A global multicenter study on reference values: 1. Assessment of methods for derivation and comparison of reference intervals

Committee on Reference Intervals and Decision Limits, International Federation of Clinical Chemistry and Laboratory Medicine

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Objectives The IFCC Committee on Reference Intervals and Decision Limits coordinated a global multicenter study on reference values (RVs) to explore rational and harmonizable procedures for derivation of reference intervals (RIs) and investigate the feasibility of sharing RIs through evaluation of sources of variation of RVs on a global scale. Methods For the common protocol, rather lenient criteria for reference individuals were adopted to facilitate harmonized recruitment with planned use of the latent abnormal values exclusion (LAVE) method. As of July 2015, 12 countries had completed their study with total recruitment of 13,386 healthy adults. 25 analytes were measured chemically and 25 immunologically. A serum panel with assigned values was measured by all laboratories. RIs were derived by parametric and nonparametric methods. Results The effect of LAVE methods is prominent in analytes which reflect nutritional status, inflammation and muscular exertion, indicating that inappropriate results are frequent in any country. The validity of the parametric method was confirmed by the presence of analyte-specific distribution patterns and successful Gaussian transformation using the modified Box-Cox formula in all countries. After successful alignment of RVs based on the panel test results, nearly half the analytes showed variable degrees of between-country differences. This finding, however, requires confirmation after adjusting for BMI and other sources of variation. The results are reported in the second part of this paper. Conclusion The collaborative study enabled us to evaluate rational methods for deriving RIs and comparing the RVs based on real-world datasets obtained in a harmonized manner.

Original languageEnglish (US)
Pages (from-to)70-82
Number of pages13
JournalClinica Chimica Acta
StatePublished - Apr 1 2017


  • Ethnic differences
  • Harmonization
  • Latent abnormal values exclusion method
  • Modified Box-Cox power transformation
  • Multicenter study
  • Reference intervals
  • Serum panel
  • Standard deviation ratio
  • Standardization

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Biochemistry, medical


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