AHA Offers Help for Clinicians Weighing the Results of DTC Genetic Tests

With the marketplace for direct-to-consumer (DTC) genetic tests showing rapid growth, cardiologists must put the information these tools produce into context before applying the results to clinical care, according to a new scientific statement from the American Heart Association (AHA).

The statement, published online last week in Circulation on behalf of several AHA committees, follows a similar 2021 document on genetic testing for CVD in children, but this paper focuses solely on DTC tests that are widely available and generally more affordable than those advised for patients who meet certain criteria for genetic testing.

“Increasingly we’re seeing that many more people have access to their genetic data, often in the form of direct-to-consumer testing, and while this has many potential benefits, oftentimes clinicians may be confronted with outside testing that they did not initiate and then have to apply clinical context and interpretation after the fact,” writing group chair Leland E. Hull, MD, MPH (Massachusetts General Hospital, Boston), told TCTMD.

The goal of the document was to provide a “framework to help to guide cardiovascular clinicians encountering” DTC genetic test results, she added.

Monogenic, Polygenic, and Pharmacogenetic

The writing group outlines different models used by DTC testing companies to market and process genetic information, and stratifies the test results into three categories: monogenic disease risk, polygenic disease risk, and pharmacogenetic results.

For the first, the authors list the most commonly tested genes associated with dyslipidemias, cardiomyopathies, inherited arrhythmias, and thoracic aortic disease. As many people who undergo DTC genetic testing do so without clinical suspicion of disease, the authors warn that “individual risk prediction and interpretation” of a positive monogenic finding is “challenging” and requires further evaluation.

Polygenic risk scores have seen a rise in use more recently, according to Hull, but the statement is careful to note a few caveats for interpreting those tools. First, no DTC polygenic risk score has received the US Food and Drug Administration’s signoff. “Second, genotyping technology can influence the performance of polygenic risk scores,” they write, explaining that DTC tests often rely on technologies that look for specific genotype variations in DNA sequences rather than more-expensive full nucleotide sequencing. “[These] may not fully reflect the diversity of the target population, limiting coverage of relatively important alleles in some populations.”

Hull and colleagues also point out the “often opaque” construction and derivation of polygenic risk scores by DTC companies, the “highly variable” incorporation of ancestry into score results, and overall inconsistency among tests when it comes to reporting scores.

“Ultimately, an integrated risk score conveying absolute risk estimates and incorporating clinical risk factors is desired, because genetics should not be considered in isolation,” they write. “Integrated risk scores are emerging for clinical use.”

For the third category, pharmacogenetic testing, clinical use has waxed and waned in recent years and is generally guided by hospital policy. However, DTC tests are available for assessing the loss-of-function variations in the CYP2C19 gene that can affect the mechanisms of both clopidogrel and citalopram, and these fall under the definition of a laboratory-developed test and are subject to additional FDA oversight. As such, the authors say these tests can be relied upon to make clinical decisions for cardiovascular drugs.

There are considerations for specific populations that might use DTC genetic testing, including athletes, adoptees, older individuals, and those from limited-resource communities, according to the AHA statement.

What are some of the initial ways that we can start to parse through and triage some of this information? Leland E. Hull

Overall, the authors highlight the importance following an algorithm when patients bring a DTC genetic test result to their attention. They suggest first assessing whether the results are actionable based on their pertinence to the patient, associated risk of disease, and link to health-related information as opposed to ancestry or trait results. From there, they advocate performing confirmatory genetic testing before making clinical decisions or starting any interventions.

While DTC genetic tests aren’t brand new, Hull said, there have been “multiple barriers” to integrating genetics more generally within clinical care, including “ethical, legal, and social implications of testing, access to care, [and] both objective and subjective feelings of inadequate knowledge.”

She urged clinicians to always assess quality of the test before moving forward.

“With any new technology, you’re working with a scenario in which there’s not enough volume and experience, necessarily, and also a rapidly evolving field where, if you don’t have high volume, it can be challenging to feel like you’re keeping up with it,” Hull said. Although many of these things will continue to evolve, a goal of this statement is to ask: “What are some of the initial ways that we can start to parse through and triage some of this information?”