Continuous age- and sex-adjusted reference intervals of urinary markers for cerebral creatine deficiency syndromes: a novel approach to the definition of reference intervals

Clinical Chemistry
Lars MørkridPiero Rinaldo

Abstract

Urinary concentrations of creatine and guanidinoacetic acid divided by creatinine are informative markers for cerebral creatine deficiency syndromes (CDSs). The renal excretion of these substances varies substantially with age and sex, challenging the sensitivity and specificity of postanalytical interpretation. Results from 155 patients with CDS and 12 507 reference individuals were contributed by 5 diagnostic laboratories. They were binned into 104 adjacent age intervals and renormalized with Box-Cox transforms (Ξ). Estimates for central tendency (μ) and dispersion (σ) of Ξ were obtained for each bin. Polynomial regression analysis was used to establish the age dependence of both μ[log(age)] and σ[log(age)]. The regression residuals were then calculated as z-scores = {Ξ - μ[log(age)]}/σ[log(age)]. The process was iterated until all z-scores outside Tukey fences ±3.372 were identified and removed. Continuous percentile charts were then calculated and plotted by retransformation. Statistically significant and biologically relevant subgroups of z-scores were identified. Significantly higher marker values were seen in females than males, necessitating separate reference intervals in both adolescents and adults. Comparison between...Continue Reading

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Citations

Jan 6, 2017·Genetics in Medicine : Official Journal of the American College of Medical Genetics·J Daniel SharerSarah Young
Nov 3, 2017·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Silvia TortorelliPiero Rinaldo
Nov 10, 2017·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Melissa M Minter BaergPiero Rinaldo
Apr 22, 2019·Clinical Chemistry and Laboratory Medicine : CCLM·Jakob ZierkMarkus Metzler
Mar 20, 2020·International Journal of Neonatal Screening·Gang PengCurt Scharfe
Apr 24, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sigrun HopeOle A Andreassen
Jun 12, 2020·The Journal of Clinical Endocrinology and Metabolism·Michael R LasarevPatrice K Held
Sep 18, 2016·Journal of Neuroscience Research·Joseph J OrsiniMichele Caggana
Apr 21, 2016·Journal of Developmental and Behavioral Pediatrics : JDBP·Audrey ThurmNuria Carrillo
Jun 17, 2020·International Journal of Laboratory Hematology·Marzia RahmanPaul Monagle
Feb 13, 2020·NPJ Digital Medicine·Reed T SuttonKaren I Kroeker
Aug 18, 2020·International Journal of Neonatal Screening·Karen A SandersDietrich Matern
Nov 6, 2020·International Journal of Neonatal Screening·Sabrina MalvagiaGiancarlo la Marca
Feb 6, 2021·NPJ Digital Medicine·Reed T SuttonKaren I Kroeker

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