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

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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Pediatric reference interval verification for endocrine and fertility hormone assays on the Abbott Alinity system

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2021-0337 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Mary Kathryn Bohn ◽

Siobhan Wilson ◽

Alexandra Hall ◽

Khosrow Adeli

Keyword(s):

Clinical Decision Making ◽

De Novo ◽

Reference Interval ◽

Clinical Decision ◽

Reference Intervals ◽

Healthy Children ◽

Confidence Limits ◽

Test Results ◽

Serum Samples ◽

Abbott Architect

Abstract Objectives The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) has developed an extensive database of reference intervals (RIs) for several biomarkers on various analytical systems. In this study, pediatric RIs were verified for key immunoassays on the Abbott Alinity system based on the analysis of healthy children samples and comparison to comprehensive RIs previously established for Abbott ARCHITECT assays. Methods Analytical performance of Alinity immunoassays was first assessed. Subsequently, 100 serum samples from healthy children recruited with informed consent were analyzed for 16 Alinity immunoassays. The percentage of test results falling within published CALIPER ARCHITECT reference and confidence limits was determined. If ≥ 90% of test results fell within the confidence limits, they were considered verified based on CLSI guidelines. If <90% of test results fell within the confidence limits, additional samples were analyzed and new Alinity RIs were established. Results Of the 16 immunoassays assessed, 13 met the criteria for verification with test results from ≥ 90% of healthy serum samples falling within the published ARCHITECT confidence limits. New CALIPER RIs were established for free thyroxine and prolactin on the Alinity system. Estradiol required special considerations in early life. Conclusions Our data demonstrate excellent concordance between ARCHITECT and Alinity immunoassays, as well as the robustness of previously established CALIPER RIs for most immunoassays, eliminating the need for de novo RI studies for most parameters. Availability of pediatric RIs for immunoassays on the Alinity system will assist clinical laboratories using this new platform and contribute to improved clinical decision-making.

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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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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

Clinical Chemistry ◽

10.1373/clinchem.2013.204123 ◽

2013 ◽

Vol 59 (8) ◽

pp. 1215-1227 ◽

Cited By ~ 50

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.

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Paediatric reference intervals for 17 Roche cobas 8000 e602 immunoassays in the CALIPER cohort of healthy children and adolescents

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2019-0707 ◽

2019 ◽

Vol 57 (12) ◽

pp. 1968-1979 ◽

Cited By ~ 2

Author(s):

Mary Kathryn Bohn ◽

Victoria Higgins ◽

Shervin Asgari ◽

Felix Leung ◽

Barry Hoffman ◽

...

Keyword(s):

Children And Adolescents ◽

Reference Values ◽

Laboratory Tests ◽

Clinical Decision Making ◽

Reference Intervals ◽

Healthy Children ◽

Serum Samples ◽

Clinical Laboratories ◽

Age And Sex ◽

Roche Cobas

Abstract Background The diagnostic utility of laboratory tests in paediatric medicine relies heavily on the availability of appropriate reference intervals (RIs). The Canadian Laboratory Initiative on Paediatric Reference Intervals (CALIPER) has established a comprehensive database of covariate-stratified RIs for many paediatric laboratory tests using a large, healthy reference population. Several automated analysers in widespread use in clinical laboratories have already been studied. Here, we extend the testing to Roche immunoassays and report, for the first time, comprehensive paediatric RIs for 17 endocrine and special chemistry markers. Methods A total of 741 healthy children and adolescents (1 day to <19 years) were recruited and serum samples were analysed for 17 immunoassays on the Roche cobas 8000 e602 Immunoassay Analyzer. Age and sex-specific RIs were established and corresponding 90% confidence intervals (CIs) were calculated in accordance with Clinical and Laboratory Standards Institute guidelines. Results Reference values for all analytes measured required age partitioning, particularly during early life and throughout adolescence. Of the 17 analytes measured, eight required sex partitioning, including ferritin, thyroid stimulating hormone (TSH), total triiodothyronine (TT3) and all fertility/sex hormones, except prolactin. Conclusions This is the first study to determine accurate paediatric RIs for Roche immunoassays. RIs were generally similar to those previously published by CALIPER on other analytical platforms, highlighting the reproducibility of age- and sex-specific trends in reference values observed across the paediatric age range. The RIs established in this study will improve the accuracy of test result interpretation and clinical decision-making in clinical laboratories utilising Roche immunoassays.

