Reference Intervals for Hemoglobin and Hematocrit Adjusted for Altitude, Sex, and Age: A Big Data-Based Study in the...

Background: Hemoglobin (Hb) and hematocrit (Hct) reference intervals (RIs) are critical for diagnosing hematological disorders. However, existing reference values often do not account for demographic and environmental variability. Particularly in countries with altitude gradients, such as Colombia, the absence of locally adjusted intervals may lead to the misclassification of anemia and polycythemia. Therefore, this study aims to establish sex-, age-, and altitude-specific reference intervals for Hb and Hct within the Colombian adult population via an indirect, big-data-based methodology. Methods: This retrospective cross-sectional study used 3.1 million Hb and Hct test results nationwide between 2022 and 2024. After applying the exclusion criteria, Hb data from 667,857 individuals and Hct data from 662,024 individuals were included. The population was stratified by sex, age, and altitude into <1100 m above sea level (m.a.s.l.), 1100-2000 m.a.s.l., and 2000-3000 m.a.s.l. Reference intervals (RIs) were estimated via the refineR algorithm, and the results were compared across altitude categories and against World Health Organization (WHO) anemia and polycythemia thresholds. Results: Hb and Hct concentrations increased with altitude in all sexes and age groups. Compared with women, men presented higher mean values and narrower RIs, whereas older adults presented greater variability. Compared with WHO thresholds, a significant proportion of individuals living above 2000 m exceeded polycythemia cutoffs without clinical evidence of disease, suggesting the need for altitude-adjusted diagnostic criteria. Conclusions: This study provides the first large-scale, data-driven reference intervals for Hb and Hct in Colombia, adjusted for altitude, sex, and age. The implementation of locally derived RIs may improve diagnostic accuracy and prevent the over- or underdiagnosis of hematological disorders, with direct implications for clinical decision-making and public health policy.