The evolution of the reference value concept

Clin Chem Lab Med. 2004;42(7):692-7. doi: 10.1515/CCLM.2004.118.


This manuscript reviews the introduction of the concept of reference values, the corresponding philosophy, and subsequent recommendations reflecting the different subtopics of the field. The generally unrecognised phenomenon that laboratory results of the population tended to be lognormal instead of Gaussian attracted the attention of the author, who became sceptical of the concept of normal values because of its ambiguity. Together with N.-E. Saris a new concept of reference values was launched at a congress in 1969. Briefly, clinical measurements should be interpreted against values from proper control subjects. Subsequently international, regional and national societies established expert panels which produced recommendations covering the general principles and terminology of reference values, the concept of health, standardised specimen collection and preanalytical factors, statistical treatment of collected values, stratification of data, relating observed (patient) values to reference values, etc. The importance of using correct terminology, taking into consideration the aim of ordering the laboratory test and some neglected procedures (e.g., survival values) are emphasised. New developments such as reference changes are mentioned. The field has evolved largely as the result of constructive international teamwork.

Publication types

  • Historical Article
  • Review

MeSH terms

  • Chemistry, Clinical / history
  • Chemistry, Clinical / standards*
  • Clinical Chemistry Tests / history
  • Clinical Chemistry Tests / standards
  • History, 20th Century
  • History, 21st Century
  • Humans
  • Philosophy, Medical / history
  • Practice Guidelines as Topic
  • Reference Values*
  • Statistical Distributions