scholarly journals Advances in Pediatric Reference Intervals for Biochemical Markers: Establishment of the Caliper Database in Healthy Children and Adolescents/Napredak U Oblasti Pedijatrijskih Referentnih Intervala Za Biohemijske Markere: Izrada Baze Podataka Caliper Kod Zdrave Dece I Adolescenata

2014 ◽  
Vol 34 (1) ◽  
pp. 23-30 ◽  
Author(s):  
Kimiya Karbasy ◽  
Petra Ariadne ◽  
Stephanie Gaglione ◽  
Michelle Nieuwesteeg ◽  
Khosrow Adeli
Keyword(s):  
Children And Adolescents ◽  
Biochemical Markers ◽  
Clinical Laboratory ◽  
Reference Interval ◽  
Reference Intervals ◽  
Healthy Children ◽  
Medical Practitioners ◽  
Laboratory Test Results ◽  
Laboratory Reference ◽  
And Gender

Summary Clinical laboratory reference intervals provide valuable information to medical practitioners in their interpretation of quantitative laboratory test results, and therefore are critical in the assessment of patient health and in clinical decisionmaking. The reference interval serves as a health-associated benchmark with which to compare an individual test result. Unfortunately, critical gaps currently exist in accurate and upto-date pediatric reference intervals for accurate interpretation of laboratory tests performed in children and adolescents. These critical gaps in the available laboratory reference intervals have the clear potential of contributing to erroneous diagnosis or misdiagnosis of many diseases. To address these important gaps, several initiatives have begun internationally by a number of bodies including the KiGGS initiative in Germany, the Aussie Normals in Australia, the AACC-National Children Study in USA, the NORICHILD Initiative in Scandinavia, and the CALIPER study in Canada. In the present article, we will review the gaps in pediatric reference intervals, challenges in establishing pediatric norms in healthy children and adolescents, and the major contributions of the CALIPER program to closing the gaps in this crucial area of pediatric laboratory medicine. We will also discuss the recently published CALIPER reference interval database (www.caliperdatabase.com) developed to provide comprehensive age and gender specific pediatric reference intervals for a larger number of biochemical markers, based on a large and diverse healthy children cohort. The CALIPER database is based on a multiethnic population examining the influence of ethnicity on laboratory reference intervals. Thus the database has proved to be of global benefit and is being adopted by hospital laboratories worldwide.

Pediatric reference intervals for 1,25-dihydroxyvitamin D using the DiaSorin LIAISON XL assay in the healthy CALIPER cohort

2018 ◽  
Vol 56 (6) ◽  
pp. 964-972 ◽  
Author(s):  
Victoria Higgins ◽  
Dorothy Truong ◽  
Nicole M.A. White-Al Habeeb ◽  
Angela W.S. Fung ◽  
Barry Hoffman ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Critical Role ◽  
Reference Interval ◽  
Reference Intervals ◽  
Biologically Active ◽  
Specific Reference ◽  
Healthy Children ◽  
Serum Samples ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D

Abstract Background: 1,25-dihydroxyvitamin D (1,25(OH)2D), the biologically active vitamin D metabolite, plays a critical role in calcium and phosphate homeostasis. 1,25(OH)2D is measured to assess calcium and phosphate metabolism, particularly during periods of profound growth and development. Despite its importance, no reliable pediatric reference interval exists, with those available developed using adult populations or out-dated methodologies. Using the fully automated chemiluminescence immunoassay by DiaSorin, we established 1,25(OH)2D pediatric reference intervals using healthy children and adolescents from the CALIPER cohort. Methods: Serum samples from healthy subjects (0 to <19 years) were analyzed for 1,25(OH)2D using the DiaSorin LIAISON XL assay and age-specific reference intervals were established. The Mann-Whitney U-test was used to determine seasonal differences. Pooled neonatal and infantile samples were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine if elevated concentrations during the first year of life may be attributed to cross-reacting moieties. Results: Three reference interval age partitions were required with highest levels in subjects 0 to <1 year (77–471 pmol/L), which declined and narrowed after 1 year (113–363 pmol/L) and plateaued at 3 years (108–246 pmol/L). 1,25(OH)2D concentration was not significantly affected by seasonal variation or sex. Elevated 1,25(OH)2D concentrations in neonatal and infantile samples may be the result of an interfering substance. The absence of 3-epi-1,25-dihydroxyvitamin D in the pooled samples makes it unlikely to be the interfering moiety. Conclusions: Pediatric reference intervals for 1,25(OH)2D were established to improve test result interpretation in children and adolescents. 1,25(OH)2D is elevated in a proportion of neonates and infants, which may be the result of a cross-reacting moiety.

