Evaluation Of Genomic Applications Research Articles

Evidence-based consensus guidelines for ALS genetic testing and counseling.

Advances in amyotrophic lateral sclerosis (ALS) gene discovery, ongoing gene therapy trials, and patient demand have driven increased use of ALS genetic testing. Despite this progress, the offer of genetic testing to persons with ALS is not yet "standard of care." Our primary goal is to develop clinical ALS genetic counseling and testing guidelines to improve and standardize genetic counseling and testing practice among neurologists, genetic counselors or any provider caring for persons with ALS. Core clinical questions were identified and a rapid review performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) 2015 method. Guideline recommendations were drafted and the strength of evidence for each recommendation was assessed by combining two systems: the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) System and the Evaluation of Genomic Applications in Practice and Prevention (EGAPP). A modified Delphi approach was used to reach consensus among a group of content experts for each guideline statement. A total of 35 guideline statements were developed. In summary, all persons with ALS should be offered single-step genetic testing, consisting of a C9orf72 assay, along with sequencing of SOD1, FUS, and TARDBP, at a minimum. The key education and genetic risk assessments that should be provided before and after testing are delineated. Specific guidance regarding testing methods and reporting for C9orf72 and other genes is provided for commercial laboratories. These evidence-based, consensus guidelines will support all stakeholders in the ALS community in navigating benefits and challenges of genetic testing.

Defining Clinical Utility of Tumor Biomarker Tests: A Clinician's Viewpoint.

Tumor biomarker tests (TBTs) are used to guide therapeutic strategies for patients with cancer. However, the regulatory environment for TBTs in the United States is inconsistent and, in general, TBTs are poorly valued. The National Academy of Medicine has recommended that TBTs should not be used in general practice until they are shown to have analytical validity and clinical utility. The latter term, first coined by the Evaluation of Genomic Applications in Practice and Prevention Initiative, has been widely stated but is indeterminately defined. In considering whether a TBT has clinical utility, several factors need to be considered: (1) What is the intended use of the TBT? (2) What are the end points that are used to determine clinical utility? (3) How substantial does the difference in end points between groups defined by the TBT need to be to determine therapeutic strategies? (4) What is the risk tolerance of the stakeholders? and (5) Who are the stakeholders that make the decision? For all these factors, the data used to consider clinical utility must be derived from level I evidence studies. In conclusion, there is no strict definition of clinical utility for a TBT. However, consideration of these factors will lead to more objective conclusions. Doing so will facilitate value-based decisions regarding whether a TBT should be used to guide patient care.

OP523 Towards A Health Technology Assessment Framework For Omics-Technologies: Preliminary Results Of The ExACT project.

IntroductionOmics technologies enable the measurements of genes (genomics), mRNA (transcriptomics), proteins (proteomics) and metabolites (metabolomics) and thus proved to be valuable tools for personalized decision-making in clinical practice. For their evaluation, a health technology assessment (HTA) framework is not standardized and accepted, yet. Therefore, we aim at designing an omics-technologies HTA evaluation framework to facilitate their assessment, through a mixed-method approach. This work is part of the ExACT project, which aims to produce a range of tools to facilitate the implementation of precision health in clinical practice.MethodsA systematic review was conducted to identify the existing HTA frameworks used for the evaluation of omics-technologies. Desk research on the HTA agencies’ websites was performed to identify the reports on omics-technologies HTA evaluation frameworks used by these agencies. A questionnaire evaluating HTA agencies’ experience on evaluation of omics-technologies was designed. The new framework will be elaborated based on the findings from the three methodological steps, and will be validated through a Delphi process.ResultsTwenty-three articles were included in the systematic review. The main identified HTA frameworks were ACCE and “Evaluation of Genomic Applications in Practice and Prevention” (EGAPP). The desk research showed that these frameworks were seldom used by HTA agencies, which for the evaluation of omics-technologies mostly refer to the HTA Core Model®, mainly assessing the following domains: clinical effectiveness and economic evaluation. Data collection process of the questionnaire HTA agencies’ experience is in progress.ConclusionsAlthough two main HTA frameworks for the evaluation of omics-technologies have been identified, these frameworks are sporadically used by HTA agencies in their practice. The particular interest of HTA agencies on clinical effectiveness and economic evaluation, might potentially reflect the uncertainty and difficulties when evaluating omics-technologies. This could indicate that these HTA frameworks are not feasible and practical to be used in routine HTA agency processes for omics technologies, emphasizing the need for a new framework. Our methodological approach might contribute to the development of a new HTA framework, feasible and practical to use not only for HTA agencies.

