This document represents an update to the proposed approach of the American College of Medical Genetics and Genomics (ACMG) to categorize laboratory-developed tests (LDTs) for inherited conditions according to risk.1 Risk classification has historically been a determinant of whether, and to what extent, the US Food and Drug Administration (FDA) has overseen and regulated clinical tests. LDTs for constitutional variants continue to proliferate without a comprehensive federal regulatory framework in place. Therefore, an ACMG-appointed workgroup of laboratory and clinical geneticists considered the analytical and health care–related risks and implications resulting from laboratory testing of constitutional genetic information in a variety of contexts to develop a proposed approach. This document is provided as a proposed framework to guide federal agencies, policymakers, and other stakeholders.
The ACMG, through this document, has categorized testing for inherited conditions by utilizing a three-tiered risk-based system (Table 1) incorporating two elements. The first element is consistent with the usual FDA determination of testing-associated risk, whereby the FDA aligns risk with medical decision making based on the test results and the clinical significance of an erroneous result. The second element considers factors that impact analytical performance and the likelihood of an erroneous result based on methodology. It is recognized that novel technologies for an otherwise lower risk clinical application could temporarily place that test in a higher risk category until additional experience with the methodology is gained. The risk model specifies criteria that define each level of risk and identifies mitigating factors that could potentially lower the chance of inappropriate or harmful clinical action based on the test result. It should be recognized that genetic testing is a process including not only the analytical phase addressed in this document, but also preanalytical and postanalytical components, which are beyond the scope of this document. Patient harm can occur in the preanalytical phase (e.g., lack of education/counseling, disregard for the informed consent process, incorrect test ordered) as well as postanalytically in the delivery of results and subsequent clinical follow-up.
Although the ACMG agrees that the elements recommended by the College of American Pathologists be included in the oversight framework for LDTs,2 we recommend additional considerations for clinical constitutional genetic testing. When initially considering risk level, there are elements that can reduce overall risk of a test, irrespective of the indication for testing (e.g., diagnostic, presymptomatic, predisposition, and pharmacogenomic genetic testing; carrier detection; preimplantation genetic diagnosis; and prenatal testing). These elements include factors such as (1) using nonproprietary methods or algorithms, (2) being amenable to interlaboratory comparisons, and (3) being evaluated by external proficiency testing. We are also proposing recommendations for laboratory director oversight of testing based upon risk (Table 1). Published data are available demonstrating that LDTs developed, validated, and performed within an experienced laboratory supervised by appropriately credentialed individuals are generally accurate.3 Finally, as risk also exists in the pre- and postanalytical phases, we recommend pre- and post-test educational content/counseling developed and/or delivered by an appropriately trained professional, particularly for higher complexity tests.
Monaghan KG, Benkendorf J, Cherry AM, et al. Risk categorization for oversight of laboratory-developed tests for inherited conditions. Genet Med. 2013;15:314–315.
College of American Pathologists. Summary of CAP’s legislative proposal for the regulatory framework of laboratory-developed tests (LDTs). 2015. https://documents.cap.org/documents/2015-cap-ldt-legislative-proposal.pdf. Accessed 3 July 2019.
Weck E, Schrijver I. A panoramic view of the accuracy of molecular genetic testing. Genet Med. 2016;18:1188–1199.
E.D.E. wishes to disclose stock ownership in Invitae and S.T.S. wishes to disclose stock ownership in 23andMe, Ancestry, and Peel Therapeutics. The other authors declare no conflicts of interest. All authors (except S.T.S., M.M., J.B., and M.S.W.) direct clinical testing laboratories that use laboratory-developed tests.
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This statement is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.
Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.
The Board of Directors of the American College of Medical Genetics and Genomics approved this position statement on 16 December 2019.
Correspondence: ACMG (email@example.com)
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South, S.T., McClure, M., Astbury, C. et al. Risk categorization for oversight of laboratory-developed tests for inherited conditions: an updated position statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med 22, 983–985 (2020). https://doi.org/10.1038/s41436-020-0765-x