scholarly journals Marked Biological Variance in Endocrine and Biochemical Markers in Childhood: Establishment of Pediatric Reference Intervals Using Healthy Community Children from the CALIPER Cohort

2013 ◽  
Vol 59 (9) ◽  
pp. 1393-1405 ◽  
Author(s):  
Dana Bailey ◽  
David Colantonio ◽  
Lianna Kyriakopoulou ◽  
Ashley H Cohen ◽  
Man Khun Chan ◽  
...  
Keyword(s):  
Reference Values ◽  
Biochemical Markers ◽  
Troponin I ◽  
Reference Intervals ◽  
Thyroid Stimulating Hormone ◽  
Healthy Children ◽  
Free Triiodothyronine ◽  
Laboratory Test Results ◽  
Total Triiodothyronine ◽  
Total Thyroxine

BACKGROUND Reference intervals are indispensable in evaluating laboratory test results; however, appropriately partitioned pediatric reference values are not readily available. The Canadian Laboratory Initiative for Pediatric Reference Intervals (CALIPER) program is aimed at establishing the influence of age, sex, ethnicity, and body mass index on biochemical markers and developing a comprehensive database of pediatric reference intervals using an a posteriori approach. METHODS A total of 1482 samples were collected from ethnically diverse healthy children ages 2 days to 18 years and analyzed on the Abbott ARCHITECT i2000. Following the CLSI C28-A3 guidelines, age- and sex-specific partitioning was determined for each analyte. Nonparametric and robust methods were used to establish the 2.5th and 97.5th percentiles for the reference intervals as well as the 90% CIs. RESULTS New pediatric reference intervals were generated for 14 biomarkers, including α-fetoprotein, cobalamin (vitamin B12), folate, homocysteine, ferritin, cortisol, troponin I, 25(OH)-vitamin D [25(OH)D], intact parathyroid hormone (iPTH), thyroid-stimulating hormone, total thyroxine (TT4), total triiodothyronine (TT3), free thyroxine (FT4), and free triiodothyronine. The influence of ethnicity on reference values was also examined, and statistically significant differences were found between ethnic groups for FT4, TT3, TT4, cobalamin, ferritin, iPTH, and 25(OH)D. CONCLUSIONS This study establishes comprehensive pediatric reference intervals for several common endocrine and immunochemical biomarkers obtained in a large cohort of healthy children. The new database will be of global benefit, ensuring appropriate interpretation of pediatric disease biomarkers, but will need further validation for specific immunoassay platforms and in local populations as recommended by the CLSI.

scholarly journals Complex Biological Pattern of Fertility Hormones in Children and Adolescents: A Study of Healthy Children from the CALIPER Cohort and Establishment of Pediatric Reference Intervals

2013 ◽  
Vol 59 (8) ◽  
pp. 1215-1227 ◽  
Author(s):  
Danijela Konforte ◽  
Jennifer L Shea ◽  
Lianna Kyriakopoulou ◽  
David Colantonio ◽  
Ashley H Cohen ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Clinical Laboratory ◽  
Pediatric Population ◽  
Pubertal Development ◽  
Tanner Stage ◽  
Reference Intervals ◽  
Sex Hormone Binding Globulin ◽  
Specific Reference ◽  
Healthy Children ◽  
Pubertal Stage

