The diagnostic utility of laboratory tests in paediatric medicine relies heavily on the availability of appropriate reference intervals (RIs). The Canadian Laboratory Initiative on Paediatric Reference Intervals (CALIPER) has established a comprehensive database of covariate-stratified RIs for many paediatric laboratory tests using a large, healthy reference population. Several automated analysers in widespread use in clinical laboratories have already been studied. Here, we extend the testing to Roche immunoassays and report, for the first time, comprehensive paediatric RIs for 17 endocrine and special chemistry markers.
A total of 741 healthy children and adolescents (1 day to <19 years) were recruited and serum samples were analysed for 17 immunoassays on the Roche cobas 8000 e602 Immunoassay Analyzer. Age and sex-specific RIs were established and corresponding 90% confidence intervals (CIs) were calculated in accordance with Clinical and Laboratory Standards Institute guidelines.
Reference values for all analytes measured required age partitioning, particularly during early life and throughout adolescence. Of the 17 analytes measured, eight required sex partitioning, including ferritin, thyroid stimulating hormone (TSH), total triiodothyronine (TT3) and all fertility/sex hormones, except prolactin.
This is the first study to determine accurate paediatric RIs for Roche immunoassays. RIs were generally similar to those previously published by CALIPER on other analytical platforms, highlighting the reproducibility of age- and sex-specific trends in reference values observed across the paediatric age range. The RIs established in this study will improve the accuracy of test result interpretation and clinical decision-making in clinical laboratories utilising Roche immunoassays.
Funding source: Canadian Institutes of Health Research
Award Identifier / Grant number: 353989
Funding statement: The study was financially supported by a Foundation Grant from the Canadian Institutes of Health Research (CIHR, Funder Id: http://dx.doi.org/10.13039/501100000024, Grant Number: 353989) as well as a research grant and material support from Roche Diagnostics Canada. M.K. Bohn was supported by the Restracomp SickKids Scholarship.
This study would not have been possible without the generous participation of children from the community. We thank all participants, their families and the numerous CALIPER volunteers whose dedication and time commitment made this study possible. We would also like to thank technical and managerial staff at Mount Sinai Hospital for analysis of paediatric samples on the Roche cobas systems.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
1. Horowitz GL, Altaie S, Boyd JC. Defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline – 3rd ed. Wayne, PA, USA: CLSI, 2010.Search in Google Scholar
2. Indirect methods for reference interval determination – review and recommendations. Clinical Chemistry and Laboratory Medicine (CCLM) [Internet]. [cited 2019 Jul 5]. Available from: https://www.degruyter.com/view/j/cclm.2019.57.issue-1/cclm-2018-0073/cclm-2018-0073.xml.Search in Google Scholar
3. Colantonio DA, Kyriakopoulou L, Chan MK, Daly CH, Brinc D, VennerAA, 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;58:854–68.10.1373/clinchem.2011.177741Search in Google Scholar PubMed
4. Karbasy K, Lin DC, Stoianov A, Chan MK, Bevilacqua V, Chen Y, et al. Pediatric reference value distributions and covariate-stratified reference intervals for 29 endocrine and special chemistry biomarkers on the Beckman Coulter Immunoassay Systems: a CALIPER study of healthy community children. Clin Chem Lab Med 2015;54:643–57.10.1515/cclm-2015-0558Search in Google Scholar PubMed
5. Higgins V, Fung AW, Chan MK, Macri J, Adeli K. Pediatric reference intervals for 29 Ortho VITROS 5600 immunoassays using the CALIPER cohort of healthy children and adolescents. Clin Chem Lab Med 2018;56:327–40.10.1515/cclm-2017-0349Search in Google Scholar PubMed
6. Kelly J, Raizman JE, Bevilacqua V, Chan MK, Chen Y, Quinn F, et al. Complex reference value distributions and partitioned reference intervals across the pediatric age range for 14 specialized biochemical markers in the CALIPER cohort of healthy community children and adolescents. Clin Chim Acta 2015;450:196–202.10.1016/j.cca.2015.08.020Search in Google Scholar PubMed
