title: Dynamic biological changes in metabolic disease biomarkers in childhood and adolescence: A CALIPER study of healthy community children.
abstract: BACKGROUND
  Understanding age- and sex-specific biological changes in metabolic disease biomarkers is essential for their appropriate utilization in management of children with inborn errors of metabolism (IEM). The CALIPER program aimed to establish pediatric reference values in healthy community children for common metabolic biomarkers and determine the effects of key covariates including age and sex across the pediatric age.
  
  
  METHODS
  A cohort of 500 healthy children and adolescents from birth to 19years were initially recruited to establish pediatric reference intervals according to the CLSI C28-A3 guidelines. Serum samples were used to measure 37 amino acids by ultra-performance liquid chromatography, 32 acylcarnitines, as well as free and total carnitine by tandem mass spectrometry, and β-hydroxybutyrate and free fatty acids using the Vitros 5.1 chemistry analyzer. P ediatric reference intervals were calculated using non-parametric statistics and partitioned based on age- and sex-distributions.
  
  
  RESULTS
  Approximately 80% of all analytes required 2 to 4 age-dependent partitions, with over 50% of amino acids and over 70% of acylcarnitines exhibiting significant physiological changes during the neonatal period. Also, 21% of all analytes required partitioning during puberty and adolescence, half of which produced sex-specific distributions.
  
  
  CONCLUSIONS
  A comprehensive reference interval database for metabolic disease biomarkers established in this study will improve detection of IEMs by providing appropriate age- and sex-related information in the pediatric population. It will also aid newborn screening programs and guide the management of patients with known metabolic diseases, especially pubertal and adolescent boys and girls that display sex-specific concentrations.
authors.affiliation: Caliper Program, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada.
authors.forename: Tracy
authors.initials: T
authors.lastname: Teodoro-Morrison
authors.affiliation: Caliper Program, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada.
authors.forename: Lianna
authors.initials: L
authors.lastname: Kyriakopoulou
authors.affiliation: Caliper Program, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Canada.
authors.forename: Yunqi K
authors.initials: YK
authors.lastname: Chen
authors.affiliation: Caliper Program, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Raizman
authors.affiliation: Caliper Program, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada.
authors.forename: Victoria
authors.initials: V
authors.lastname: Bevilacqua
authors.affiliation: Caliper Program, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Canada.
authors.forename: Man Khun
authors.initials: MK
authors.lastname: Chan
authors.affiliation: Caliper Program, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Canada.
authors.forename: Betty
authors.initials: B
authors.lastname: Wan
authors.affiliation: Caliper Program, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Canada.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Yazdanpanah
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulze
authors.affiliation: Caliper Program, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada. Electronic address: khosrow.adeli@sickkids.ca.
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
mesh_terms: D000293:Adolescent; D000596:Amino Acids / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D002331:Carnitine / Q000031:analogs & derivatives / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006262:Health; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008661:Metabolism, Inborn Errors / Q000097:blood*; D012016:Reference Values; D012111:Residence Characteristics; D055815:Young Adult
chemical_list: D000596:Amino Acids; D015415:Biomarkers; C116917:acylcarnitine; D002331:Carnitine
keywords: Acylcarnitines; Amino acids; Inborn errors of metabolism; Pediatrics; Reference intervals