Pediatric healthcare is critically dependent on availability of accurate and precise laboratory tests/biomarkers of pediatric disease, and on availability of "reference intervals" (or “normal values”) to allow appropriate clinical interpretation. Children are not small adults; child development and growth profoundly influence laboratory test reference intervals. Adult reference intervals cannot be used to interpret laboratory test results in children until they reach adult levels after puberty. Unfortunately, there is a lack of clearly defined pediatric reference intervals for most tests performed in children and adolescents. There is also a paucity of information on the effects of age, gender, BMI, sexual development (Tanner Stage), and ethnic origin on pediatric reference intervals. Most available reference intervals have been determined on Caucasians and do not consider population diversity. These critical gaps seriously compromise the ability of pediatricians to accurately diagnose medical conditions in their patients and significantly increase healthcare costs. It is thus critical and of utmost urgency that the influence of covariates be determined and a comprehensive database of covariate stratified reference intervals be established in the diverse pediatric populations in North America and elsewhere.
The Pediatric Focus Group of the Canadian Society of Clinical Chemists (CSCC) has recently initiated a collaborative project among pediatric centers across Canada to address the critical gaps in pediatric reference intervals by determining the influence of key covariates and establishing a national database for Canada-wide communication and knowledge translation. This project has been named: CALIPER, ‘CAnadian Laboratory Initiative on PEdiatric Reference Intervals’ (www.caliperproject.com). A major community outreach and recruitment effort has begun, leading to initial collection of over 4500 blood samples from healthy community children in the three Ontario centers. The first major report from the CALIPER initiative has now been published in Clinical Chemistry (http://www.ncbi.nlm.nih.gov/pubmed/22371482). Customizable pediatric reference intervals are also now available on the caliper website: www.caliperdatabase.com.
Although the CALIPER initiative has been welcomed by most, some in the clinical chemistry community have argued that attempts should be made at determining common reference intervals rather than establishing intervals on specific analytical platforms. A number of groups have proposed establishing “common reference intervals” using a multicenter study design. These reference intervals are determined through the collaboration of laboratories from different regions or countries that use analytical methods that are traceable to a reference method. The concept of common reference intervals has been touted to represent, at least in part, “the way forward”. However, the major obstacles to the common reference interval approach are the lack of harmonization of methods by manufacturers and the lack of availability of reference materials and reference methods for the majority of analytes. It also remains to be tested whether common reference intervals are robust when applied to ethnically diverse populations. Until these problems are characterized and resolved, establishing and validating laboratory- specific reference intervals as mandated will remain the status quo for the foreseeable future.
Posted by Jocelyn Hicks-Brody
I think that CALIPER is doing great work in a very challenging field.
There is no question that harmonization is the ultimate goal, but until instrument manufacturers agree to aim for the same results, the reference range approach by CALIPER for Pediatrics is MUCH BETTER than has been available. I should know as I personally struggled with this isue many years ago. I think we owe a lot to the teamwork in Canada and to Khosrow
Posted by Khosrow Adeli
I agree that sample collection location and time are very important. In the CALIPER study, we went to schools and community centers where children are and therefore had to collect samples at different times of day. Based on a recent sub-study comparing fasting samples to those obtained at different times throughout the day (manuscript submitted for publication), many biochemical markers do not change appreciably in children and adolescents. This is very helpful as requiring children to fast for prolonged periods of time is not feasible either in research studies or during routine medical tests. Fasting is however needed for some analytes such as triglyceride, although non-fasting triglyceride also has value as a marker of hypertriglyceridemia based on a number of studies.
Posted by Peter Kissinger
I am wondering if the means of obtaining samples (where from) and if the time of day they are collected could also be important. Is the concept of "fasting" established at all in this population?
Posted by Sridevi Devaraj
Just as the CSCC, AACC must form a multicenter initiative focusing on centers with diverse ethnic populations to define pediatric reference ranges
Colantonio DA, Kyriakopoulou L, Chan MK, et al: Closing the Gaps in Pediatric Laboratory Reference Intervals: A CALIPER Database of 40 Biochemical Markers in a Healthy and Multiethnic Population of Children. Clin Chem 2012 May;58(5):854-68.