[Multicenter study on the establishment of continuous reference intervals for capillary blood IGF-1 and IGFBP-3 in...

Objective: To establish continuous reference intervals and curves for insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) measured in capillary blood among children aged 0-6 years in Jiangsu Province. Methods: This multicenter cross-sectional study was conducted from December 1, 2023 to November 30, 2024, enrolling children aged 0-6 years who underwent routine health examinations in the Department of Children Health Care at eight medical institutions across southern and northern Jiangsu Province. All participants completed clinical data collection and anthropometric measurements, and provided fingertip capillary blood samples. The levels of IGF-1 and IGFBP-3 were measured using chemiluminescence immunoassay (CLIA). Generalized additive models for location, scale, and shape (GAMLSS) were used to establish age- and sex- stratified continuous reference intervals and percentile curves for IGF-1 and IGFBP-3 in children aged 0-6 years. To assess sex differences, absolute and relative differences in P₅₀ values between boys and girls were calculated for each age group. Mann-Whitney U tests were employed to conduct age-stratified comparisons of IGF-1, IGFBP-3 levels, and their ratios among children with different weight statuses. An additional 1 013 independent children were included as an external validation sample. They were stratified by age and sex, and the proportions of measurements falling within the corresponding P₃-P₉₇ reference intervals were calculated to evaluate the applicability of the established reference intervals. An interactive online web application was developed to facilitate clinical application and interpretation. Results: A total of 3 195 children were included, comprising 1 679 boys (52.55%) and 1 516 girls (47.45%), with the sample covering southern and northern Jiangsu Province. In both boys and girls, IGF-1 and IGFBP-3 levels were positively correlated with age, height, and weight (r=0.62-0.72, all P<0.001). GAMLSS fitting showed that the P₅₀ of IGF-1 in boys increased from 49.52 ng/ml in the >0-<0.5 years age group to 139.68 ng/ml in the ≥6-<7 years age group, while the corresponding P₃-P₉₇ reference interval changed from 22.05-96.41 ng/ml to 73.61-241.54 ng/ml. In girls, the P₅₀ of IGF-1 increased from 48.63 ng/ml to 154.74 ng/ml, and the corresponding reference interval changed from 16.07-98.90 ng/ml to 77.87-257.91 ng/ml. The P₅₀ of IGFBP-3 in boys increased from 2.00 μg/ml to 3.93 μg/ml, with the corresponding reference interval changing from 1.01-3.16 μg/ml to 2.44-5.62 μg/ml. In girls, the P₅₀ of IGFBP-3 increased from 1.99 μg/ml to 4.23 μg/ml, and the corresponding reference interval changed from 0.96-3.01 μg/ml to 2.47-5.99 μg/ml. Except for the >0-<0.5 years age group, IGF-1 levels were higher in girls than in boys across all other age groups, and IGFBP-3 showed a similar sex-related pattern. In addition, IGF-1 levels were higher in overweight/obese children than in normal-weight children only in the ≥2-<3 years and ≥6-<7 years age groups (Z=-2.155 and -2.629; P=0.031 and 0.009), and IGFBP-3 levels were also elevated only in these two age groups (Z=-2.711 and -2.646; P=0.007 and 0.008). The IGF-1/IGFBP-3 molar ratio showed no significant difference between the two groups in any age group (Z=-0.870 to -0.232, all P>0.05). External validation showed that 90.16%-100.00% of IGF-1 and IGFBP-3 measurements in each age-and sex-specific group fell within the corresponding P₃-P₉₇ reference intervals. The developed online web application automatically determines a child's percentile position on the corresponding age-and sex-stratified reference curve based on sex, age, and measured values. Conclusion: This study established continuous reference intervals for capillary blood IGF-1 and IGFBP-3 and developed an online assessment tool for children aged 0-6 years in Jiangsu Province. These findings may provide reference data and a convenient tool for regional assessment of childhood growth and development, nutritional status screening, and early identification of growth faltering.