Pediatric Population Reference Value Distributions for Cancer Biomarkers and Covariate-Stratified Reference Intervals in the CALIPER Cohort Victoria Bevilacqua, 1,2 Man Khun Chan, 1 Yunqi Chen, 1 David Armbruster, 3 Beth Schodin, 3 and Khosrow Adeli 1,2* BACKGROUND: Cancer biomarkers are commonly used in pediatrics to monitor cancer progression, recur- rence, and prognosis, but pediatric reference value dis- tributions have not been well established for these markers. The Canadian Laboratory Initiative on Pedi- atric Reference Intervals (CALIPER) sought to develop a pediatric database of covariate-stratified reference value distributions for 11 key circulating tumor mark- ers, including those used in assessment of patients with childhood or adult cancers. METHODS: Healthy community children from birth to 18 years of age were recruited to participate in the CALIPER project with informed parental consent. We analyzed serum samples from 400 –700 children (de- pending on the analyte in question) on the Abbott Ar- chitect ci4100 and established reference intervals for -fetoprotein (AFP), antithyroglobulin (anti-Tg), hu- man epididymis protein 4 (HE4), cancer antigen 125 (CA125), CA15-3, CA19-9, progastrin-releasing pep- tide (proGRP), carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), and total and free prostate specific antigen (PSA) according to CLSI C28-A3 statistical guidelines. RESULTS: We observed significant fluctuations in bio- marker concentrations by age and/or sex in 10 of 11 biomarkers investigated. Age partitioning was re- quired for CA153, CA125, CA19-9, CEA, SCC, proGRP, total and free PSA, HE4, and AFP, whereas sex partitioning was also required for CA125, CA19-9, and total and free PSA. CONCLUSIONS: This CALIPER study established a data- base of childhood reference intervals for 11 tumor bio- markers and revealed dramatic fluctuations in tumor marker concentrations between boys and girls and throughout childhood. In addition, important differ- ences between the adult and pediatric population were observed, further highlighting the need for pediatric- specific reference intervals. © 2014 American Association for Clinical Chemistry Increasingly, cancer biomarkers have become an impor- tant tool in the fight against the growing rates of child- hood and adult cancers. Although there may be limita- tions to how and when cancer biomarkers can be used in patient diagnosis, there is great potential for these cancer biomarkers to aid in monitoring and follow-up assess- ments of cancer patients. However, information on nor- mal concentrations of these markers in the pediatric pop- ulation is sorely lacking. Table 1 provides a summary of the current clinical applications for 11 key cancer bio- markers in both pediatric and adult cancers. Table 1 also provides a summary of the pediatric reference intervals currently available for these 11 key cancer biomarkers. The gaps are evident, with little to no information avail- able for 7 of the 11 markers of interest. To harness the full potential of tumor biomarkers in predicting patient outcomes and monitoring treatment, it is important to have age- and sex-stratified reference in- tervals for comparison. Indeed, the importance of age- and sex-stratified reference intervals for tumor biomark- ers has been previously noted in the adult population (1 ). It is reasonable to assume that this may also apply to the pediatric population, where pivotal developmental changes such as puberty are likely to affect the concentra- tions of these markers. In addition to the clinical impor- tance of reference intervals, understanding how the con- centrations of key biomarkers fluctuate in the healthy population is also important from a research perspective. Several studies have noted and illustrated the ways in 1 CALIPER Program, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, and 2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; 3 Abbott Diagnostics, Abbott Laboratories, Abbott Park, IL. * Address correspondence to this author at: Clinical Biochemistry, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8 Canada. Received July 6, 2014; accepted September 4, 2014. Previously published online at DOI: 10.1373/clinchem.2014.229799 © 2014 American Association for Clinical Chemistry Clinical Chemistry 60:12 1532–1542 (2014) Pediatric Clinical Chemistry 1532 Downloaded from https://academic.oup.com/clinchem/article/60/12/1532/5621645 by guest on 11 November 2022