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Review
. 2022 Jul 1;176(7):699-714.
doi: 10.1001/jamapediatrics.2022.0794.

Current State of Pediatric Reference Intervals and the Importance of Correctly Describing the Biochemistry of Child Development: A Review

Alicia N Lyle  1 , Fidelia Pokuah  1 , Dennis J Dietzen  2 , Edward C C Wong  3 , Amy L Pyle-Eilola  4 , John S Fuqua  5   6 , Alison Woodworth  7 , Patricia M Jones  8 , Lara J Akinbami  9 , Luigi R Garibaldi  10 , Hubert W Vesper  1
Affiliations
Review

Current State of Pediatric Reference Intervals and the Importance of Correctly Describing the Biochemistry of Child Development: A Review

Alicia N Lyle et al. JAMA Pediatr. .

Abstract

Importance: Appropriately established pediatric reference intervals are critical to the clinical decision-making process and should reflect the physiologic changes that occur during healthy child development. Reference intervals used in pediatric care today remain highly inconsistent across a broad range of common clinical biomarkers.

Observations: This narrative review assesses biomarker-specific pediatric reference intervals and their clinical utility with respect to the underlying biological changes occurring during development. Pediatric reference intervals from PubMed-indexed articles published from January 2015 to April 2021, commercial laboratory websites, study cohorts, and pediatric reference interval books were all examined. Although large numbers of pediatric reference intervals are published for some biomarkers, very few are used by clinical and commercial laboratories. The patterns, extent, and timing of biomarker changes are highly variable, particularly during developmental stages with rapid physiologic changes. However, many pediatric reference intervals do not capture these changes and thus do not accurately reflect the underlying biochemistry of development, resulting in significant inconsistencies between reference intervals.

Conclusions and relevance: There is a need to correctly describe the biochemistry of child development as well as to identify strategies to develop accurate and consistent pediatric reference intervals for improved pediatric care.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Dietzen reported personal fees from Danaher Diagnostics, Roche Diagnostics Point of Care, Waters Inc, and Becton Dickinson for serving on the scientific advisory board outside the submitted work. Dr Wong reported royalties from Elsevier and AACC Press. Dr Pyle-Eilola reported personal fees from Becton Dickinson for serving on a scientific advisory board outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Thyrotropin and Free Thyroxine (FT4) Pediatric Reference Interval (PRI) Patterns
PRI patterns are heterogeneous and illustrate dynamic changes at different ages. A, Thyrotropin PRIs from birth to age 12 months from 4 PRI sources. B, FT4 PRIs from birth to age 12 months corresponding with the same 4 PRI sources as thyrotropin panel A.
Figure 2.
Figure 2.. Insulin-like Growth Factor 1 (IGF-1) and Ferritin Pediatric Reference Interval (PRI) Patterns
PRI patterns are heterogeneous and illustrate dynamic changes at different ages. A, IGF-1 PRIs from birth to age 18 individuals from 4 PRI sources. years for males and female individuals from 2 PRI sources. B, Ferritin PRIs from birth to age 18 years for male
See this image and copyright information in PMC

Comment in

  • Defining Normal.
    Schroeder AR, Dang R. Schroeder AR, et al. JAMA Pediatr. 2022 Jul 1;176(7):644-645. doi: 10.1001/jamapediatrics.2022.0801. JAMA Pediatr. 2022. PMID: 35467711 No abstract available.

References

    1. Bohn MK, Higgins V, Asgari S, et al. Paediatric reference intervals for 17 Roche Cobas 8000 e602 immunoassays in the CALIPER cohort of healthy children and adolescents. Clin Chem Lab Med. 2019; 57(12):1968–1979. doi:10.1515/cclm-2019-0707 - DOI - PubMed
    1. Wong E, Brungnara C, Straseski J, Kellogg M, Khosrow A. Pediatric Reference Intervals. 8th ed: Academic Press; 2020.
    1. Léger J, Olivieri A, Donaldson M, et al.; ESPE-PES-SLEP-JSPE-APEG-APPES-ISPAE; Congenital Hypothyroidism Consensus Conference Group. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metab. 2014;99 (2):363–384. doi:10.1210/jc.2013-1891 - DOI - PMC - PubMed
    1. Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory: CLSI document EP28-A3c. Clinical and Laboratory Standards Institute; 2010.
    1. Katayev A, Fleming JK, Luo D, Fisher AH, Sharp TM. Reference intervals data mining: no longer a probability paper method. Am J Clin Pathol. 2015; 143(1):134–142. doi:10.1309/AJCPQPRNIB54WFKJ - DOI - PubMed