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Antimicrobial stewardship involves a delicate balance between the risk of undertreating individuals and the potential societal burden of overprescribing antimicrobials. This balance is especially crucial in neonatal care. In this observational study, the usefulness of biomarkers of infectious diseases (calprotectin, procalcitonin (PCT), C-reactive protein (CRP), and white blood cells (WBCs) were evaluated in 141 febrile infants aged 28-90 days presenting to an emergency department. Since our focus was on the usefulness of serum calprotectin, this biomarker was not part of clinical decision-making. A significant difference was observed in the levels of all biomarkers, related to final discharge diagnosis and disposition status. The difference in levels related to antibiotic prescription was significant for all biomarkers but WBCs. The performance of calprotectin in the detection of bacterial infections (AUC (95% CI): 0.804 (0.691, 0.916)) was comparable to the performance of both PCT (0.901 (0.823, 0.980)) and CRP (0.859 (0.764, 0.953)) and superior to the WBC count (0.684 (0.544, 0.823)). Procalcitonin and CRP demonstrated a statistically significantly higher specificity relative to calprotectin. In this cohort, antibiotic use did not always correlate to a definite diagnosis of confirmed bacterial infection. The sample size was limited due to associated challenges with recruiting febrile infants. Hence, there is a need for adequate diagnostic tools to help discriminate between various kinds of infections. This study suggests serum calprotectin, procalcitonin, and CRP may serve as valuable biomarkers to differentiate between types of infection, in addition to clinical input and decision-making.

Background: The reference intervals (RIs) for liver function tests (LFTs) were determined in Iranian children for the first time., Methods: A total of 344 healthy pediatrics aged 3 days to 30 months old were recruited. Serum levels of ALT, AST, ALP, direct bilirubin, and total bilirubin were measured. RIs were determined using CLSI Ep28-A3 guidelines., Results: All analytes demonstrated age-specific differences except AST. ALT and ALP demonstrated significantly elevated levels in infants 0 to <5 months relative to the remainder of the age range. Direct and total bilirubin demonstrated markedly elevated levels in early life with mean of 0.28 mg/dL and 1.64 mg/dL observed for direct and total bilirubin, respectively, decreasing by ~50% in the adjacent partition., Conclusion: These novel data will help improve the clinical interpretation of biochemical test results in young Iranian neonates and children and can be of value to clinical laboratories with similar populations., (© 2023 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Physiological changes during pregnancy invalidate use of general population reference intervals (RIs) for pregnant people. The complete blood count (CBC) is commonly ordered during pregnancy, but few studies have established pregnancy RIs suitable for contemporary Canadian mothers. Prospective RI studies are challenging to perform during pregnancy while retrospective techniques fall short as pregnancy and health status are not readily available in the laboratory information system (LIS). This study derived pregnancy RIs retrospectively using LIS data linked to provincial perinatal registry data., Methods: A 5-year healthy pregnancy cohort was defined from the British Columbia Perinatal Data Registry and linked to laboratory data from two laboratories. CBC and differential RIs were calculated using direct and indirect approaches. Impacts of maternal and pregnancy characteristics, such as age, body mass index, and ethnicity, on laboratory values were also assessed., Results: The cohort contained 143 106 unique term singleton pregnancies, linked to >972 000 CBC results. RIs were calculated by trimester and gestational week. Result trends throughout gestation aligned with previous reports in the literature, although differences in exact RI limits were seen for many tests. Trimester-specific bins may not be appropriate for several CBC parameters that change rapidly within trimesters, including red blood cells (RBCs), some leukocyte parameters, and platelet counts., Conclusions: Combining information from comprehensive clinical databases with LIS data provides a robust and reliable means for deriving pregnancy RIs. The present analysis also illustrates limitations of using conventional trimester bins during pregnancy, supporting use of gestational age or empirically derived bins for defining CBC normal values during pregnancy., (© Association for Diagnostics & Laboratory Medicine 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Significant practice variation exists in managing young infants with fever. Quality improvement strategies can aid in risk stratification and standardization of best care practices, along with a reduction of unnecessary interventions. The aim of this initiative was to safely reduce unnecessary admissions, antibiotics, and lumbar punctures (LPs) by 10% in low-risk, febrile infants aged 29 to 90 days presenting to the emergency department (ED) over a 12-month period., Methods: Using the Model for Improvement, a multidisciplinary team developed a multipronged intervention: an updated clinical decision tool (CDT), procalcitonin (PCT) adoption, education, a feedback tool, and best practice advisory (BPA) banner. Outcome measures included the proportion of low-risk infants that were admitted, received antibiotics, and had LPs. Process measures were adherence to the CDT and percentage of PCT ordered. Missed bacterial infections and return visits were balancing measures. The analysis was completed using descriptive statistics and statistical process control methods., Results: Five hundred and sixteen patients less than 90 days of age were included in the study, with 403 patients in the 29- to 90-day old subset of primary interest. In the low-risk group, a reduction in hospital admissions from a mean of 24.1% to 12.0% and a reduction in antibiotics from a mean of 15.2% to 1.3% was achieved. The mean proportion of LPs performed decreased in the intervention period from 7.5% to 1.8%, but special cause variation was not detected. Adherence to the CDT increased from 70.4% to 90.9% and PCT was ordered in 92.3% of cases. The proportion of missed bacterial infections was 0.3% at baseline and 0.5% in the intervention period while return visits were 6.7% at baseline and 5.0% in the intervention period., Conclusions: The implementation of a quality improvement strategy, including an updated evidence-based CDT for young infant fever incorporating PCT, safely reduced unnecessary care in low-risk, febrile infants aged 29 to 90 days in the ED., Purpose: To develop and implement a multipronged improvement strategy including an evidence-based CDT utilizing PCT to maximize value of care delivered to well-appearing, febrile infants presenting to EDs., Competing Interests: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.There are otherwise no recognized conflicts of interest to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: It is essential that clinicians have evidence-based benchmarks to support accurate diagnosis and clinical decision making. Recent studies report poor reliability for diagnostic judgments and identifying mechanisms of impairment from videofluoroscopy (VFSS). Establishing VFSS reference values for healthy swallowing would help resolve such discrepancies. Steele et al. (2019) released preliminary reference data for quantitative VFSS measures in healthy adults aged < 60 years. Here, we extend that work to provide reference percentiles for VFSS measures across a larger age span., Method: Data for 16 VFSS parameters were collected from 78 healthy adults aged 21-82 years (39 male). Participants swallowed three comfortable sips each of thin, slightly, mildly, moderately, and extremely thick barium (20% w/v). VFSS recordings were analyzed in duplicate by trained raters, blind to participant and task, using the Analysis of Swallowing Physiology: Events, Kinematics and Timing (ASPEKT) Method. Reference percentiles (p2.5, 5, 25, 50, 75, 95, and 97.5) were determined as per Clinical and Laboratory Standards Institute EP28-A3c guidelines., Results: We present VFSS reference percentile tables, by consistency, for (a) timing parameters (swallow reaction time; the hyoid burst-to-upper esophageal sphincter (UES)-opening interval; UES opening duration; time-to-laryngeal vestibule closure (LVC); and LVC duration) and (b) anatomically scaled pixel-based measures of maximum UES diameter, pharyngeal area at maximum pharyngeal constriction and rest, residue (vallecular, pyriform, other pharyngeal locations, total), and hyoid kinematics (X, Y, XY coordinates of peak position; speed). Clinical decision limits are proposed to demarcate atypical values of potential clinical concern., Conclusion: These updated reference percentiles and proposed clinical decision limits are intended to support interpretation and reliability for VFSS assessment data., Supplemental Material: https://doi.org/10.23641/asha.24043041.