EVIDENCE REQUIRED BY HEALTH TECHNOLOGY ASSESSMENT AND REIMBURSEMENT BODIES EVALUATING DIAGNOSTIC OR PROGNOSTIC ALGORITHMS THAT INCLUDE OMICS DATA

Multi-analyte assays with algorithmic analyses (MAAAs) use combinations of circulating and clinical markers including omics-based sources for diagnostic and/or prognostic purposes. Assessing MAAAs is challenging under existing health technology assessment (HTA) methods or practices. We undertook a scoping review to explore the HTA methods used for MAAAs to identify the criteria used for clinical research and reimbursement purposes. This review included only non-companion (stand-alone) tests that are actionable and that have been evaluated by leading HTA or insurer/reimbursement bodies up to September 2017. Twenty-five reports and articles evaluating seventeen MAAAs were examined, most of which have been developed in oncology. The two main models used were the EUnetHTA Core model and the Evaluation of Genomic Applications in Practice and Prevention ACCE framework. Clinical validity and utility criteria were used, as were economic, ethical, legal, and social aspects. Economic evidence on MAAAs was scarce, and there is no consensus on whether the perspectives used are sufficiently broad to include all relevant stakeholders. Clinical utility and efficiency were the most used criteria, with stronger evidence needed linking the use of the algorithm with the clinical outcomes in real-life practice. HTA bodies must as well consider questions related to the analytical validity of MAAAs or with organizational aspects. The two main models, the EUnetHTA Core model and the ACCE framework, could be adapted to the assessment of MAAAs.

EVIDENCE REQUIRED BY HEALTH TECHNOLOGY ASSESSMENT AND REIMBURSEMENT BODIES EVALUATING DIAGNOSTIC OR PROGNOSTIC ALGORITHMS THAT INCLUDE OMICS DATA - ERRATUM.

Objectives Multi-analyte assays with algorithmic analyses (MAAAs) use combinations of circulating and clinical markers including omics-based sources for diagnostic and/or prognostic purposes. Assessing MAAAs is challenging under existing health technology assessment (HTA) methods or practices. We undertook a scoping review to explore the HTA methods used for MAAAs to identify the criteria used for clinical research and reimbursement purposes. Methods This review included only non-companion (stand-alone) tests that are actionable and that have been evaluated by leading HTA or insurer/reimbursement bodies up to September 2017. Results Twenty-five reports and articles evaluating seventeen MAAAs were examined, most of which have been developed in oncology. The two main models used were the EUnetHTA Core model and the Evaluation of Genomic Applications in Practice and Prevention ACCE framework. Clinical validity and utility criteria were used, as were economic, ethical, legal, and social aspects. Economic evidence on MAAAs was scarce, and there is no consensus on whether the perspectives used are sufficiently broad to include all relevant stakeholders. Conclusions Clinical utility and efficiency were the most used criteria, with stronger evidence needed linking the use of the algorithm with the clinical outcomes in real-life practice. HTA bodies must as well consider questions related to the analytical validity of MAAAs or with organizational aspects. The two main models, the EUnetHTA Core model and the ACCE framework, could be adapted to the assessment of MAAAs.

OA01.04 A Comparability Study Verifying the Analytic Performance of a Blood-based Gene Expression Classifier to Identify Benign Pulmonary Nodules: Topic: Pulmonology

