Reference Values for IGF-I Serum Concentrations: Comparison of Six Immunoassays

Abstract

Context:Measurement of IGF-I is essential for diagnosis and management of patients with disorders affecting the somatotropic axis. However, even when IGF-I kit manufacturers follow recent consensus guidelines, different kits can give very different results for a given sample.Objectives:We sought to establish normative data for six IGF-I assay kits based on a large random sample of the French general adult population.Subjects and Methods:In a cross-sectional multicenter cohort study, we measured IGF-I in 911 healthy adults (18–90 years) with six immunoassays (iSYS, LIAISON XL, IMMULITE, IGFI RIACT, Mediagnost ELISA, and Mediagnost RIA). Pairwise concordance between assays was assessed with Bland-Altman plots for both IGF-1 raw data and standard deviation scores (SDS), as well as with the percentage of observed agreement and the weighted Kappa coefficient for categorized IGF-I SDS.Results:Normative data included the range of values (2.5–97.5 percentiles) given by the six IGF-I assays according to age group and sex. A formula for SDS calculation is provided. Although the lower limits of the reference intervals of the six assays were similar, the upper limits varied markedly. Pairwise concordances were moderate to good (0.38–0.70).Conclusion:Despite being obtained in the same healthy population, the reference intervals of the six commercial IGF-1 assay kits showed noteworthy differences. Agreement between methods was moderate to good.

Classification of Patients With GH Disorders May Vary According to the IGF-I Assay

“…In each patient, IGF-I values were measured with the six assay kits (see below) used in the recently published VARIETE study (13). The main characteristics of the assays are shown in Supplementary Table 1.…”

“…The normative reference data that we used to classify patients as having "normal", "high" or "low" IGF-I levels were obtained in the VARIETE study (13). In brief, this study was a cross-sectional, multicenter (24 centers), French nationwide cohort study (ClinicalTrials.gov ID NCT01831648) designed to develop reference normative sexand age-adjusted IGF-I data for the adult general population, for each of the different …”

“…and were reported in mass units and SDS. Nevertheless, although we ensured the same pre-analytical conditions for all six immunoassays, and although four of the six assays were calibrated against the same international reference standard 02/254, concordance across the assays remained variable, both for raw data and IGF-I SDS (13).…”

“…Furthermore, the distribution of IGF-I levels in healthy populations is non Gaussian, and transformations are thus necessary to obtain normal distributions and to calculate standard deviation scores (SDS). This prompted us to conduct the VARIETE study (VAleurs de Référence de l'IGF-I Et Transformation En Z-score) in order to establish normative reference values for six IGF-I immunoassays in the same healthy adult population, using the same statistical method to calculate SDS (13). We postulated that this would help to longitudinally assess disease control in a given patient using the IGF-I SDS, even if IGF-I was measured with more than one assay during follow up.…”

Diagnosis of acromegaly: black, white… and sometimes gray!

“…Reference IGF-I values may therefore be influenced by the inclusion criteria used to select the reference population. Elsewhere, comparisons of IGF-I assay kits show that, even in the same healthy population, IGF-I reference ranges can differ: as a result, some individuals considered to have "high" IGF-I levels measured with one assay kit may have "normal" levels when another kit is used (9). Finally, by definition, 5% of the healthy population have IGF-I levels either above the 97.5 th percentile or below the 2.5 th percentile.…”