancer Detection and Management (pending)

EGAPP™-commissioned evidence reports currently in progress are:

  • UGT1A1 Mutation Analysis in Colorectal Cancer Patients Treated with Irinotecan (non-EPC, in review)
  • DNA Testing Strategies Aimed at Reducing Morbidity and Mortality from Lynch Syndrome (non-EPC, pending)
  • Impact of Factor V Leiden Mutation Testing on Health Outcomes in Individuals with a History of or Increased Risk for Thromboembolic Events (in development)
  • Use of Genomic Profiling to Assess Risk for Cardiovascular Disease and Identify Individualized Prevention Strategies (non-EPC, in progress)

OPHG is supporting the development of an EGAPP™ Stakeholders Group (ESG). ESG is composed of a broad range of stakeholders with the expertise, experience, and ability to represent the perspectives of their stakeholder categories. Thirty-five ESG members were selected in fall 2007 by a six-person ESG Steering Committee. A stakeholder is considered to be anyone who has an interest in EGAPP™ products, and suggested categories of stakeholders include: health care providers, public health professionals, health care payers, policy makers, targeted consumer advocacy groups, educators, researchers, clinical professionals, information technologists, and media and science writers. Among other potential roles, the ESG proposes to assist EGAPP™ in the identification of central or core messages for evidence reports and recommendation statements, and act as facilitators in framing these messages in ways that are appropriate and accessible for specific constituents.


Next Steps

OPHG will continue to provide technical and organizational support to the EGAPP™ Working Group as they address objectives for the immediate future, that include publishing recommendation statements and articles on EGAPP™ methods, topics and outcomes. OPHG is facilitating the development and dissemination of translational materials for different target audiences based on evidence developed, soliciting feedback through the ESG, and evaluation of the EGAPP™ project. Long-terms plans for EGAPP™ include: investigating approaches and methods that may improve the flexibility, cost, speed and efficiency of evaluating evidence on genomic applications; seeking strategic public-private partnerships that will add value to EGAPP™ processes; engaging ESG talent and expertise to increase the public health impact of EGAPP™ products; and promoting the transition of EGAPP™ into a sustainable and transferable entity.


Selected Publications and Products
ACCE
  1. Haddow JE, Palomaki GE: ACCE: A Model Process for Evaluating Data on Emerging Genetic Tests. In: Human Genome Epidemiology: A Scientific Foundation for Using Genetic Information to Improve Health and Prevent Disease. Khoury M, Little J, Burke W (eds.), Oxford University Press, pp. 217-233, 2003.
  2. Palomaki GE, Bradley LA, Richards CS, Haddow JE. Analytic validity of cystic fibrosis testing: a preliminary estimate. Genet Med. 2003;5(1):15-20.
  3. Palomaki GE, Haddow JE, Bradley LA, Richards CS, Stenzel TT, Grody WW. Estimated analytic validity of HFE C282Y mutation testing in population screening: the potential value of confirmatory testing. Genet Med. 2003;5(6):440-3.
  4. Haddow JE and Palomaki GE. Population-based prenatal screening for cystic fibrosis via carrier testing: ACCE review. (http://www.cdc.gov/genomics/gtesting/ACCE/fbr.htm)
  5. Rowley, PT and Haddow, JE and Palomaki GE. DNA testing strategies aimed at reducing morbidity and mortality from hereditary non-polyposis colorectal cancer (HNPCC): An ACCE Mini-Review. (http://www.cdc.gov/genomics/gtesting/ACCE/fbr.htm)
  6. Screening for Hereditary Hemochromatosis in Adults via HFE Mutation Testing: AACE review. (http://www.cdc.gov/genomics/gtesting/ACCE/fbr.htm)
  7. Testing for Factor V Leiden and Prothrombin Mutations as a Risk Factor for Recurrent Venous Thrombosis in Adults: AACE review. (http://www.cdc.gov/genomics/gtesting/ACCE/fbr.htm)
  8. Family History and BRCA 1/2 Testing for Identifying Women at Risk for Inherited Breast/Ovarian Cancer: AACE review. (http://www.cdc.gov/genomics/gtesting/ACCE/fbr.htm)
EGAPP™ Working Group Recommendation Statement
  • Recommendations from the EGAPP™ Working Group: Testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors. Gene Med. 2007:9(12):819-825.
AHRQ Evidence Reports and Associated Publications
  • Genomic Tests for Ovarian Cancer Detection and Management (http://www.ahrq.gov/clinic/tp/genovctp.htm)
  • Testing for Cytochrome P450 Polymorphisms (CYP450) in Adults with Non-Psychotic Depression Prior to Treatment with Selective Serotonin Reuptake Inhibitors (SSRIs) (http://www.ahrq.gov/clinic/tp/cyp450tp.htm#Report)
  • Hereditary Nonpolyposis Colorectal Cancer: Diagnostic Strategies and Their Implications (http://www.ahrq.gov/clinic/tp/hnpcctp.htm#Report)
  • Thakur M, Grossman I, McCrory DC, Orlando LA, Steffens DC, Cline KE, Gray RN, Farmer J, DeJesus G, O'Brien C, Samsa G, Goldstein DB, and Matchar D. No evidence for the utility of genetic testing for CYP450 polymorphisms as a guide to management of patients with non-psychotic depression with Selective Serotonin Reuptake Inhibitors (SSRIs). Gene Med. 2007:9(12).