We developed a blood gene expression classifier for lung cancer in current and former smokers with pulmonary nodules. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group and the Centers for Disease Control’s ACCE Project (analytic validity, clinical validity, clinical utility, and associated ethical, legal, and social implications) recommend studies to evaluate analytical validity of novel genomic tests. Here we report results of the test’s analytic performance. A total of 299 previous or current smokers with nodules ranging from 5-30mm were enrolled in a multicenter prospective observational study. A blood sample was obtained at baseline. RNA was isolated from PAXgene tubes and analyzed utlilizing three separate NanoString nCounter® gene expression platforms. Using NanoString’s recommended protocol, we evaluated: accuracy across repeat samples (n=134); reproducibility across multiple instruments (n=24) and across multiple operators (6 unique runs); analytical precision (one benign and one malignant pool run 33 times, total n=66); analytic sensitivity/limits of detection (two benign and two malignant samples at eight different concentrations, total n=32); and analytic specificity/interfering substances (n=10). The accuracy study resulted in sensitivity 94.4% and specificity 67.5%. Reproducibility was measured at 93.1% and analytic precision at 100%. The analytic sensitivity study confirmed NanoString’s published RNA input recommendations, and the presence of interfering substances did not impact final test results. We developed a gene expression classifier that demonstrated reproducibility and robustness across multiple studies. These studies are consistent with EGAPP recommendations. Additional studies to show consistent performance when the test is transferred from the research lab to a CLIA setting as well as to demonstrate clinical validity and clinical utility are planned.

Abstract IA07: Using genetic information in screening and prevention: Perspective of clinicians and policy-makers

Abstract How can genetic information be effectively used in screening and prevention? The conceptual framework and rules of evidence for answering this question - widely used by clinicians, policy-makers, and payors - has been developed over decades in the field of Evidence-Based Medicine, exemplified by the approach of the USPSTF (US Preventive Services Task Force) and EGAPP (Evaluation of Genomic Applications in Practice and Prevention). The framework's principles include using the best evidence (clinical trials where available, and observational data where necessary) assessed in systematic searches that consider quality of each study using specific rules of evidence. Outcomes are projected quantitatively to assess net benefit (benefits vs harms) of prevention and screening strategies. In this framework, genetic data may provide information about the magnitude of lifetime risk of developing a specific cancer, while other data (including genomic data) may provide information about the current risk that a cancer is present. Risks of appropriate magnitude may direct interventions that can prevent cancer (for example chemoprevention or preventive surgery) or that can detect the presence of early curable cancer or an important precursor. This talk will describe the quantitative conceptual framework and its rationale, along with the implications, challenges, and opportunities for the use of genetic and genomic information for cancer prevention and screening. Citation Format: David F. Ransohoff. Using genetic information in screening and prevention: Perspective of clinicians and policy-makers. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr IA07.

Systematic immunohistochemical screening for Lynch syndrome in colorectal cancer: a single centre experience of 486 patients.

Germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause autosomal dominantly inherited Lynch syndrome. Lynch syndrome patients and their families benefit from life-saving intensive cancer surveillance. Approximately one in 30 colorectal cancers arises in the setting of Lynch syndrome. The aim of this study was to assess the detection rate of Lynch syndrome at our institution after introduction of systematic immunohistochemical screening for MMR deficiency in colorectal cancers from 2011 to 2015. Following the recommendations by the Evaluation of Genomic Applications in Practice and Prevention working group all colorectal cancers were immunohistochemically stained for the presence of MMR proteins MLH1, PMS2, MSH2 and MSH6, independent of clinical criteria. In the case of loss of MLH1, the somatic BRAF mutation V600E was assessed with molecular testing and/or immunohistochemistry. Clinical follow-up of potential Lynch syndrome carriers (patients with tumours showing loss of MLH1 expression with absence of BRAFV600E, loss of PMS2, MSH2 or MSH6) was evaluated. Of all patients (n = 486), loss of MMR protein expression was found in 73 (15.0%) tumours. Twenty-eight (6.0%) were classified as potential Lynch syndrome carriers. Of the genetically tested potential Lynch syndrome carriers (10 out of 28 patients), 40% were first diagnosed with Lynch syndrome. Implementation of systematic immunohistochemistry screening for Lynch syndrome showed that 6% of colorectal cancers were potentially Lynch-syndrome related. Tumour board protocols should systematically contain information on MMR status of all colorectal cancers and, in MMR deficient cases, include clear recommendations for genetic counselling for all potential Lynch syndrome patients.