7. Teodoro-Morrison T, Kyriakopoulou L, Chen YK, Raizman JE, Bevilacqua V, Chan MK, et al. Dynamic biological changes in metabolic disease biomarkers in childhood and adolescence: a CALIPER study of healthy community children. Clin Biochem 2015;48:828–36.10.1016/j.clinbiochem.2015.05.005Search in Google Scholar PubMed
8. Bevilacqua V, Chan MK, Chen Y, Armbruster D, Schodin B, AdeliK. Pediatric population reference value distributions for cancer biomarkers and covariate-stratified reference intervals in the CALIPER cohort. Clin Chem 2014;60:1532–42.10.1373/clinchem.2014.229799Search in Google Scholar PubMed
9. Konforte D, Shea JL, Kyriakopoulou L, Colantonio D, Cohen AH, Shaw J, et al. 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 2013;59:1215–27.10.1373/clinchem.2013.204123Search in Google Scholar PubMed
10. Bailey D, Colantonio D, Kyriakopoulou L, Cohen AH, Chan MK, Armbruster D, et al. Marked biological variance in endocrine and biochemical markers in childhood: establishment of pediatric reference intervals using healthy community children from the CALIPER cohort. Clin Chem 2013;59:1393–405.10.1373/clinchem.2013.204222Search in Google Scholar PubMed
11. Kulasingam V, Jung BP, Blasutig IM, Baradaran S, Chan MK, Aytekin M, et al. Pediatric reference intervals for 28 chemistries and immunoassays on the Roche cobas 6000 analyzer – a CALIPER pilot study. Clin Biochem 2010;43:1045–50.10.1016/j.clinbiochem.2010.05.008Search in Google Scholar PubMed
12. Estey MP, Cohen AH, Colantonio DA, Chan MK, Marvasti TB, Randell E, et al. CLSI-based transference of the CALIPER database of pediatric reference intervals from Abbott to Beckman, Ortho, Roche and Siemens Clinical Chemistry Assays: direct validation using reference samples from the CALIPER cohort. Clin Biochem 2013;46:1197–219.10.1016/j.clinbiochem.2013.04.001Search in Google Scholar PubMed
13. Abou El Hassan M, Stoianov A, Araújo PA, Sadeghieh T, ChanMK, Chen Y, et al. CLSI-based transference of CALIPER pediatric reference intervals to Beckman Coulter AU biochemical assays. Clin Biochem 2015;48:1151–9.10.1016/j.clinbiochem.2015.05.002Search in Google Scholar PubMed
14. Araújo PA, Thomas D, Sadeghieh T, Bevilacqua V, Chan MK, Chen Y, et al. CLSI-based transference of the CALIPER database of pediatric reference intervals to Beckman Coulter DxC biochemical assays. Clin Biochem 2015;48:870–80.10.1016/j.clinbiochem.2015.06.002Search in Google Scholar PubMed
15. Higgins V, Chan MK, Nieuwesteeg M, Hoffman BR, BrombergIL, Gornall D, et al. Transference of CALIPER pediatric reference intervals to biochemical assays on the Roche cobas 6000 and the Roche Modular P. Clin Biochem 2016;49:139–49.10.1016/j.clinbiochem.2015.08.018Search in Google Scholar PubMed
16. Higgins V, Truong D, Woroch A, Chan MK, Tahmasebi H, Adeli K. CLSI-based transference and verification of CALIPER pediatric reference intervals for 29 Ortho VITROS 5600 chemistry assays. Clin Biochem 2018;53:93–103.10.1016/j.clinbiochem.2017.12.011Search in Google Scholar PubMed
19. Government of Canada SC. Census Profile, 2016 Census [Internet]. 2017 [cited 2019 Jan 4]. Available from: https://www12.statcan.gc.ca/census-recensement/2016/dp-pd/prof/index.cfm?Lang=E.Search in Google Scholar
21. Tukey JW. Exploratory data analysis. In: Addison-Wesley Series in Behavioral Science. Reading, MA: Addison-Wesley Pub. Co, 1977. 688 p.Search in Google Scholar
24. Sheehan MT. Biochemical testing of the thyroid: TSH is the best and, oftentimes, only test needed – a review for primary care. Clin Med Res 2016;14:83–92.10.3121/cmr.2016.1309Search in Google Scholar PubMed PubMed Central
27. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al. Clinical Practice Guidelines for Hypothyroidism in Adults: Cosponsored by the American Association of Clinical Endocrinologists and the American. Thyroid 2012;22:1200–35.10.1089/thy.2012.0205Search in Google Scholar PubMed
28. Kapelari K, Kirchlechner C, Högler W, Schweitzer K, Virgolini I, Moncayo R. Pediatric reference intervals for thyroid hormone levels from birth to adulthood: a retrospective study. BMC Endocr Disord 2008;8:15.10.1186/1472-6823-8-15Search in Google Scholar PubMed PubMed Central