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Annex 1: ACCE: A CDC-Sponsored Project Carried Out by the Foundation of Blood Research


Introduction to ACCE

ACCE, which takes its name from the four components of evaluation—analytic validity, clinical validity, clinical utility and associated ethical, legal and social implications—is a model process for evaluating data on emerging genetic tests. The process includes collecting, evaluating, interpreting, and reporting data about DNA (and related) testing for disorders with a genetic component in a format that allows policy makers to have access to up-to-date and reliable information for decision making.

Goals and Attributes of the ACCE Model System:
  • Assesses data on DNA-based testing for disorders with a genetic component
    • Broad focus – "first look" at all available data
    • Ad hoc approach to grading quality of evidence to extract maximum information
    • Review, analyze, and integrate data
    • Does not suggest policy or make recommendations
  • Provides up-to-date, accurate and complete summaries of available information
  • Creates formats useful to policy makers, health care providers and the general public


An important by-product of this process is the identification of gaps in knowledge. The ACCE approach builds on a methodology originally described by Wald and Cuckle1 and on terminology introduced by the Secretary's Advisory Committee on Genetic Testing 2.

Additional information and ACCE reports are available at http://www.cdc.gov/genomics/gtesting/ACCE/FBR/.


Components of ACCE
link to larger version

Figure 1. The ACCE evaluation process for genetic testing (text description)

The ACCE wheel (Figure 1) shows the relation among each of the four components of evaluation and the elements of each component. At the hub are the clinical disorder being evaluated and the setting in which testing is done (e.g., classic cystic fibrosis in the setting of prenatal screening). The evaluation process begins only after the clinical disorder and setting have been clearly established. Specific questions 1 through 7 in Table 1 help to define the disorder, the setting, and the type of testing.

The analytic validity of a genetic test defines its ability to accurately and reliably measure the genotype of interest. This aspect of evaluation focuses on the laboratory component. The four specific elements of analytic validity include analytic sensitivity (or the analytic detection rate), analytic specificity, laboratory quality control, and assay robustness. Analytic sensitivity defines how effectively the test identifies specific mutations that are present in a sample. Analytic specificity defines how effectively the test correctly classifies samples that do not have specific mutations (although the term "mutation" is used here, the terms "polymorphism" or "variant" may be more appropriate for certain situations). Quality control assesses the procedures for ensuring that results fall within specified limits. Robustness measures how resistant the assay is to changes in pre-analytic and analytic variables. Specific questions 8 through 17 in Table 1 help organize the information available to document analytic validity.

The clinical validity of a genetic test defines its ability to detect or predict the associated disorder (phenotype). The four elements of analytic validity are all relevant to assessing clinical validity, along with six additional elements: clinical sensitivity (or the clinical detection rate), clinical specificity, prevalence of the specific disorder, positive and negative predictive values, penetrance, and modifiers (gene or environmental). Penetrance defines the relation between genotype and phenotype and allows the frequency of the clinical expression of a genotype (expressivity) to be determined. Clinical sensitivity measures the proportion of individuals who have a well-defined clinical disorder (or who will get the disorder in the future) and whose test values are positive. Clinical specificity measures the proportion of individuals who do not have the well-defined clinical disorder and whose test results are negative. Prevalence measures the proportion of individuals in the selected setting who have, or who will develop, the phenotype. The positive and negative predictive values more meaningfully define the genetic test performance by taking into account clinical sensitivity, clinical specificity and prevalence. Specific questions 18 through 25 in Table 1 help organize the information available to document clinical validity.

