Publications by authors named "Khosrow Adeli"

289 Publications

Pediatric reference intervals for 32 routine biochemical markers using the siemens healthineers atellica® CH assays in healthy children and adolescents.

Clin Biochem 2021 Oct 20. Epub 2021 Oct 20.

CALIPER Program, Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.clinbiochem.2021.10.006DOI Listing
October 2021

Physiological and metabolic adaptations in pregnancy: importance of trimester-specific reference intervals to investigate maternal health and complications.

Crit Rev Clin Lab Sci 2021 Sep 29:1-17. Epub 2021 Sep 29.

CALIPER Program, Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1080/10408363.2021.1978923DOI Listing
September 2021

Complex biological patterns of soluble cytokines and CD163 in childhood necessitating age-specific reference intervals for evidence-based clinical interpretation.

Clin Biochem 2021 Sep 9. Epub 2021 Sep 9.

Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; SickKids Research Institute, 686 Bay Street, Toronto, ON M5G 0A4, Canada.

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.
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http://dx.doi.org/10.1016/j.clinbiochem.2021.09.004DOI Listing
September 2021

Multi-Inflammatory Syndrome in Children: A View into Immune Pathogenesis from a Laboratory Perspective.

J Appl Lab Med 2021 Aug 31. Epub 2021 Aug 31.

Department of Pediatric Laboratory Medicine & Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Multi-inflammatory syndrome in children (MIS-C) is a novel and rare inflammatory disorder associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in school-age children. Reports in the past year have suggested a multi-system pathophysiology characterized by hyperinflammation, gastrointestinal distress, and cardiovascular complications. Clinical laboratory investigations, including routine blood testing for inflammatory (e.g., CRP, 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.
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http://dx.doi.org/10.1093/jalm/jfab114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499820PMC
August 2021

POCT: An Inherently Ideal Tool in Pediatric Laboratory Medicine.

EJIFCC 2021 Jun 29;32(2):145-157. Epub 2021 Jun 29.

Division of Clinical Biochemistry, Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343051PMC
June 2021

Continuous reference curves for common hematology markers in the CALIPER cohort of healthy children and adolescents on the Sysmex XN-3000 system.

Int J Lab Hematol 2021 Aug 1. Epub 2021 Aug 1.

CALIPER Program, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1111/ijlh.13670DOI Listing
August 2021

Age- and sex-specific reference intervals for superoxide dismutase enzyme and several minerals in a healthy adult cohort.

J Clin Lab Anal 2021 Sep 17;35(9):e23897. Epub 2021 Jul 17.

Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Introduction: The aim of this study was to establish RIs for clinically important markers including superoxide dismutase (SOD), serum copper, zinc, calcium, magnesium, and phosphate in a cohort of healthy Iranian adults.

Materials: A subsample from MASHAD cohort study was used to assess serum SOD, copper, zinc, calcium, magnesium and phosphate. Serum SOD was measured according to its inhibitory potential of pyrogallol oxidation. Micro- and macro-minerals were measured using flame atomic absorption spectrometry and a BT3000 autoanalyzer, respectively. Sex- and age-specific RIs were then calculated based on CLSI Ep28-A3 guidelines.

Results: Reference value distributions for studied parameters did not demonstrate any age-specific differences that were statistically significant. In addition, sex partitioning was not required for all parameters, apart from serum magnesium, which showed a wider range in females (0.81-1.26 mg/dl) compared with males (0.82-1.23 mg/dl).

Conclusion: The RIs established in this study can be expected to improve mineral assessment and clinical decision-making in the Iranian adult population.
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http://dx.doi.org/10.1002/jcla.23897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418512PMC
September 2021

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

Clin Chem Lab Med 2021 Sep 30;59(10):1680-1687. Epub 2021 Jun 30.

CALIPER Program, Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.

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 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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http://dx.doi.org/10.1515/cclm-2021-0337DOI Listing
September 2021

Discovery of analogues of non-β oxidizable long-chain dicarboxylic fatty acids as dual inhibitors of fatty acids and cholesterol synthesis: Efficacy of lead compound in hyperlipidemic hamsters reveals novel mechanism.

Nutr Metab Cardiovasc Dis 2021 07 1;31(8):2490-2506. Epub 2021 Jun 1.