Objectives: Prominent physiological changes occurring throughout childhood and adolescence necessitate the consideration of age and sex in biomarker interpretation. Critical gaps exist in pediatric reference intervals (RIs) for specialized endocrine markers, despite expected influence of growth and development. The current study aimed to establish and/or verify RIs for six specialized endocrine markers on a specialized immunoassay system., Methods: Samples were collected from healthy children and adolescents (5 to <19 years) and apparently healthy outpatients (0 to <5 years) as part of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER). Serum samples were analysed for aldosterone, renin (plasma), thyroglobulin, anti-thyroglobulin, growth hormone, and insulin-like growth factor-1 (IGF-1) on the Liaison XL (DiaSorin) immunoassay platform. RIs (2.5th and 97.5th percentiles) were established for aldosterone, renin, thyroglobulin, anti-thyroglobulin, and growth hormone. Manufacturer-recommended pediatric RIs for IGF-1 were verified., Results: Age-specific RIs were established for aldosterone, renin, and thyroglobulin, while no age-specific differences were observed for anti-thyroglobulin or growth hormone. IGF-1 was the only endocrine marker studied that demonstrated significant sex-specific differences. Manufacturer-recommended IGF-1 RIs were verified for children aged 6 to <19 years, while those for children aged 0 to <6 years did not verify., Conclusions: This study marks the first time that pediatric RIs for aldosterone and renin were established in the CALIPER cohort and highlights the dynamic changes that occur in water and sodium homeostasis during the first years of life. Overall, these data will assist pediatric clinical laboratories in test result interpretation and improve clinical decision-making for patients tested using Liaison immunoassays., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Humoral response against SARS-CoV-2 is increasingly accepted as the central correlate of immune protection. Recent pediatric seroprevalence data are extremely limited. Significant knowledge gaps also exist in immune response to mRNA SARS-CoV-2 vaccination in children. As children demonstrate distinct response to naïve infection relative to adults, it is essential to investigate age-specific differences in seroprevalence and antibody response to SARS-CoV-2 vaccination., Methods: Seroprevalence was assessed through two cross-sectional serosurveys prior to COVID-19 vaccination approval in children <5 years using residual patient specimens (n = 2902). To assess antibody response post-vaccination, 842 participants (580 children, 262 adults) were prospectively recruited with informed consent. Participation required completion of a health questionnaire and blood donation. Samples were collected at varying times post-vaccination and assayed using the Abbott AdviseDx SARS-CoV-2 IgG II and DiaSorin LIAISON SARS-CoV-2 TrimericS IgG assays., Results: Significant increases in seroprevalence were observed between the first and second serosurveys in unvaccinated children <6 months to 5 years (38-75%). In the prospective vaccination cohort, serokinetic response decreased with time post-dose of an mRNA vaccine. Measured IgG titres were significantly higher in children relative to adults across all time points., Conclusions: This is the largest evaluation of quantitative SARS-CoV-2 antibody assays in a cohort of Canadian children, adolescents, and adults. Findings suggest high rates of SARS-CoV-2 exposure among unvaccinated young children in the Toronto community. Additional data supports children have higher antibody titres relative to adults post-vaccination., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Harmonization in laboratory medicine is essential for consistent and accurate clinical decision-making. There is significant and unwarranted variation in reference intervals (RIs) used by laboratories for assays with established analytical traceability. The Canadian Society of Clinical Chemists (CSCC) Working Group on Reference Interval Harmonization (hRI-WG) aims to establish harmonized RIs (hRIs) for laboratory tests and support implementation., Methods: Harnessing the power of big data, laboratory results were collected across populations and testing platforms to derive common adult RIs for 16 biochemical markers. A novel comprehensive approach was established, including: (a) analysis of big data from community laboratories across Canada; (b) statistical evaluation of age, sex, and analytical differences; (c) derivation of hRIs using the refineR method; and (d) verification of proposed hRIs across 9 laboratories with different instrumentation using serum and plasma samples collected from healthy Canadian adults., Results: Harmonized RIs were calculated for all assays using the refineR method, except free thyroxine. Derived hRIs met proposed verification criterion across 9 laboratories and 5 manufacturers for alkaline phosphatase, albumin (bromocresol green), chloride, lactate dehydrogenase, magnesium, phosphate, potassium (serum), and total protein (serum). Further investigation is needed for some analytes due to failure to meet verification criteria in one or more laboratories (albumin [bromocresol purple], calcium, total carbon dioxide, total bilirubin, and sodium) or concern regarding excessively wide hRIs (alanine aminotransferase, creatinine, and thyroid stimulating hormone)., Conclusions: We report a novel data-driven approach for RI harmonization. Findings support feasibility of RI harmonization for several analytes; however, some presented challenges, highlighting limitations that need to be considered in harmonization and big data analytics., (© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hematological parameters vary significantly throughout growth and development due to physiological processes such as fetal-to-adult erythropoiesis and puberty. Pediatric age- and sex-specific reference intervals (RIs) are thus essential for appropriate clinical decision-making. The current study aimed to establish RIs for both common and novel hematology parameters on the Mindray BC-6800Plus system., Methods: Six hundred and eighty-seven healthy children and adolescents (30 days to 18 years) were enrolled. Participants were recruited as part of the Canadian Laboratory Initiative on Pediatric Reference Intervals Program upon informed consent or identified from apparently healthy outpatient clinics. Whole blood was collected and assayed for 79 hematology parameters on the BC-6800Plus system (Mindray). Age- and sex-specific RIs were established as per Clinical and Laboratory Standards Institute EP28-A3c guidelines., Results: Dynamic reference value distributions were observed for several hematology parameters, including erythrocytes, leukocytes, platelets, reticulocytes, and research-use-only markers. Age partitioning was required for 52 parameters, demonstrating changes in infancy and puberty. Sex partitioning was required for 11 erythrocyte parameters (i.e., red blood cell (RBC), hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, RBC distribution width coefficient of variation, hemoglobin distribution width, macrocyte count, macrocyte percentage, RBC (optical), and reticulocyte production index). Few parameters had undetectable levels in our healthy cohort (i.e., nucleated RBC count and immature granulocyte count)., Conclusions: The current study completed hematological profiling for 79 parameters on the BC-6800Plus system in a healthy cohort of Canadian children and adolescents. These data emphasize the complex biological patterns of hematology parameters in childhood, particularly at the onset of puberty, and support the need for age- and sex-specific RIs for clinical interpretation., (© 2023 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Background: Assessment of trace and toxic element status is important for the diagnosis and monitoring of several pediatric conditions. Elemental deficiency and toxicity have serious implications, particularly in pediatrics wherein risk is higher. Pediatric reference intervals (RIs) for trace elements and normal exposure limits for toxic elements are lacking on modern analytical systems. Herein, reference values were established for 13 plasma and 22 whole blood trace elements in the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort of healthy children and adolescents., Methods: Approximately 320 healthy children and adolescents were recruited with informed consent. Trace elements were measured in whole blood and plasma samples using 2 technologies: (a) triple quadrupole inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) (n = 172) and (b) high-resolution sector field ICPMS (HR-SF-ICPMS) (n =161). RIs and normal exposure limits were then established according to Clinical and Laboratory Standards Institute guidelines., Results: Of all elements assessed, none required sex partitioning and 8 required age partitioning (e.g., copper, manganese, and cadmium). Reference value distributions determined via ICP-MS/MS and HR-SF-ICPMS demonstrated excellent concordance, with few exceptions (e.g., molybdenum, cobalt, and nickel)., Conclusions: These data represent the first study wherein pediatric RIs and normal exposure limits were derived simultaneously on 2 different clinically validated MS platforms which provide urgently needed data to inform clinical decision-making for trace elements in pediatrics. Study findings suggest some trace elements require age-specific consideration for appropriate interpretation. Highly concordant observations across the 2 analytical methods also demonstrate the comparability and reliability of results obtained on both platforms., (© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cardiac biomarkers have increasing application in pediatric populations, including congenital heart disease, myocarditis, and heart failure. Clinical practice is limited by evidence gaps in pediatric reference limits to inform clinical decision-making. The current study aimed to establish comprehensive pediatric reference limits for N-terminal (NT)-pro hormone brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI) in