PHP134 - PAYER DECISION MAKING FOR NOVEL GENOMIC DIAGNOSTICS FOR PRECISION MEDICINE

Genomic-based diagnostic products combined with targeted therapeutics are increasingly contributing to better clinical decisions by early detection, accurate prediction and maximizing health outcomes for patients. However, the reimbursement landscape for these novel diagnostics is not well understood. Our objective was to better understand the criteria and evidentiary frameworks that the major insurers in the United States use for reimbursement decisions for novel genomic diagnostics and drug-diagnostic combinations products. We conducted a review of publicly available data and the literature from January 2004 to November 2015, to assess the evidence that payers used to evaluate genomic diagnostics and drug-diagnostic products. A search of PubMed and Ovid databases was conducted. We included studies that were relevant to novel genomic diagnostics and FDA approved drug-diagnostic combination products. We also studied policies relevant to genomic diagnostics of the 10 largest payers. We initially identified 205 studies of which 25 studies met our inclusion criteria. We found variation among payers in the type of health technology assessments and levels of evidence in evaluating novel genomic diagnostics and drug-diagnostics. Clinical utility, safety and benefits were key criteria used to decide for coverage of novel products. Reimbursement decisions of the major insurers were primarily based on data from randomized clinical trials, clinical practice guidelines, and approval from regulatory bodies. The CDC’s Evaluation of Genomic Applications in Practice and Prevention (EGAPP) recommendations was one of the most commonly used evidentiary frameworks. There appears to be considerable variation among US payers in conducting health technology assessments to evaluate novel genomic diagnostics and drug-diagnostics for reimbursement decisions. Standards for coverage criteria and health technology assessments, based upon evidentiary frameworks and accepted levels of evidence will facilitate the reduction of the current uncertainty around coverage of novel genomic diagnostics and drug-diagnostics, ultimately impacting manufacturers, providers and patients.

Personalized PREvention of Chronic DIseases (PRECeDI): a Marie Curie RISE project

Funded in the context of the first call of the Marie Curie Research and Innovation Staff Exchange (RISE) 2014 of Horizon 2020, the PREvention of Chronic DIseases consortium (PRECeDI, http://www.precedi.eu/) aims to provide high-quality, multidisciplinary knowledge through training and research in personalized medicine with specific focus on the personalized prevention of chronic diseases. There is a large consensus that personalized medicine is a driver of innovation for research and health care, and also for the health care system and industry as a whole [1]. In order to harness the potential of this new concept, the “PRECeDI” consortium aims to train staff from academic and non-academic institutions on several research topics related to personalized prevention of cancer and neurodegenerative diseases. The acquisition of skills from researchers will come from dedicated secondments aimed at training on different research topics not available at the home institutions; attendance to training courses, workshops, seminars, conferences. In details, five research domains will be addresses: 1) identification and validation of biomarkers for primary prevention of cardiovascular diseases, secondary prevention of Alzheimer, and tertiary prevention of head and neck cancer; 2) economic evaluation of genomic applications; 3) ethical-legal and policy issues surrounding personalized medicine; 4) sociotechnical analysis of the pros-and cons of informing healthy individuals on their genome; 5) identification of organizational models for the provision of predictive genetic testing. PRECeDI is embedded in existing cooperation structures, such as the Erasmus Mundus ERAWEB II program, with additional leading small-medium enterprises (SMEs) in Europe and Canada as beneficiaries. The consortium consists of 9 beneficiaries, namely the Institute of Public Health, Universita del Sacro Cuore, Rome, Italy; Better Value Healthcare Ltd, Oxford, United Kingdom; Department of Infectiuos Diseaseses and Hygiene, Universita La Sapienza, Rome, Italy; Section Community Genetics, VU University Amsterdam, The Netherlands; LINKCARE Health Services S.L., Barcelona, Spain; Erasmus Universitait Medisch Centrum, Department of Epidemiology, Rotterdam, (1) Section of Hygiene, Institute of Public Health, Universita

Tissue Heterogeneity as a Pre-analytical Source of Variability.

A low level of reproducibility is the shortcoming of clinical studies where human tissues are used, especially in oncology (EGAAP, Evaluation of Genomic Applications and Prevention Working Group (2013) Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy? Genet Med: Off J Am Coll Med Genet 15:517–527, Simon RM, Paik S, Hayes DF (2009) Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 101:1446–1452). This could be due to the high variability of the pre-analytical conditions of tissue managing and preservation, but also to other two causes. One is the low level of standardization of the methods that is pertinent to the analytical phase. Heterogeneity of tissues is the other problem and it can be considered to be actually related to pre-analytical procedures. Indeed, it is a pre-condition that has to be taken into consideration before the specific analysis. Not all the consequences of heterogeneity can be more or less easily avoided by carefully choosing the tissues to be analyzed.