Espervita Therapeutics Inc, Ann Arbor, MI, USA.

Background And Aims: Cholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead molecule for therapeutic indications.

Methods And Results: Primary hepatocytes from rat, hamster, rabbit, and humans were compared for suitability to screen compounds by de novo lipogenesis (DNL) usingC-acetate. Hyperlipidemic hamsters were used to evaluate efficacy and mode of action. In rat hepatocytes DNL assay, both the central moiety and carbon chain length influenced the potency of lipogenesis inhibition. In hyperlipidemic hamsters, ETC-1002 decreased plasma cholesterol and triglycerides by 41% and 49% at the 30 mg/kg dose. Concomitant decreases in non-esterified fatty acids (-34%) and increases in ketone bodies (20%) were associated with induction of hepatic CPT1-α. Reductions in proatherogenic VLDL-C and LDL-C (-71% and -64%) occurred partly through down-regulation of DGAT2 and up-regulation of LPL and PDK4. Activation of PLIN1 and PDK4 dampened adipogenesis and showed inverse correlation with adipose mass. Hepatic concentrations of cholesteryl ester and TG decreased by 67% and 64%, respectively. Body weight decreased with concomitant decreases in epididymal fat. Plasma and liver concentrations of ETC-1002 agreed with the observed dose-response efficacy.

Conclusions: Taken together, ETC-1002 reduced proatherogenic lipoproteins, hepatic lipids and adipose tissues in hyperlipidemic hamsters via induction of LPL, CPT1-α, PDK4, and PLIN1, and downregulation of DGAT2. These characteristics may be useful in the treatment of fatty livers that causes non-alcoholic steatohepatitis.
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http://dx.doi.org/10.1016/j.numecd.2021.05.024DOI Listing
July 2021

Cardiac Biomarkers in Pediatrics: An Undervalued Resource.

Clin Chem 2021 Jul;67(7):947-958

CALIPER Program, Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1093/clinchem/hvab063DOI Listing
July 2021

Defining and Reporting on Critical Values in Genetics: A Laboratory Survey.

J Appl Lab Med 2021 09;6(5):1299-1304

Quality Council, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

Background: Although an obvious critical value in metabolic genetics would be ammonia, it is more challenging to define critical values in molecular genetics and cytogenetics. The objective of this study was to survey genetic laboratories in Ontario, Canada, to determine whether different centers considered similar results as critical and thus potentially deserving of a different reporting process.

Methods: An online 11-question survey was emailed to Ontario laboratory directors, and the results were analyzed.

Results: The response rate was 82% (9/11). Cytogenetics and molecular genetics services were each provided by 7 of the 9 centers, with 3 centers providing biochemical/metabolic genetics services and 1 providing maternal marker serum screening services. The case type (e.g., prenatal, newborn, or expedited by the ordering physician) was one factor. Quantitative fluorescence PCR for autosomal aneuploidy, pathogenic variants in both prenatal and postnatal settings, and oncological results were considered critical cytogenetics results. Pathogenic prenatal cases, indeterminate results, and unexpected results were considered more critical for molecular genetics. Critical results were more likely to prompt a telephone call or email to the ordering physician.

Conclusion: Ontario genetics laboratories tended to have similar reporting processes for critical results. Both the types of cases and the pathogenicity of the result define what values are considered critical.
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http://dx.doi.org/10.1093/jalm/jfab040DOI Listing
September 2021

Pediatric Reference Intervals for Critical Point-of-Care Whole Blood Assays in the CALIPER Cohort of Healthy Children and Adolescents.

Am J Clin Pathol 2021 May 29. Epub 2021 May 29.

CALIPER Program, Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada.

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.
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http://dx.doi.org/10.1093/ajcp/aqab064DOI Listing
May 2021

Age and sex-specific reference intervals for prooxidant-antioxidant balance, anti-heat-shock protein 27 (anti-hsp27), and routine laboratory tests in the middle-aged adult population.

Biotechnol Appl Biochem 2021 May 24. Epub 2021 May 24.

Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

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 , 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.
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http://dx.doi.org/10.1002/bab.2203DOI Listing
May 2021

Reference intervals for hemoglobin and mean corpuscular volume in an ethnically diverse community sample of Canadian children 2 to 36 months.