BACKGROUND Pediatric endocrinopathies are commonly diagnosed and monitored by measuring hormones of the hypothalamic-pituitary-gonadal axis. Because growth and development can markedly influence normal circulating concentrations of fertility hormones, accurate reference intervals established on the basis of a healthy, nonhospitalized pediatric population and that reflect age-, gender-, and pubertal stage–specific changes are essential for test result interpretation. METHODS Healthy children and adolescents (n = 1234) were recruited from a multiethnic population as part of the CALIPER study. After written informed parental consent was obtained, participants filled out a questionnaire including demographic and pubertal development information (assessed by self-reported Tanner stage) and provided a blood sample. We measured 7 fertility hormones including estradiol, testosterone (second generation), progesterone, sex hormone–binding globulin, prolactin, follicle-stimulating hormone, and luteinizing hormone by use of the Abbott Architect i2000 analyzer. We then used these data to calculate age-, gender-, and Tanner stage–specific reference intervals according to Clinical Laboratory Standards Institute C28-A3 guidelines. RESULTS We observed a complex pattern of change in each analyte concentration from the neonatal period to adolescence. Consequently, many age and sex partitions were required to cover the changes in most fertility hormones over this period. An exception to this was prolactin, for which no sex partition and only 3 age partitions were necessary. CONCLUSIONS This comprehensive database of pediatric reference intervals for fertility hormones will be of global benefit and should lead to improved diagnosis of pediatric endocrinopathies. The new database will need to be validated in local populations and for other immunoassay platforms as recommended by the Clinical Laboratory Standards Institute.

scholarly journals Closing the Gaps in Pediatric Laboratory Reference Intervals: A CALIPER Database of 40 Biochemical Markers in a Healthy and Multiethnic Population of Children

2012 ◽  
Vol 58 (5) ◽  
pp. 854-868 ◽  
Author(s):  
David A Colantonio ◽  
Lianna Kyriakopoulou ◽  
Man Khun Chan ◽  
Caitlin H Daly ◽  
Davor Brinc ◽  
...  
Keyword(s):  
Biochemical Markers ◽  
Pediatric Population ◽  
Reference Interval ◽  
Reference Intervals ◽  
Healthy Children ◽  
Childhood Diseases ◽  
Closing The Gaps ◽  
Multiethnic Population ◽  
Statistical Guidelines ◽  
Laboratory Biomarkers

Abstract BACKGROUND Pediatric healthcare is critically dependent on the availability of accurate and precise laboratory biomarkers of pediatric disease, and on the availability of reference intervals to allow appropriate clinical interpretation. The development and growth of children profoundly influence normal circulating concentrations of biochemical markers and thus the respective reference intervals. There are currently substantial gaps in our knowledge of the influences of age, sex, and ethnicity on reference intervals. We report a comprehensive covariate-stratified reference interval database established from a healthy, nonhospitalized, and multiethnic pediatric population. METHODS Healthy children and adolescents (n = 2188, newborn to 18 years of age) were recruited from a multiethnic population with informed parental consent and were assessed from completed questionnaires and according to defined exclusion criteria. Whole-blood samples were collected for establishing age- and sex-stratified reference intervals for 40 serum biochemical markers (serum chemistry, enzymes, lipids, proteins) on the Abbott ARCHITECT c8000 analyzer. RESULTS Reference intervals were generated according to CLSI C28-A3 statistical guidelines. Caucasians, East Asians, and South Asian participants were evaluated with respect to the influence of ethnicity, and statistically significant differences were observed for 7 specific biomarkers. CONCLUSIONS The establishment of a new comprehensive database of pediatric reference intervals is part of the Canadian Laboratory Initiative in Pediatric Reference Intervals (CALIPER). It should assist laboratorians and pediatricians in interpreting test results more accurately and thereby lead to improved diagnosis of childhood diseases and reduced patient risk. The database will also be of global benefit once reference intervals are validated in transference studies with other analytical platforms and local populations, as recommended by the CLSI.

scholarly journals Resampling Approach for Determination of the Method for Reference Interval Calculation in Clinical Laboratory Practice

2010 ◽  
Vol 17 (8) ◽  
pp. 1217-1222 ◽  
Author(s):  
Igor Y. Pavlov ◽  
Andrew R. Wilson ◽  
Julio C. Delgado
Keyword(s):  
Clinical Laboratory ◽  
Parametric Method ◽  
Reference Interval ◽  
Reference Intervals ◽  
Complement Factor ◽  
Factor B ◽  
Laboratory Test Results ◽  
Resampling Procedure ◽  
The Right ◽  
Normally Distributed