Clinical utility of gene-expression profiling in women with early breast cancer: an overview of systematic reviews.

This overview systematically evaluates the clinical utility of using Oncotype DX and MammaPrint gene-expression profiling tests to direct treatment decisions in women with breast cancer. The findings are intended to inform an updated recommendation from the Evaluation of Genomic Applications in Practice and Prevention Working Group. Evidence reported in systematic reviews evaluating the clinical utility of Oncotype DX and MammaPrint, as well as the ability to predict treatment outcomes, change in treatment decisions, and cost-effectiveness, was qualitatively synthesized. Five systematic reviews found no direct evidence of clinical utility for either test. Indirect evidence showed Oncotype DX was able to predict treatment effects of adjuvant chemotherapy, whereas no evidence of predictive value was found for MammaPrint. Both tests influenced a change in treatment recommendations in 21 to 74% of participants. The cost-effectiveness of Oncotype DX varied with the alternative compared. For MammaPrint, lack of evidence of the predictive value led to uncertainty in the cost-effectiveness. No studies were identified that provided direct evidence that using gene-expression profiling tests to direct treatment decisions improved outcomes in women with breast cancer. Three ongoing studies may provide direct evidence for determining the clinical utility of gene-expression profiling testing.

Clinical evidence supporting pharmacogenomic biomarker testing provided in US Food and Drug Administration drug labels.

Genetic biomarkers that predict a drug's efficacy or likelihood of toxicity are assuming increasingly important roles in the personalization of pharmacotherapy, but concern exists that evidence that links use of some biomarkers to clinical benefit is insufficient. Nevertheless, information about the use of biomarkers appears in the labels of many prescription drugs, which may add confusion to the clinical decision-making process. To evaluate the evidence that supports pharmacogenomic biomarker testing in drug labels and how frequently testing is recommended. Publicly available US Food and Drug Administration databases. We identified drug labels that described the use of a biomarker and evaluated whether the label contained or referenced convincing evidence of its clinical validity (ie, the ability to predict phenotype) and clinical utility (ie, the ability to improve clinical outcomes) using guidelines published by the Evaluation of Genomic Applications in Practice and Prevention Working Group. We graded the completeness of the citation of supporting studies and determined whether the label recommended incorporation of biomarker test results in therapeutic decision making. Of the 119 drug-biomarker combinations, only 43 (36.1%) had labels that provided convincing clinical validity evidence, whereas 18 (15.1%) provided convincing evidence of clinical utility. Sixty-one labels (51.3%) made recommendations about how clinical decisions should be based on the results of a biomarker test; 36 (30.3%) of these contained convincing clinical utility data. A full description of supporting studies was included in 13 labels (10.9%). Fewer than one-sixth of drug labels contained or referenced convincing evidence of clinical utility of biomarker testing, whereas more than half made recommendations based on biomarker test results. It may be premature to include biomarker testing recommendations in drug labels when convincing data that link testing to patient outcomes do not exist.

Creation of a network to promote universal screening for Lynch syndrome: the LynchSyndrome Screening Network.

The Evaluation of Genomic Applications in Practice and Prevention Working Group published an evidence-based recommendation stating that every newly diagnosed colorectal cancer (CRC) should undergo tumor screening for Lynch syndrome (LS). In 2011, leading cancer institutions and public health agencies created the Lynch Syndrome Screening Network (LSSN) in order to promote routine LS screening on all newly diagnosed CRCs and endometrial cancers (EC). The LSSN facilitates implementation of appropriate screening via shared resources, protocols and data through network collaboration. The LSSN website contains resources for institutions interested in initiating screening, including materials for program development, implementation and sustainability. The LSSN listserv gives providers access to experts in LS screening and implementation. The LSSN database will allow exploration of key gaps in implementation as a consortia-wide endeavor. To date, the LSSN's membership includes 85 institutions involved in the care of CRC patients and nine official partners such as national and state public health entities and other non-profit institutions. Nearly 80% of the LSSN's members have already implemented routine or universal CRC and/or EC screening. LSSN serves to further the population health potential of universal LS screening through collaborative efforts and resources.