BMC Pediatr 2021 05 19;21(1):241. Epub 2021 May 19.

Pediatric Outcomes Research Team (PORT), Division of Pediatric Medicine and Sick Kids Research Institute, Hospital for Sick Children, Toronto, Canada.

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 .
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http://dx.doi.org/10.1186/s12887-021-02709-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132375PMC
May 2021

Pediatric reference interval verification for common biochemical assays on the Abbott Alinity system.

Clin Chem Lab Med 2021 Aug 19;59(9):1554-1562. Epub 2021 May 19.

CALIPER Program, Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1515/cclm-2021-0336DOI Listing
August 2021

Pediatric reference intervals for endocrine markers and fertility hormones in healthy children and adolescents on the Siemens Healthineers Atellica immunoassay system.

Clin Chem Lab Med 2021 Jul 7;59(8):1421-1430. Epub 2021 May 7.

CALIPER Program, Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1515/cclm-2021-0050DOI Listing
July 2021

IFCC interim guidelines on rapid point-of-care antigen testing for SARS-CoV-2 detection in asymptomatic and symptomatic individuals.

Clin Chem Lab Med 2021 08 28;59(9):1507-1515. Epub 2021 Apr 28.

Department of Paediatric Laboratory Medicine, CALIPER Program, The Hospital for Sick Children, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1515/cclm-2021-0455DOI Listing
August 2021

Continuous reference intervals for 19 endocrine, fertility, and immunochemical markers in the CALIPER cohort of healthy children and adolescents.

Clin Biochem 2021 Aug 18;94:35-41. Epub 2021 Apr 18.

CALIPER Program, Pediatric Laboratory Medicine & Molecular Medicine, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.clinbiochem.2021.04.014DOI Listing
August 2021

A Snapshot of Lipid-Reporting Practices in Canadian Clinical Laboratories: An Urgent Need for Harmonisation.

Can J Cardiol 2021 Jun 26;37(6):933-937. Epub 2021 Mar 26.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address:

To effectively implement the Canadian Cardiovascular Society (CCS) guidelines for dyslipidemia management into clinical laboratories, clear recommendations for lipid reporting are essential. In this study, the Canadian Society of Clinical Chemists Working Group on Reference Interval Harmonisation surveyed Canadian laboratories on adult lipid reporting practices to set a foundation for the development and implementation of harmonised lipid reporting across Canada. Key aspects of the survey asked laboratories: what reporting parameters were in place to assess lipid results; what interpretative comments were provided; whether nonfasting lipids were permitted and, if so, what strategy was used to document fasting status; and whether there was interest in implementing a harmonised lipid report. A total of 101 laboratories were represented by 24 respondents, as many responses were submitted by laboratory networks that included more than 1 laboratory. There was at least 1 response from 9 Canadian provinces and representation across 5 testing platforms. Upper and lower limits for lipid parameters and referenced source of limits varied substantially across laboratories, with only 56% of laboratories (9 respondents) referencing the 2016 CCS guidelines. Eighty-six percent of laboratories (19 respondents) report nonfasting lipids, although the method of documenting nonfasting status varied. Overall, 36% of laboratories (8 respondents) reported interest in implementing a harmonised lipid report. Assessment of current lipid-reporting practices supports the need for harmonised lipid reporting across Canada. Development of a harmonised lipid report for the adult population, consistent with up-to-date Canadian guidelines, will improve continuity of lipid test interpretation across Canada and improve clinical decision making.
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http://dx.doi.org/10.1016/j.cjca.2021.03.018DOI Listing
June 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Pediatric evaluation of clinical specificity and sensitivity of SARS-CoV-2 IgG and IgM serology assays.

Clin Chem Lab Med 2021 05 22;59(6):e235-e237. Epub 2021 Jan 22.

CALIPER Program, The Hospital for Sick Children, Toronto, ON, Canada.

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http://dx.doi.org/10.1515/cclm-2020-1822DOI Listing
May 2021

High Fat-High Fructose Diet-Induced Changes in the Gut Microbiota Associated with Dyslipidemia in Syrian Hamsters.