The clinical utility of a genetic test defines the elements that need to be considered when evaluating the risks and benefits associated with its introduction into routine practice. The natural history of the specific disorder needs to be understood so that considerations such as optimal age for testing might be taken into account. Another factor to be considered is the availability and effectiveness of interventions aimed at avoiding adverse clinical consequences (if no interventions are available, for example, testing may not be warranted). Quality assurance assesses procedures in place for controlling pre-analytic, analytic, and post-analytic factors that could influence the risks and benefits of testing. Pilot trials assess the performance of testing under real-world conditions. Health risks define adverse consequences of testing or interventions in individuals with either positive or negative test results. Economic evaluation helps define financial costs and benefits of testing. Facilities assess the capacity of existing resources to manage all aspects of the service. Education assesses the quality and availability of informational materials and expertise for all aspects of a screening service. Monitoring and evaluation assess a program's ability to maintain surveillance over its activities and make adjustments. Specific questions 26 through 41 in Table 1 help organize the information available to document clinical utility.

Ethical, legal, and social issues (ELSI) surrounding a genetic test are represented in Figure 1 by a penetrating pie slice, implying that the safeguards and impediments should be considered in the context of the other components. Specific questions 42 through 44 in Table 1 help organize the information available to document these issues.

Table 1. The ACCE Model's List of Targeted Questions Aimed at a Comprehensive Review of Genetic Testing 3


References
  1. Wald N, Cuckle H. Reporting the assessment of screening and diagnostic tests. Br J Obstet Gynaecol 1989 Apr;96(4):389-96.
  2. Department of Health and Human Services, Secretary's Advisory Committee on Genetic Testing. Request for public comment on a proposed classification methodology for determining level of review for genetic tests. Federal Register 2000;65(236):76643-76645.
  3. Haddow JE, Palomaki GE. ACCE: A Model Process for Evaluating Data on Emerging Genetic Tests. In: Human Genome Epidemiology: A Scientific Foundation for Using Genetic Information to Improve Health and Prevent Disease. Khoury M, Little J, Burke W (eds.), Oxford University Press, pp. 217-233, 2003.

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Annex 2: The EGAPP™ Working Group

Chair
Alfred O. Berg, MD, MPH

Chair, Department of Family Medicine
University of Washington

Katrina Armstrong, MD, MSCE
Director of Research
Leonard Davis Institute of Health Economics
University of Pennsylvania School of Medicine

Jeffrey Botkin, MD, MPH
Associate Vice President for Research
Professor of Pediatrics and Medical Ethics
University of Utah.

Ned Calonge, MD, MPH
Chair of USPSTF
Chief Medical Officer and State Epidemiologist
Associate Professor
Colorado Department of Public Health and Environment
University of Colorado Health Sciences Center

James Haddow, MD
Director, Division of Medical Screening
Women & Infants Hospital
Providence, RI

Maxine Hayes, MD, MPH
Washington State Department of Health

Celia Kaye, MD, PhD
Senior Associate Dean, Education
School of Medicine University of Colorado at Denver and Health Sciences Center

Kathryn A. Phillips, PhD
Prof. of Health Economics and Health Services Research
School of Pharmacy, Institute for Health Policy Studies, and UCSF Comprehensive Cancer Center
University of California, San Francisco

Margaret Piper, PhD, MPH
Associate Director
Blue Cross/Blue Shield Association Technology Evaluation Center

Carolyn Sue Richards, PhD, FACMG
Scientific Director, OHSU Molecular Diagnostic Center
Director, OHSU DNA Diagnostic Laboratory
Oregon Health & Science University

Joan A. Scott, MS, CGC
Deputy Director
Genetics and Public Policy Center
Johns Hopkins University

Ora Strickland, PhD
Nell Hodgson Woodruff School of Nursing
Emory University

Steven Teutsch, MD, MPH
Executive Director of Outcomes Research
Merck & Company, Inc.

