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Licensed Unlicensed Requires Authentication Published by De Gruyter February 10, 2021

High-resolution pediatric reference intervals for 15 biochemical analytes described using fractional polynomials

Jakob Zierk, Hannsjörg Baum, Alexander Bertram, Martin Boeker, Armin Buchwald, Holger Cario, Jürgen Christoph, Michael C. Frühwald, Hans-Jürgen Groß, Arndt Groening, Thomas Gscheidmeier, Torsten Hoff, Reinhard Hoffmann, Rainer Klauke, Alexander Krebs, Ralf Lichtinghagen, Sabine Mühlenbrock-Lenter, Michael Neumann, Peter Nöllke, Charlotte M. Niemeyer, Hans-Georg Ruf, Udo Steigerwald, Thomas Streichert, Antje Torge, Ayami Yoshimi-Nöllke, Hans-Ulrich Prokosch, Markus Metzler and Manfred Rauh



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.

Corresponding author: Dr. Jakob Zierk, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Loschgestr. 15, 91054Erlangen, Germany; and Center of Medical Information and Communication Technology, University Hospital Erlangen, Erlangen, Germany, Phone: +49 9131/85 33731, Fax: +49 9131/85 35742, E-mail:


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.

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Ethical approval: The study was approved by the Institutional Review Board of the University Hospital Erlangen (reference number 97_17 Bc).


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Supplementary Material

The online version of this article offers supplementary material (

Received: 2020-09-09
Accepted: 2021-01-28
Published Online: 2021-02-10
Published in Print: 2021-06-25

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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