Impact of age partitioning on classification discordance in pediatric ferritin reference intervals

To evaluate how alternative age-partitioning strategies affect result classification using discrete pediatric ferritin reference intervals (RIs).

In a prospective cohort of 3,322 apparently healthy individuals aged birth to <19 years, serum ferritin was measured on the Cobas Pro platform. A common preprocessing pipeline, including Horn's algorithm, was applied once before all comparisons. Five age-partitioning schemes were evaluated: a data-driven classification and regression tree (CART)-based scheme (Scheme 1, reference), a physiology-informed high-resolution scheme, a CLSI-informed scheme, and two progressively broader pragmatic schemes. Nonparametric RIs were derived, and classification performance was assessed using apparent and out-of-bag (OOB) flagging rates, age-resolved analyses, discordance relative to Scheme 1, and boundary-focused and Lahti's evaluations.

Overall flagging rates were similar across schemes (5.06-5.33 % apparent; 5.23-5.80 % OOB). However, substantial age-specific differences were observed. Discordance relative to Scheme 1 was lowest for Scheme 3 (1.99 %) and similarly low for Scheme 2 (2.26 %), but increased for Schemes 4 and 5 (3.76-4.64 %). Boundary discordance reached 15.0 % at 6 months in broader schemes and reached 11.84 % at adolescent transitions. Age-resolved analyses showed marked heterogeneity during infancy, with overall flagging rates varying up to threefold between schemes within adjacent monthly bins. Lahti's evaluation confirmed non-interchangeability of adjacent partitions, particularly in early infancy.

Despite similar overall flagging rates, marked age-specific classification differences occur, particularly in early infancy and around key developmental boundaries. Broader partitions may obscure physiological variation and increase classification discordance. Age-resolved evaluation should complement statistical criteria when defining pediatric RIs.