Review of potentials and limitations of indirect approaches for estimating reference limits/intervals of quantitative procedures in laboratory medicine

Abstract

Reference intervals (RIs) can be determined by direct and indirect procedures. Both approaches identify a reference population from which the RIs are defined. The crucial difference between direct and indirect methods is that direct methods select particular individuals after individual anamnesis and medical examination have confirmed the absence of pathological conditions. These individuals form a reference subpopulation. Indirect methods select a reference subpopulation in which the individuals are not identified. They isolate a reference population from a mixed population of patients with pathological and non-pathological conditions by statistical reasoning. At present, the direct procedure internationally recommended is the "gold standard". It has, however, the disadvantage of high expenses which cannot easily be afforded by most medical laboratories. Therefore, laboratories adopt RIs established by direct methods from external sources requiring a high responsibility for transference problems which are usually neglected by most laboratories. These difficulties can be overcome by indirect procedures which can easily be performed by most laboratories without causing economic problems. The present review focuses on indirect approaches. Various procedures are presented with their benefits and limitations. Preliminary simulation studies indicate that more recently developed concepts are superior to older approaches.