[What is (not) considered normal? - Contemporary challenges of establishing laboratory reference intervals]

One of the foundations of medical decision-making is laboratory diagnostics, an interpretive field of science. The interpretation of results requires the definition of normal and pathological values based on reference intervals. The modern framework of reference intervals has gradually evolved, in parallel with the development of clinical chemistry and laboratory medicine. Nowadays, there are numerous statistical methods available for determining reference intervals, regulated by international guidelines. Based on the approaches to select the required samples for establishing a reference population, current guidelines distinguish between direct and indirect methods for determining reference intervals. In addition to the direct method, which is considered the gold standard, methods based on indirect sampling are gaining ground with the development of laboratory medicine, computer technology and statistics. The indirect methods enable the processing of data sets consisting of tens or hundreds of thousands of results generated during routine measurement, and through retrospective analysis, the calculation of reference intervals. The aim of this review is to present the concept of the reference interval and to provide a concise overview of the main direct and indirect methods used for its establishment. Orv Hetil. 2026; 167(36): 1415-1428.