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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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Nomogram of age-specific anti-Müllerian hormone levels in healthy Egyptian females

PLoS ONE ◽

10.1371/journal.pone.0254858 ◽

2021 ◽

Vol 16 (7) ◽

pp. e0254858

Author(s):

Eman Ahmed El-Attar ◽

Tamer A. Hosny ◽

Kiyoshi Ichihara ◽

Rania N. Bedair ◽

Ahmed Salah El-Din Tork

Keyword(s):

Reference Interval ◽

Reference Intervals ◽

Specific Reference ◽

Clinical Settings ◽

Power Transformation ◽

Serum Samples ◽

Female Age ◽

Age Related ◽

Age Dependent ◽

Age Range

Background Anti-Müllerian hormone (AMH) is an important determinant of ovarian reserve in fertility workups in many clinical settings. Thus, we investigated the age dependent decline in AMH specific to the Egyptian population and sought to establish an age dependent reference interval parametrically. Methods Serum samples were collected from 841 apparently healthy women. AMH was measured using an electro-chemiluminescent technique. Box-Cox power transformation was used to make the AMH distribution Gaussian for parametric derivation of reference intervals. Results Power of 0.4 was found optimal for Gaussian transformation of AMH reference values. We demonstrate the strong negative relation between circulating AMH and female age with Spearman’s correlation coefficient of rS = −0.528. Age-specific reference interval was determined for every 5 years of age from 16 to 49, and nomogram was constructed by smoothing the lines connecting adjacent lower and upper reference limits. Conclusion The age-specific reference intervals and the age-AMH nomogram could be valuable in the clinical practice of in reproductive medicine. To our knowledge, this is the first study to confirm AMH levels in Egyptian females. We were able to explore age-related AMH levels specific to Egyptian females in the fertile age group and to treat skewed AMH data in a multi-step scheme using power transformation. Thus, a more accurate nomogram was constructed accommodating a profile delineated for a wide age range and a rescaled AMH axis improving its usability.

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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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Determination of a Beckman Coulter AU turbidometric method-specific caeruloplasmin reference interval

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/0004563221989360 ◽

2021 ◽

pp. 000456322198936

Author(s):

Olivia E Kaye ◽

Paul Cook

Keyword(s):

Renal Stones ◽

Reference Interval ◽

Reference Intervals ◽

University Hospital ◽

Specific Reference ◽

Serum Samples ◽

Rank Analysis ◽

Local Reference ◽

Local Determination

Background Method-dependent variation of caeruloplasmin measurement is significant and necessitates the requirement for assay-specific reference intervals. Local determination becomes necessary in the absence of suitable published or manufacturer-quoted reference intervals. Methods Applicability of the Beckman Coulter AU-quoted reference interval was determined by assay of 20 surplus serum samples from patients attending the medical renal stones clinic at University Hospital Southampton. Subsequently, 60 additional samples were collected for local reference interval determination. Samples were analysed for caeruloplasmin using the Beckman Coulter AU turbidometric kit on an AU680 analyser. Outliers were removed, and non-parametric rank analysis of the results was performed. Results The Beckman Coulter-quoted reference interval of 200–600 mg/L was unsuitable with 40% of the verification samples falling below 200 mg/L. A caeruloplasmin reference interval of 150–320 mg/L was established. Conclusion Users should be aware the quoted Beckman Coulter AU turbidometric reference interval may not be appropriate. We have established a method-specific adult reference interval for routine use.

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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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