Separating disease and health for indirect reference intervals

Abstract The indirect approach to defining reference intervals operates ‘ a posteriori ’, on stored laboratory data. It relies on being able to separate healthy and diseased populations using one or both of clinical techniques or statistical techniques. These techniques are also fundamental in a priori , direct reference interval approaches. The clinical techniques rely on using clinical data that is stored either in the electronic health record or within the laboratory database, to exclude patients with possible disease. It depends on the investigators understanding of the data and the pathological impacts on tests. The statistical technique relies on identifying a dominant, apparently healthy, typically Gaussian distribution, which is unaffected by the overlapping populations with higher (or lower) results. It depends on having large databases to give confidence in the extrapolation of the narrow portion of overall distribution representing unaffected individuals. The statistical issues involved can be complex, and can result in unintended bias, particularly when the impacts of disease and the physiological variations in the data are under appreciated.