Harmonization of IGF1 immunoassays towards a higher-order LC-MS/MS reference anchor

Area of Science:

• Clinical Chemistry
• Biomarker Measurement
• Analytical Chemistry

Background:

• Commercial insulin-like growth factor 1 (IGF1) immunoassays exhibit significant inter-assay variability despite universal calibration.
• This variability leads to inconsistent patient classification and challenges in clinical interpretation.
• Harmonization using a higher-order analytical anchor is proposed to mitigate these issues.

Purpose of the Study:

• To develop and evaluate matrix-matched, commutable serum reference materials (RMs) for harmonizing IGF1 immunoassays.
• To assess the impact of recalibration using a higher-order liquid chromatography-tandem mass spectrometry (LC-MS/MS) anchor on inter-assay variability.
• To construct harmonized, age- and sex-specific reference intervals.

Main Methods:

• Four multi-level, matrix-matched serum RMs were prepared and value-assigned using an LC-MS/MS method.
• Commutability of RMs was assessed across four commercial immunoassays (Cobas, iSYS, Immulite, Liaison).
• Deming regression was used to derive recalibration equations, and the reduction in standard error of estimate (SEE) was the primary endpoint.

Main Results:

• Prior to recalibration, immunoassays showed positive bias up to 60% compared to LC-MS/MS.
• Recalibration using commutable RMs significantly reduced pooled SEE by 37.4% in patient samples and 71.5% in healthy samples.
• Cross-platform dispersion was substantially attenuated, although harmonization effects varied by assay.

Conclusions:

• Matrix-matched, commutable RMs value-assigned by a higher-order LC-MS/MS method effectively reduce inter-assay bias and variability in IGF1 immunoassays.
• Harmonization toward a higher-order analytical anchor is feasible in routine practice.
• This approach provides a foundation for consistent cross-platform interpretation of IGF1 results.