The focus of this evidence review is on genetic testing to assess clinical actionability in cardiovascular disease, and whether the evidence is adequate to draw conclusions about improved health outcomes for the Medicare population. In general, improved health outcomes of interest include patient mortality and morbidity, as well as patient quality of life and function. For genetic testing to be considered medically reasonable and necessary in the Medicare population, standardized evaluation of analytical validity, clinical validity, and clinical utility should be fully elucidated, and reflect the level of confidence that the performance of this test will directly benefit patients. Tests with analytic and clinical validity, with demonstrated clinical utility that provide confidence to accurately enhance clinician decision-making and satisfy requirements for accurate patient information, have the potential to alter clinical management leading to improved patient outcomes. Ideal patient outcomes demonstrate reduced mortality and morbidity and improved patient quality of life and function.
Genetic testing for genetic variants associated with cardiovascular disease endeavors to improve patient outcomes by guiding appropriate treatment, thereby maximizing treatment effectiveness. Outcomes of interest remain the patient-centered outcomes noted above.
Internal Technology Assessment
PubMed was searched for publications of clinical trials including the terms molecular cardiac and molecular cardiovascular, looking for evidence of clinical health outcomes. All countries of origin were included if broad inclusion for the clinical studies met the criteria with only publications in English considered. No studies were located. A search utilizing the terms cardiovascular genomics found no new studies. The terms panel and cardiac/cardiovascular had >100 results. A cardiovascular gene search within the Journal of Genetic Counseling had 38 results and PubMed had 28 results respectively. These studies were then screened for inclusion of adults and Medicare population that demonstrated evidence of clinical health outcomes, resulting in no applicable studies.
In a search for professional society guidelines for genetic testing in cardiovascular diseases, a professional society scientific statement was identified. A government funded publicly available resource was identified in the professional society statement article. Another professional society statement was identified in addition to a guideline within the same article.
Hershberger et al1 is a practice guideline for genetic evaluation of cardiomyopathy, done in collaboration between the Heart Failure Society of America (HFSA) and the American College of Medical Genetics and Genomics (ACMG). Recommendations are considered expert opinion as no systematic approach to literature review was conducted.
Professional Society Statements
Ackerman et al2 is an international consensus statement developed in partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA) to provide the state of genetic testing for channelopathies and cardiomyopathies in 2011. Recommendations are based on consensus of the writing group following the Heart Rhythm Society’s consensus process.
Musunuru et al3 is a scientific statement from the American Heart Association regarding genetic testing for inherited cardiovascular diseases. The statement “summarizes current best practices with respect to genetic testing and its implications for the management of inherited cardiovascular diseases.”3 Included in this publication are: an approach to the evaluation of patients with confirmed or suspected diagnosis of inherited cardiovascular disease; an approach to the evaluation of individuals with secondary or incidental genetic findings; a table listing genetics-guided diagnosis and management of cardiovascular conditions with condition listed, role in diagnosis, role in management, and source of information; and, a list of genes to be considered for testing from guidelines and statements. The authors note a “dearth of clinical trial evidence for the use of genetic testing in the practice of cardiovascular medicine.”3
Decision of the scope of testing is important. Testing can range from a single gene or a few genes to large panels. Next-generation sequencing has made complete genome sequencing readily available. However, these panels can include genes with little support for the gene-phenotype under investigation and may not increase the likelihood of clinically actionable results. These panels may also increase the number of variants of uncertain significance identified, or pick up secondary or incidental findings, causing confusion and uncertainty for both provider and patient. The authors note ClinGen is engaged in efforts to develop lists of genes with strong evidence linking them to diseases.3 Generally, genetic testing may not reveal a cause or confirm a diagnosis as the yield of genetic testing for any inherited cardiovascular disease is usually much less than 100%.1
Interpreting and acting on genetic test results for a patient should include post-test genetic counseling. As a result of the current rapid gain in knowledge and privately held information, interpretations can vary between genetic testing laboratories as well as providers, and over time. The ACMG and the Association for Molecular Pathology have published a variant framework to promote standardization, and ClinGen is engaged in modifying the framework for specific genes. The authors state, “It is the implicit responsibility of patients’ providers to ensure that genetic testing is up to date, although formal mechanisms by which providers can ensure that this happens remain to be established.”3
It is acknowledged there is sparse clinical trial evidence for the use of genetic testing for clinical management in cardiovascular medicine. Guidance for disease specific testing from guidelines and statements include information from the HFSA, the ACMG, the Heart Rhythm Society/European Heart Rhythm Association, and the NIH-funded ClinGen. Methodologic evaluation of evidence is not included in this publication. Condition and gene association are listed.2
The authors note the field of clinical genetics is changing rapidly and that reliable classification of variants identified in genetic testing will remain a challenge.3 Efforts by ClinGen will be critical to refine gene-specific variant classification criteria.