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Annex 3: The EGAPP™ Steering Committee

Muin Khoury, MD, PhD
Director, Office of Public Health Genomics
Centers for Disease Control and Prevention

Robert L. Becker, MD, PhD
Director, Division of Immunology and Hematology Devices, Office of In Vitro Diagnostic Device
Evaluation and Safety

Amber Berrian
Public Health Analyst
HIV/AIDS Bureau
Health Resources and Services Administration

D. Joe Boone, Ph.D.
Associate Director for Science
Division of Laboratory Systems
National Center for Preparedness, Detection, and Control of Infectious Diseases
Centers for Disease Control and Prevention

Barbara A. Bowman, PhD
Associate Director for Science
National Center for Chronic Disease
Prevention & Health Promotion
Centers for Disease Control and Prevention

Linda A. Bradley, PhD, FACMG
Geneticist / Technical Monitor for EGAPP™
Office of Public Health Genomics
Centers for Disease Control and Prevention

Peter Briss, PhD
Science Officer, Captain
Coordinating Center for Environmental
Health and Injury Prevention
Centers for Disease Control and Prevention

Andrea Ferreira-Gonzalez, PhD
Virginia Commonwealth University

Phyllis D. Frosst, PhD
Acting Chief and Science Policy Analyst
Policy and Program Analysis Branch
National Human Genome Research Institute
National Institute of Health

Althea M. Grant, MPH, PhD
LCDR, U.S. Public Health Services
National Center for Birth Defects and Developmental
Disabilities/Division of Blood Disorders
Centers for Disease Control and Prevention

Scott Grosse, PhD
National Center on Birth Defects & Developmental Disabilities, Centers for Disease Control and Prevention

Gurvaneet Randhawa, MD, MPH
Center for Outcomes and Evidence
Agency for Healthcare Research and Quality

Steve I. Gutman, MD
Director, In-Vitro Diagnostics Device Evaluation and Safety, FDA/DHHS

R. Rodney Howell, MD
Professor of Pediatrics,
Miller School of Medicine/University of Miami
On Assignment as Special Assistant to the Director
National Institute of Health
National Institute of Child Health and Human Development

Jon F. Kerner, PhD
Deputy Director
Research Dissemination & Diffusion
National Cancer Institute

Marie Y. Mann, MD, MPH
Genetic Services Branch
DSCSHN/MCHB/HRSA/HHS

Shawna Mercer, MSc, PhD
Health Scientist
Community Guide
Centers for Disease Control and Prevention

Rochelle M. Long, PhD, chief
Pharmacological and Physiological Sciences Branch
Division of Pharmacology, Physiology, and Biological Chemistry
National Institute of General Medical Sciences National Institutes of Health

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Annex 4: Process for Review, Prioritization and Selection of Topics for Evidence Review


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Annex 5: Topics Under Consideration by the EGAPP™ Working Group


