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

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.

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

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2017-0767 ◽

2018 ◽

Vol 56 (6) ◽

pp. 964-972 ◽

Cited By ~ 7

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.

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Age- and sex-specific reference intervals for the serum cystatin C/creatinine ratio in healthy children (0–18 years old)

Journal of International Medical Research ◽

10.1177/0300060519855575 ◽

2019 ◽

Vol 47 (7) ◽

pp. 3151-3159 ◽

Cited By ~ 2

Author(s):

Changjin Liu ◽

Jing Wen ◽

Jialin Xiang ◽

Xuhong Ouyang ◽

Yan Yang ◽

...

Keyword(s):

Cystatin C ◽

Pediatric Population ◽

Age Groups ◽

Serum Markers ◽

Reference Intervals ◽

Specific Reference ◽

Healthy Children ◽

Serum Samples ◽

Serum Cystatin C ◽

Age And Sex

Objective This study aimed to investigate serum levels of the cystatin C (CysC)/creatinine (Cr) ratio and renal serum markers (CysC, Cr, urea, and uric acid [UA]) for different ages and by sex. We also aimed to establish pediatric reference intervals for the serum CysC/Cr ratio. Methods Serum samples were collected from 4765 healthy children (0–18 years old). Serum markers of renal function were measured, and the CysC/Cr ratio of each participant was calculated and statistically analyzed. Results The renal marker CysC did not substantially change after 1 year old. Cr, urea, and UA levels generally increased with age. However, the serum CysC/Cr ratio steadily decreased with age. The CysC/Cr ratio showed significant differences in age among all age groups and varied with sex, except for in the 1 to 6-year-old groups. The overall serum CysC/Cr ratio in girls was higher than that in boys. Conclusion Reference intervals of the serum CysC/Cr ratio in the pediatric population were established. These intervals need to be partitioned by age and sex.

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Influence of ethnicity on biochemical markers of health and disease in the CALIPER cohort of healthy children and adolescents

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2019-0876 ◽

2020 ◽

Vol 58 (4) ◽

pp. 605-617 ◽

Cited By ~ 2

Author(s):

Houman Tahmasebi ◽

Shervin Asgari ◽

Alexandra Hall ◽

Victoria Higgins ◽

Ashfia Chowdhury ◽

...

Keyword(s):

Children And Adolescents ◽

Clinical Decision Making ◽

Pediatric Population ◽

Statistical Significance ◽

Immunoglobulin A ◽

Clinical Decision ◽

Reference Intervals ◽

Immunoglobulin M ◽

Healthy Children ◽

Pediatric Study

AbstractBackgroundAccurate pediatric reference intervals (RIs) for laboratory tests determined in a healthy pediatric population are essential for correct laboratory test interpretation and clinical decision-making. In pediatrics, RIs require partitioning by age and/or sex; however, the need for partitioning based on ethnicity is unclear. Here, we assessed the influence of ethnicity on biomarker concentrations in the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort of healthy children and adolescents and compared the results with the National Health and Nutrition Examination Survey (NHANES).MethodsA total of 52 biomarkers were measured in a multiethnic population of 846–1179 healthy children (aged 5 to <19 years) upon informed consent. Biomarker concentrations were retrospectively compared between four major ethnic groups (i.e. Black, Caucasian, East Asian, and South Asian, determined by parental ethnicity). Retrospective results were verified prospectively using an additional 500 healthy pediatric samples with equal sample size across ethnicities. Ethnic-specific differences were assessed based on statistical significance and biological and analytical variations. Appropriate age-, sex-, and ethnic-specific RIs were calculated.ResultsEthnic-specific differences were not observed for 34 biomarkers examined in the retrospective analysis, while 18 demonstrated statistically significant ethnic differences. Among these, seven analytes demonstrated ethnic-specific differences in the prospective analysis: vitamin D, amylase, ferritin, follicle-stimulating hormone (FSH), immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM). Analysis of select NHANES data confirmed CALIPER findings.ConclusionsThis is the first comprehensive Canadian pediatric study examining ethnic-specific differences in common biomarkers. While the majority of biomarkers did not require ethnic partitioning, ethnic-specific RIs were established for seven biomarkers showing marked differences. Further studies in other populations are needed to confirm our findings.

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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

Journal of Medical Biochemistry ◽

10.2478/jomb-2014-0063 ◽

2014 ◽

Vol 34 (1) ◽

pp. 23-30 ◽

Cited By ~ 7

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.

