Multicenter reference intervals studies: a promising perspective for the future?

Abstract

Up to now the establishment of reference limits has been based on the recommendations of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC-LM) which give greater place to determining reference intervals (RIs) in each laboratory [ 1 ]. In fact, the situation is complex: regulations (e.g., European Directive 98/79/EC [ 2 ] and the new revised version pending approval) require that manufacturers mention RIs in the package inserts (for all countries). Clinical laboratories are responsible for RIs printed on laboratory reports (ISO 15189) [ 3 ]. Laboratories should also verify them if they use RIs from literature or manufacturers. Also, producing RIs is actually too expensive and a heavy task for most laboratories. Alternatives have been proposed, such as the determination of RIs from databases from each laboratory (data mining) [ 4 ], but relevant clinical information, needed to select healthy individuals, is rarely available. That is why the IFCC/ CLSI remains reserved on this method. The production of common RIs for homogeneous populations shared by all laboratories within a country or a region has attracted a lot of interest. In Spain, the Catalan Association for Clinical Laboratory Science has demonstrated that it is possible to establish common RIs for an entire country for laboratories using the same equipment and reagents, with ensured metrological traceability [ 5 ]. Almost simultaneously, a Nordic European Group proposed a new concept of shared reference values based on the recommendations of the IFCC-LM, but specifying prerequisites [ 6 ]. This protocol is based on the need for a common standardization and traceability throughout the production phase of the reference values. A process of external quality control using commutable materials (no matrix effect) and traceable to the same reference method is implemented. The analytical specifications will be defined beforehand. These authors point out that there are no recommendations for the selection of reference individuals, these being dependant on the study objectives. However, if the subgroups are large enough ( > 500) the partitioning criteria can be applied and the confidence limits for RIs will be small. This protocol applied to a group of laboratories in several Scandinavian countries has shown its effectiveness. On behalf of the IFCC-LM, Ceriotti [ 7 , 8 ] completed these prerequisites to determine common RIs: 1) the population that the laboratory services is similar to the one studied; 2) careful study design; 3) use of traceable analytical methods; 4) predefined analytical goals; 5) adequate statistical treatment.In this issue, Ichihara et al. present two very ambitious articles [ 9 , 10 ] attempting to provide answers to many questions: 1) observe possible differences between the populations studied in seven regions of East and SouthEast Asia and in seven regions of Japan; 2) assess the possible need for partitioning RIs; 3) derive common RIs for standardized analytes (traceable to a reference method); 4) propose a ...

Serum Thymidine Kinase Activity: Analytical Performance, Age-Related Reference Ranges and Validation in Chronic Lymphocytic Leukemia

“…These differences make it difficult to obtain universally applicable reference intervals, even though the applied methodology is traceable to reference measurement systems [46], [47]. As producing reference ranges is an expensive task for an individual laboratory, one possible solution is to establish reference ranges for a homogeneous population by involving all the laboratories measuring the certain analyte with the same method [47]. Siest et al emphasized that the boundaries between healthy and pathological conditions are not clear-cut, and reference intervals or cut-off values should be established to expedite clinical decision making [48].…”