the CALIPER cohort of healthy children and adolescents., Methods: Analytical immunoassay performance was assessed through precision, linearity, and method comparison (Abbott Alinity ci system). Subsequently, approximately 200 serum samples collected from apparently healthy children (birth to 18 years) were analyzed for hs-cTnI and NT-proBNP. Reference limits (2.5th, 97.5th, and 99th percentiles) were established as per Clinical and Laboratory Standards Institute EP-28A3c guidelines with associated 90% confidence intervals., Results: Of all pediatric serum samples analyzed, 46% had detectable hs-cTnI concentrations (limit of detection: 1.3 ng/L). Both hs-cTnI and NT-proBNP demonstrated markedly elevated neonatal concentrations with 99th percentiles of 55.8 and 1785 ng/L, respectively. No statistically significant age-specific differences were observed beyond 1 year of age across all cardiac biomarkers examined. No sex-specific association was observed between hs-cTnI and NT-proBNP concentration and adolescence., Conclusions: We report age-specific reference limits for hs-cTnI and NT-proBNP in a healthy Canadian cohort of children and adolescents measured using Alinity immunoassays for the first time. These data support the need for pediatric-specific interpretation to reduce misinformed clinical decision-making and calls to action larger cohort studies such that reference limits can be more robustly defined., (© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Special chemistry parameters are useful in the diagnosis and management of inherited disorders, liver disease, and immunopathology. Evidence-based pediatric reference intervals (RIs) are required for appropriate clinical decision-making and need to be verified as new assays are developed. This study aimed to evaluate the applicability of pediatric RIs established for biochemical markers on the ARCHITECT for use on newer Alinity assays., Methods: An initial method validation was completed for 16 assays, including precision, linearity, and method comparison. Sera collected from approximately 100 healthy children and adolescents as part of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) were also analyzed on the Alinity c system. Percentage of results within established ARCHITECT RIs were calculated and considered verified if ≥90 % fell within established limits. New RIs were established for three electrolytes, glucose, and lactate wherein no data were previously reported., Results: Of the 11 assays for which CALIPER pediatric RIs were previously established on ARCHITECT assays, 10 met the verification criteria. Alpha-1-antitrypsin did not meet verification criterion and a new RI was established. For the other 5 assays, de novo RIs were derived following analysis of 139-168 samples from healthy children and adolescents. None required age- and sex-partitioning., Conclusions: Herein, pediatric RIs were verified or established for 16 chemistry markers in the CALIPER cohort on Alinity assays. Findings support excellent concordance between ARCHITECT and Alinity assays with one exception (alpha-1-antitrypsin) as well as robustness of age- and sex-specific patterns originally reported by CALIPER in healthy Canadian children and adolescents., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Monitoring estradiol (E2) is important for determining the onset of pubertal development as well as in the evaluation of girls with precocious puberty. However, E2 measurement remains an analytical challenge in children, who have lower circulating levels. We developed and evaluated a simple and sensitive LC-MS/MS procedure for serum E2 quantification in pediatric populations and established age- and sex-specific pediatric reference intervals., Methods: Residual patient serum samples were used to evaluate the analytical performance of our in-house LC-MS/MS E2 assay. The evaluation included accuracy, precision, linearity, functional sensitivity (LLoQ), and method comparison. Age- and sex-specific pediatric E2 reference intervals were also established from a cohort of 405 healthy children (birth to 18 years) recruited with informed consent. Age- and sex-specific differences were assessed, and outliers were removed. Reference intervals were established using the robust method., Results: The assay imprecision was <5.3 %. Assay linearity ranged from 13.7 to 1923.3 pmol/L. The LLoQ corresponding to a CV of 20 % was determined to be 8.9 pmol/L. Bland-Altman analysis revealed a mean bias of 29.3 pmol/L or 9.1 % between our LC-MS/MS E2 assay and an external reference laboratory measuring E2 by LC-MS/MS., Conclusions: Our LC-MS/MS E2 assay shows acceptable accuracy, precision, functional sensitivity (LLoQ), and linearity for E2 quantification. Our LC-MS/MS E2 assay also showed good agreement with an external reference laboratory measuring E2 by LC-MS/MS. In addition, using CALIPER samples, we established robust age- and sex-specific pediatric E2 reference intervals to improve accuracy of test result interpretation and clinical decision making., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Marked physiological changes in growth and development present challenges in defining pediatric reference intervals for biomarkers of health and disease. Lambda, Mu, and Sigma (LMS)-based statistical modeling provides a continuous normal distribution by negating skewness and variation, and is commonly used to establish growth charts. Such LMS reference curves are suggested to enhance laboratory test result interpretation. The current study establishes LMS-based continuous reference percentiles for 14 biomarkers in the CALIPER cohort of healthy children and adolescents., Methods: Data from healthy children and adolescents aged 1-<19 years were used to establish continuous reference percentiles using a novel LMS-based statistical method, including 2.5th, 25th, 50th, 75th, and 97.5th percentiles. The LMS approach applies a Box-Cox data transformation and summarizes continuous distributions by age via three curves: skewness (Lambda), median (Mu), and coefficient of variation (Sigma)., Results: LMS-based percentiles and z-scores were generated for 14 common pediatric biomarkers that demonstrate dynamic concentration patterns with age (e.g., alkaline phosphatase) and/or wherein the magnitude of difference from the population mean may be clinically relevant (e.g., triglycerides). The LMS model captured age- and sex-specific distributions accurately and was not substantially influenced by outlying points., Conclusions: This is the first study to establish LMS-based continuous reference percentiles for biochemical markers in a healthy Canadian pediatric population. The current LMS-based approach builds upon previous continuous reference interval models by providing graded percentiles to improve test result interpretation, particularly with repeated measures over time. This method may assist in facilitating a patient-centered approach to laboratory medicine., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Age and sex need to be considered in the establishment of reference intervals (RIs), especially in early life when there are dynamic physiological changes. Since data for important biomarkers in healthy neonates and infants are limited, particularly in Iranian populations, we have determined age-specific RIs for 7 laboratory biochemical parameters. This cross-sectional study comprised a total of 344 paediatric participants (males: 158, females: 186) between the ages of 3 days and 30 months (mean age: 12.91 ± 7.15 months). Serum levels of creatinine, urea, uric acid, calcium, phosphate, vitamin D and high-sensitivity C-reactive protein (hs-CRP) were measured using an Alpha classic-AT plus auto-analyser. We determined age-specific RIs using CLSI Ep28-A3 and C28-A3 guidelines. No sex partitioning was required for any of the biomarkers. Age partitioning was required for kidney function tests and phosphate. The serum concentration of urea and creatinine increased with age, while phosphate and uric acid decreased with age. Age partitioning was not required for serum calcium, vitamin D, and hs-CRP, which remained relatively constant throughout the age range. Age-specific RIs for 7 routine biochemical markers were determined to address critical gaps in RIs in early life to help improve clinical interpretation of blood test results in young children, including neonates. Established age partitions demonstrate the biochemical changes that take place during child growth and development. These novel data will ultimately better disease management in the Iranian paediatric population and can be of value to clinical and hospital laboratories with similar populations., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Clinical laboratories play a vital role in the healthcare system. Objective medical data provided by clinical laboratories supports approximately 60-70% of clinical decisions, however, evidence supporting this claim is poorly documented and laboratories still lack visibility, despite their indisputable impact on patient care and public health. The International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on Outcome Studies in Laboratory Medicine (TF-OSLM) was recently developed to support directed research evaluating the role of laboratory medicine on clinical outcomes. Establishing and documenting this evidence is key to enhance visibility of the field in the eye of the public and other healthcare professionals together with optimizing patient outcomes and health care system operations. In this review, we discuss four areas that exemplify the contribution of laboratory medicine directly to patient care. This includes high-sensitivity cardiac troponin (hs-cTn) and N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptides (NT-proBNP/BNP) for the diagnosis and prognosis of myocardial infarction and heart failure, respectively, and procalcitonin for the management of sepsis and antibiotic stewardship. Emerging markers of traumatic brain injury and the role of laboratory medicine in the fight against the COVID-19 pandemic are discussed along with an introduction to plans of IFCC TF-OSLM., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

