Written in collaboration with Jacalyn Kelly, Michelle Nieuwesteeg, and Khosrow Adeli 
CALIPER Program, The Hospital for Sick Children, University of Toronto

Accurate and efficient diagnosis of children with medical concerns is dependent upon the availability of reliable pediatric reference intervals (‘normal’ values). Reference intervals guide the interpretation of laboratory test results, and are therefore essential for ensuring that the appropriate medical care is administered. Regrettably, there is a surprising lack of information for many pediatric tests, though need for reference intervals is widely acknowledged.

Establishment of robust reference intervals is important in any age group, but for pediatric populations in particular, correctly defined reference intervals are all the more necessary. Not only can the changes that take place over the course of growth and development substantially alter the levels of many circulating biomarkers, the concentrations of many analytes may also be considerably different between males and females, especially during puberty. Unfortunately, determining reference intervals for pediatric populations is also more challenging due to difficulties in obtaining sufficient blood sample volumes from young children, and the frequent need for multiple age- and sex-specific partitions for different developmental periods. As a result, pediatric reference intervals are often based on adult values, or are inappropriately calculated using samples acquired from hospital patients rather than healthy children, which can increase the risk of misdiagnoses.

The CALIPER (Canadian Laboratory Initiative on Pediatric Reference intervals) Project is a Canadian research initiative carried out by the Hospital for Sick Children (Toronto, ON) in collaboration with several other children’s hospitals across the country. CALIPER has collected blood samples from 8,600 children over the past 5 years, and our team has been working toward establishing a complete and comprehensive database of pediatric reference intervals that is readily available to physicians and appropriately stratified based on age and gender (1). Importantly, participants with a history of chronic illness or metabolic disease, acute illnesses, or recent use of prescribed medications are excluded from CALIPER studies to ensure that reference values are calculated from only healthy community children.

Through the first four phases of the project, CALIPER has established and published reference values for over 60 biochemical markers (2,3). The recently completed fifth phase (CALIPER V), determined additional reference intervals for a number of specialty immunoassays and chemistry markers in children aged 0-18 years, using the Abbott ARCHITECT ci4100 analytical system. Several analytes showed dynamic changes in concentration based on age and/or sex, including albumin BCG, albumin BCP, Beta-2 microglobulin, ceruloplasmin, cholinesterase E, C-peptide, high-sensitivity CRP, cystatin C, DHEA-S, insulin, pancreatic amylase, SHBG and testosterone (2nd GEN). These data can benefit healthcare centers using the Abbott immunoassay systems worldwide, to improve monitoring and diagnosis of pediatric patients.

CALIPER V, along with previous phases of the CALIPER project, has profiled a multitude of clinically relevant biomarkers and demonstrated complex changes in expression patterns throughout development. This data emphasizes the need for comprehensive reference intervals that are partitioned by gender and age to allow for accurate and physiologically relevant interpretation of patient laboratory test results.

1. Dignman, S. (2014). Experts question Google’s new ‘moonshot’ project: mapping human genome biomarkers. The Globe and Mail. Retrieved July 28, 2014 from http://www.theglobeandmail.com/life/health-and-fitness/health/experts-question-googles-new-moonshot-project-mapping-human-genome-biomarkers/article19791828/

2. Colantonio, D., Kyriakopoulou, L., Chan, M.K., Daily, C., Brinc, D.,Venner, A., Pasic, M., Armbruster, D., and Adeli, k. (2012). Closing the gaps in pediatric laboratory referene intervals: A CALIPER database of 40 biochemical markers in a healthy and multiethnic population of children. Clin Chem, 58(5):584–868.

3. Konforte, D., Shea, J, Kyriakopoulou, L., Colantonio, D., Cohen, A., Shaw, J., Bailey, D., Chan, M.K., Armbruster, D., and Adeli, K. (2013). Complex Biological Pattern of Fertility Hormones in Children and Adolescents: A study of healthy children from the CALIPER cohort and establishment of pediatric reference intervals. Clin chem, 59(8):1215-1227.