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CALIPER Hematology Reference Standards (II)

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqaa057 ◽

2020 ◽

Vol 154 (3) ◽

pp. 342-352 ◽

Cited By ~ 1

Author(s):

Victoria Higgins ◽

Houman Tahmasebi ◽

Mary Kathryn Bohn ◽

Alexandra Hall ◽

Khosrow Adeli

Keyword(s):

Children And Adolescents ◽

Hemoglobin Concentration ◽

Reference Intervals ◽

Reference Standards ◽

Reference Database ◽

Specific Reference ◽

Mean Corpuscular Hemoglobin ◽

Healthy Children ◽

Cell Percentage ◽

Age And Sex

Abstract Objectives The objective of this study was to establish comprehensive age- and sex-specific reference intervals for hematologic parameters in the CALIPER cohort of healthy children and adolescents. Methods A total of 536 healthy children and adolescents (birth to 21 years) were recruited with informed consent, and whole blood samples were analyzed for 27 hematologic parameters on the Beckman Coulter DxH 520 system. Age- and sex-specific pediatric reference standards were established. Reference values obtained on the DxH 520 were also compared with data obtained on a larger laboratory-based instrument (DxH 900). Results Most hematologic parameters showed significant age- and/or sex-specific changes during growth and development. Of the 27 hematologic parameters, all except four (mean corpuscular hemoglobin concentration, basophil percentage, low hemoglobin density, immature cell percentage) required age partitioning, and eight required sex partitioning. Conclusions This study establishes a robust pediatric hematology reference database that will assist in more accurate test result interpretation. Our data clearly demonstrate significant variation in hematologic parameter concentrations in children and adolescents, necessitating the use of pediatric-specific reference standards.

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Normative Values of High-Sensitivity Cardiac Troponin T and N-Terminal pro-B-Type Natriuretic Peptide in Children and Adolescents: A Study from the CALIPER Cohort

The Journal of Applied Laboratory Medicine ◽

10.1093/jalm/jfaa090 ◽

2020 ◽

Author(s):

Emily Lam ◽

Victoria Higgins ◽

Liyong Zhang ◽

Man Khun Chan ◽

Mary Kathryn Bohn ◽

...

Keyword(s):

Children And Adolescents ◽

Natriuretic Peptide ◽

Cardiac Troponin ◽

Troponin T ◽

Pediatric Population ◽

High Sensitivity ◽

Reference Intervals ◽

Normative Values ◽

Healthy Children ◽

Serum Samples

Abstract Background Cardiac troponin (cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are increasingly used clinically to evaluate and prognosticate acute myocardial infarction and heart failure, respectively. Pediatric reference intervals and cut-offs have not been established for Roche’s Elecsys Troponin T hs (high sensitive) assay. Although pediatric reference intervals exist for NT-proBNP, cut-off values do not exist. In this study, we report reference intervals and 99th percentile cut-offs in a large, healthy Canadian pediatric population using the CALIPER cohort. Methods Blood samples from 484 healthy children and adolescents between 0 and <19 years old were recruited from hospital outpatient clinics and community settings. Serum samples were analyzed using Roche’s Cobas e411 and evaluated for high-sensitivity cTnT (hs-cTnT) and NT-proBNP concentrations. 95% reference intervals and 99th percentile cut-off values were established. Results Three hs-cTnT age partitions were established (0 to <6 months, 6 months to <1 year, and 1 to <19 years) with highest concentrations observed in children under 1 year. Two NT-proBNP age partitions were established (0 to <1 year, and 1 to <19 years), also with higher concentrations in infants under 1 year of age. For each of these age partitions, the 99th percentile cut-off, 95% reference interval, and proportion of detectable concentrations were determined. Conclusions This is the first study to examine hs-cTnT and NT-proBNP reference values together in a healthy pediatric cohort without other clinical indications. We present 99th percentile cut-offs, which will allow clinicians to appropriately evaluate cardiovascular disease in children and adolescents.

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

Biochemia Medica ◽

10.11613/bm.2020.020710 ◽

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.

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Normative data for adiponectin, resistin, interleukin 6, and leptin/receptor ratio in a healthy Spanish pediatric population: relationship with sex steroids

Acta Endocrinologica ◽

10.1530/eje.1.02227 ◽

2006 ◽

Vol 155 (3) ◽

pp. 429-434 ◽

Cited By ~ 49

Author(s):

Gabriel Á Martos-Moreno ◽

Vicente Barrios ◽

Jesús Argente

Keyword(s):

