Canadian Society of Clinical Chemists Harmonized Pediatric Lipid Reporting Recommendations for Clinical Laboratories.

Detecting dyslipidemia early is important because atherosclerosis originates in childhood and early treatment can improve outcomes. In 2022, the Canadian Cardiovascular Society (CCS) and Canadian Pediatric Cardiology Association (CPCA) published a clinical practice update to detect, evaluate, and manage pediatric dyslipidemia. However, guidance on its translation into clinical laboratories is lacking. The Canadian Society of Clinical Chemists Working Group on Reference Interval Harmonization Lipid Team aims to assist guideline implementation and promote harmonized pediatric lipid reporting across Canada. The 2022 CCS/CPCA clinical practice update, 2011 National Heart, Lung, and Blood Institute integrated guidelines, and new data analysis (Canadian pediatric reference values from the Canadian Laboratory Initiative on Pediatric Reference Intervals [CALIPER] and retrospective patient data from large community laboratories) were incorporated to develop 5 key recommendations. These include recommendations to: (1) offer nonfasting and fasting lipid testing; (2) offer a lipid panel including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and triglycerides, with apolipoprotein B and lipoprotein(a) available as individually orderable tests; (3) flag total cholesterol, LDL-C, and non-HDL-C results ≥ 95th percentile, and HDL-C results < 10th percentile, as recommended by CCS/CPCA/National Heart, Lung, and Blood Institute and validated by CALIPER, and flag apolipoprotein B and nonfasting triglyceride results ≥ 95th percentile on the basis of CALIPER, and do not flag Lp(a) results but mention the adult cutoff in the interpretive comments; (4) implement interpretive comments listed in the current report; and (5) implement the National Institutes of Health LDL-C equation. The Canadian Society of Clinical Chemists Working Group on Reference Interval Harmonization Lipid Team will support clinical laboratories to implement these recommendations using knowledge translation strategies. Harmonizing pediatric lipid reporting across Canadian clinical laboratories will optimize clinical decision-making and improve cardiovascular risk management in youth.

Extending the cystatin C based EKFC-equation to children - validation results from Europe.

BACKGROUND: A new cystatin C based European Kidney Function Consortium (EKFCCysC) equation was recently developed for adults, using the same mathematical form as the previously published full age spectrum creatinine based EKFC-equation (EKFCCrea). In the present study the cystatin C based EKFC-equation is extended to children, by defining the appropriate cystatin C rescaling factor QCysC. METHODS: Rescaling factor QCysC for cystatin C was defined as: a) 0.83 mg/L, exactly as it was defined for young adults in the adult equation, and b) a more complex QCysC-age relationship based on 4th degree cystatin C-age polynomials after evaluation of data from Uppsala, Stockholm and Canada and aggregated data from Germany. The EKFCCysC equation was then validated in an independent dataset in European children (n = 2,293) with measured GFR, creatinine, cystatin C, age, height and sex available. RESULTS: The EKFCCysC with the simple QCysC-value of 0.83 had a bias of -7.6 [95%CI -8.4;-6.5] mL/min/1.73 m2 and a P30-value of 85.8% [95%CI 84.4;87.3] equal to the EKFCCysC with the more complex 4th degree QCysC-value. The arithmetic mean of the EKFCCrea and EKFCCysC with the simple QCysC of 0.83 had a bias of -4.0 [95%CI -4.5;-3.1] mL/min/1.73 m2 and P30 of 90.4% [95%CI 89.2;91.6] similar to using the more complex 4th degree QCysC-polynomial. CONCLUSION: Using exactly the same QCysC of 0.83 mg/L, the adult EKFCCysC can easily be extended to children, with some bias but acceptable P30-values. The arithmetic mean of EKFCCrea and EKFCCysC results in bias closer to zero and P30 slightly over 90%.

Pediatric reference intervals for serum neurofilament light and glial fibrillary acidic protein using the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort.

