Functional reference limits: a case study of serum ferritin

Reference intervals depend on the distribution of results within a reference population and can be influenced by subclinical disease. Functional reference limits present an opportunity to derive clinically relevant reference limits from routinely collected data sources, which consist of mixed populations of unhealthy and healthy groups. Serum ferritin is a good example of the utility of functional reference limits. Several studies have identified clinically relevant reference limits through examining the relationship between serum ferritin and erythrocyte parameters. These ferritin functional limits often represent the inflection point at which erythrocyte parameters change significantly. Comparison of ferritin functional reference limits with those based on population distributional reference limits reveals that the lower reference limit may fall below the point at which patients become clinically unwell. Functional reference limits may be considered for any biomarker that exhibits a correlated relationship with other biomarkers.