National Institute of Health funded Clinical Genome Resource (ClinGen)
Strande et al4 describes a framework to define and evaluate the clinical validity of gene-disease pairs developed by the NIH-funded ClinGen. The framework evaluates evidence supporting or contradicting a gene-disease relationship. Validation of the posted framework using a set of representative gene-disease pairs is demonstrated. The framework provides a strength of evidence for the relationship. This standardized framework was developed as there is substantial variability in the level of evidence supporting claims of gene-disease relationships; therefore, a systematic method is needed to more confidently determine the clinical validity of a gene-disease relationship. The authors state, “This framework aims to provide a systematic, transparent method to evaluate a gene-disease relationship in an efficient and consistent manner suitable for a diverse set of users.”4
The framework classifies gene-disease relationships by both quantity and quality of evidence. The validity classification of evidence includes the levels definitive, strong, moderate, limited, no reported evidence, and conflicting evidence reported, with descriptions of each. Classes of genetic evidence and their relative weights used in the ClinGen clinical validity framework is provided, dividing the genetic evidence into the two categories of case-level data and case-control data with separate subtypes. Scoring varies based on a scoring matrix with detailed guidance. Additionally, experimental evidence at the gene-level is scored based on a separate framework.4
Use of the framework was evaluated with a number of gene-disease pairs. Reproducibility was examined. Experts agreed with the preliminary classifications for 87.1% of the gene-disease pairs with published evidence. Discrepancies between expert and curator classification were discussed and explained and differed only by a single category. The authors conclude, “Ultimately, our systematic, evidence-based method for evaluating gene-disease associations will provide a strong foundation for genomic medicine.”4
Hunter et al5 explains the approach of the NIH sponsored ClinGen to assess clinical actionability of genetic disorders associated with genomic variation. The assessment of clinical actionability is part of the effort to create a central resource of information for the clinical relevance of genomic variation. They developed a standardized protocol to identify evidence, generate a summary report of actionability with an applied metric for an actionability score. This effort is aimed at improving patient health outcomes.
In general, the evidence supporting clinical actionability for most genetic disorders varies significantly. Therefore, ClinGen developed and implemented a standardized, evidence-based method to determine actionability of genomic testing, as described in this article.5 The intent is to identify genetic disorders with greater clinical utility when identified by testing in previously undiagnosed adults. The working definition of clinical actionability is a clinically prescribed intervention specific to the genetic disorder under consideration, effective for prevention or delay of clinical disease, lowered clinical burden, or improved clinical outcome in a previously undiagnosed adult.5 Intervention included patient management, but also interventions to improve outcomes for at-risk family members, however genetic testing recommendations for at-risk family members alone did not meet the criteria for actionability.
The method for knowledge synthesis is described in the article and accompanying supplemental materials.5 The NIH funded ClinGen is a consortium of researchers and clinicians. They create the open-access and centralized resource to define the clinical relevance and actionability based on the documented framework. The clinical actionability scoring metric is described. The final product summary includes scoring for severity of disease, likelihood of disease, effectiveness of specific interventions, nature of intervention, and state of the knowledge base, i.e., level of evidence.
Furthermore, ClinGen provides a resource which is available to all clinicians and patients. It is a publicly available website that “provides a structure to enable research and clinical communities to make clear, streamlined, and consistent determinations of clinical actionability based on transparent criteria to guide analysis and reporting of genomic variation.”5(p2)
The authors conclude, “The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.”5(p10)