Implementing Lynch syndrome screening utilizing a community partnership.

203 Background: Lynch syndrome (LS) is an autosomal dominant condition associated with an 80% risk of colorectal cancer, a 60% risk of endometrial cancer, and additional risks for extra-colonic cancers. Amsterdam and Bethesda criteria can be used to identify patients who may be at risk. However, 25% of colon cancer and 65% of endometrial cancer patients with LS will be missed by using family history criteria alone. LS is caused by mutations in mismatch repair genes (MMR): MLH1, MSH2, MSH6, PMS2, and EPCAM. Tumor screening by immunohistochemistry (IHC) is available, and abnormal results can be flagged for more definitive genetic counseling and testing. Recommendations from the 2009 EGAPP (Evaluation of Genomic Applications in Practice and Prevention) Working Group concluded there is sufficient evidence to use this tumor testing for LS, and the screening would provide moderate population benefits. Cost effectiveness studies have shown universal screening detects nearly twice as many cases of LS and is < $25,000 per life year saved. Methods: St. Luke’s Mountain States Tumor Institute (MSTI) implemented these recommendations in 2012 using a unique strategy: collaborating with a community organization. The Brian Olson Foundation (BOF) strives to “prevent(ing) colon cancer through community outreach and education and saving lives by detecting colon cancer as early as possible.”These objectives were aligned with the MSTI screening program for LS in Idaho by using BOF funding to eliminate a financial burden to the patient for 12 months. Results: 204 specimens were screened for LS using IHC with the following results: 73% normal, 21% abnormal staining for MLH1/PMS2, and 6% abnormal staining for a single protein. Three families were confirmed to have LS after molecular genetic testing, and 6 families have genetic test results pending. Conclusions: Our system had IHC numbers consistent with national data, if not slightly higher. MSTI has elected to continue the program long-term. This kind of collaboration eased the change in practice such that LS screening could become a standard of care in Idaho.

Recommendations from the EGAPP Working Group: does PCA3 testing for the diagnosis and management of prostate cancer improve patient health outcomes?

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found insufficient evidence to recommend prostate cancer antigen 3 (PCA3) testing to inform decisions for when to rebiopsy previously biopsy-negative patients for prostate cancer or to inform decisions to conduct initial biopsies for prostate cancer in at-risk men (e.g., previous elevated prostate-specific antigen test or suspicious digital rectal examination).The EGAPP Working Group found insufficient evidence to recommend PCA3 testing in men with cancer-positive biopsies to determine if the disease is indolent or aggressive in order to develop an optimal treatment plan.Based on the available evidence, the overall certainty of clinical validity to predict the diagnosis of prostate cancer using PCA3 is deemed "low." The EGAPP Working Group discourages clinical use for diagnosis unless further evidence supports improved clinical validity.Based on the available evidence, the overall certainty of net health benefit is deemed "low." The EGAPP Working Group discourages clinical use unless further evidence supports improved clinical outcomes. It has been suggested that PCA3 testing in the general male population might lead to earlier diagnosis and management changes (e.g., earlier detection and earlier initiation or higher rates of medical interventions) that improve outcomes. EGAPP Working Group found no direct evidence to support this possibility, so we sought indirect evidence aimed at documenting the extent to which PCA3 testing alters prostate cancer diagnosis or management, alone and in combination with traditional clinical management factors, and the extent to which this testing improves health outcomes. Assay-related evidence was deemed adequate for the PROGENSA PCA3 assay approved by the US Food and Drug Administration, available from Gen-Probe. Very few studies were available that investigated preanalytical effects, analytical performance, and diagnostic accuracy of other quantitative assays for PCA3. Evidence on clinical validity was rated inadequate to derive any conclusions about performance of PCA3 testing to inform decisions for when to rebiopsy previously biopsy-negative patients for prostate cancer, or to inform decisions to conduct initial biopsies for prostate cancer in at-risk men (e.g., previous elevated prostate-specific antigen test or suspicious digital rectal examination). Furthermore, there was little evidence to derive any conclusions about performance of PCA3 testing in men with cancer-positive biopsies to determine if the disease is indolent or aggressive in order to develop an optimal treatment plan. No studies were available to provide direct evidence on the balance of benefits and harms related to PCA3 testing for diagnosis and management in the general male population. Evidence for other populations (e.g., high risk) was not evaluated in the review. Early diagnosis of prostate cancer is central to minimizing morbidity and mortality. Prevention of prostate cancer mortality is a public health priority. Improvements in outcomes associated with PCA3 testing could have important impacts.

