Increasingly, healthcare providers are ordering large multi-gene panel tests for many areas of genomic medicine. While the growth of genetic knowledge has grown rapidly, the evidence for clinical utility of precision genomics has lagged behind predictions and expectations. Large panel genetic testing is widely available, heavily advertised, and appeals to providers as a one-size-fits-all solution to complex genetic testing.
The ability to detect disease risks that a provider may not have considered is particularly appealing to providers treating patients with complex disease presentations or overlapping clinical symptoms. This approach seems to be promising, even though such testing may not be indicated and the results may be highly ambiguous with no clear course of action. In many cases, targeted test ordering, coupled with pre- and post-test genetic counseling, helps avoid undue cost, risk, and anxiety. The benefits of large panel genetic testing for genetic diseases are maximized when access to genetics experts is available. Below, some of our experts shed some light on the complex topic.
How has panel genetic testing changed the way providers practice?
It is becoming more common for healthcare providers to order larger multigene panel testing, instead of cancer-specific or single-gene tests. We have even seen this when there is a known mutation in the family. Large panel tests may seem to be perceived as a safer option for healthcare providers, lessening the pressure to analyze family history to determine appropriate tests, but these tests may lead to inconclusive and worrisome results. For example, providers unfamiliar with hereditary cancer syndromes may order broad genetics panels, creating a false sense of confidence that if there is a mutation present it will be detected.
Large panel genetic testing casts a wide net for potential diagnoses. The genetics community has learned that some genes cause a broader set of symptoms than was originally thought, and this is another factor causing testing to move toward a less specific approach. As long as access to genetics expertise is available, this expanse of diagnostic ability can more easily be reconciled with potential for more ambiguous results.
Are there some diseases where larger genetics panels make more sense and some diseases where larger panels do not have as much utility?
Access to expert clinical genetics judgment is very helpful in evaluating the use of large panel genetic testing. For some conditions, the number of genes associated with a single clinical condition is growing rapidly. For example, with heritable cardiac conditions such as hypertrophic cardiomyopathy (HCM), multigene panel testing makes much more sense than single gene testing, as variants in more than 40 genes on an HCM panel could present clinically with the same symptoms and clinical diagnosis.
For other diseases, large panel genetic testing has little utility, most evident for conditions where variants in only a few genes have been associated with the condition, or where clear clinical diagnostic guidelines are available. If a provider can diagnose a patient with a genetic condition based upon well-established clinical criteria or testing of just a few genes, then larger genetics panels do not add value and may create more confusion due to variants of unknown significance (VUS) in off-target genes.
The Troublesome Nature of Variants of Unknown Significance
A variant of unknown significance, or VUS, means “the result is not usual, but we don’t know if it’s harmful.” Everybody has thousands of variants of unknown significance that only come to light during genetic testing, but a VUS in someone with a strong family history of certain types of cancer can lead to misinterpretation, inappropriate treatment, and unnecessary worry. Multigene panel testing can be useful in this scenario.
How have providers who are not genetics experts responded to the availability of large panel genetic testing?
Large genetics panels seem to have increased providers’ confidence in ordering genetic testing because it eliminates the need to determine which test is the most appropriate based on clinical history. Large panel genetic testing decreases the need to thoroughly assess personal and family history. By ordering broad panels, providers may identify genetic risks in their patients beyond the initial differential diagnoses, effectively providing a diagnostic safety net in their eyes. Their confidence is sometimes further buoyed by laboratory representatives who encourage them to order larger tests, providing a one-size-fits-all approach.
Unfortunately, ordering large panel genetic testing can be harmful without adequate genetics knowledge, especially if a family history meets clinical criteria for a diagnosis or if a patient is still at increased risk based on family history even though genetic testing is negative. These patients may still need medical management alterations based on their family history, or they may have other relatives who need multigene panel testing to truly determine what is going on in the family.
What are the challenges of large panel genetic testing, say 100 genes or more for a particular disease or group of diseases?
