Obtaining reference intervals traceable to reference measurement systems

An issue associated with the standardization efforts is the need to develop scientifically sound and globally useful reference intervals. Lack of proper reference intervals may indeed hamper the implementation of standardization in Laboratory Medicine as: a) the implementation of standardization can modify analyte results, b) without adequate reference intervals, this situation can impair the interpretation of the results and, paradoxically, worsen the patient\u2019s outcome, c) the absence of reliable reference intervals for newly standardized commercial methods may hamper their adoption, and d) usually, a single clinical laboratory or manufacturer may not have the means to adequately produce reference intervals. The reference measurement system represents a trueness-based approach. With this approach, different commercial methods that provide results traceable to the system are able to produce comparable results in clinical laboratories using these assays. Thus, reference intervals obtained with analytical procedures that produce results traceable to the corresponding reference system can be transferred among laboratories (becoming \u201ccommon\u201d or \u201cuniversal\u201d), providing that they use commercial assays that produce results traceable to the same reference system and populations have the same characteristics or, alternatively whether it is known that the specific analyte is not influenced by ethnicity or environmental factors. The definition of common reference intervals should hopefully cause the disappearance of different intervals employed for the same analyte, providing more effective information to clinicians. Using the approach described above, some examples of common reference intervals can be found in literature (1, 2). Large multicenter studies are needed for a robust definition of common reference intervals, using a protocol for collaborative experiments that include well defined prerequisites. The difficulties are related to the need for verifying traceability of participating laboratories by the distribution of commutable frozen sera, with values assigned by the reference measurement procedure. Other difficulties include the co-ordination among participating centers for the performance of thousands of tests and enrolment of hundreds of individuals, which entails considerable cost. Particularly, in the development of reference intervals, the methods that are employed must produce results that are traceable to the reference measurement system for that specific measurand. For this reason, the trueness of participating laboratories should be verified and, if necessary, experimental results corrected in accordance with correlation results with the reference procedure. Alternatively, the samples from reference individuals can be collected at the different centers, frozen and then shipped to a central laboratory where all the analyses are performed. The latter approach is simpler and allows better control of the analytical phase. However, this approach uses frozen samples and thus introduces a variable not typical for the clinical laboratories. In summary, the production of common reference intervals may pose numerous practical problems to solve. However, the possibility of providing reference intervals that are applicable to any laboratory, able to produce results traceable to the reference measurement system, seems to be quite realistic