Sex and race shape serum protein biomarkers and bias diagnostic reference intervals

Authors

Son, A., Ji, J., Han, E., Choi, Y., Park, J., Lee, H., Park, S., Kim, H.

Abstract

Clinical protein biomarkers, whether measured by FDA-cleared in-vitro diagnostic (IVD) assays or deployed as laboratory-developed tests (LDTs), are routinely interpreted against fixed, population-agnostic reference intervals. Whether the baseline serum concentrations of these proteins differ systematically by sex and by self-reported race in healthy individuals has not been tested across a broad clinical panel on a single standardized platform. Using scheduled multiple reaction monitoring-mass spectrometry (MRM-MS) with stable-isotope-labelled internal standards, we quantified 87 proteins (39 FDA-cleared analytes; 48 LDT/research markers) in 60 healthy, age-matched donors balanced across three races (White, Hispanic, Black) and both sexes. Sex was a pervasive axis of variation: donors separated by sex in unsupervised multivariate space (PERMANOVA p = 0.020) but not by race (p = 0.14). Three FDA-target proteins differed by sex at FDR q < 0.05: sex hormone-binding globulin, haemoglobin-, and albumin, with directions preserved within every race. Race differences were real but protein-specific, exemplified by ancestry-associated CD14. Critically, applying a single pooled 95% reference interval mis-flagged as many as ~25% of a demographic subgroup as abnormal, versus the 5% expected. Demographic context should therefore be incorporated into reference intervals and decision thresholds for protein-based diagnostics.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 24 Jul 2026.

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