Abstract
OBJECTIVE: Despite the universal calibration of commercial IGF1 immunoassays to WHO IS 02/254, substantial inter-assay variability persists, leading to inconsistent patient classification. Harmonization towards a higher-order analytical anchor may reduce such variability. METHODS: Four matrix-matched, multi-level serum reference materials (RMs) were prepared from donor serum and value-assigned using an LC-MS/MS method calibrated to WHO IS 02/254. Commutability was assessed according to IFCC recommendations across four immunoassays (Cobas, iSYS, Immulite, Liaison). Deming regression-based recalibration equations derived from commutable RMs were applied to patient samples and healthy donor samples. The primary quantitative endpoint was reduction in standard error of estimate (SEE) relative to the LC-MS/MS method. Age- and sex-specific LC-MS/MS-anchored reference intervals were constructed as a downstream application. RESULTS: Prior to recalibration, immunoassays showed positive bias relative to LC-MS/MS of up to 60%. All four RMs were commutable for Liaison and iSYS, whereas the lowest concentration RM was classified as non-commutable for Cobas and Immulite. Recalibration towards the LC-MS/MS anchor resulted in marked alignment towards the identity line and reduced pooled SEE from 7.82 to 4.89 nmol/L (-37.4%) in patient samples and from 7.34 to 2.09 nmol/L (-71.5%) in healthy samples. Although harmonization effects were assay-dependent at the individual platform level, overall cross-platform dispersion was substantially attenuated. CONCLUSIONS: Matrix-matched, commutable serum RMs value-assigned by a higher-order LC-MS/MS procedure enable substantial reduction of inter-assay bias and variability among IGF1 immunoassays. Harmonization towards a higher-order analytical anchor is achievable in routine practice and provides a robust foundation for consistent cross-platform interpretation.