Reference intervals: the way forward

New facts have recently enhanced interest in the topic of reference intervals. In particular, the International Organization for Standardization standard 15189, requesting that 'biological reference intervals shall be periodically reviewed', and the directive of the European Union on in vitro diagnostic medical devices asking manufacturers to provide detailed information on reference intervals, have renewed interest in the subject. This review presents an update on the topic, discussing the theoretical aspects and the most critical issues. The basic approach to the definition of reference intervals proposed in the original International Federation of Clinical Chemistry documents still remain valid. The use of data mining to obtain reference data from existing databases has severe limitations. New statistical approaches to discard outliers and to compute reference limits have been recommended. On the other hand, perspectives opened by the improvement in standardization through the implementation of the concept of traceability suggest new models to define 'common' reference intervals that can be transferred and adopted by different clinical laboratories in order to decrease the proliferation of different reference intervals not always justified by differences in population characteristics or in analytical methodology.