Next-generation reference intervals for pediatric hematology

Jakob Zierk 1 , Johannes Hirschmann 2 , Dennis Toddenroth 2 , Farhad Arzideh 3 , Rainer Haeckel 4 , Alexander Bertram 5 , Holger Cario 6 , Michael C. Frühwald 7 , Hans-Jürgen Groß 8 , Arndt Groening 5 , Stefanie Grützner 9 , Thomas Gscheidmeier 8 , Torsten Hoff 10 , Reinhard Hoffmann 11 , Rainer Klauke 12 , Alexander Krebs 13 , Ralf Lichtinghagen 12 , Sabine Mühlenbrock-Lenter 10 , Michael Neumann 14 , Peter Nöllke 15 , Charlotte M. Niemeyer 15 , Oliver Razum 16 , Hans-Georg Ruf 11 , Udo Steigerwald 14 , Thomas Streichert 17 , Antje Torge 18 , Wolfgang Rascher 19 , Hans-Ulrich Prokosch 2 , Manfred Rauh 19 ,  and Markus Metzler 19
  • 1 Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Loschgestr. 15, 91054 Erlangen, Germany
  • 2 Chair of Medical Informatics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • 3 Department of Statistics, University of Bremen, Bremen, Germany
  • 4 Bremer Zentrum für Laboratoriumsmedizin, Klinikum Bremen Mitte, Bremen, Germany
  • 5 MVZ wagnerstibbe, amedes Gruppe, Hannover, Germany
  • 6 Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
  • 7 Department of Pediatric Oncology/Hematology, Klinikum Augsburg, Augsburg, Germany
  • 8 Core Facility of Clinical Chemistry, University Medical Center Ulm, Ulm, Germany
  • 9 Department of Transfusion Medicine and Haemostasis, Klinikum Augsburg, Augsburg, Germany
  • 10 Central Laboratory, Gesundheit Nord – Bremen Hospital Group, Bremen, Germany
  • 11 Institute for Laboratory Medicine and Microbiology, Klinikum Augsburg, Augsburg, Germany
  • 12 Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany
  • 13 MVZ Labor PD Dr. Volkmann und Kollegen, Karlsruhe, Germany
  • 14 Division of Laboratory Medicine, University Hospital of Würzburg, Würzburg, Germany
  • 15 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
  • 16 Department of Epidemiology & International Public Health, School of Public Health, Bielefeld University, Bielefeld, Germany
  • 17 Department of Clinical Chemistry, University Hospital of Cologne, Cologne, Germany
  • 18 Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
  • 19 Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany
Jakob Zierk
  • Corresponding author
  • Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Loschgestr. 15, 91054 Erlangen, Germany
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, Johannes Hirschmann
  • Chair of Medical Informatics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
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, Dennis Toddenroth
  • Chair of Medical Informatics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
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, Farhad Arzideh, Rainer Haeckel, Alexander Bertram, Holger Cario
  • Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
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, Michael C. Frühwald, Hans-Jürgen Groß, Arndt Groening, Stefanie Grützner
  • Department of Transfusion Medicine and Haemostasis, Klinikum Augsburg, Augsburg, Germany
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, Thomas Gscheidmeier, Torsten Hoff, Reinhard Hoffmann
  • Institute for Laboratory Medicine and Microbiology, Klinikum Augsburg, Augsburg, Germany
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, Rainer Klauke, Alexander Krebs, Ralf Lichtinghagen, Sabine Mühlenbrock-Lenter, Michael Neumann
  • Division of Laboratory Medicine, University Hospital of Würzburg, Würzburg, Germany
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, Peter Nöllke
  • Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
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, Charlotte M. Niemeyer
  • Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
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, Oliver Razum
  • Department of Epidemiology & International Public Health, School of Public Health, Bielefeld University, Bielefeld, Germany
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, Hans-Georg Ruf
  • Institute for Laboratory Medicine and Microbiology, Klinikum Augsburg, Augsburg, Germany
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, Udo Steigerwald
  • Division of Laboratory Medicine, University Hospital of Würzburg, Würzburg, Germany
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, Thomas Streichert
  • Department of Clinical Chemistry, University Hospital of Cologne, Cologne, Germany
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, Antje Torge
  • Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
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, Wolfgang Rascher
  • Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany
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, Hans-Ulrich Prokosch
  • Chair of Medical Informatics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
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, Manfred Rauh
  • Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany
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and Markus Metzler
  • Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany
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Abstract

Background

Interpreting hematology analytes in children is challenging due to the extensive changes in hematopoiesis that accompany physiological development and lead to pronounced sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, and limitations in current approaches to laboratory test result displays restrict their use when guiding clinical decisions.

Methods

We employed an improved data-driven approach to create percentile charts from laboratory data collected during patient care in 10 German centers (9,576,910 samples from 358,292 patients, 412,905–1,278,987 samples per analyte). We demonstrate visualization of hematology test results using percentile charts and z-scores (www.pedref.org/hematology) and assess the potential of percentiles and z-scores to support diagnosis of different hematological diseases.

Results

We created percentile charts for hemoglobin, hematocrit, red cell indices, red cell count, red cell distribution width, white cell count and platelet count in girls and boys from birth to 18 years of age. Comparison of pediatricians evaluating complex clinical scenarios using percentile charts versus conventional/tabular representations shows that percentile charts can enhance physician assessment in selected example cases. Age-specific percentiles and z-scores, compared with absolute test results, improve the identification of children with blood count abnormalities and the discrimination between different hematological diseases.

Conclusions

The provided reference intervals enable precise assessment of pediatric hematology test results. Representation of test results using percentiles and z-scores facilitates their interpretation and demonstrates the potential of digital approaches to improve clinical decision-making.

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Clinical Chemistry and Laboratory Medicine ( CCLM) publishes articles on novel teaching and training methods applicable to laboratory medicine. CCLM welcomes contributions on the progress in fundamental and applied research and cutting-edge clinical laboratory medicine. It is one of the leading journals in the field, with an impact factor of over three. CCLM is the official journal of nine national clinical societies and associated with EFLM.

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