Biological variation: back to basics.

The appreciation of the substantial influence of biological variation (BV) on laboratory testing and interpretation of laboratory results has represented a milestone in the history of laboratory medicine. It has paved the way for a wide series of studies aimed to accurately define the components of BV, set analytical quality specifications and related goals for internal quality control and external quality assessment programs, along with specific criteria for data interpretation, including the reference change value (RCV) [1–3]. The unquestionable importance of quality specifications based on BV in the hierarchy of models defined in the Stockholm Conference in 1999 [4, 5] represented a breakthrough in promoting the generation and application of data on BV. This issue has been for long recognized in Clinical Chemistry and Laboratory Medicine as an essential concept for defining the appropriateness of reference values for specific constituents, and for supporting the adoption of RCV in the interpretation of data from serial measurements [6–16]. In this issue of the journal, we publish an article about structure and criteria used for the generation of the BV database [17] along with a commenting Editorial, which are aimed to update our knowledge in this field and encouraging the revision and update of BV database, to reassure that the information is prominently evidence-based [18]. A number of problems are increasingly recognized as a source of debate and concern. First, in an era of global harmonization, mystification should be prevented in the broad range of terms and symbols used to define the components of BV [19]. Therefore, we recognize and support the recent proposition by Simundic et al. to adopt a consistent and harmonized use of terms and symbols as follows [20]: – CVI: within-subject biological variation (variation within a single individual estimated as a pooled variation from a group of individuals); – CVG: between-subject biological variation (variation between the central tendencies of a group of individuals); – CVA: analytical variation (analytical imprecision); should always be clarified, giving mode of derivation and type (such as reproducibility, reliability, or total) and number of analyses, runs, and time period; – RCV: reference change value (difference required for significance for 2 serial results from an individual); should always be accompanied by the formula used, namely, × × 1 2 1 2 2 2 A I 2 ( CV CV ) ; Z the Z-score should be defined to state the probability and whether unidirectional or bidirectional differences were calculated; and – II: index of individuality (ratio of analytical and withinsubject to between-subject biological variation); should always be accompanied with the formula used for calculation: the preferred × 1 2 2 2 A I G ( CV CV ) /CV or the now seemingly more usual CVI/CVG.