Assessment of children’s laboratory test results requires consideration of the extensive changes that occur during physiological development and result in pronounced sex- and age-specific dynamics in many biochemical analytes. Pediatric reference intervals have to account for these dynamics, but ethical and practical challenges limit the availability of appropriate pediatric reference intervals that cover children from birth to adulthood. We have therefore initiated the multi-center data-driven PEDREF project (Next-Generation Pediatric Reference Intervals) to create pediatric reference intervals using data from laboratory information systems.
We analyzed laboratory test results from 638,683 patients (217,883–982,548 samples per analyte, a median of 603,745 test results per analyte, and 10,298,067 test results in total) performed during patient care in 13 German centers. Test results from children with repeat measurements were discarded, and we estimated the distribution of physiological test results using a validated statistical approach (kosmic).
We report continuous pediatric reference intervals and percentile charts for alanine transaminase, aspartate transaminase, lactate dehydrogenase, alkaline phosphatase, γ-glutamyl-transferase, total protein, albumin, creatinine, urea, sodium, potassium, calcium, chloride, anorganic phosphate, and magnesium. Reference intervals are provided as tables and fractional polynomial functions (i.e., mathematical equations) that can be integrated into laboratory information systems. Additionally, Z-scores and percentiles enable the normalization of test results by age and sex to facilitate their interpretation across age groups.
The provided reference intervals and percentile charts enable precise assessment of laboratory test results in children from birth to adulthood. Our findings highlight the pronounced dynamics in many biochemical analytes in neonates, which require particular consideration in reference intervals to support clinical decision making most effectively.
We thank the members of the German Society for Clinical Chemistry and Laboratory Medicine’s working group on guide limits (“AG Richtwerte der DGKL”) for their valuable input.
Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Ethical approval: The study was approved by the Institutional Review Board of the University Hospital Erlangen (reference number 97_17 Bc).
2. CLSI. Defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline, 3rd ed. Report No.: CLSI document C28-A3. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.Search in Google Scholar
5. Adeli, K, Higgins, V, Trajcevski, K, Habeeb, NW-A. The Canadian laboratory initiative on pediatric reference intervals: a CALIPER white paper. Crit Rev Clin Lab Sci 2017;54:358–413. https://doi.org/10.1080/10408363.2017.1379945.Search in Google Scholar PubMed
6. Asgari, S, Higgins, V, McCudden, C, Adeli, K. Continuous reference intervals for 38 biochemical markers in healthy children and adolescents: comparisons to traditionally partitioned reference intervals. Clin Biochem 2019;73:82–9. https://doi.org/10.1016/j.clinbiochem.2019.08.010.Search in Google Scholar PubMed
7. Hoq, M, Matthews, S, Karlaftis, V, Burgess, J, Cowley, J, Donath, S, et al.. Reference values for 30 common biochemistry analytes across 5 different analyzers in neonates and children 30 Days to 18 Years of age. Clin Chem 2019;65:1317–26. https://doi.org/10.1373/clinchem.2019.306431.Search in Google Scholar PubMed
8. Kohse, KP, Thamm, M. KiGGS-the German survey on children’s health as data base for reference intervals. Clin Biochem 2011;44:479. https://doi.org/10.1016/j.clinbiochem.2011.02.016.Search in Google Scholar PubMed
9. Quante, M, Hesse, M, Döhnert, M, Fuchs, M, Hirsch, C, Sergeyev, E, et al.. The LIFE child study: a life course approach to disease and health. BMC Publ Health 2012;12:1021. https://doi.org/10.1186/1471-2458-12-1021.Search in Google Scholar PubMed PubMed Central
10. Zierk, J, Arzideh, F, Haeckel, R, Rascher, W, Rauh, M, Metzler, M. Indirect determination of pediatric blood count reference intervals. Clin Chem Lab Med 2013;51:863–72. https://doi.org/10.1515/cclm-2012-0684.Search in Google Scholar PubMed
