Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter December 14, 2021

Indirectly determined hematology reference intervals for pediatric patients in Berlin and Brandenburg

  • Ingo Mrosewski EMAIL logo , Tobias Dähn , Jörg Hehde , Elena Kalinowski , Ilona Lindner , Thea Marie Meyer , Michael Olschinsky-Szermer , Jana Pahl , Monika Puls , Kristin Sachse and Rafael Switkowski



Establishing direct reference intervals (RIs) for pediatric patients is a very challenging endeavor. Indirectly determined RIs can address this problem by utilization of existing clinical laboratory databases. In order to provide better laboratory services to the local pediatric population, we established population-specific hematology RIs via data mining.


Our laboratory information system (LIS) was searched for pediatric blood counts of patients aged from 0 days to 18 years, performed from 1st of January 2018 until 31st of March 2021. In total, 27,554 blood counts on our SYSMEX XN-9000 were initially identified. After application of pre-defined exclusion criteria, 18,531 sample sets remained. Age- and sex-specific RIs were established in accordance with International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and Clinical & Laboratory Standards Institute (CLSI) recommendations.


When compared to pediatric RIs supplied by other authors, the RIs determined specifically for pediatric patients from Berlin and Brandenburg showed several relevant differences, especially with regard to white blood cell counts (WBCs), red blood cell counts (RBCs), red cell distribution widths (RDW) and platelet counts (PLTs) within the distinct age groups. Additionally, alterations to several published age-specific partitions had to be made, while new sex-specific partitions were introduced for WBCs and PLTs.


Generic RIs from textbooks, manufacturer information and medical publications – even from nationwide or multicenter studies – commonly used in many laboratories might not reflect the specifics of local patient populations properly. RIs should be tailored to the serviced patient population whenever possible. Careful data mining appears to be suitable for this task.

Corresponding author: Dr. Ingo Mrosewski, Department of Laboratory Medicine, MDI Limbach Berlin GmbH, Aroser Allee 84, 13407 Berlin, Germany, Phone: +49 30 443364 533, Fax: +49 30 443364 111, E-mail:


The authors thank Christin Renner for data retrieval from the laboratory information system.

  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. Informed consent: Not applicable.

  5. Ethical approval: Research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013), and has been approved by the authors’ Institutional Review Board (Ärztekammer Berlin) or equivalent committee. (Register-Nr.: 225128: 03/2021).


1. Zierk, J, Arzideh, F, Haeckel, R, Rauh, M, Metzler, M, Ganslandt, T, et al.. Indirect determination of hematology reference intervals in adult patients on Beckman Coulter UniCell DxH 800 and Abbott CELL-DYN Sapphire devices. Clin Chem Lab Med 2019;57:730–9. in Google Scholar PubMed

2. Rohr, UP, Binder, C, Dieterle, T, Giusti, F, Messina, CG, Toerien, E, et al.. The value of in vitro diagnostic testing in medical practice: a status report. PLoS One 2016;11:e0149856. in Google Scholar PubMed PubMed Central

3. Friedberg, RC, Souers, R, Wagar, EA, Stankovic, AK, Valenstein, PN, College of American Pathologists. The origin of reference intervals. Arch Pathol Lab Med 2007;131:348–57. in Google Scholar PubMed

4. Ambayya, A, Su, AT, Osman, NH, Nik-Samsudin, NR, Khalid, K, Chang, KM, et al.. Haematological reference intervals in a multiethnic population. PLoS One 2014;9:e91968. in Google Scholar PubMed PubMed Central

5. Adeli, K, Raizman, JE, Chen, Y, Higgins, V, Nieuwesteeg, M, Abdelhaleem, M, et al.. Complex biological profile of hematologic markers across pediatric, adult, and geriatric ages: establishment of robust pediatric and adult reference intervals on the basis of the Canadian Health Measures Survey. Clin Chem 2015;61:1075–86. in Google Scholar PubMed

6. Horowitz, GL. The power of asterisks. Clin Chem 2015;61:1009–11. in Google Scholar PubMed

7. Nebe, T, Bentzien, F, Bruegel, M, Fiedler, GM, Gutensohn, K, Heimpel, H, et al.. Multicentric determination of reference ranges for automated blood counts. J Lab Med 2011;35:3–28. in Google Scholar

