There was a clear distinction between healthy reference values measured in healthy populations or individuals and patient
reference values measured in patients having various diseases. It is now commonly accepted that reference values describe
fluctuations observed in healthy populations or individuals, which makes the definition of health or characterization of health
status a critical step.
From 1987 to 1991, the International Federation of Clinical Chemistry (IFCC) published a series of 6 papers, in which it was
recommended that each laboratory follow defined procedures to produce its own reference values. Although there were very
important developments and implementations between the 1990s and 2008; the C28- A3 guideline, published in 2008 by Clinical
and Laboratory Standards Institute (CLSI) and IFCC constituted the most significant step in the development of RIs and is still in
From its inception, and according to IFCC definition, reference values are measured in a well-characterized population of
individuals selected according to predefined criteria such as age, sex, nutritional status, and diet. In addition, it is presumed that
reference individuals are healthy, which raises the question of the definition of health. There is no accepted consensus on the
definition of health.
The RIs are descriptive of a specific population and are derived from a reference distribution (usually 95% interval), whereas
CDLs are thresholds above or below which a specific medical decision is recommended and are derived from Receiver Operating
Characteristic (ROC) curves and predictive values. CDLs are based on the diagnostic question and are obtained from specific clinical
studies to define the probability of the presence of a certain disease or a different outcome. These limits lead to the decision that
individuals with values above or below the decision limit should be treated differently. CDLs are defined by consensus and vary
among different populations. It is important that RIs are not confused with CDLs.
To avoid confusion, the C28-A3 recommended reporting decision limits or RIs but not both, with a clear indication of which has
Keywords: Reference Intervals (RIs); Normal Values; Health Status And Clinical Decision Limits (CDLs)