OBJECTIVES: Blood biomarkers have the potential to transform diagnosis and prognosis for multiple neurological indications. Establishing normative data is a critical benchmark in the analytical validation process. Normative data are important in children as little is known about how brain development may impact potential biomarkers. The objective of this study is to generate pediatric reference intervals (RIs) for serum neurofilament light (NfL), an axonal marker, and glial fibrillary acidic protein (GFAP), an astrocytic marker. METHODS: Serum from healthy children and adolescents aged 1 to <19 years were obtained from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort. Serum NfL (n=300) and GFAP (n=316) were quantified using Simoa technology, and discrete RI (2.5th and 97.5th percentiles) and continuous RI (5th and 95th percentiles) were generated. RESULTS: While there was no association with sex, there was a statistically significant (p<0.0001) negative association between age and serum NfL (Rho -0.400) and GFAP (Rho -0.749). Two statistically significant age partitions were generated for NfL: age 1 to <10 years (lower, upper limit; 3.13, 20.6 pg/mL) and 10 to <19 years (1.82, 7.44 pg/mL). For GFAP, three statistically significant age partitions were generated: age 1 to <3.5 years (80.4, 601 pg/mL); 3.5 to <11 years (50.7, 224 pg/mL); and 11 to <19 years (26.2, 119 pg/mL). CONCLUSIONS: Taken together with the literature on adults, NfL and GFAP display U-shaped curves with high levels in infants, decreasing levels during childhood, a plateau during adolescence and early adulthood and increasing levels in seniors. These normative data are expected to inform future pediatric studies on the importance of age on neurological blood biomarkers.

Age-specific reference intervals for liver function tests in healthy neonates, infants, and young children in Iran.

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.

Mining the Gap: Deriving Pregnancy Reference Intervals for Hematology Parameters Using Clinical Datasets.

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.

SARS-CoV-2 serology in pediatrics: Seroprevalence studies in unvaccinated children and humoral antibody response post vaccination.

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.

Pediatric reference intervals for hematology parameters in healthy infants and young children in Iran.

INTRODUCTION: Defining accurate age- and sex-specific reference intervals (RIs) for hematology parameters, especially for the pediatric population, is important for making an appropriate clinical diagnosis. To address gaps, we established age-specific RIs for 11 hematologic parameters in Iranian children younger than 30 months for the first time. METHODS: Fresh whole blood samples collected from a total of 344 participants (males: 158 and females: 186) ages 3 days to 30 months, with a mean age of 12.91 ± 7.15 months, were recruited from healthcare centers in Mashhad, Iran. Hematologic parameters, including complete blood count (CBC), were analyzed on the Sysmex auto-analyzer system (KX-21 N). RIs were calculated with 90% confidence intervals using the direct method based on CLSI Ep28-A3 and C28-A3 guidelines. RESULTS: None of the CBC parameters required sex partitioning. Of 11 CBC parameters, six required age partitions of 3 days-<4 months, 4-<10, 10-<15, and 4-<30 months. Five parameters (i.e., white blood cell count, mean corpuscular hemoglobin concentration, mean platelet volume, red cell distribution width, and platelet distribution width) did not demonstrate age-specific changes. RIs of red blood cell count and hematocrit, as well as hemoglobin, increased with age, while mean corpuscular volume, mean corpuscular hemoglobin, and platelet count, decreased with age. CONCLUSION: In this study, we established RIs for 11 hematology parameters in young children. Age partitioning was required for six parameters demonstrating marked changes during the early period of growth and development and necessitating the use of pediatric-specific reference standards.

Reference Interval Harmonization: Harnessing the Power of Big Data Analytics to Derive Common Reference Intervals across Populations and Testing Platforms.

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.

Resveratrol intervention attenuates chylomicron secretion via repressing intestinal FXR-induced expression of scavenger receptor SR-B1.

Two common features of dietary polyphenols have hampered our mechanistic understanding of their beneficial effects for decades: targeting multiple organs and extremely low bioavailability. We show here that resveratrol intervention (REV-I) in high-fat diet (HFD)-challenged male mice inhibits chylomicron secretion, associated with reduced expression of jejunal but not hepatic scavenger receptor class B type 1 (SR-B1). Intestinal mucosa-specific SR-B1-/- mice on HFD-challenge exhibit improved lipid homeostasis but show virtually no further response to REV-I. SR-B1 expression in Caco-2 cells cannot be repressed by pure resveratrol compound while fecal-microbiota transplantation from mice on REV-I suppresses jejunal SR-B1 in recipient mice. REV-I reduces fecal levels of bile acids and activity of fecal bile-salt hydrolase. In Caco-2 cells, chenodeoxycholic acid treatment stimulates both FXR and SR-B1. We conclude that gut microbiome is the primary target of REV-I, and REV-I improves lipid homeostasis at least partially via attenuating FXR-stimulated gut SR-B1 elevation.

