New Reference Measurement Procedure Standardizes Nucleic Acid Amplification Test Results

Nucleic acid amplification tests (NAATs) play a key role in diagnosing a wide range of infectious diseases. These tests are generally known for their high sensitivity and specificity, and they can be developed and adjusted quickly. However, creating standards to confirm that NAATs are operating correctly is much more difficult. Developing reference materials is time-consuming, and appropriate reference measurement procedures (RMPs) have been lacking. A global team of laboratory measurement specialists has now demonstrated that the accuracy of digital PCR can be used to establish an RMP capable of harmonizing results from nucleic acid amplification-based diagnostic tests across laboratories. This method may also offer a solution for performing quality assurance even when physical control materials are unavailable.

The National Measurement Laboratory (NML) at LGC (Middlesex, UK), which serves as the UK's Designated Institute for Chemical and Biological Metrology, has a long-standing reputation for delivering high-accuracy reference methods and materials to ensure the reliability of diagnostic measurements for infectious diseases. In their research, the team employed digital PCR as a reference method to align test outcomes across various labs. This kind of standardization is especially crucial for diagnostic tests used in the absence of clinical criteria—for example, in screening asymptomatic individuals or when immediate clinical decisions are needed and there is no time for confirmatory tests. By leveraging the precision of digital PCR, the international research team led by the NML at LGC has created an RMP that aligns NAAT results. Their findings, published in the journal Clinical Chemistry, offer a path to support quality assurance even before international reference materials are available to ensure traceability.

An editorial in Clinical Chemistry underscored how, during the COVID-19 pandemic, diagnostic labs rapidly developed and deployed NAATs to help control the spread of the virus. Initially, the sensitivity of these tests was unknown, and it was later discovered that performance varied significantly. In the worst cases, tests with low sensitivity produced false-negative results, which, if relied upon, could contribute to the unchecked transmission of the disease. Physical reference materials allow labs to compare NAAT outcomes as part of external quality assurance (EQA) programs. But these materials are slow to produce and cannot be created and distributed at the same speed as the diagnostic tests they are intended to support.

This work examines how RMPs can be used as an additional pathway to support standardization alongside physical reference materials. Unlike the latter, RMPs can be developed and applied as rapidly as new diagnostic tests, which is particularly important for managing infectious diseases. The research aligns with the broader efforts of the NML at LGC and the global metrology community to emphasize the critical role of accurate and timely diagnostics in preparing for future pandemics, recognizing that it is not a question of if another outbreak will occur, but when.

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