Disorder/Effect Test to be Used* Clinical Scenario
Target Population Indication
Acne G6PD Individuals prior to treatment for acne Treatment with dapsone
Acute Lymphoblastic Leukemia (ALL) TPMT Individuals prior to treatment for ALL Treatment with 6-mercaptopurine
Acute Myeloid Leukemia (AML) FLT3 Individuals prior to treatment for AML Treatment with standard chemotherapeutic agents or tyrosine kinase inhibitor drugs
Alzheimer's Disease (AD) ApoE 1) Dementia patients; 2) Individuals with a family history of dementia; and 3) General population 1) Diagnosis; 2) and 3) Predictive testing/ risk assessment
Asthma ADRB2 Individuals treated for asthma Treatment with albuterol
Breast Cancer (BrCa) Multigene panel General population of women Predictive testing/risk assessment
Breast Cancer HER-2/neu Individuals prior to treatment for BrCa Treatment with trastuzumab and progression/outcome prediction
Breast Cancer BRCA1/2 Individuals diagnosed with BrCa and their family members Management of individuals and early detection/prevention for family members
Breast Cancer CYP2D6 Individuals prior to treatment for BrCa Treatment with tamoxifen
Cardiac Channelopathies Multigene panel Clinical suspicion or family history of cardiac channelopathies Diagnosis and management
Cardiovascular Disease (CVD) CYP450 Individuals treated for CVD Treatment with beta-blockers and proton pump inhibitor drugs
Cardiovascular Disease MTHFR Individuals with family history of CVD Prevention and management
Type III Hyperlipoproteinemia ApoE Individuals with family history or clinical symptoms of CVD Diagnosis of Type III hyperlipoproteinemia
Cardiovascular Disease ApoE General population Predictive testing - Risk determination
Chronic Myelogenous Leukemia (CML) BCR/ABL Individuals with a diagnosis, clinical suspicion or family history of CML Diagnosis and treatment monitoring
Colorectal Cancer (CRC) fecal DNA General population Population screening
Cystic Fibrosis (CF) CFTR Individuals with clinical suspicion or family history of CF Diagnosis and carrier testing
Deafness GJB1, GJB2, GJB3, GJB6 Individuals who failed initial newborn screening hearing tests Newborn screening follow-up
Diabetes, Type II PPARg2 1) Individuals with clinical suspicion or family history of diabetes; 2) General population 1) Diagnosis; and 2) Predictive testing/risk assessment
Diabetes, Type II TCF7L2 General population Predictive testing/risk assessment
Mature-Onset Diabetes of the Young (MODY) Multigene panel Individuals with suspected or diagnosed MODY Diagnosis and management
Hereditary Hemochromatosis (HHC) HFE 1) Individuals with clinical suspicion of HHC; 2) General population 1) Diagnosis; 2) Predictive testing/risk assessment
Lung Cancer GSTM1 Individuals with clinical suspicion of lung cancer Predictive testing/risk assessment
Lung Cancer, Non-Small Cell (NSC) EGFR Individuals prior to treatment for NSC lung cancer Treatment with tyrosine kinase inhibitor (TKI) drugs (gefitinib, erlotinib)
Malignant Hyperthermia RYR1 High risk individuals prior to surgery Management in surgery
Melanoma / Pancreatic Cancer p16 General population Predictive testing/risk assessment
Myeloproliferative disorders JAK2 Individuals with clinical suspicion of myeloproliferative disorders Confirm diagnosis
Pain Management CYP450 Individuals treated for chronic or acute pain Treatment with codeine and derivative drugs
Parkinson disease LRRK2 Individuals with clinical suspicion or family history of Parkinson's disease Diagnosis and treatment of individuals and family members
Periodontal disease IL-1 General population Population screening
Prostate Cancer uPM3 General adult male population Population screening
Retinitis pigmentosa (RP) ARRP1 Individuals with clinical suspicion or family history of RP Diagnosis and carrier testing
Thrombophilia F5, F2 Individuals with family history or clinical suspicion of thrombophilia Prevention and management
Thrombophilia VKORC1, CYP2C9 Individuals prior to treatment for thrombophilia Treatment with warfarin

*variants or mutations in the identified gene or genes

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Annex 6: Topics Under Consideration by the EGAPP™ Working Group

Analytic Framework from the evidence report: Testing for Cytochrome P450 Polymorphisms in Adults With Non-Psychotic Depression Treated With Selective Serotonin Reuptake Inhibitors (SSRIs). Numbers refer to the Key Questions shown below.

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Key Questions

Question 1: (overarching question): Does testing for cytochrome P450 (CYP450) polymorphisms in adults entering selective serotonin reuptake inhibitor (SSRI) treatment for non-psychotic depression lead to improvement in outcomes, or are testing results useful in medical, personal, or public health decision making?

Question 2: What is the analytic validity of tests that identify key CYP450 polymorphisms?

Question 3a: How well do particular CYP450 genotypes predict metabolism of particular SSRIs? Do factors such as race/ethnicity, diet, or other medications, affect this association?

Question 3b: How well does CYP450 testing predict drug efficacy? Do factors such as race/ethnicity, diet, or other medications, affect this association?

Question 3c: How well does CYP450 testing predict adverse drug reactions? Do factors such as race/ethnicity, diet, or other medications, affect this association?

Question 4a: Does CYP450 testing influence depression management decisions by patients and providers in ways that could improve or worsen outcomes?

Question 4b: Does the identification of the CYP450 genotypes in adults entering SSRI treatment for non-psychotic depression lead to improved clinical outcomes compared to not testing?

Question 4c: Are the testing results useful in medical, personal or public health decision making?

Question 5: What are the harms associated with testing for CYP450 polymorphisms and subsequent management options?

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