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


CONCLUSIONS
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.
Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan. Electronic address: ichihara@yamaguchi-u.ac.jp.
Kiyoshi
K
Ichihara
Dept of Medical Biochemistry, Uludag University School of Medicine, Bursa, Turkey.
Yesim
Y
Ozarda
Blood Sciences, Leeds General Infirmary, Leeds, UK.
Julian H
JH
Barth
Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
George
G
Klee
Dept of Clinical Laboratory, Peking Union Medical College, Beijing, China.
Ling
L
Qiu
Chemical Pathology, University of Stellenbosch and National Health Laboratory Services, Tygerberg, South Africa.
Rajiv
R
Erasmus
King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Pathology, King Abdulaziz Medical City, Jeddah, Saudi Arabia.
Anwar
A
Borai
Beckman Coulter LLC, Moscow, Russia.
Svetlana
S
Evgina
Dept of Laboratory Medicine, P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India.
Tester
T
Ashavaid
Dept of Pathology, National University of Medical Sciences, Rawalpindi, Pakistan.
Dilshad
D
Khan
Dept of Clinical Biochemistry, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.
Laura
L
Schreier
Newborn Screening Center Visayas, West Visayas State University Medical Center, Iloilo, Philippines.
Reynan
R
Rolle
Dept of Medical Life Science, Faculty of Medical Bioscience, Kyushu University of Health and Welfare, Nobeoka, Japan.
Yoshihisa
Y
Shimizu
Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Shogo
S
Kimura
Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan; Clinical Research Center, Yamaguchi University Hospital, Ube, Japan.
Reo
R
Kawano
Abbott Laboratories, Abbott Park, IL, USA.
David
D
Armbruster
Beckman Coulter Japan, Tokyo, Japan.
Kazuo
K
Mori
Dept of Biochemistry, Maharajgunj Medical Campus, Institute of Medicine, Kathmandu, Nepal.
Binod K
BK
Yadav
D019411:Clinical Laboratory Techniques / Q000592:standards*; D064368:Healthy Volunteers; D006801:Humans; D038622:Internationality; D016011:Normal Distribution; D012016:Reference Values
Ethnic differences; Harmonization; Latent abnormal values exclusion method; Modified Box-Cox power transformation; Multicenter study; Reference intervals; Serum panel; Standard deviation ratio; Standardization