The assessment of anti-mullerian hormone (AMH) pre- and post-gonadotoxic treatment helps define reproductive potential in young female adults facing cancer treatment. Normative childhood AMH levels are not well defined. Our objective was to help establish accurate pediatric reference intervals (RIs) for which AMH can be used to assess AMH in pediatric/adolescent survivors. Healthy female volunteers aged 6-<19 years were recruited from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort. 300 serum samples were analyzed for AMH using an automated assay. Basic demographics and menstrual cycle data on the subjects were recorded at time of sample collection. Serum AMH distribution and RIs (2.5th and 97.5th percentiles) were established in four age groups. One recommended RI (0.98-7.84 ng/mL) was established for females aged 6-<19 years after outlier removal. Females 6-<9 years demonstrated significantly lower mean AMH concentration than did females 9-<12 years (Mean ± SD: 3.18 ± 1.62 and 4.16 ± 2.55 ng/mL, respectively), who in turn demonstrated significantly higher AMH concentrations than those aged 12-<15 years (Mean ± SD: 3.75 ± 1.61 ng/mL). Statistical differences are unlikely to be clinically meaningful. Menstrual status and ethnicity did not significantly impact AMH concentrations (p = 0.787 and p = 0.0965, respectively). This is the largest series of its kind using a contemporary, automated, single-batched AMH assay in a healthy pediatric female cohort. In conjunction with future data points and longitudinal data, the RI established may be a useful adjunct to reproductive health counselling delivered to pediatric cancer patients requiring fertility damaging therapies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: The objective of this study was to establish pediatric reference limits for autoimmune disease markers in the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort of healthy children and adolescents to support their interpretation and clinical decision making. The CALIPER is a national study of healthy children aiming to close gaps in pediatric laboratory medicine by establishing a robust database of pediatric reference intervals for pediatric disease biomarkers (caliperdatabase.org)., Methods: Healthy children and adolescents (n=123, aged 1-19) were recruited to CALIPER with informed consent. Serum autoantibody testing conducted on the BIO-FLASH analyzer (Werfen, Barcelona, Spain) included anti-dsDNA IgG, anti-Sm IgG, anti-RNP IgG, anti-SSB/La IgG, anti-Ro60 IgG, anti-Ro52 IgG, anti-cardiolipin IgG, anti-MPO IgG, anti-PR3 IgG, and anti-tTG IgA. Pediatric reference limits representing 95th, 97.5th, and 99th percentiles were calculated using the non-parametric rank method according to Clinical Laboratory Standards Institute C28-A3 guidelines., Results: The proportion of samples with results above the lower limit of the analytical measuring range were: anti-cardiolipin IgG 90%, anti-dsDNA 22%, anti-Sm 13%, anti-RNP 0.8%, anti-SSB/La 0%, anti-Ro60 0%, anti-Ro52 0%, anti-MPO 25%, anti-PR3 9%, and anti-tTG IgA 28%. Pediatric reference limits and associated 90% confidence intervals were established for all 10 markers. All autoantibodies could be described by one age range except for anti-cardiolipin IgG and anti-MPO. A sex-specific difference was identified for anti-tTG IgA., Conclusions: Robust pediatric reference limits for 10 commonly clinically utilized autoimmune markers established herein will allow for improved laboratory assessment and clinical decision making in pediatric patients using the BIO-FLASH assay platform worldwide., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Clinical laboratory investigation of autoimmune, metabolic, and oncologic disorders in children and adolescents relies on appropriateness of reference intervals (RIs). The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) previously established comprehensive pediatric RIs for specialized immunoassays on the Abbott ARCHITECT system. Herein, we aim to verify performance on new Alinity i assays by evaluating sera collected from healthy children as per Clinical and Laboratory Standards Institute (CLSI) EP-28A3C guidelines., Methods: Precision, linearity, and method comparison experiments were completed for 17 specialized Alinity immunoassays, including cancer antigens, autoimmune peptides, and hormones. Sera collected from healthy children and adolescents (birth-18 years, n=100) were evaluated. CLSI-based verification was completed using previously established CALIPER RIs for ARCHITECT assays as the reference., Results: Of 17 specialized immunoassays assays, only anti-cyclic citrullinated peptides (anti-CCP) did not meet acceptable verification criterion (i.e., ≥90% of results within ARCHITECT reference CI). Anti-thyroglobulin, anti-thyroid peroxidase, and carcinoembryonic antigen did not require age-specific consideration beyond one year of age, with 63, 91, and 80% of samples equalling the limit of detection, respectively. Estimates were separated by sex for relevant assays (e.g., sex hormone binding globulin, total and free prostate specific antigen)., Conclusions: Findings support transferability of pediatric RIs on ARCHITECT system to the Alinity system for 16 specialized immunoassays in the CALIPER cohort and will be a useful resource for pediatric clinical laboratories using Alinity assays. Further work is needed to establish evidence-based interpretative recommendations for anti-CCP and continue to evaluate pediatric RI acceptability for newly available assay technologies., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Sex differences in the prevalence and development of diabetes and associated cardiometabolic complications are well established. The objective of this study was to analyze the effects of estrogen on the maintenance of β-cell health/function and atherosclerosis progression, using a mouse model of hyperglycemia-induced atherosclerosis, the ApoE -/- : Ins2 +/Akita mouse. ApoE -/- : Ins2 +/Akita mice exhibit sexual dimorphism in the control of blood glucose levels. Male ApoE -/- : Ins2 +/Akita mice are chronically hyperglycemic due to a significant reduction in pancreatic β-cell mass. Female mice are only transiently hyperglycemic, maintain β-cell mass, and blood glucose levels normalize at 35 ± 1 days of age. To determine the effects of estrogen on pancreatic β-cell health and function, ovariectomies and estrogen supplementation experiments were performed, and pancreatic health and atherosclerosis were assessed at various time points. Ovariectomized ApoE -/- : Ins2 +/Akita mice developed chronic hyperglycemia with significantly reduced β-cell mass. To determine whether the observed effects on ovariectomized ApoE -/- : Ins2 +/Akita mice were due to a lack of estrogens, slow-releasing estradiol pellets were inserted subcutaneously. Ovariectomized ApoE -/- : Ins2 +/Akita mice treated with exogenous estradiol showed normalized blood glucose levels and maintained β-cell mass. Exogenous estradiol significantly reduced atherosclerosis in both ovariectomized female and male ApoE -/- : Ins2 +/Akita mice relative to controls. Together, these findings suggest that estradiol confers significant protection to pancreatic β-cell health and can directly and indirectly slow the progression of atherosclerosis. NEW & NOTEWORTHY This study examines the effect(s) of estrogen on β cell and cardiometabolic health/function in a novel mouse model of hyperglycemia-induced atherosclerosis ( ApoE -/- : Ins2 +/Akita ). Using a combination of estrogen deprivation (ovariectomy) and supplementation strategies, we quantify effects on glucose homeostasis and atherogenesis. Our results clearly show a protective role for estrogen on pancreatic β-cell health and function and glucose homeostasis. Furthermore, estrogen supplementation dramatically reduces atherosclerosis progression in both male and female mice.

