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Establishing gender- and age-specific reference ranges for eight tumor markers in adults based on real-world data
Yanting Li1, Jinyu Zhao1, Huidi Peng1
1Department of Clinical Laboratory, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
Objectives:
To establish and validate age- and sex-specific reference intervals (RIs) for eight common tumor markers using large-scale real-world data (RWD) and to compare the performance of five indirect statistical algorithms for RI derivation.
Methods:
This retrospective study included 404,347 individuals undergoing health examinations at The University of Hong Kong-Shenzhen Hospital between October 2022 and December 2024. Distribution characteristics and age-related trends were evaluated using kernel density estimation and generalized additive models. After age and sex stratification, RIs for AFP, CA125, CA15-3, CA19-9, CEA, fPSA, tPSA, and the fPSA/tPSA ratio were established using the Tukey, Z-score, Gaussian mixture model (GMM), isolation forest (IF), and local outlier factor (LOF) methods. Performance was assessed by bias ratios and validated using an independent cohort.
Results:
Most tumor markers exhibited markedly right-skewed distributions, whereas the fPSA/tPSA ratio showed only moderate skewness. AFP and CEA showed negligible sex differences. Age-specific stratification was identified for male AFP, female CA125 and CA15-3, CA19-9, CEA, and prostate-related markers. Tukey and Z-score methods showed the greatest agreement and achieved validation pass rates of ≥90 % across all demographic and analyte subgroups. In contrast, GMM and IF failed validation in 11 subgroups, and LOF failed in 6 subgroups, mainly because of the over-exclusion of high-end values.
Conclusions:
Large-scale RWD enabled robust age- and sex-specific RIs for eight tumor markers. For highly right-skewed tumor marker data, the Tukey and Z-score methods outperformed GMM, IF, and LOF, providing reliable and practical approaches for clinical RI establishment.