ABSTRACT Reference intervals (RI) play a key role in clinical interpretation of laboratory test results. Numerous articles are devoted to analyzing and discussing various methods of RI determination. The two most widely used approaches are the parametric method, which assumes data normality, and a nonparametric, rank-based procedure. The decision about which method to use is usually made arbitrarily. The goal of this study was to demonstrate that using a resampling approach for the comparison of RI determination techniques could help researchers select the right procedure. Three methods of RI calculation—parametric, transformed parametric, and quantile-based bootstrapping—were applied to multiple random samples drawn from 81 values of complement factor B observations and from a computer-simulated normally distributed population. It was shown that differences in RI between legitimate methods could be up to 20% and even more. The transformed parametric method was found to be the best method for the calculation of RI of non-normally distributed factor B estimations, producing an unbiased RI and the lowest confidence limits and interquartile ranges. For a simulated Gaussian population, parametric calculations, as expected, were the best; quantile-based bootstrapping produced biased results at low sample sizes, and the transformed parametric method generated heavily biased RI. The resampling approach could help compare different RI calculation methods. An algorithm showing a resampling procedure for choosing the appropriate method for RI calculations is included.

scholarly journals RIA for Serum Holo-Transcobalamin: Method Evaluation in the Clinical Laboratory and Reference Interval

2003 ◽  
Vol 49 (3) ◽  
pp. 455-462 ◽  
Author(s):  
Saila Loikas ◽  
Minna Löppönen ◽  
Pauli Suominen ◽  
Jan Møller ◽  
Kerttu Irjala ◽  
...  
Keyword(s):  
Biochemical Markers ◽  
Methylmalonic Acid ◽  
Clinical Laboratory ◽  
Reference Interval ◽  
Reference Population ◽  
Reference Intervals ◽  
Method Evaluation ◽  
Elderly Individuals ◽  
Reference Limit ◽  
Total Homocysteine

Abstract Background: Decreased serum holo-transcobalamin (holoTC) could be the earliest marker of cobalamin (Cbl) deficiency, but there has been no method suitable for routine use. We evaluated a new commercial holoTC RIA, determined reference values, and assessed holoTC concentrations in relation to other biochemical markers of Cbl deficiency. Methods: The reference population consisted of 303 individuals 22–88 years of age, without disease or medication affecting Cbl or homocysteine metabolism. In elderly individuals (≥65 years), normal Cbl status was further confirmed by total homocysteine (tHcy; &lt;19 μmol/L) and methylmalonic acid (MMA; &lt;0.28 μmol/L) concentrations within established reference intervals. HoloTC in Cbl deficiency was studied in a population of 107 elderly individuals with normal renal function. The Cbl deficiency was graded as potential (total Cbl ≤150 pmol/L or tHcy ≥19 μmol/L), possible (total Cbl ≤150 pmol/L and either tHcy ≥19 μmol/L or MMA ≥0.45 μmol/L), and probable (tHcy ≥19 μmol/L and MMA ≥0.45 μmol/L). Results: The intra- and between-assay imprecision (CV) for the holoTC RIA were 4–7% and 6–8%, respectively. A 95% central reference interval for serum holoTC was 37–171 pmol/L. All participants (n = 16) with probable Cbl deficiency, 86% of those with possible, and 30% of those with potential Cbl deficiency had holoTC below the reference limit (&lt;37 pmol/L). The holoTC correlated with total Cbl (rs = 0.80; P &lt;0.0001) and inversely with MMA (rs = −0.52; P &lt;0.0001). HoloTC concentrations were significantly (P = 0.01) higher in women than in men. Conclusions: The new holoTC RIA is precise and simple to perform. Low holoTC is found in individuals with biochemical signs of Cbl deficiency, but the sensitivity and specificity of low holoTC in diagnosis of Cbl deficiency need to be further evaluated.

scholarly journals Verification of the Canadian Laboratory Initiative on Paediatric Reference Intervals (CALIPER) reference values in Croatian children and adolescents