Pediatric Reference Value Profiling of Essential Trace and Toxic Elements in Healthy Children and Adolescents Using High-Resolution and Triple Quadrupole Inductively Coupled Plasma Mass Spectrometry.

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.

Comprehensive Pediatric Reference Limits for High-Sensitivity Cardiac Troponin I and NT-proBNP in the CALIPER Cohort.

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.

Highly sensitive tandem mass spectrometric measurement of serum estradiol without derivatization and pediatric reference intervals in children and adolescents.

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.

Pediatric reference interval verification for 16 biochemical markers on the Alinity ci system in the CALIPER cohort of healthy children and adolescents.

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.

Comparison of reference intervals for biochemical and hematology markers derived by direct and indirect procedures based on the Isfahan cohort study.

INTRODUCTION: Indirect methods for reference interval (RI) establishment apply statistical techniques to generate RIs for test result interpretation using stored laboratory data. They present unique advantages relative to traditional direct approaches such as fewer resource requirements; however, there is debate regarding their performance. Herein, we aimed to compare indirect and direct approaches for RI establishment by harnessing data from the Isfahan Cohort Study (ICS). This cohort includes both healthy individuals and those with a history of disease, enabling a direct comparison. METHODS: Participants were recruited as part of ICS, including 6504 adults aged 34 years and older. Sociodemographic characteristics, anthropometry, blood pressure, various biochemical indices, and hematology parameters were collected. The refineR method was used to establish indirect RIs (before applying exclusion criteria). Direct RIs were calculated using nonparametric methods per CLSI EP28-A3 guidelines (after applying exclusion criteria). Bias ratios were calculated for each parameter to assess significant differences in estimations. RESULTS: Direct and indirect RI estimations for most hematological and biochemical parameters were comparable. Statistically significant bias ratios between methods were observed for the upper limits of total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), hemoglobin (female), and platelet count as well as the lower limits of mean corpuscular hemoglobin (female), mean corpuscular volume, hemoglobin, and hematocrit (female). CONCLUSION: Data presented indicate RIs derived from direct and indirect approaches are similar, but not identical. Further work should focus on the clinical significance of such differences as well as the investigation of necessary data-cleaning criteria before indirect method application.

Comprehensive pediatric reference intervals for 79 hematology markers in the CALIPER cohort of healthy children and adolescents using the Mindray BC-6800Plus system.

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.

High-sensitivity cardiac troponin T in infants exposed to anti-Ro antibodies.

OBJECTIVES: Cardiac involvement in neonatal lupus erythematosis (NLE) can present as myocarditis/endocardial fibroelastosis (EFE). It is unknown whether high-sensitivity cardiac troponin T (hs-cTnT) is useful in identifying subclinical myocardial inflammation in infants exposed prenatally to anti-Ro antibodies. This study reports hs-cTnT levels in infants exposed to anti-Ro antibodies with/without cardiac NLE and reports cardiac MRI (CMR) findings in a subset of these children. METHODS: The study included 45 consecutive infants exposed prenatally to anti-Ro antibodies with (n = 7) or without (n = 38) cardiac NLE, who were seen at the SickKids NLE Clinic between 2012 and 2014. Hs-cTnT levels were measured at least once, and those infants with values of ≥30 ng/l were offered the opportunity to undergo CMR. Descriptive statistics were performed. RESULTS: Of 38 infants without cardiac NLE, 25 had a hs-cTnT level of ≥30 ng/l (including 1 of >113 ng/l); of these, 8 underwent CMR (all without myocarditis/EFE). All 7 infants with cardiac NLE had at least one hs-cTnT level of ≥30 ng/l, but only 2/7 had a level of >113 ng/l; 4/7 infants with cardiac NLE had CMR (all without myocarditis/EFE); 6/7 infants with cardiac NLE had their steroid treatment adjusted based on the trend in their hs-cTnT levels. CONCLUSION: Only 3/45 anti-Ro antibodies-exposed infants had hs-cTnT values outside the reference range reported in healthy infants. None of 12 infants who had CMR had subclinical myocarditis/EFE. Routine measurement of hs-cTnT in every anti-Ro antibody-exposed infant is not indicated. Further studies are needed to define the role of hs-cTnT as a biomarker for cardiac NLE.

LMS-based continuous reference percentiles for 14 laboratory parameters in the CALIPER cohort of healthy children and adolescents.

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.