Introduction: We aimed to define specific reference intervals (RIs) for 11 biomarkers including inflammatory and oxidative stress biomarkers, liver, and renal function tests in a healthy Iranian adult population for the first time., Methods: CLSI Ep28-A3 guidelines were then used to calculate accurate age- and sex- as well as body mass index (BMI)-specific RIs., Results: RIs for studied biomarkers showed no significant age and sex-specific differences, except for uric acid, which had higher concentrations in men when compared to women. Additionally, after partitioning the participants based on the BMI with a cutoff point of 25 kg/m 2 , only the levels of hs-CRP were positively associated with higher BMI (RI for BMI>25: 0.51-7.85 mg/L and for BMI<25: 0.40-4.46 mg/L). RI for PAB and anti-hsp-27 were reported 4.69-155.36 HK and 0.01-0.70 OD in men and women aged 35-65 years old., Conclusion: Partitioning by sex and BMI was only required for uric acid and hs-CRP, respectively, while other biomarkers required no partitioning. These results can be expected to valuably contribute to improve laboratory test result interpretation in adults for improved monitoring of various diseases in the Iranian population., (© 2021 International Union of Biochemistry and Molecular Biology, Inc.)

Background: Glucose testing at the point-of-care (POC) is routinely used in the diagnosis, prognosis, and monitoring of diabetic states and other clinical conditions. Accurate reference intervals (RIs) are essential in appropriate clinical decision-making. In this study, RIs were established for random glucose (whole blood) in the Canadian Laboratory Initiative on Pediatric Reference (CALIPER) cohort using 2 POC instruments: the Nova Biomedical StatStrip (handheld glucometer) and Radiometer ABL90 FLEX Plus (benchtop instrument). An analytical comparison was also completed between the 2 POC systems and a laboratory-based analyzer (Ortho Vitros 5600)., Methods: Approximately 400 healthy children and adolescents (birth to 18 years) were recruited with informed consent from community schools or clinics providing care to metabolically stable/healthy children. Random venous samples were collected and run sequentially on the Nova Biomedical StatStrip (whole blood), Radiometer ABL90 FLEX Plus (whole blood), and Ortho Vitros 5600 (serum). RIs and method comparisons between analytical platforms were completed according to CLSI guidelines., Results: Significantly different glucose concentrations were observed in infancy, requiring age-specific partitioning (0-<1 month, 1-<6 months, 6 months-<19 years) on all platforms. Excellent concordance was observed between POC platforms (Pearson r > 0.90), with a small negative bias. Good comparability was observed between POC and laboratory-based platforms (Pearson r > 0.80)., Conclusion: This study established comprehensive pediatric RIs for random glucose (whole blood) on modern POC systems in the CALIPER cohort for the first time. Results demonstrate excellent concordance in glucose values between POC systems and good comparability with a laboratory-based analyzer. These data will assist in more accurate clinical decision-making in pediatric healthcare institutions., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Diagnosis, prognostication, and monitoring of maternal health throughout pregnancy relies on laboratory testing, including but not limited to key markers of thyroid, hepatic, cardiac, hematology, and renal function. Dynamic physiological processes during gestation significantly influence the maternal biochemistry that supports both the mother and fetus. Resultant changes in blood biochemistry alter the expected values of common laboratory tests. However, the importance of pregnancy-specific reference intervals for laboratory test result interpretation and appropriate monitoring of maternal health and complications is underappreciated. Most clinical laboratories continue to use non-pregnant adult reference intervals for laboratory test interpretation in pregnancy. The current review summarizes and critically evaluates the available literature regarding physiological and metabolic adaptations in pregnancy and their influence on common biomarkers of health and disease. The main laboratory parameters discussed include thyroid, hepatic, metabolic, renal, hematology, inflammatory, and cardiac markers. Considering the available data, further studies are urgently needed to establish trimester-specific reference intervals in healthy pregnant women on updated analytical platforms. Without such data, the standard of clinical laboratory service in pregnancy remains compromised and affects the quality of maternal-fetal healthcare.

Background: Multiinflammatory syndrome in children (MIS-C) is a novel and rare inflammatory disorder associated with severe acute respiratory syndrome coronavirus 2 infection in school-age children. Reports in the past year have suggested a multisystem pathophysiology characterized by hyperinflammation, gastrointestinal distress, and cardiovascular complications. Clinical laboratory investigations, including routine blood testing for inflammatory (e.g., C-reactive protein, ferritin) and cardiac (e.g., troponin, brain natriuretic peptides) markers have provided insight into potential drivers of disease pathogenesis, highlighting the role of the laboratory in the differential diagnosis of patients presenting with similar conditions (e.g., Kawasaki disease, macrophage activating syndrome)., Content: While few studies have applied high-dimensional immune profiling to further characterize underlying MIS-C pathophysiology, much remains unknown regarding predisposing risk factors, etiology, and long-term impact of disease onset. The extent of autoimmune involvement is also unclear. In the current review, we summarize and critically evaluate available literature on potential pathogenic mechanisms underlying MIS-C onset and discuss the current and anticipated value of various laboratory testing paradigms in MIS-C diagnosis and monitoring., Summary: From initial reports, it is clear that MIS-C has unique inflammatory signatures involving both adaptive and innate systems. Certain cytokines, inflammatory markers, and cardiac markers assist in the differentiation of MIS-C from other hyperinflammatory conditions. However, there are still major gaps in our understanding of MIS-C pathogenesis, including T cell, B cell, and innate response. It is essential that researchers not only continue to decipher initial pathogenesis but also monitor long-term health outcomes, particularly given observed presence of circulating autoantibodies with unknown impact., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Pediatric reference intervals are essential for test interpretation. With development of newer analytical systems, de novo reference interval establishment is of necessary importance. In the current study, pediatric reference intervals were determined for 32 analytes using Siemens Healthineers Atellica® CH assays in the CALIPER cohort of healthy children and adolescents., Methods: Approximately 600 healthy children and adolescents were recruited with informed consent and collected serum samples were analyzed on the Siemens Healthineers Atellica® CH platform. Assays studied included enzymes, proteins, lipids, electrolytes, and additional markers Reference intervals were established according to Clinical and Laboratory Standards Institute (CLSI) guidelines., Results: Of the 32 parameters, 26 required age partitioning and 18 required sex partitioning. Reference value distributions included consistent increases, decreases, and dynamic variation across the age continuum. Chloride, LDL cholesterol, glucose, lipase, sodium, and triglyceride demonstrated no age or sex-specific differences., Conclusion: The current study expands the clinical utility of the CALIPER database to include 32 Siemens Atellica® chemistry assays. Reference value distributions for Siemens assays mirrored those observed on other comparable assays/systems with few exceptions (e.g. lipase, direct and total bilirubin). These finding support the robustness of previously derived reference intervals in the CALIPER cohort and other global cohorts., (Copyright © 2021 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Introduction: The major clinical problem presently confronting the Chinese newborn screening (NBS) programs by tandem mass spectrometry (MS/MS) is the lack of comprehensive reference intervals (RIs) for disease biomarkers. To close this gap, the Chinese National Center for Clinical Laboratories (NCCL) launched a nationwide study to investigate the dynamic pattern of 35 MS/MS NBS biomarkers and establish accurate and robust RIs. Methods: Blood spot samples from 4,714,089 Chinese neonates were tested in participating centers/laboratories and used for study analysis. MS/MS NBS biomarker trends were visually assessed by their concentrations over age. Specific partitions were determined arbitrarily by each day and sex or by the statistical method of Harris and Boyd. RIs, corresponding to the 2.5th and 97.5th percentiles, as well as the 1th, 25th, 75th and 99th percentiles were calculated for each reference partition using a non-parametric rank approach. Results: Most MS/MS NBS biomarkers fluctuated during the first week of life, followed by a relatively stable concentration. Age and sex-specific RIs were established and presented an improved specificity over the RIs used in participating centers/laboratories. Females demonstrated higher 2.5th and 97.5th percentiles in all amino acids except arginine and ornithine than males, whereas males showed higher 2.5th and 97.5th percentiles in most acylcarnitines. Conclusion: The present study determined the dynamic trends of 35 MS/MS biomarkers and established age and sex-specific RIs, valuably contributing to the current literature and timely evaluation of neonatal health and disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 He, Yang, Huang, Tian, Pei, Bohn, Zou, Wang, Li, Wang, Gu, Jiang, Chen, Zou, Wei, Tian, Tang, Adeli and Wang.)

