As the world becomes more mobile and connected, interpretation of biomarkers is becoming more challenging for laboratory medicine professionals and clinicians. Many assays may be available for a biomarker. But do they all give the same result? Not necessarily. This is especially a problem for immunoassays because they are so complex. While international standardization and harmonization efforts have improved this situation for some tests, challenges remain that impact patient care. These topics were covered in yesterday’s short course, “Challenges and Clinical Impacts of Standardization of Immunoassays,” by Bernard Cook, PhD, Catherine Sturgeon, PhD, and Dina Greene, PhD.
Cook described the challenges and successes in standardizing cancer antigen assays. Found in healthy subjects as well as in those with disease, these analytes are poorly defined and are mainly peptides measured by immunoassays. Depending on antibody selection, epitope recognition, and standards used, the assays give widely different results. The solution is international harmonization, by which assay manufacturers try to coordinate so that all assays give the same results for a recognized international reference material. Cook said, that if harmonization succeeded for endocrine and cardiac markers, it should work for cancer markers too. He cautioned about the challenges—how commercial assay manufacturers find it difficult to change standardization because of regulatory burdens.
It is true that international reference materials have improved harmonization for cardiac troponin I (cTnI). Across multiple assays, imprecision reduced from a median 88% to 15.5% because of harmonization. But commutability of reference material and analyte heterogeneity makes further improvement difficult. Now as the marker is increasingly used in assessing cardiac health, what analytical cutoffs need to be used? The Third Universal Definition of Myocardial Infarction includes a rise or fall in cardiac biomarkers with at least one value above the 99th percentile upper reference limit. But the difficulty of immunoassay standardization is amplified in these very low analytical results. Greene demonstrated how the interpretation of cTnI test results in the low ranges can lead to misdiagnosis and adverse patient outcomes.
Finally, Sturgeon described standardization of endocrine, and especially steroid assays. Even though steroids are available as pure compounds, harmonization has been difficult. One challenge is the availability of a reliable reference range. On the other hand, thyroid analytes are examples of a successful harmonization program. Sturgeon noted recent successes for vitamin D and testosterone testing.
The success stories were inspiring. Leaders in laboratory medicine have initiated global harmonization efforts for many analytes. We may not remove interassay variability completely, but the situation is definitely improving.