11. Zierk, J, Arzideh, F, Rechenauer, T, Haeckel, R, Rascher, W, Metzler, M, et al.. Age- and sex-specific dynamics in 22 hematologic and biochemical analytes from birth to adolescence. Clin Chem 2015;61:964–73. https://doi.org/10.1373/clinchem.2015.239731.Search in Google Scholar PubMed
12. Zierk, J, Arzideh, F, Haeckel, R, Cario, H, Frühwald, MC, Groß, H-J, et al.. Pediatric reference intervals for alkaline phosphatase. Clin Chem Lab Med 2017;55:102–10. https://doi.org/10.1515/cclm-2016-0318.Search in Google Scholar PubMed
13. Zierk, J, Hirschmann, J, Toddenroth, D, Arzideh, F, Haeckel, R, Bertram, A, et al.. Next-generation reference intervals for pediatric hematology. Clin Chem Lab Med 2019;57:1595–607. https://doi.org/10.1515/cclm-2018-1236.Search in Google Scholar PubMed
14. Zierk, J, Arzideh, F, Kapsner, LA, Prokosch, H-U, Metzler, M, Rauh, M. Reference interval estimation from mixed distributions using truncation points and the Kolmogorov-Smirnov distance (kosmic). Sci Rep 2020;10:1704. https://doi.org/10.1038/s41598-020-58749-2.Search in Google Scholar PubMed PubMed Central
15. Ricós, C, Alvarez, V, Cava, F, García-Lario, JV, Hernández, A, Jiménez, CV, et al.. Current databases on biological variation: pros, cons and progress. Scand J Clin Lab Invest 1999;59:491–500.10.1080/00365519950185229Search in Google Scholar PubMed
16. Royston, P, Sauerbrei, W. Multivariable model-building. A pragmatic approach to regression analysis based on fractional polynomials for modelling continuous variables. Chichester, England: John Wiley & Sons, Ltd; 2008. https://onlinelibrary.wiley.com/doi/book/10.1002/9780470770771.Search in Google Scholar
17. Haeckel, R, Wosniok, W, Gurr, E, Postma, T, Streichert, T. Quantity quotient reporting versus z-value for standardizing quantitative laboratory results. J Lab Med 2017;41:93–7. https://doi.org/10.1515/labmed-2017-0007.Search in Google Scholar
18. Loh, TP, Antoniou, G, Baghurst, P, Metz, MP. Development of paediatric biochemistry centile charts as a complement to laboratory reference intervals. Pathology 2014;46:336–43. https://doi.org/10.1097/pat.0000000000000118.Search in Google Scholar
20. Hoq, M, Karlaftis, V, Mathews, S, Burgess, J, Donath, SM, Carlin, J, et al.. A prospective, cross-sectional study to establish age-specific reference intervals for neonates and children in the setting of clinical biochemistry, immunology and haematology: the HAPPI Kids study protocol. BMJ Open 2019;9:e025897. https://doi.org/10.1136/bmjopen-2018-025897.Search in Google Scholar PubMed PubMed Central
21. Rieger, K, Vogel, M, Engel, C, Ceglarek, U, Thiery, J, Kratzsch, J, et al.. Reference intervals for iron-related blood parameters: results from a population-based cohort study (LIFE Child). J Lab Med 2016;40:000010151520160019. https://doi.org/10.1515/labmed-2016-0019.Search in Google Scholar
22. Bussler, S, Vogel, M, Pietzner, D, Harms, K, Buzek, T, Penke, M, et al.. New pediatric percentiles of liver enzyme serum levels (ALT, AST, GGT): effects of age, sex, BMI and pubertal stage. Hepatology; 2018;68:1319–30.10.1002/hep.29542Search in Google Scholar PubMed
23. Jones, GRD, Haeckel, R, Loh, TP, Sikaris, K, Streichert, T, Katayev, A, et al.. Indirect methods for reference interval determination - review and recommendations. Clin Chem Lab Med 2018;57:20–9. https://doi.org/10.1515/cclm-2018-0073.Search in Google Scholar PubMed
25. Hepp, T, Zierk, J, Rauh, M, Metzler, M, Mayr, A. Latent class distributional regression for the estimation of non-linear reference limits from contaminated data sources. BMC Bioinf 2020;21:524. https://doi.org/10.1186/s12859-020-03853-3.Search in Google Scholar PubMed PubMed Central
26. Colantonio, DA, Kyriakopoulou, L, Chan, MK, Daly, CH, Brinc, D, Venner, AA, 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. https://doi.org/10.1373/clinchem.2011.177741.Search in Google Scholar PubMed
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2020-1371).
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