Background: Cytokine measurements to support clinical laboratory and research investigations have become increasingly common in pediatrics. However, there is a paucity of accurate pediatric reference intervals (RIs) essential to the interpretation of cytokine results. To address this gap, here, we establish age- and sex-specific pediatric reference values for clinically relevant inflammatory markers including CD163, and the cytokines IL-1β, IL-6, IL-10, IL-18, TNF-α, IFN-γ, and CXCL-9., Methods: Healthy children and adolescents (n = 311, 1-19 years) were recruited as part of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) study. Multi-analyte measurements in plasma and analytical performance verification were conducted on the ProteinSimple® Ella™ automated immunoassay platform (Bio-Techne, MN, USA). Age- and sex-specific RIs were calculated based on Clinical and Laboratory Standards Institute guidelines. Additionally, 75th and 95th percentile cut-offs were determined., Results: Three types of reference value distributions were observed: (a) consistent levels throughout age and sex: IL-6, and IFN-γ, (b) gradual decline in concentration with age: CD163, TNF-α, CXCL-9, and IL-10, (c) significantly higher concentrations during ages 4-14 years than earlier and later ages: IL-1β and IL-18. Reference values for CXCL-9, IL-10, and TNF-α under 8 years of age differed significantly from older children. CD163, IL-18 and IL-1β required three age partitions. CD163 demonstrated significant sex differences in ages 8-13 years., Conclusion: The circulating profile of cytokines in children is complex and can vary by age and sex. This necessitates careful interpretation of test results based on age and/or sex specific RIs facilitating more accurate clinical decision making., (Copyright © 2021 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Introduction: Clinicians and healthcare professionals rely heavily on health-associated standards, such as reference intervals (RIs), for appropriate laboratory test result interpretation. RIs are commonly partitioned into discrete age/sex bins based on statistical and/or clinical significance. In pediatric hematology, such partitioning does not adequately represent complex variation in analyte concentrations throughout maturation. The objective of this study was to establish continuous RIs for common hematological parameters in the healthy pediatric Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort., Methods: Data from healthy CALIPER children and adolescents (6 months-<19 years) were used to generate continuous RIs (ie, 2.5th and 97.5th quantiles) for 19 hematological parameters. Continuous curves were statistically established with nonparametric quantile regressions. Flagging rate analysis was completed for the established continuous upper and lower reference limits and subsequently compared to previously published discrete CALIPER reference intervals for all parameters., Results: Continuous RIs were established for 19 hematology parameters, where seven required sex-specific reference curves. Based on flagging rate assessment, continuous RIs appear to more accurately estimate hematological reference limits over the pediatric age range, especially for analytes with complex age- and sex-specific reference value patterns., Conclusions: This is the first study to generate continuous RIs for a breadth of hematological markers in a healthy pediatric Canadian population. The increased power of continuous reference intervals to accurately estimate the complex relationship between hematological analyte concentration and age during a time of extensive growth and development is expected to improve laboratory test result interpretation and, subsequently, pediatric clinical decision-making., (© 2021 John Wiley & Sons Ltd.)

Objectives: Point-of-care testing (POCT) is being increasingly adopted to support clinical care. Data for critical care parameters in healthy children on POCT instruments are lacking. We established comprehensive reference standards for several whole blood parameters on the Radiometer ABL90 FLEX PLUS blood gas analyzer in the Canadian Laboratory Initiative on Paediatric Reference Intervals (CALIPER) cohort., Methods: Approximately 300 healthy children and adolescents (age range, birth to <19 years; sex, boys and girls) were recruited with informed consent. Venous whole blood was collected (using heparinized syringes) and rapidly analyzed at the point of collection for pH, Pco2, Po2, carboxyhemoglobin, methemoglobin, lactate, and electrolytes on the ABL90 FLEX PLUS instrument. Reference intervals were established according to Clinical and Laboratory Standards Institute guidelines., Results: Of the parameters assessed, 6 required age partitioning; none required sex partitioning. Reference value distributions were consistent across the pediatric age range, demonstrating higher variation in the early neonatal period., Conclusions: This study established reference standards for 10 critical care analytes in the CALIPER cohort for the first time. These data contribute to our understanding of normative pediatric values for venous electrolytes, metabolites, and blood gases on a modern POCT instrument, facilitating test interpretation in clinical settings that use these assays., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Reference intervals are traditionally partitioned into discrete ranges by major covariates such as age and sex. However, discrete reference intervals often oversimplify the complex relationship between analyte concentration and age. Continuous reference intervals have been suggested to more accurately represent this complex relationship, particularly in pediatrics. The objective of this study was to establish continuous reference intervals for endocrine, fertility, and additional immunochemical parameters in the CALIPER cohort of healthy children and adolescents., Methods: Continuous reference intervals from 1 to 18.5 years of age were established using retrospective CALIPER data collected from healthy Canadian children and adolescents. Continuous reference intervals (2.5th and 97.5th percentiles) were determined for 19 parameters by nonparametric quantile regression. Total and yearly flagging rates were calculated for the upper and lower continuous reference limits and compared to previously published partitioned reference limits., Results: Continuous reference intervals were established for 19 endocrine, fertility, and additional immunochemical parameters, with 11 requiring sex-specific reference curves. Continuous reference intervals assessed both visually and by flagging rate analysis more accurately represented the relationship between analyte concentration and age, particularly for parameters with complex reference value patterns., Conclusion: This is the first comprehensive report to establish continuous reference intervals for several immunochemical parameters including endocrine and fertility markers in a healthy paediatric Canadian cohort. The ability of continuous reference intervals to provide a better estimate of age-related changes in reference values suggest their potential to improve paediatric laboratory test result interpretation and clinical decision-making., (Copyright © 2021 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: The clinical use of common cardiac biomarkers, such as brain natriuretic peptides and troponins, has traditionally been limited to adult populations in the assessment of heart failure and acute coronary syndrome, respectively. While many have discounted the value of these markers in pediatric populations, emerging evidence suggests they may be useful in the diagnosis and prognostication of many cardiac and noncardiac pathologies in neonates, children, and adolescents, and an increasing number of pediatric hospitals are routinely measuring cardiac markers in their clinical practice., Content: This review summarizes and critically evaluates the current literature regarding the application of cardiac biomarkers for clinical decision-making in the pediatric population. Main potential clinical indications discussed herein include primary cardiac disease, immune-related conditions, and noncardiac disease. Important diagnostic and interpretative challenges are also described in relation to each potential indication., Summary: Despite a general lack of clinical awareness regarding the value of cardiac biomarkers in pediatrics, there is increasing literature to support their application in various contexts. Cardiac biomarkers should be considered an undervalued resource in the pediatric population with potential value in the diagnosis and prognosis of myocarditis, congenital heart disease, and heart failure, as well as in the assessment of severity and cardiac involvement in immune-related and other systemic conditions. While interpretation remains challenging in pediatrics due to the age- and sex-specific dynamics occurring throughout growth and development, this should not prevent their application. Future research should focus on defining evidence-based cut-offs for specific indications using the most up-to-date assays., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Point of care testing (POCT) is important in the provision of timely laboratory test results and continues to gain specific appreciation in the setting of pediatric healthcare. POCT platforms offer several advantages compared to central laboratory testing, including improved clinical outcomes, reduced time to diagnosis, length of stay, and blood volume requirements, as well as increased accessibility. These advantages are most pronounced in acute care settings such as pediatric emergency departments, intensive care units, and in remote settings, wherein rapid patient assessment and prognostication is essential to patient outcomes. The current review provides an overview and critical discussion of the evidence supporting clinical implementation of POCT systems in pediatric clinical decision-making, including but not limited to the diagnosis of viral and bacterial infection, identification of critical glucose and electrolyte dysregulation, and prognostication of post-operative inpatients. Important considerations for test result reporting and interpretation are also discussed, including analytical concordance between POCT systems and central laboratory analyzers as well as availability of pediatric reference intervals for key analytes on POCT systems. Notably, a paucity of evidence-based pediatric reference intervals for test interpretation for critical care parameters on POCT platforms is highlighted, warranting further study and unique consideration prior to clinical implementation., (Copyright © 2021 International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). All rights reserved.)

