This is a very exciting era in laboratory medicine as virtually every day new genetic tests and emerging laboratory technologies enter the market. With these advancements also comes the (fun) challenge of distinguishing clinical testing from research testing. Making this distinction matters in two key ways. First, from a regulatory standpoint, it would be financially irresponsible to bill patients and insurers for research testing. Second, in terms of clinical implications, we have to demonstrate the value of classifying variants (clinical validity), then show that variant classification impacts patient clinical outcomes (clinical utility). Laboratory test stewardship programs provide an important foundation for striking an appropriate balance between implementing new genetic tests and meeting standards for clinical validity and utility, paying particular attention to the size of genetic panels.
Since the 1980s, identification of genetic markers has supported tailored clinical diagnoses and therapies, and as such, genetic testing has become an attractive diagnostic tool. Single gene testing has progressed to more expansive gene panels, exome, and even genome sequencing. While novel technologies provide the potential for increased efficiency, more comprehensive analysis, and reduced invasive testing to guide clinical care, the financial impact and potential secondary findings of these methods necessitate a balanced approach to responsibly implement precision medicine in clinical practice.
A Question of Value
To be good laboratory testing stewards, we must address questions about the value of new and emerging technologies. Simply defined, value is the quality of a test divided by its cost. While mathematical equations are straightforward precisely because they are objective, the perspective of “value” varies for each stakeholder (patients, providers, laboratorians, and payers), and these perspectives often have competing interests.
A crucial consideration is the timeline in which novel technologies are implemented clinically and, perhaps even more challenging, the elements that distinguish research testing from clinical testing. Clinical testing (for all laboratory tests) encompasses analytical validity, clinical validity, and demonstrated clinical utility. In some cases, genetic tests are Food and Drug Administration (FDA)-cleared for specific clinical applications. Patients and insurers typically are responsible for the cost of clinical testing. As new assays appear on the market, they might demonstrate analytical validity, but lack evidence establishing clinical validity and utility.
Requiring patients or insurers to cover the cost of building this evidence for a new assay is contrary to laboratory stewardship principles. Lab stewards have the difficult task of distinguishing true research from ancillary testing. Advancing research and providing evidence of clinical validity and clinical utility remain critical for enhancing our overall understanding of genetic testing. One approach to balancing both needs is to find alternative funding for clinical research in order to achieve alignment with insurers while also supporting patients.
It goes without saying that strict standards for validation and documentation exist for clinical testing, and although only a minority of tests are FDA-cleared, all laboratory developed tests must adhere to CLIA regulations. This is a minimum standard; even laboratories that perform research-use only testing and return results to participants must have a CLIA license. Compliance with CLIA regulations is not the only factor in assessing a laboratory’s or test’s quality. Evaluating a laboratory’s comprehensive services also matters, including its result reporting processes, adherence to professional society guidelines, report formatting, test billing, and sample coordination logistics.
The Troubling Issue of VUS
When adopting new genetic tests, a second consideration is the size of a panel. A bigger panel with more genes or genetic markers does not necessarily improve diagnostic clarity. With an increased number of assayed genes comes greater potential for variants of uncertain significance (VUS). These variants can be particularly challenging because genomics is still relatively new and we collectively lack sufficient data to confidently classify variants as pathogenic or benign. In the absence of evidence supporting these classifications, laboratories assign variants to a VUS “holding cell” category. Once sufficient evidence arises, variants originally classified as VUS will be upgraded (to pathogenic or likely pathogenic) or downgraded (to benign or likely benign).
One would predict that approximately half of all VUS would be upgraded and half downgraded. However, in what is termed the “VUS paradox,” there is significant discordance between the expected and observed reclassification of variants. It is much more common for VUS to be reclassified as benign or likely benign (downgraded) than to be upgraded (1). Given the large body of evidence demonstrating that VUS can cause patient harm, labs act irresponsibly if they inappropriately classify variants as VUS. As laboratory stewards, we need to ensure that any gene panel ordered is the best fit for the clinical question at hand instead of using an inappropriately large gene panel likely to result in challenging VUS.
From the perspectives of patients and insurers, it is critical to demonstrate how outcomes will improve as a result of using this new technology. Are these new tests preforming better than current standard of care? In many cases, additional evidence is needed before a test is offered broadly. The following examples in cancer and prenatal settings highlight the promise of novel technologies and questions that should be considered before adopting/implementing more broadly.
Case Example: Cell-free DNA Screening
Cell-free DNA screening was launched in 2012 and meta-analyses have demonstrated superior performance for detecting chromosomal aneuploidies such as Down syndrome relative to existing maternal serum screening tests like the combined and fully integrated screening tests. Since then, cell-free DNA prenatal screening has expanded rapidly, including the recent ability to detect all aneuploidies and even sub-chromosomal copy number alterations such as microdeletions and microduplications.
From a consumer perspective, cell-free DNA prenatal screening is appealing—it’s less invasive than diagnostic testing like amniocentesis and can reveal a baby’s sex in the first trimester of pregnancy. However, this new modality remains a screening test and actually can complicate decision-making when used as a diagnostic test. This is because it tests both maternal and fetal cell-free DNA and uncovers findings that can be difficult to interpret.
For example, numerous cases have been reported of detecting unknown maternal cancer, which is called occult maternal malignancy. If a cell-free DNA prenatal screen identifies a potential maternal cancer, the affected patient necessarily will embark on a diagnostic hunt for a tumor during an already difficult period of pregnancy. This can be challenging from an insurer’s perspective as well because finding a tumor based on cell-free DNA prenatal screening results might necessitate expensive imaging studies.
While there is great promise in expanding the technology of cell-free DNA to detect single-gene Mendelian disorders, the American College of Obstetricians and Gynecologists has issued a practice advisory that, “there has not been sufficient information regarding accuracy and positive and negative predictive value ... [and thus,] single-gene cell-free DNA screening is not currently recommended in pregnancy” (2).
The pace at which new technology is being developed and implemented in clinical settings will undoubtedly stay in the fast lane. As such, laboratorians need to consider how to best integrate novel technologies into clinical practice (or not), striking a responsible balance between true clinical research and ancillary testing.
Using alternate funding sources for clinical research, including risk-sharing partnerships with insurers, has proven successful and may pave the way for clinical research to become true clinical testing.
Practice guidelines are extremely valuable but often lag behind advances in technology precisely because they require a high burden of published evidence. An institutional approach utilizing an oversight committee, such as a laboratory stewardship committee, is an effective vehicle for evaluating implementation of new technologies and shifting appropriately from research to clinical testing when sufficient evidence exists for clinical validity and utility.
The genomic testing era is very exciting, and responsibly implementing a collaborative stewardship program is critical for ensuring that we offer the right test to the right patient at the right time.
- Mersch J, Brown N, Pirzadeh-Miller S, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA 2018;320:1266-74.
- American College of Obstetricians and Gynecologists. Practice advisory: Cell-free DNA to screen for single-gene disorders. https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Advisories/Cell-free-DNA-to-Screen-for-Single-Gene-Disorders (Accessed February 28, 2020).
Tina Lockwood, PhD, DABCC, DABMGG, is an associate professor in the department of laboratory medicine and director of the genetics and solid tumor diagnostics laboratory at the University of Washington in Seattle. +Email: firstname.lastname@example.org