Central laboratory reassessment of IGF-I, IGFBP-3 and GH serum concentrations measured at local treatment centers in growth-impaired children: implications for the agreement between outpatient screening and the results of somatotropic axis functional testing

Childhood GH deficiency, suspected in the presence of decreased height velocity and short stature, is usually characterized by low IGF-I and IGFBP-3 serum concentrations, and is conventionally confirmed by diminished GH peak responses to pharmacological stimuli. We evaluated the agreement between different IGF-I, IGBPB-3 and GH assays in predicting and confirming GH deficiency. We tested whether variability between growth factor screening and pharmacological testing could be diminished by reassessment of growth factor and GH peak concentrations in a single laboratory. Methods: 699 peak GH sera obtained during GH functional testing of 382 children and adolescents with growth disorders from 19 centers were remeasured using 3 GH reference assays and compared with the results obtained with the local assays. Further, 317 (321) sera from these children from which IGF-I and IGFBP-3 measurements had been obtained, were reanalysed using the Tuebingen IGF-I (IGFBP-3) RIA. A subgroup of 132 (103) patients with the combination of insulin hypoglycemia test and arginine test was evaluated for changes in the assignment to the diagnostic group of GH deficiency (changes in the association between growth factor screening and GH functional testing). Results: GH: The mean difference between GH methods ranged from 5.4 to 10.3 mU/L, slopes of the regression lines from 1.28 to 1.65. Significant nonlinearity was detected in 5 of 6 assay comparisons. Overall agreement between reference and local assays was only moderate. Based on GH remeasurement by one reference assay, 36 of 132 patients were categorized differently, with 35 patients changing into the GH-deficient group. Similar findings were obtained with the other reference assays. Locally measured IGF-I correlated better than IGFBP-3 with the results of the central laboratory (Tuebingen) assay (slope of the regression curve 1.05; 95% CI 1.01–1.1 vs. 1.18; 95% CI 1.09–1.3). Agreement between local and central laboratory assays in predicting GH deficiency was better for IGF-I than for IGFBP-3 assays (kappa=0.59 vs. kappa=0.47). The poor agreement between growth factor screening and GH pharmacological testing was not improved when hormone concentrations were remeasured in the central laboratory (kappa local=0.0031, central=0.12). Conclusions: To decrease variability in GH testing related to assays and cutoff values, we recommend nationwide reassessment of GH peak sera in reference centers. Decisions to treat GH deficiency should incorporate the reference center results. Further, in children with impaired growth, growth factor screening reflects different aspects of GH insufficiency than does functional testing. Agreement between these approaches is poor and could not be improved by reduction of assay-related variability.