A global multicenter study on reference values: 2. Exploration of sources of variation across the countries.

This global multicenter study on reference values (RVs) allowed us to explore biological sources of variation (SVs) of RVs across the world.As described in the first part of this paper, RVs of 50 major analytes from 13,396 healthy individuals living in 12 countries were obtained. Analyzed in this study were 23 clinical chemistry analytes and 8 analytes measured by immunoturbidimetry. Multiple regression analysis was performed for each gender, country by country, analyte by analyte, by setting four major SVs (age, BMI, and levels of drinking and smoking) as a fixed set of explanatory variables. For analytes with skewed distributions, log-transformation was applied. The association of each source of variation with RVs was expressed as partial correlation coefficient (rp).Obvious gender and age-related changes in the RVs were observed in many analytes, almost consistently between countries. Compilation of age-related change profiles of RVs after adjusting for between-country differences revealed peculiar patterns specific to each analyte. Judged fromrp, BMI related changes were observed in many nutritional and inflammatory markers in almost all countries. However, the slope of linear BMI vs. RV relationship differed greatly among countries for some analytes. Alcohol and smoking-related changes were observed less conspicuously in a limited number of analytes.Features of sex, age, alcohol, and smoking-related changes in RVs of major analytes were almost comparable worldwide. The finding of differences in BMI-related changes among countries in some analytes is quite relevant to understanding ethnic differences in susceptibility to nutritionally related diseases.