2020 ◽  
Vol 30 (2) ◽  
pp. 307-314
Author(s):  
Renata Zrinski Topić ◽  
Jasna Leniček Krleža
Keyword(s):  
Children And Adolescents ◽  
Follicle Stimulating Hormone ◽  
Reference Interval ◽  
Reference Intervals ◽  
Sex Hormone ◽  
Sex Hormone Binding Globulin ◽  
Total Testosterone ◽  
Healthy Children ◽  
Hormone Binding ◽  
Stimulating Hormone

Introduction: The aim of this study was to examine whether the Canadian Laboratory Initiative on Paediatric Reference Intervals (CALIPER) could be applied to Croatian children and adolescents. Materials and methods: A total of 295 outpatient healthy children and adolescents of age 1 to 18 were selected using the direct a posteriori sampling method. According to current guidelines, 20 samples were tested for each of a total of 51 reference intervals for ferritin, cortisol, dehydroepiandrosterone sulfate, follicle stimulating hormone, lutein stimulating hormone, prolactin, progesterone, sex hormone binding globulin, thyroid stimulating hormone, total testosterone, total thyroxine and total triiodothyronine. Serum samples were analysed on the Beckman Coulter DxI600 immunoassay analyser by chemiluminescence immunoassay method. A reference interval was adopted if < 10% of the results fall outside CALIPER reference interval range. For analytes in which this criterion is not met in the first set of samples, a new set of 20 samples were collected. Results: After the first set of measurements, 96% of all tested reference intervals were adopted for use. The additional sets of 20 reference subjects were tested for only two reference intervals; follicle stimulating hormone for female aged 1 to 9 years, and irrespective of the gender, sex hormone binding globulin for children aged 8 to 11 years. All results of additional samples were within the specified interval limits. Conclusions: CALIPER reference intervals for ferritin and 11 hormones defined for Beckman Coulter DxI600 immunoassay analyser can be implemented into the Croatian laboratories and clinical practice.

scholarly journals Marked Influence of Adiposity on Laboratory Biomarkers in a Healthy Cohort of Children and Adolescents

2019 ◽  
Vol 105 (4) ◽  
pp. e1781-e1797 ◽  
Author(s):  
Victoria Higgins ◽  
Arghavan Omidi ◽  
Houman Tahmasebi ◽  
Shervin Asgari ◽  
Kian Gordanifar ◽  
...  
Keyword(s):  
Uric Acid ◽  
Waist Circumference ◽  
Children And Adolescents ◽  
Biochemical Markers ◽  
Biochemical Marker ◽  
Reference Intervals ◽  
Healthy Children ◽  
Height Ratio ◽  
Waist To Height Ratio ◽  
Age And Sex

Abstract Background The prevalence of pediatric obesity is increasing worldwide and strongly associates with metabolic abnormalities, including inflammation, insulin resistance, and dyslipidemia. This study assessed the influence of 3 measures of adiposity on levels of routinely assessed biochemical markers in apparently healthy children and adolescents. Methods The influence of adiposity on 35 biochemical markers was examined in the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort of healthy children and adolescents by comparing serum biomarker levels between subjects with a normal weight, overweight, and obese body mass index (BMI). The cohort comprised 1332 subjects 5.1 to 19.0 years of age with a BMI ranging from 13.4 to 65.0 kg/m2. The association between each biochemical marker and BMI, waist circumference, and waist-to-height ratio z-scores was assessed, while adjusting for age and sex. Reference intervals were established for all biochemical markers before and after removing overweight/obese subjects. Results In children and adolescents, levels of 13 routinely assessed biochemical markers, including alanine aminotransferase, apolipoprotein B, complement components 3 and 4, cholinesterase, high sensitivity C-reactive protein, gamma-glutamyl transferase, haptoglobin, high-density lipoprotein cholesterol, iron, transferrin, triglycerides, and uric acid, were significantly different between BMI categories. BMI, waist circumference, and/or waist-to-height ratio were significantly associated with the serum concentration of 24 of the 35 markers examined, after adjusting for age and sex. Conclusions Excess adiposity significantly influences circulating levels of routinely assessed laboratory markers, most notably liver enzymes, lipids/lipoproteins, inflammatory markers, and uric acid in children and adolescents. Although it is unknown whether altered biochemical marker levels in subjects with overweight/obesity reflect health or indolent disease, clinicians should be aware of the effect of weight status on several laboratory tests.

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