29. Hübner U, Englisch C, Werkmann H, Butz H, Georgs T, ZabranskyS, et al. Continuous age-dependent reference ranges for thyroid hormones in neonates, infants, children and adolescents established using the ADVIA Centaur Analyzer. Clin Chem Lab Med 2002;40:1040–7.10.1515/CCLM.2002.182Search in Google Scholar PubMed
30. Clarkson J, Herbison AE. Hypothalamic control of the male neonatal testosterone surge. Philos Trans R Soc B Biol Sci [Internet] 2016 [cited 2018 Sep 26];371. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785901/.10.1098/rstb.2015.0115Search in Google Scholar PubMed PubMed Central
31. Kuijper EA, Ket JC, Caanen MR, Lambalk CB. Reproductive hormone concentrations in pregnancy and neonates: a systematic review. Reprod Biomed Online 2013;27:33–63.10.1016/j.rbmo.2013.03.009Search in Google Scholar PubMed
32. Bergadá I, Milani C, Bedecarrás P, Andreone L, Ropelato MG, Gottlieb S, et al. Time course of the serum gonadotropin surge, inhibins, and anti-Müllerian hormone in normal newborn males during the first month of life. J Clin Endocrinol Metab 2006;91:4092–8.10.1210/jc.2006-1079Search in Google Scholar PubMed
33. Corbier P, Dehennin L, Castanier M, Mebazaa A, Edwards DA, Roffi J. Sex differences in serum luteinizing hormone and testosterone in the human neonate during the first few hours after birth. J Clin Endocrinol Metab 1990;71:1344–8.10.1210/jcem-71-5-1344Search in Google Scholar PubMed
34. Stricker R, Eberhart R, Chevailler M-C, Quinn FA, Bischof P, Stricker R. Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT® analyzer. Clin Chem Lab Med 2011;44:883–7.10.1515/CCLM.2006.160Search in Google Scholar PubMed
36. Kalme T, Loukovaara M, Koistinen R, Koistinen H, Angervo M, Leinonen P, et al. Estradiol increases the production of sex hormone-binding globulin but not insulin-like growth factor binding protein-1 in cultured human hepatoma cells. Fertil Steril 1999;72:325–9.10.1016/S0015-0282(99)00229-0Search in Google Scholar
37. Pasquali R, Vicennati V, Bertazzo D, Casimirri F, Pascal G, Tortelli O, et al. Determinants of sex hormone – binding globulin blood concentrations in premenopausal and postmenopausal women with different estrogen status. Metab Clin Exp 1997;46:5–9.10.1016/S0026-0495(97)90159-1Search in Google Scholar
38. Siddappa AM, Rao R, Long JD, Widness JA, Georgieff MK. The assessment of newborn iron stores at birth: a review of the literature and standards for ferritin concentrations. Neonatology 2007;92:73–82.10.1159/000100805Search in Google Scholar
39. Rios E, Lipschitz DA, Cook JD, Smith NJ. Relationship of maternal and infant iron stores as assessed by determination of plasma ferritin. Pediatrics 1975;55:694–9.10.1542/peds.55.5.694Search in Google Scholar
40. Valberg LS, Sorbie J, Ludwig J, Pelletier O. Serum ferritin and the iron status of Canadians. Can Med Assoc J 1976;114:417–21.Search in Google Scholar
41. Cooper MJ, Cockell KA, L’Abbé MR. The iron status of Canadian adolescents and adults: current knowledge and practical implications. Can J Diet Pract Res Markham 2006;67:130–8.10.3148/67.3.2006.130Search in Google Scholar
43. Pauniaho S-L, Tatti O, Lahdenne P, Lindahl H, Pakarinen M, Rintala R, et al. Tumor markers AFP, CA 125, and CA 19-9 in the long-term follow-up of sacrococcygeal teratomas in infancy and childhood. Tumor Biol 2010;31:261–5.10.1007/s13277-010-0026-8Search in Google Scholar
45. Waldmann TA, McIntire KR. The use of a radioimmunoassay for alpha-fetoprotein in the diagnosis of malignancy. Cancer 1974;34(S4):1510–5.10.1002/1097-0142(197410)34:8+<1510::AID-CNCR2820340824>3.0.CO;2-YSearch in Google Scholar
46. Soldin SJ, Morales A, Albalos F, Lenherr S, Rifai N. Pediatric reference ranges on the Abbott IMx for FSH, LH, prolactin, TSH, T4, T3, free T4, free T3, T-uptake, IgE, and ferritin. Clin Biochem 1995;28:603–6.10.1016/0009-9120(95)00038-5Search in Google Scholar
47. Tahmasebi H, Trajcevski K, Higgins V, Adeli K. Influence of ethnicity on population reference values for biochemical markers. Crit Rev Clin Lab Sci 2018;55:359–75.10.1080/10408363.2018.1476455Search in Google Scholar PubMed
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2019-0707).
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