Interleukin 6 ◽

Normative Data ◽

Leptin Receptor ◽

Pediatric Population ◽

Pubertal Development ◽

Sex Hormone Binding Globulin ◽

Pubertal Stage ◽

The Relationship ◽

Circulating Levels ◽

Estradiol Levels

Objectives: To investigate the circulating levels of adiponectin, resistin, interleukin 6 (IL-6), and leptin/receptor ratio in healthy Spanish children throughout the different stages of pubertal development. To analyze the relationship between adipokines and sex steroid level changes during puberty. Study design: Serum adiponectin, resistin, IL-6 levels, and leptin/receptor ratio were studied in 160 healthy Spanish children grouped according to their pubertal stage (Tanner I, 23 girls and 22 boys; Tanner II, 19 girls and 16 boys; Tanners III and IV, 21 girls and 20 boys; and Tanner V, 20 girls and 19 boys). In addition, circulating levels of sex hormone-binding globulin (SHBG) were determined in every subject, and testosterone and estradiol levels in boys and girls respectively. Results: Adiponectin levels decreased in boys from mid puberty (P < 0.05) to become significantly lower than in girls (P < 0.001), whereas IL-6 decreased in both sexes (P < 0.05). Resistin levels and leptin/receptor ratio showed no differences between sexes or according to pubertal stage, except in adult females, who had the highest levels of both parameters (P < 0.001). Serum IL-6 levels correlated significantly (P < 0.05) with testosterone and estradiol levels (r=−0.37 and −0.42 respectively), whereas estradiol, but not testosterone, correlated with leptin/receptor ratio (r=0.59; P < 0.001). Furthermore, a positive relationship was found between SHBG and adiponectin and IL-6 (P < 0.001 and P < 0.05 respectively). In addition, a direct correlation between leptin/receptor and body mass index was found in both sexes (P < 0.001). Conclusion: Variations in adipokine profiles throughout pubertal development appear to be related with progression of gonadal function.

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Comparing Ethnicity-Specific Reference Intervals for Clinical Laboratory Tests from EHR Data

The Journal of Applied Laboratory Medicine ◽

10.1373/jalm.2018.026492 ◽

2018 ◽

Vol 3 (3) ◽

pp. 366-377 ◽

Cited By ~ 3

Author(s):

Nadav Rappoport ◽

Hyojung Paik ◽

Boris Oskotsky ◽

Ruth Tor ◽

Elad Ziv ◽

...

Keyword(s):

Race And Ethnicity ◽

Laboratory Tests ◽

Clinical Laboratory ◽

Local Population ◽

Reference Intervals ◽

Medical Decision ◽

Specific Reference ◽

Healthy Individuals ◽

Electronic Health Record Data ◽

Novel Approach

Abstract Background The results of clinical laboratory tests are an essential component of medical decision-making. To guide interpretation, test results are returned with reference intervals defined by the range in which the central 95% of values occur in healthy individuals. Clinical laboratories often set their own reference intervals to accommodate variation in local population and instrumentation. For some tests, reference intervals change as a function of sex, age, and self-identified race and ethnicity. Methods In this work, we develop a novel approach, which leverages electronic health record data, to identify healthy individuals and tests for differences in laboratory test values between populations. Results We found that the distributions of >50% of laboratory tests with currently fixed reference intervals differ among self-identified racial and ethnic groups (SIREs) in healthy individuals. Conclusions Our results confirm the known SIRE-specific differences in creatinine and suggest that more research needs to be done to determine the clinical implications of using one-size-fits-all reference intervals for other tests with SIRE-specific distributions.

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Reference intervals for follicle-stimulating hormone, luteinizing hormone and prolactin in children and young adults on the bioMérieux Mini-Vidas system

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2007.086 ◽

2007 ◽

Vol 45 (4) ◽

Cited By ~ 6

Author(s):

Thu Koskas ◽

Karamo Souaré ◽

Tarik Ouahabi ◽

Dominique Porquet ◽

Didier Chevenne

Keyword(s):

Luteinizing Hormone ◽

Pediatric Population ◽

Follicle Stimulating Hormone ◽

Reference Intervals ◽

Age Group ◽

Pubertal Stage ◽

Significant Difference ◽

Class 1 ◽

Children And Young Adults ◽

Stimulating Hormone

AbstractWe measured serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin concentrations on a bioMérieux Mini Vidas system in a pediatric population ranging in age from 1 to 19 years. Reference intervals were established separately for females and males, with stratification by age group and by Tanner's pubertal stage. FSH values were higher in females than in males, and were lowest in both sexes of age class 2 (4–8 years), increasing thereafter to the upper limit for stage PIV (females) and stage PV (males). LH values showed a similar pattern of change: concentrations were lowest for class 1 (1–3 years) and class 2 (4–8 years), and highest for stage PII (females) and stage PV (males). No significant difference was observed according to gender. Prolactin values did not differ markedly according to gender or pubertal status.Clin Chem Lab Med 2007;45:541–5.

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