Nutrients 2020 Nov 20;12(11). Epub 2020 Nov 20.

Molecular Medicine Programs, Research Institute, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

The objective of this study was to characterize the early effects of high fructose diets (with and without high fat) on both the composition of the gut microbiota and lipid metabolism in Syrian hamsters, a reproducible preclinical model of diet-induced dyslipidemia. Eight-week-old male hamsters were fed diets consisting of high-fat/high-fructose, low-fat/high-fructose or a standard chow diet for 14 days. Stool was collected at baseline (day 0), day 7 and day 14. Fasting levels of plasma triglycerides and cholesterol were monitored on day 0, day 7 and day 14, and nonfasting levels were also assayed on day 15. Then, 16S rRNA sequencing of stool samples was used to determine gut microbial composition, and predictive metagenomics was performed to evaluate dietary-induced shifts in deduced microbial functions. Both high-fructose diets resulted in divergent gut microbiota composition. A high-fat/high-fructose diet induced the largest shift in overall gut microbial composition, with dramatic shifts in the Firmicute/Bacteroidetes ratio, and changes in beta diversity after just seven days of dietary intervention. Significant associations between genus level taxa and dietary intervention were identified, including an association with in high-fat/high-fructose fed animals and an association with with the low-fat/high-fructose diet. High-fat/high-fructose feeding induced dyslipidemia with increases in plasma triglycerides and cholesterol, and hepatomegaly. Dietary-induced changes in several genus level taxa significantly correlated with lipid levels over the two-week period. Differences in microbial metabolic pathways between high-fat/high-fructose and low-fat/high-fructose diet fed hamsters were identified, and several of these pathways also correlated with lipid profiles in hamsters. The high-fat/high-fructose diet caused shifts in the host gut microbiota. These dietary-induced alterations in gut microbial composition were linked to changes in the production of secondary metabolites, which contributed to the development of metabolic syndrome in the host.
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http://dx.doi.org/10.3390/nu12113557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699731PMC
November 2020

Setting minimum clinical performance specifications for tests based on disease prevalence and minimum acceptable positive and negative predictive values: Practical considerations applied to COVID-19 testing.

Clin Biochem 2021 Feb 20;88:18-22. Epub 2020 Nov 20.

Department of Clinical Chemistry, New South Wales Health Pathology, Prince of Wales Hospital, Sydney, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.clinbiochem.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678449PMC
February 2021

Establishing hematological reference intervals in healthy adults: Ravansar non-communicable disease cohort study, Iran.

Int J Lab Hematol 2021 Apr 23;43(2):199-209. Epub 2020 Oct 23.

Department of Clinical Biochemistry, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran.

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.
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http://dx.doi.org/10.1111/ijlh.13371DOI Listing
April 2021

Editorial and Executive Summary: IFCC Interim Guidelines on Clinical Laboratory testing during the COVID-19 Pandemic.

Clin Chem Lab Med 2020 10 7;58(12):1965-1969. Epub 2020 Oct 7.

University Hospital of Verona, Verona, Italy.

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http://dx.doi.org/10.1515/cclm-2020-1415DOI Listing
October 2020

IFCC Interim Guidelines on Biochemical/Hematological Monitoring of COVID-19 Patients.

Clin Chem Lab Med 2020 10 7;58(12):2009-2016. Epub 2020 Oct 7.

Taskforce on COVID-19, International Federation of Clinical Chemistry (IFCC), Milan, Italy.

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.
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http://dx.doi.org/10.1515/cclm-2020-1414DOI Listing
October 2020

IFCC Interim Guidelines on Serological Testing of Antibodies against SARS-CoV-2.

Clin Chem Lab Med 2020 10 7;58(12):2001-2008. Epub 2020 Oct 7.

Paediatric Laboratory Medicine, The Hospital for Sick Children, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1515/cclm-2020-1413DOI Listing
October 2020

IFCC Interim Guidelines on Molecular Testing of SARS-CoV-2 Infection.

Clin Chem Lab Med 2020 10 7;58(12):1993-2000. Epub 2020 Oct 7.

University Hospital of Verona, Verona, Italy.

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.
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http://dx.doi.org/10.1515/cclm-2020-1412DOI Listing
October 2020
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