The EGAPP initiative: lessons learned

The Evaluation of Genomic Applications in Practice and Prevention Working Group was first convened in 2005 to develop and test evidence-based methods for the evaluation of genomic tests in transition from research to clinical and public health practice. Over the ensuing years, the Working Group has met 26 times, publishing eight recommendation statements, two methods papers, and one outcomes paper, as well as planning and serving as technical experts on numerous associated systematic reviews. Evaluation of Genomic Applications in Practice and Prevention methods have evolved to address implications of the proliferation of genome-wide association studies and are currently expanding to face challenges expected from clinical implementation of whole-genome sequencing tests. In this article, we review the work of the Evaluation of Genomic Applications in Practice and Prevention Working Group over the first 8 years of its existence with an emphasis on lessons learned throughout the process. It is hoped that in addition to the published methods of the Working Group, the lessons we have learned along the way will be informative to others who are producers and consumers of evidence-based guidelines in the field of genomic medicine.

Tumor-Based Screening for Hereditary Nonpolyposis Colorectal Cancer: Does Age-Based Selection Optimize Yield?

Tumor-Based Screening for Hereditary Nonpolyposis Colorectal Cancer: Does Age-Based Selection Optimize Yield?

Recommendations from the EGAPP Working Group: does genomic profiling to assess type 2 diabetes risk improve health outcomes?

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found insufficient evidence to recommend testing for predictive variants in 28 variants (listed in Table 1) to assess risk for type 2 diabetes in the general population, on the basis of studies in populations of northern European descent. The EWG found that the magnitude of net health benefit from the use of any of these tests alone or in combination is close to zero. The EWG discourages clinical use unless further evidence supports improved clinical outcomes.The EWG found insufficient evidence to recommend testing for the TCF7L2 gene to assess risk for type 2 diabetes in high-risk individuals. The EWG found that the magnitude of net health benefit from the use of this test is close to zero. The EWG discourages clinical use unless further evidence supports improved clinical outcomes.On the basis of the available evidence for both the scenarios, the overall certainty of net health benefit is deemed "low." It has been suggested that genomic profiling in the general population or in high-risk populations for type 2 diabetes might lead to management changes (e.g., earlier initiation or higher rates of medical interventions, or targeted recommendations for behavioral change) that improve type 2 diabetes outcomes or prevent type 2 diabetes. The EWG found no direct evidence to support this possibility; therefore, this review sought indirect evidence aimed at documenting the extent to which genomic profiling alters type 2 diabetes risk estimation, alone and in combination with traditional risk factors, and the extent to which risk classification improves health outcomes. Assay-related evidence on available genomic profiling tests was deemed inadequate. However, on the basis of existing technologies that have been or may be used, the analytic sensitivity and specificity of tests for individual gene variants might be at least satisfactory. Twenty-eight candidate markers were evaluated in the general population. Evidence on clinical validity was rated inadequate for 24 of these associations (86%) and adequate for 4 (14%). Inadequate grades were based on limited evidence, poor replication, existence of possible biases, or combinations of these factors. Type 2 diabetes genomic profiling provided areas under the receiver operator characteristics curve of 55%-57%, with 4, 8, and 28 genes. Only TCF7L2 had convincing evidence of an association with type 2 diabetes with an odds ratio of 1.39 (95% confidence interval: 1.33-1.46).TCF7L2 was evaluated for high-risk populations, and the overall odds ratio was 1.66 (95% confidence interval: 1.22-2.27) for association with progression to type 2 diabetes. No studies were available to provide direct evidence on the balance of benefits and harms for genetic profiling for type 2 diabetes alone or in addition to traditional risk factors in the general population.Evidence for high-risk populations and TCF7L2 was inadequate on the basis of two identified studies. These studies found close to zero additional benefit with the addition of genomic markers to traditional risk factors (diet, body mass index, and glucose tolerance). Prevention of type 2 diabetes is a public health priority. Improvements in the outcomes associated with genomic profiling could have important impacts. Traditional risk factors (e.g., body mass index, weight, fat mass, and exercise) have an advantage in clinical screening and risk assessment strategies because they measure the actual targets for therapy (e.g., fasting plasma glucose and medical interventions). To be useful in predicting disease risk, genomic testing should improve the predictive value of these traditional risk factors. Some issues important for clinical utility remain unknown, such as the level of risk that changes intervention, whether long-term disease outcomes will improve, how individuals being tested will understand/respond to test results and interact with the health-care system, and whether testing will motivate behavior change or amplify potential harms.

Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy?

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found that, for patients with metastatic colorectal cancer (mCRC) who are being considered for treatment with cetuximab or panitumumab, there is convincing evidence to recommend clinical use of KRAS mutation analysis to determine which patients are KRAS mutation positive and therefore unlikely to benefit from these agents before initiation of therapy. The level of certainty of the evidence was deemed high, and the magnitude of net health benefit from avoiding potentially ineffective and harmful treatment, along with promoting more immediate access to what could be the next most effective treatment, is at least moderate.The EWG found insufficient evidence to recommend for or against BRAF V600E testing for the same clinical scenario. The level of certainty for BRAF V600E testing to guide antiepidermal growth factor receptor (EGFR) therapy was deemed low. The EWG encourages further studies of the potential value of testing in patients with mCRC who were found to have tumors that are wild type (mutation negative) for KRAS to predict responsiveness to therapy.The EWG found insufficient evidence to recommend for or against testing for mutations in NRAS, or PIK3CA, and/or loss of expression of PTEN or AKT proteins. The level of certainty for this evidence was low. In the absence of supporting evidence, and with consideration of other contextual issues, the EWG discourages the use of these tests in guiding decisions on initiating anti-EGFR therapy with cetuximab or panitumumab unless further evidence supports improved clinical outcomes. It has been suggested that patients with mCRC whose tumors harbor certain mutations affecting EGFR pathway signaling are typically unresponsive to therapy with anti-EGFR antibodies (cetuximab and panitumumab). The EWG identified recent evidence reviews that have addressed this topic, and this recommendation statement is based on results of these reviews. In developing these recommendations the EWG considered evidence in the areas described below. Although no research syntheses that have formally evaluated analytic validity of these tests were found, the EWG was able to draw the following conclusions from assessments included in the evidence reviews under consideration. There is adequate evidence that KRAS mutation analysis reliably and accurately detects common mutations (codons 12 and 13), whereas evidence was inadequate for less frequent KRAS mutations (e.g., codon 61). There is also adequate evidence that testing for BRAF V600E accurately and reliably detects the mutation. For common mutations in NRAS, PIK3CA, and expression of PTEN AKT, there is adequate evidence of accurate and reliable detection. However, much less data exist in support. Furthermore, in the specific context of mCRC, no evidence was found on the analytic validity of immunohistochemistry (IHC) assays for PTEN or AKT expression. For KRAS mutation analysis, the EWG found convincing evidence for association with treatment response to anti-EGFR therapy, independent of prognostic association. For BRAF V600E mutation testing, the EWG found insufficient evidence for association with treatment response to anti-EGFR therapy independent of prognostic association. The EWG found insufficient evidence for association of results of testing for mutations in NRAS or PIK3CA, and loss of expression of PTEN or ATK proteins, with treatment response to anti-EGFR therapy. For KRAS mutation analysis, the EWG found adequate evidence that improved health outcomes are achieved by avoiding ineffective chemotherapy and potential side effects and expediting access to the next most effective treatment. Inadequate evidence was found regarding association of BRAF V600E mutation testing or loss of PTEN expression with improved health outcomes among patients with mCRC undergoing anti-EGFR therapy as compared with patients with tumors bearing wild-type BRAF sequence and PTEN expression levels, respectively. No evidence was found to support improved health outcomes associated with testing results for NRAS or PIK3CA variants, or AKT protein expression levels in this clinical scenario. CRC is an important and highly prevalent health problem. Improvements in mCRC outcomes associated with pharmacogenetic testing could have important clinical, and potentially public health, impacts. Adverse events related to cancer chemotherapy can be common and severe. Therefore, successfully optimizing treatment to maximize efficacy and minimize side effects is important for reducing mCRC-related morbidity and mortality.