A major area of focus in recent years has centered on improving the analytical quality of laboratory testing process. Perhaps equally important is how the test results are interpreted in the clinical setting; a topic that has received considerably less attention. Reference intervals (the ‘normal’ range of values expected in a healthy population), are essential for clinical interpretation of test results. Unfortunately, large-scale reference interval studies on healthy individuals have been severely lacking. As a result, reference intervals are often inappropriate, based on patient data or outdated technologies. In many cases, reference intervals are unavailable for specific age groups, particularly pediatrics and geriatrics, where data collection is challenging and the definition of ‘health’ is variable. Physicians are often forced to rely on what is available, which in many cases is not sufficient. Pediatric test results, for example, are commonly interpreted against adult reference values – a practice that can lead to misdiagnosis, prolonged testing and unnecessary stress to the child and family.

CALIPER (Canadian Laboratory Initiative on Pediatric Reference Intervals) is a Canadian research project based at the Hospital for Sick Children in Toronto, Canada. CALIPER has focused on establishing a database of accurate and up-to-date pediatric reference intervals, with over 100 biomarkers of pediatric disease examined to date. Recently, CALIPER collaborated with Statistics Canada to obtain and analyze data from the Canadian Health Measures Survey (CHMS). The CHMS is a Canada-wide population health survey that collected general health information, blood and urine samples from approximately 12,000 individuals, representative of 96% of the Canadian household population.

The CALIPER/CHMS study was an enormous undertaking and achievement, with age- and sex-specific intervals established for more than 50 biochemical, endocrine and hematological markers1-3. While most reference interval studies have focused on only a single age group (e.g., pediatrics, adults, or geriatrics), the CHMS data has facilitated a comprehensive examination across a continuous age range, from 3-79 years1-3. A rigorous statistical approach including outlier and exclusion criteria combined with the extensive sample size, permitted robust reference interval determination based on healthy individuals. The dramatic changes in concentration observed for many analytes over the course of development and aging emphasize the requirement for appropriately partitioned reference intervals for accurate clinical interpretation of laboratory test results. 

Even for those analytes where decision limits are used clinically, the analysis performed in this study provides important population health information for researchers and medical professionals. For instance, hemoglobin A1c showed a marked age-dependent increase in concentration, where the  upper limit for adults and geriatrics surpassed the cutoff for prediabetes, indicating that many Canadians in the 40-79 year age range are at risk2.

The reference intervals developed in this study should ideally be validated by each local laboratory before implementation as recommended by CLSI. This will ensure applicability to an increasing number of healthcare centers across Canada, the US and internationally. It is our hope that development of nationally-representative reference intervals will also be a first step toward harmonization, and future studies will focus on this goal.

References:

  1. Adeli K, Higgins V, Nieuwesteeg M, Raizman JE, Chen Y, Wong SL, Blais D. Biochemical marker reference values for pediatric, adult and geriatric age groups: Establishment of robust pediatric and adult reference intervals based on the Canadian Health Measures Survey. Clin Chem 2015; 61(8):1049-62.
  2. Adeli K, Higgins V, Nieuwesteeg M, Raizman JE, Chen Y, Wong SL, Blais D. Complex reference value distributions for endocrine and special chemistry biomarkers across pediatric, adult and geriatric age: Establishment of robust pediatric and adult reference intervals based on the Canadian Health Measures Survey. Clin Chem 2015b; 61(8):1063-74.
  3. Adeli K, Raizman JE, Chen Y, Higgins V, Nieuwesteeg M, Abdelhaleem M, et al. Complex biological profile of hematological markers across pediatric, adult, and geriatric ages: Establishment of robust pediatric and adult reference intervals based on the Canadian Health Measures Survey. Clin Chem 2015c; 61(8):1075-86.

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