The greatest challenge with any genetic testing is interpretation of results. Laboratories and genetics panels have made great strides to standardize and improve their reporting practices, enabling providers to understand their interpretations. Still, larger panels often include genes for which there is limited information. It’s possible that the clinical presentation is not completely described, the risks of developing the disease with the gene mutation hasn’t been quantified (e.g., specific risks to develop cancer), and/or evidence-based medical management guidelines may not be available. Additionally, the rate of VUS is higher, leading to unanswerable questions about normal genetic variation vs. disease-causing. As large panel testing increases, the number of patients being mismanaged (e.g., unnecessary surgeries and surveillance) based on VUS results also increases. Recent lawsuits have highlighted the danger of misinterpretation of genetics results in the care of patients with hereditary cancer.
There doesn’t seem to be a lot of transparency in the way panel genetic testing is priced and billed. How do you think the opacity of pricing/billing/reimbursement impacts providers’ use of panels?
Current marketplace trend indicates that providers are often influenced by laboratories that offer out-of-pocket (OOP) maximums and/or handle preauthorization requirements, citing these as reasons for choosing multigene panel testing rather than technical or clinical validity. While this reduces administrative burden on providers, it limits transparency. Adding to the complexity in provider decision making is the reality that there is significant variation in the industry due to reimbursements that come from many payers with diverse systems and processes. Some in the genetics panel industry may offer incorrect reassurance that testing will be covered, that patients will be notified of OOP costs, and that the lab will work with the patient to provide affordable options- only to result in a surprise bill.
What are some of the economic consequences of panel genetic testing, both now and in the future?
When used correctly, panel genetic testing is a powerful and cost-effective information resource for patients and healthcare providers. For example:
- Panels may standardize diagnostic pathways
- Genetics panels may increase access of testing to patients, especially when a disease state overlaps many genetic causes
- When a panel’s gene content is expertly curated, there can be a higher likelihood of diagnosis and a lower likelihood of VUS
- Payers may benefit from a cost-effective approach when panels are well designed and do not contain genes of limited evidence
- Patients may get an answer more quickly than in cascade or step-wise testing
When used incorrectly, panel genetic testing not only causes worry and anxiety, but also drives up costs in many ways. For example:
- Misinterpretation of results such as a VUS can lead to unnecessary screening, treatment, and preventive care.
- Panels — which contain many genes for which there is no recommended action — drive up administrative, personnel, and technology costs.
- Outsourcing of clinical rationale to the laboratory curating the panel leaves providers dependent on costly third-party interpretation.
- Providers without a compelling differential diagnosis for a patient likely feel pressure to pay attention to VUS, ordering imaging, biochemical or other clarifying tests.
- Payers are subject to a wide variation in contracted prices for identical tests due to a lack of transparency in the industry.
- Patients may face high out-of-pocket costs for testing that is not covered by insurance, when a targeted test would likely be covered.
How have patients reacted to larger panel genetic testing and how do they tend to react to results — whether positive, negative or VUS?
This depends largely on pre-test discussions. When patients have a rich and informed discussion about all the benefits and limitations of a genetic test, they are more likely to be satisfied with their outcomes. This discussion includes not only the diagnostic and technical aspects of a panel, but also the cost and coverage. When counseled correctly, by a certified genetics provider, patients may expect and cope with all types of genetic testing results.
Patients who have not had adequate pre-test genetic counseling can have stronger reactions to the results. They may be less prepared for a positive or VUS result; the medical management options and decisions to make; and the implications for family members. They may even be upset if the large panel testing did not identify an explanation for the history (negative result). Many patients think that “more is better,” which isn’t always the case. More genes on a genetics panel can lead to more questions (higher VUS rate) and fewer answers. With appropriate, targeted test ordering and pre-test genetic counseling, patients and their providers are well-prepared to make informed decisions based on reliable results.
What is the role of genetic counselors in large panel genetic testing?
Genetic counselors (GCs) play an important role in pre-and post-test counseling. As trusted, objective advisors across the continuum of care, they help determine what the patient and/or family is expecting or wanting from genetic testing, then manage expectations. GCs also help patients understand negative, positive, and VUS test results as well as medical management guidelines related to screening, risk, surveillance, and treatment options.
As genetics and genomics knowledge grows exponentially, we can expect the rise in larger genetics panel test offerings to continue. In the hands of a genetics expert, i.e. a board-certified genetic counselor, there is a place for the safe and effective use of large panels, with some conditions. Pre-test genetic counseling by certified genetic counseling is one way to mitigate the risk of harm from large genetic panels. Genetic counseling includes risk assessment and identification of the most appropriate test strategy.
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