8. Herklotz, R, Lüthi, U, Ottiger, C, Huber, AR. Metaanalysis of reference values in hematology. Ther Umsch 2006;63:5–24. in Google Scholar PubMed

9. Schmidt, BM, Tameris, M, Geldenhuys, H, Luabeya, A, Bunyasi, E, Hawkridge, T, et al.. Comparison of haematology and biochemistry parameters in healthy South African infants with laboratory reference intervals. Trop Med Int Health 2018;23:63–8. in Google Scholar PubMed PubMed Central

10. Zelijkovic, A, Balog, ZC, Dukai, E, Vekic, J, Jelic-Ivanovic, Z, Spasojevic-Kalimanovska, V. Indirect reference intervals for haematological parameters in capillary blood of pre-school children. Biochem Med 2021;31:010709. in Google Scholar PubMed PubMed Central

11. 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. in Google Scholar PubMed PubMed Central

12. Jones, GR, 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. in Google Scholar PubMed

13. Hoq, M, Matthews, S, Donath, S, Carlin, J, Ignjatovic, V, Monagle, P. Paediatric reference intervals: current status, gaps, challenges and future considerations. Clin Biochem Rev 2020;41:43–52. in Google Scholar PubMed PubMed Central

14. Ceriotti, F, Hinzmann, R, Panteghini, M. Reference intervals: the way forward. Ann Clin Biochem 2009;46:8–17. in Google Scholar PubMed

15. Poole, S, Schroeder, LF, Shah, N. An unsupervised learning method to identify reference intervals from a clinical database. J Biomed Inf 2016;59:276–84. in Google Scholar PubMed PubMed Central

16. Sinclair, L, Hall, S, Badrick, T. A survey of Australian haematology reference intervals. Pathology 2014;46:538–43. in Google Scholar PubMed

17. Arzideh, F, Brandhorst, G, Gurr, E, Hinsch, W, Hoff, T, Roggenbuck, L, et al.. An improved indirect approach for determining reference limits from intra-laboratory data bases exemplified by concentrations of electrolytes. J Lab Med 2009;33:52–66. in Google Scholar

18. Arzideh, F, Wosniok, W, Haeckel, R. Reference limits of plasma and serum creatinine concentrations from intra-laboratory data bases of several German and Italian medical centres: comparison between direct and indirect procedures. Clin Chim Acta 2010;411:215–21. in Google Scholar PubMed

19. Arzideh, F, Wosniok, W, Haeckel, R. Indirect reference intervals of plasma and serum thyrotropin (TSH) concentrations from intra-laboratory data bases from several German and Italian medical centres. Clin Chem Lab Med 2011;49:659–64. in Google Scholar PubMed

20. 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. in Google Scholar PubMed

21. 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. in Google Scholar PubMed

22. Özcürümez, MK, Haeckel, R, Gurr, E, Streichert, T, Sack, U. Determination and verification of reference interval limits in clinical chemistry. Recommendations for laboratories on behalf of the Working Group Guide Limits of the DGKL with respect to ISO Standard 15189 and the Guideline of the German Medical Association on Quality Assurance in Medical Laboratory Examinations (Rili-BAEK). J Lab Med 2019;43:127–33. in Google Scholar

23. CLSI. Defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline, 3rd ed. Wayne, PA: Clinical and Laboratory Standards Institute; 2008, Report No.: CLSI document C28-A3.Search in Google Scholar

24. Haeckel, R, Wosniok, W, Arzideh, F. Equivalence limits of reference intervals for partitioning of population data. Relevant differences of reference limits. J Lab Med 2016;40:199–205. in Google Scholar

25. Bundesärztekammer. Guidelines of the German Medical Association on quality assurance in medical laboratory examinations. Available from: [Accessed 22 Jun 2021].Search in Google Scholar

26. Dortschy, R, Schaffrath Rosario, A, Scheidt-Nave, C, Thierfelder, W, Thamm, M, Gutsche, J, et al.. Population-based distribution of selected laboratory parameters from the national health interview and examination survey for children and adolescents. Berlin: Robert Koch-Institut; 2009.Search in Google Scholar

27. 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. in Google Scholar PubMed

28. Statistisches Bundesamt. Live births by citizenship of mother 2020. Available from: [Accessed 25 Nov 2021].Search in Google Scholar

29. Al-Mazorki, JM, Al-Maaroof, ZW, Kadhum, AD. Determination of reference ranges for full blood count parameters in neonatal cord plasma in Hilla, Babil, Iraq. Hematol Res Rev 2012;3:113–8. in Google Scholar PubMed PubMed Central

