Laboratory investigations provide physicians with objective data to aid in disease diagnosis, clinical decision making, and patient follow up. Clinical interpretation of laboratory test results relies heavily on the availability of appropriate population-based reference intervals (i.e. normative values) or decision limits developed through clinical outcome studies. Although reference intervals are fundamental to accurate laboratory test interpretation, and thus critically important to healthcare, the need for sound evidence-based reference intervals has been largely overlooked, particularly in the pediatric population. In the field of pediatric laboratory medicine, accurate age- and sex-specific reference intervals established using samples from healthy children and adolescents have not been readily available, forcing many clinical laboratories to report adult reference intervals with pediatric test results. When pediatric reference intervals are available, they have often been established with a small sample size, inpatient or outpatient samples, outdated methodologies, and/or inappropriate statistical procedures. To address these unacceptable limitations, several national and global initiatives have begun to close the critical evidence gaps in pediatric reference intervals. Notably, the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) has made significant strides towards improving pediatric healthcare in Canada and globally. The present report is a white paper summarizing CALIPER, and provides a comprehensive compendium of the data generated through this project over the past decade as a single resource for clinical laboratory specialists, clinicians, and other healthcare workers. CALIPER launched an outreach campaign in 2008 to recruit healthy community children and adolescents, and developed a robust statistical algorithm, in accordance with the Clinical and Laboratory Standards Institute (CLSI) guidelines, to develop accurate age- and sex-specific pediatric reference intervals. The first CALIPER direct reference interval study was published in 2012, with age- and sex-specific reference intervals reported for 40 common biochemical markers. To date, CALIPER has collected health information and blood samples from over 9700 community children and adolescents, and has established a comprehensive database of age- and sex-specific reference intervals for over 100 biomarkers of pediatric disease. CALIPER has also performed a series of transference and verification studies to expand the applicability of the CALIPER database to five major analytical platforms, including Abbott, Beckman, Ortho, Roche, and Siemens. Through novel knowledge translation initiatives, the CALIPER Reference Interval Database has been made freely available online ( www.caliperproject.ca ) as well as on a mobile application (CALIPER Reference App), and it is used by clinical laboratories across Canada, the United States, and globally. In addition to establishing this comprehensive pediatric reference interval database, CALIPER has also performed a series of sub-studies, including examining how reference intervals are affected by pre-analytical factors (i.e. sample stability at specific storage conditions, fasting status and time of sample collection), biological variation (i.e. intraindividual and interindividual biological variation, reference change values), and ethnicity and pubertal development stage. In this white paper, extensive tables of pediatric reference intervals are provided for easy reference for clinical laboratories worldwide. All data reported have been published in over 20 peer reviewed publications and are also available through the CALIPER Reference Interval Database as well as the CALIPER Reference App for mobile devices.

https://www.tandfonline.com/doi/pdf/10.1080/10408363.2017.1379945

The Canadian laboratory initiative on pediatric reference intervals: A CALIPER white paper.

Reference Intervals (RIs) and clinical decision limits (CDLs) are a vital part of the information supplied by laboratories to support the interpretation of numerical clinical pathology results. RIs describe the typical distribution of results seen in a healthy reference population while CDLs are associated with a significantly higher risk of adverse clinical outcomes or are diagnostic for the presence of a specific disease. However, as the two concepts are sometimes confused, there is a need to clarify the differences between these terms and to ensure they are easily distinguished, especially because CDLs have a clinical association with specific diseases and risks, thereby implying that effective clinical interventions are available. It is important to note that, because population-based RIs are derived from the range of values expected in a typical community population, laboratory results that fall outside a RI do not necessarily indicate a disease but rather that additional medical follow-up and/or treatment may be warranted. In contrast, CDLs are associated with a risk of specific adverse outcomes, and are commonly used to interpret laboratory test results, including lipid parameters, glucose, hemoglobin A1c (HbA1c), and tumor markers, to determine risk of disease, to diagnose or to treat. In recent years, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Committee on Reference Intervals and Decision Limits (C-RIDL) has focused primarily on RIs and has performed multicenter studies to obtain common RIs. However, the broader responsibility of the Committee, from its name, includes "decision limits". C-RIDL now aims to emphasize the importance of the correct use of both RIs and CDLs and to encourage laboratories to specify the appropriate information to clinicians as needed. This review discusses RIs and CDLs in detail, describes the similarities and the differences between these two important tools in laboratory medicine, and clearly explains the processes used to define them. C-RIDL encourages the involvement of laboratory professionals in the establishment of both RIs and CDLs.

Distinguishing reference intervals and clinical decision limits - A review by the IFCC Committee on Reference Intervals and Decision Limits.

Dioscin protects against ANIT–induced cholestasis via regulating Oatps, Mrp2 and Bsep expression in rats

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1002/1873-3468.13982

Mass spectrometry‐based abundance atlas of ABC transporters in human liver, gut, kidney, brain and skin

Harmonisation of reference intervals (RIs) refers to use of the same or common RI across different platforms and /or assays for a specified analyte. It occurs optimally for those analytes where there is sound calibration and traceability in place and evidence from a between-method comparison shows that bias would not prevent the use of a common RI. The selection of the RI will depend on various sources of information including local formal RI studies, published studies from the literature, laboratory surveys, manufacturer's product information, relevant guidelines, and mining of databases. Pre-analytical and partitioning issues, significant figures and flagging rates, are assessed for each analyte. Several countries and regions including the Nordic countries, United Kingdom, Japan, Turkey, and Australasia are using common RIs that have been determined either by direct studies or by a consensus process. In Canada, the Canadian Society of Clinical Chemists Taskforce is assessing the feasibility of establishing common reference values using the CALIPER (Canadian Laboratory Initiative on Pediatric Reference Intervals) and CHMS (The Canadian Health Measures Survey) databases as the basis. Development of platform-specific common reference values for each of the major analytical systems may be a more practical approach especially for the majority of analytes that are not standardised against a primary reference method and are not traceable to a primary or secondary reference material. We encourage laboratories to consider adopting reference intervals consistent with those used by other laboratories in your region where it is possible and appropriate for your local population. Local validation of the adopted reference interval is also recommended as per CLSI guidelines.

Opinion Paper: Deriving Harmonised Reference Intervals - Global Activities.

A patient with sepsis and jaundice was admitted for diagnosis and treatment. Associated biochemical changes included increased C-reactive protein, conjugated bilirubin and gamma-glutamyltransferase, the duration of which was protracted. High urine coproporphyrin isomer-1 and immunostaining of liver tissue suggested Dubin-Johnson syndrome. DNA sequencing using polymerase chain reaction amplification of the ABCC2 gene revealed the patient to have a compound heterozygous variant of MRP2, a molecule involved in canalicular transport of bilirubin. There was a history of jaundice since infancy.

https://journals.sagepub.com/doi/pdf/10.1258/acb.2012.011279

Adil M. El-Nujumi

Papers

Novel mutations in the Dubin–Johnson syndrome gene ABCC2/MRP2 and associated biochemical changes

Clinical decision limits for interpretation of direct bilirubin--a CALIPER study of healthy multiethnic children and case report reviews.