Reference intervals: current status, recent developments and future considerations.

Yesim Ozarda

doi:10.11613/bm.2016.001

Abstract

Reliable and accurate reference intervals (RIs) for laboratory analyses are an integral part of the process of correct interpretation of clinical laboratory test results. RIs given in laboratory reports have an important role in aiding the clinician in interpreting test results in reference to values for healthy populations. Since the 1980s, the International Federation of Clinical Chemistry (IFCC) has been proactive in establishing recommendations to clarify the true significance of the term ‘RIs, to select the appropriate reference population and statistically analyse the data. The C28-A3 guideline published by the Clinical and Laboratory Standards Institute (CLSI) and IFCC is still the most widely-used source of reference in this area. In recent years, protocols additional to the Guideline have been published by the IFCC, Committee on Reference Intervals and Decision Limits (C-RIDL), including all details of multicenter studies on RIs to meet the requirements in this area. Multicentric RIs studies are the most important development in the area of RIs. Recently, the C-RIDL has performed many multicentric studies to obtain common RIs. Confusion of RIs and clinical decision limits (CDLs) remains an issue and pediatric and geriatric age groups are a significant problem. For future studies of RIs, the genetic effect would seem to be the most challenging area. The aim of the review is to present the current theory and practice of RIs, with special emphasis given to multicenter RIs studies, RIs studies for pediatric and geriatric age groups, clinical decision limits and partitioning by genetic effects on RIs.

Highlights

In the mid 20th century, Grasbeck and Fellman published a paper entitled ‘Normal Values and Statistics’ as an initial study in the field of reference intervals (RIs) [1]
In the protocol for multicenter studies [18], cross-check testing is recommended to convert the RIs obtained from the multicenter study by the centralized assay to the values of each participating laboratory
International Federation of Clinical Chemistry (IFCC), Committee on Reference Intervals and Decision Limits (C-RIDL) met this need with the publication of a very detailed protocol in 2014, which can be used when conducting multicentric studies

Summary

Introduction

In the mid 20th century, Grasbeck and Fellman published a paper entitled ‘Normal Values and Statistics’ as an initial study in the field of reference intervals (RIs) [1]. The other prerequsites of multicenter studies can be summarized as a priori selection of reference subjects (i.e. inclusion-exclusion criteria, ethnicity and questionnaire), a clear definition of pre-analytical phases (i.e. blood collection, sample proccesing, storage and transportation), a clear definition of analytical phases (i.e. requirements for the central laboratories and the measurements, quality control, standardization of the assay and cross-comparison of values) and the statistical procedures for data analysis and reports of the results (i.e. validation of data, analyses of sources of variation, partitioning criteria and derivation of RI) [18] This should ensure that country-specific RIs are obtained in a more reproducible manner.

Organization of the study Establishing the inclusion and exclusion criteria

Findings

Conclusion