30. Ozarda, Y, Ichihara, K, Bakan, E, Polat, H, Ozturk, N, Baygutalp, NK, et al.. A nationwide multicentre study in Turkey for establishing reference intervals of haematological parameters with novel use of a panel of whole blood. Biochem Med 2017;27:350–77. in Google Scholar PubMed PubMed Central

31. DGKL. Decision Limits/reference data. Available from:[Accessed 29th Nov 2021].Search in Google Scholar

32. Ichihara, K, Boyd, JC. An appraisal of statistical procedures used in derivation of reference intervals. Clin Chem Lab Med 2010;48:1537–51. in Google Scholar PubMed

33. Kieh, MW, Browne, SM, Grandits, GA, Blie, J, Doe-Anderson, JW, Hoover, ML, et al.. Adult and paediatric haematology and clinical chemistry laboratory reference limits for Liberia. Afr J Lab Med 2020;9:1080. in Google Scholar PubMed PubMed Central

34. Zeh, C, Amornkul, PN, Inzaule, S, Ondoa, P, Oyaro, B, Mwaengo, DM, et al.. Population-based biochemistry, immunologic and hematological reference values for adolescents and young adults in a rural population in Western Kenya. PLoS One 2011;6:e21040. in Google Scholar PubMed PubMed Central

35. Rowland, R, O’hara, GA, Hamill, M, Pulton, ID, Donaldson, H, Dinsmore, L, et al.. Determining the validity of hospital laboratory reference intervals for healthy young adults participating in early clinical trials of candidate vaccines. Hum Vaccines Immunother 2013;9:1741–51. in Google Scholar PubMed PubMed Central

36. Ouma, JO, Mulama, DH, Otieno, L, Owuoth, J, Ogutu, B, Oyieko, J, et al.. Clinical laboratory hematology reference values among infants aged 1 month to 17 months in Kombewa Sub-County, Kisumu: a cross sectional study of rural population in Western Kenya. PLoS One 2021;16:e0244786. in Google Scholar PubMed PubMed Central

37. Inchley, J, Currie, D, Budisavljevic, S, Torsheim, T, Jåstad, A, Cosma, A, et al.. Spotlight on adolescent health and well-being. Findings from the 2017/2018 Health Behaviour in School-aged Children (HBSC) survey in Europe and Canada. Copenhagen: WHO Regional Office for Europe; 2020, International report, vol 1. Key findings.Search in Google Scholar

38. Statistisches Bundesamt. Population by nationality and sex 1970 to 2020 in Germany. Available from: [Accessed 16 Jul 2021].Search in Google Scholar

39. Statistisches Bundesamt. Population in private households by migrant background and federal states. Available from: [Accessed 13 Jul 2021].Search in Google Scholar

40. Statistisches Bundesamt. Foreign population by Land and years. Available from: [Accessed 13 Jul 2021].Search in Google Scholar

41. Statistisches Bundesamt. Glossar: Ausländische Bevölkerung. Available from: [Accessed 13 Jul 2021].Search in Google Scholar

42. Lubega, IR, Fowler, MG, Musoke, PM, Elbireer, A, Bagenda, D, Kafulafula, G, et al.. Considerations in using US-based laboratory toxicity tables to evaluate laboratory toxicities among healthy Malawian and Ugandan infants. J Acquir Immune Defic Syndr 2010;55:58–64. in Google Scholar

43. Troy, SB, Rowhani-Rahbar, A, Dyner, L, Musingwini, G, Shetty, AK, Woelk, G, et al.. Hematologic and immunologic parameters in Zimbabwean infants: a case for using local reference intervals to monitor toxicities in clinical trials. J Trop Pediatr 2011;58:59–62. in Google Scholar PubMed PubMed Central

44. Scott-Emuakpor, A, Okolo, A, Omene, J, Ukpe, S. Normal hematological values of the African neonate. Ann Hematol 1985;51:11–8. in Google Scholar PubMed

45. ISO15189:2012. Medical laboratories – requirements for quality and competence. Available from: [Accessed 14 Jul 2021].Search in Google Scholar

Received: 2021-07-30
Accepted: 2021-12-02
Published Online: 2021-12-14
Published in Print: 2022-02-23

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 25.2.2024 from
Scroll to top button