Objectives: The quality of clinical laboratory service depends on quality laboratory operations and accurate test result interpretation based on reference intervals (RIs). As new analytical systems continue to be developed and improved, previously established RIs must be verified. The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) has established comprehensive RIs for many biomarkers on several analytical systems. Here, published CALIPER RIs for 28 chemistry assays on the Abbott ARCHITECT were assessed for verification on the newer Alinity system., Methods: An analytical validation was first completed to assess assay performance. CALIPER serum samples (100) were analyzed for 28 chemistry assays on the Alinity system. The percentage of results falling within published pediatric ARCHITECT reference and confidence limits was determined for each analyte. Based on Clinical and Laboratory Standards Institute (CLSI) guidelines, if ≥90% of test results fell within confidence limits of ARCHITECT assay RIs, they were considered verified., Results: Of the 28 assays assessed, 26 met the criteria for verification. Reference values for calcium and magnesium did not meet the criteria for verification with 87% and 35% falling within previously established ARCHITECT confidence limits, respectively. However, both assays could be verified using pediatric RIs provided in the Abbott Alinity package insert., Conclusions: In this study, CALIPER ARCHITECT RIs were verified on the Alinity system for several chemistry assays. These data demonstrate excellent concordance for most assays between the Abbott ARCHITECT and Alinity systems and will assist in the implementation of the Alinity system in pediatric healthcare institutions., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: To establish reference intervals for hemoglobin and mean corpuscular volume (MCV) in an ethnically diverse community sample of Canadian children 36 months and younger., Methods: We collected blood samples from young children at scheduled primary care health supervision visits at 2 weeks, 2, 4, 6, 9, 12, 15, 18, 24, and 36 months of age. Samples were analyzed on the Sysmex XN-9000 Hematology Analyzer. We followed the Clinical and Laboratory Standards Institute guidelines in our analysis. Data were partitioned by sex and also combined. We considered large age partitions (3 and 6 months) as well as monthly partitions. Reference intervals (lower and upper limits) and 90% confidence intervals were calculated., Results: Data from 2106 children were included. The age range was 2 weeks to 36 months, 46% were female, 48% were European and 23% were of mixed ethnicity. For hemoglobin, from 2 to 36 months of age, we found a wide reference interval and the 90% confidence intervals indicated little difference across age groups or according to sex. For MCV, from 2 to 7 months of age there was considerable decrease in the reference interval, which was lowest during the second year of life, followed by a slight increase in the last months of the third year of life., Conclusion: These findings suggest adoption of a single hemoglobin reference interval for children 2-36 months of age. Further studies in children under 4 months of age are needed., Trial Registration: TARGet Kids! cohort is registered at ClinicalTrials.gov. www.clinicaltrials.gov . Identifier: NCT01869530 .

Objectives: Rapid development in childhood and adolescence combined with lack of immunoassay standardization necessitates the establishment of age-, sex-, and assay-specific reference intervals for immunochemical markers. This study established reference intervals for 11 immunoassays on the new Siemens Healthineers Atellica® IM Analyzer in the healthy CALIPER cohort., Methods: A total of 600 healthy participants (birth to 18 years) were recruited from the community, and serum samples were collected with informed consent. After sample analysis, age- and sex-specific differences were assessed, and outliers were removed. Reference intervals were established using the robust method (40-<120 participants) or nonparametric method (≥120 participants)., Results: Of the 11 immunoassays studied, nine required age partitioning (i.e., dehydroepiandrosterone-sulfate, estradiol, ferritin, folate, follicle-stimulating hormone, luteinizing hormone, progesterone, testosterone, vitamin B12), and seven required sex partitioning. Free thyroxine and thyroid-stimulating hormone demonstrated no significant age- and/or sex-specific differences., Conclusions: Overall, the age- and sex-specific trends observed closely mirrored those previously reported by CALIPER on other platforms as well as other internationally recognized studies. However, established lower and upper limits demonstrated some discrepancies between published values from healthy cohorts on alternate analytical systems, highlighting differences between manufacturers and the need for platform-specific reference intervals for informed pediatric clinical decision-making., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

With an almost unremittent progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections all around the world, there is a compelling need to introduce rapid, reliable, and high-throughput testing to allow appropriate clinical management and/or timely isolation of infected individuals. Although nucleic acid amplification testing (NAAT) remains the gold standard for detecting and theoretically quantifying SARS-CoV-2 mRNA in various specimen types, antigen assays may be considered a suitable alternative, under specific circumstances. Rapid antigen tests are meant to detect viral antigen proteins in biological specimens (e.g. nasal, nasopharyngeal, saliva), to indicate current SARS-CoV-2 infection. The available assay methodology includes rapid chromatographic immunoassays, used at the point-of-care, which carries some advantages and drawbacks compared to more conventional, instrumentation-based, laboratory immunoassays. Therefore, this document by the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Taskforce on COVID-19 aims to summarize available data on the performance of currently available SARS-CoV-2 antigen rapid detection tests (Ag-RDTs), providing interim guidance on clinical indications and target populations, assay selection, and evaluation, test interpretation and limitations, as well as on pre-analytical considerations. This document is hence mainly aimed to assist laboratory and regulated health professionals in selecting, validating, and implementing regulatory approved Ag-RDTs., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: It is necessary to establish hematological reference intervals (RIs) in each population to improve disease management and healthcare quality. This study aimed to establish age- and sex-specific hematological RIs in a healthy adult Kurdish population and evaluate the influence of select lifestyle factors., Methods: Hematological parameters were studied in 6518 individuals (3006 females, 3512 males) from Ravansar Non-Communicable Disease (RaNCD) cohort study. Hematological parameters were measured by Beckman Coulter HmX Analyzer. After combined application of exclusion criteria and statistical outlier removal, RIs for all partitions were calculated using nonparametric methods., Results: The present study established hematological RIs for 14 parameters in a healthy adult Iranian population. Reference values for some analytes demonstrated significant age- and sex-specific differences and were slightly different when compared to RIs determined in other populations. Furthermore, the current smokers had higher levels of white blood cells (WBCs), red blood cells (RBCs), hemoglobin, hematocrit, mean corpuscular hemoglobin (MCH), and mean corpuscular volume than ex- and nonsmokers. Also, in the presence of high physical activity, elevated levels of RBC, hemoglobin, hematocrit, monocytes, and MCH were observed, as well as lower WBC levels. Further, a significant positive association was observed between body mass index (BMI) and WBC, red cell distribution width, and plateletcrit levels., Conclusion: Our study suggests hematological parameters are influenced by age, sex, and lifestyle factors such as physical activity and BMI. Additionally, discrepancies when compared to other population studies suggest that ethnic-specific differences need to be considered when establishing RIs for hematological parameters., (© 2020 John Wiley & Sons Ltd.)

