Academy of Diagnostics & Laboratory Medicine - Scientific Short
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Reference intervals play a vital role in interpreting laboratory test results, ensuring precise clinical diagnosis and decision-making. In children, the establishment of reliable reference intervals is particularly complex due to fluctuating biomarker levels throughout growth and development. Since 2008, the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) has established comprehensive and accurate pediatric reference intervals for assays performed on major analytical platforms used by clinical laboratories. To date, reference intervals have been established for >200 laboratory biomarkers using specimens from healthy children recruited from the community. These data have been extensively published in peer-reviewed literature and also are freely accessible via CALIPER’s online database. Together with a no-charge CALIPER app that allows healthcare providers to enter laboratory results and compare them against evidence-based reference standards, CALIPER has contributed greatly to the delivery of precision pediatric healthcare across the globe.
Continuing in its mission to generate up-to-date accurate pediatric reference intervals, CALIPER recently collaborated with Roche Diagnostics to directly establish pediatric reference intervals for 16 electrolytes and metabolites, and 12 enzymes, proteins, and lipids on the Roche cobas pro® c503 analyzer. This work was presented via two poster abstracts at the 2025 annual ADLM meeting in Chicago, IL, USA. As the newer Roche system becomes more widely adopted in clinical laboratories, these findings will help ensure the most appropriate pediatric reference intervals are available for use.
Prior to establishing reference intervals, analytical performance verification was conducted for each assay including assessment of within and between-day imprecision, linearity, and accuracy. Within and between day imprecision were evaluated using 10 runs within the same day and 20 runs over 20 days for two levels of quality controls, respectively. Imprecision was determined through calculation of coefficients of variation for each quality control. Linearity was assessed using commercial linearity materials from Maine Standards (ME, USA). All 28 assays demonstrated analytical performance specifications including imprecision and linearity consistent with manufacturer’s claims. Accuracy was determined via method comparisons using patient samples (n=40), demonstrating biases within allowable limits defined by the IQMH (Institute for Quality Management in Healthcare).
Following analytical verification, 300–500 serum samples, collected with informed consent from healthy children and adolescents in the CALIPER cohort, were analyzed across five pediatric age groups: 0-1, 1-5, 6-10, 11-14, and 15-18 years. Minimum 30 male and 30 female participants were included in each age group. For biomarkers demonstrating dynamic changes, additional samples were included to ensure robust statistical partitioning. Statistical analysis and partitioning using R software were carried out as per CLSI guidelines and as per published CALIPER studies.
New pediatric reference intervals were established for 16 electrolytes and metabolites: sodium, potassium, chloride, calcium, phosphorus, magnesium, iron, glucose, lactate, total CO2, , creatinine, urea, uric acid, total and direct bilirubin, and also β-hydroxybutyrate (from Randox Laboratories). The pattern of changes with age and sex for each analyte was consistent with previous CALIPER data on other platforms. Except for sodium, potassium, magnesium, and glucose, age and/or sex partitions were required for all other analytes.
Additionally, new pediatric reference intervals were established for albumin, total protein, ALT, AST, ALP, GGT, amylase, CK, LDH, total cholesterol, HDL cholesterol, and triglycerides. Age-specific partitions were necessary for all analytes, while sex-specific partitions were not required for albumin, total protein, amylase, GGT, and lipids. As anticipated, reference values varied with age and sex, aligning with previous CALIPER findings from other analytical platforms. Consistent with prior CALIPER studies, several analytes showed significantly different values in the neonatal period, highlighting the need for further studies with a greater number of samples from neonates.
In summary, these two studies were the first to establish pediatric reference intervals for several common biochemical markers on the Roche cobas pro® system using the direct method in the CALIPER cohort, filling an important gap in pediatric reference interval availability for this widely used clinical chemistry system.
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