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., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Several guidelines for the evaluation of laboratory tests for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection have recommended establishing an a priori definition of minimum clinical performance specifications before test selection and method evaluation., Methods: Using positive (PPV) and negative predictive values (NPV), we constructed a spreadsheet tool for determining the minimum clinical specificity (conditional on NPV or PPV, sensitivity and prevalence) and minimum clinical sensitivity (conditional on NPV or PPV, specificity and prevalence) of tests., Results: At a prevalence of 1%, there are no minimum sensitivity requirements to achieve a desired NPV of 60%-95% for a given clinical specificity above 20%. It is not possible to achieve 60-95% PPV even with 100% clinical sensitivity, except when the clinical specificity is near 100%. The opposite trend is seen in high prevalence settings (60%), where a relatively low minimum clinical sensitivity is required to achieve a desired PPV for a given clinical specificity, and a higher minimum clinical specificity is required to achieve a desired NPV for a given clinical sensitivity., Discussion: The selection of laboratory tests and the testing strategy for SARS-CoV-2 involves delicate trade-offs between NPV and PPV based on prevalence and clinical sensitivity and clinical specificity. Practitioners and health authorities should carefully consider the clinical scenarios under which the test result will be used and select the most appropriate testing strategy that fulfils the a priori defined clinical performance specification., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: The recent global survey promoted by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Taskforce on COVID-19 (coronavirus disease 2019) described staff rostering and organization as significant operational challenges during the COVID-19 pandemic., Method: A discrete event simulation was used to explore the impact of different permutations of staff roster, including the number of shifts per day, the number of staff on duty per shift, overall number of staff accessible to work in the laboratory (i.e. overall staff pool), the frequency of shift changes (i.e. number of consecutive days worked), fixed work-rest days and split team arrangement on workplace transmission of COVID-19 by a simulated index staff who acquired the infection from the community over 21 days. Additionally, the impact of workplace social distancing (physical distancing) and use of personal protective equipment (PPE) were investigated., Results: A higher rate of transmission was associated with smaller overall staff pool (expressed as multiples of the number of staff per shift), higher number of shifts per day, higher number of staff per shift, and longer consecutive days worked. Having fixed work-rest arrangement did not significantly reduce the transmission rate unless the workplace outbreak was prolonged. Social distancing and PPE use significantly reduced the transmission rate., Conclusion: Laboratories should consider organizing the staff into smaller teams/shift and reduce the number of consecutive days worked. Additionally, our observation aligns with the IFCC biosafety recommendation of monitoring staff health (to detect early infection), split team arrangement, workplace social distancing and use of PPE., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Introduction: Hematology laboratory parameters are among the most routinely ordered tests in support of adult and pediatric care. However, appropriate interpretation of test results has been a challenge in pediatrics since accurate and up-to-date reference intervals that reflect the dynamic physiological changes associated with growth and development have not been available. Critical gaps continue to exist in pediatric hematology reference intervals for modern laboratory platforms. To address this gap, this study establishes age- and sex-specific reference intervals for 25 hematology parameters in the CALIPER cohort of healthy children and adolescents using a common platform, the Sysmex XN-3000 analytical system., Methods: Fresh whole blood samples collected from a total of 641 healthy children and adolescents (birth to <21 years) with informed consent were analyzed for 25 hematological parameters on the Sysmex XN-3000 Hematology Analyzer. Age- and sex-specific reference standards were calculated based on Clinical and Laboratory Standards Institute guidelines., Results: Of the 25 analytes assessed, 19 required age-partitioning and seven required sex-partitioning (ie, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, red blood cell distribution width-SD, red blood cell distribution width-CV, and monocyte percentage). Age- and sex-specific differences mostly coincided with the onset of puberty., Conclusion: This study establishes a comprehensive database of pediatric reference intervals for hematology parameters in the CALIPER cohort using the widely used Sysmex XN-3000 analytical platform. These data highlight the dynamic hematological profile observed in healthy children and adolescents and the need for reference interval stratification by age and sex., (© 2020 John Wiley & Sons Ltd.)

Serological testing for the detection of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is emerging as an important component of the clinical management of patients with coronavirus disease 2019 (COVID-19) as well as the epidemiological assessment of SARS-CoV-2 exposure worldwide. In addition to molecular testing for the detection of SARS-CoV-2 infection, clinical laboratories have also needed to increase testing capacity to include serological evaluation of patients with suspected or known COVID-19. While regulatory approved serological immunoassays are now widely available from diagnostic manufacturers globally, there is significant debate regarding the clinical utility of these tests, as well as their clinical and analytical performance requirements prior to application. This document by the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Taskforce on COVID-19 provides interim guidance on: (A) clinical indications and target populations, (B) assay selection, (C) assay evaluation, and (D) test interpretation and limitations for serological testing of antibodies against SARS-CoV-2 infection. These evidence-based recommendations will provide practical guidance to clinical laboratories in the selection, verification, and implementation of serological assays and are of the utmost importance as we expand our pandemic response from initial case tracing and containment to mitigation strategies to minimize resurgence and further morbidity and mortality.

Routine biochemical and hematological tests have been reported to be useful in the stratification and prognostication of pediatric and adult patients with diagnosed coronavirus disease (COVID-19), correlating with poor outcomes such as the need for mechanical ventilation or intensive care, progression to multisystem organ failure, and/or death. While these tests are already well established in most clinical laboratories, there is still debate regarding their clinical value in the management of COVID-19, particularly in pediatrics, as well as the value of composite clinical risk scores in COVID-19 prognostication. This document by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 provides interim guidance on: (A) clinical indications for testing, (B) recommendations for test selection and interpretation, (C) considerations in test interpretation, and (D) current limitations of biochemical/hematological monitoring of COVID-19 patients. These evidence-based recommendations will provide practical guidance to clinical laboratories worldwide, underscoring the contribution of biochemical and hematological testing to our collective pandemic response.

The diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection globally has relied extensively on molecular testing, contributing vitally to case identification, isolation, contact tracing, and rationalization of infection control measures during the coronavirus disease 2019 (COVID-19) pandemic. Clinical laboratories have thus needed to verify newly developed molecular tests and increase testing capacity at an unprecedented rate. As the COVID-19 pandemic continues to pose a global health threat, laboratories continue to encounter challenges in the selection, verification, and interpretation of these tests. This document by the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 provides interim guidance on: (A) clinical indications and target populations, (B) assay selection, (C) assay verification, and (D) test interpretation and limitations for molecular testing of SARS-CoV-2 infection. These evidence-based recommendations will provide practical guidance to clinical laboratories worldwide and highlight the continued importance of laboratory medicine in our collective pandemic response.

The global epidemiology of coronavirus disease 2019 (COVID-19) suggests a wide spectrum of clinical severity, ranging from asymptomatic to fatal. Although the clinical and laboratory characteristics of COVID-19 patients have been well characterized, the pathophysiological mechanisms underlying disease severity and progression remain unclear. This review highlights key mechanisms that have been proposed to contribute to COVID-19 progression from viral entry to multisystem organ failure, as well as the central role of the immune response in successful viral clearance or progression to death.

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., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Accurate hematologic test interpretation based on normative reference standards is critical to ensure appropriate clinical decision making. However, healthy pediatric reference data for most hematology parameters are lacking. To address this gap, this study establishes age- and sex-specific hematologic reference standards in the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort of healthy children and adolescents., Methods: Fresh whole blood samples collected from a total of 566 healthy children and adolescents (birth to <21 years) with informed consent were analyzed for 47 hematologic parameters on the Beckman Coulter DxH 900. Age- and sex-specific reference standards were calculated based on the Clinical and Laboratory Standards Institute guidelines., Results: Reference value distributions for most hematology parameters demonstrated dynamic changes across the pediatric age range with significant age-specific differences observed for 39 of the 47 parameters examined. Sex-specific differences were also observed for eight hematologic parameters, primarily during and after puberty., Conclusions: This study establishes a robust database of pediatric reference standards for 47 hematologic parameters in the CALIPER cohort for the first time. These comprehensive reference value data sets report potentially important and physiologically relevant trends in hematologic markers, clearly demonstrating the need for pediatric reference standards for hematologic test interpretation., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The global coronavirus disease 2019 (COVID-19) has presented major challenges for clinical laboratories, from initial diagnosis to patient monitoring and treatment. Initial response to this pandemic involved the development, production, and distribution of diagnostic molecular assays at an unprecedented rate, leading to minimal validation requirements and concerns regarding their diagnostic accuracy in clinical settings. In addition to molecular testing, serological assays to detect antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are now becoming available from numerous diagnostic manufacturers. In both cases, the lack of peer-reviewed data and regulatory oversight, combined with general misconceptions regarding their appropriate use, have highlighted the importance of laboratory professionals in robustly validating and evaluating these assays for appropriate clinical use. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 has been established to synthesize up-to-date information on the epidemiology, pathogenesis, and laboratory diagnosis and monitoring of COVID-19, as well as to develop practical recommendations on the use of molecular, serological, and biochemical tests in disease diagnosis and management. This review summarizes the latest evidence and status of molecular, serological, and biochemical testing in COVID-19 and highlights some key considerations for clinical laboratories operating to support the global fight against this ongoing pandemic. Confidently this consolidated information provides a useful resource to laboratories and a reminder of the laboratory's critical role as the world battles this unprecedented crisis.