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Objectives: This study sought to compare one-step versus two-step testing approaches for gestational diabetes mellitus (GDM) and to investigate the associations between testing approach, degree of glucose impairment, and perinatal outcomes., Methods: A retrospective population-based cohort study was conducted by combining BC's Perinatal Data Registry with laboratory and billing information from 2010 to 2014. Pregnancy characteristics were compared by GDM testing approach. Logistic regression was conducted to determine the association between testing approach, degree of glucose impairment, and outcomes., Results: Approximately 17% of pregnant individuals were diagnosed with GDM using the one-step test, compared to 6% using the two-step test. The odds ratios of adverse outcomes were below 1.75 for GDM pregnancies regardless of testing approach used (compared to the group with negative results on the two-step test). A dose-dependent trend was observed between increasing glucose intolerance and odds of preterm birth. The odds of large for gestational age infants (LGA) and shoulder dystocia were significantly higher when all 75 g test values were within one standard deviation below one-step diagnostic thresholds (adjOR 1.94[1.73-2.17] and 1.85[1.55-2.21], respectively)., Conclusion: The frequency of GDM was three times higher with the use of the one-step test versus the two-step test. Abnormal results on the two-step test are associated with preterm birth at an odds ratio below 1.75. Pregnant individuals with one-step test results just below diagnostic criteria may be at greater odds for LGA. The benefits of more stringent testing practices need to be weighed against the impact of additional GDM diagnoses., Competing Interests: Declarations. Ethics approval: The study received ethics approval from the University of British Columbia Research Ethics Board (H17-00849-A009). Consent to participate: Not applicable since this study used secondary data analysis of existing registries. Consent for publication: Not applicable. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s) under exclusive license to The Canadian Public Health Association.)

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.)

Purpose and Scope: The aim of this position statement is to provide recommendations for clinicians regarding the use of genetic and metabolic investigations for patients with neurodevelopmental disorders (NDDs), specifically, patients with global developmental delay (GDD), intellectual disability (ID) and/or autism spectrum disorder (ASD). This document also provides guidance for primary care and non-genetics specialists caring for these patients while awaiting consultation with a clinical geneticist or metabolic specialist., Methods of Statement Development: A multidisciplinary group reviewed existing literature and guidelines on the use of genetic and metabolic investigations for the diagnosis of NDDs and synthesised the evidence to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and to the Canadian Pediatric Society (Mental Health and Developmental Disabilities Committee); following incorporation of feedback, it was approved by the CCMG Board of Directors on 1 September 2022., Results and Conclusions: Chromosomal microarray is recommended as a first-tier test for patients with GDD, ID or ASD. Fragile X testing should also be done as a first-tier test when there are suggestive clinical features or family history. Metabolic investigations should be done if there are clinical features suggestive of an inherited metabolic disease, while the patient awaits consultation with a metabolic physician. Exome sequencing or a comprehensive gene panel is recommended as a second-tier test for patients with GDD or ID. Genetic testing is not recommended for patients with NDDs in the absence of GDD, ID or ASD, unless accompanied by clinical features suggestive of a syndromic aetiology or inherited metabolic disease., Competing Interests: Competing interests: TNN: spouse employed by Illumina., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Urine organic acids profiling by gas chromatography-mass spectrometry (GC-MS) is routinely performed in hospital biochemical genetics laboratories for the investigation of inborn errors of metabolism. In particular, accurate identification of urinary levels of 3-hydroxyglutaric acid (3-OHGA) is important for diagnosing glutaric aciduria type 1 (GA1), but can be challenging by routine GC-MS profiling analysis due to co-elution and spectral similarity with the isomer 2-hydroxyglutaric acid (2-OHGA). To improve analytical specificity, unique ions were selected and a simple second-tier reinjection method was developed to enhance the chromatographic separation of the 2- and 3-OHGA isomers and potential unknown interferences. Specimens flagging on the routine analysis were simply reinjected on the same GC column using a modified temperature gradient containing an isothermal hold. Correlation between the reinjection and initial methods was higher for 2-OHGA (R = 0.9612) compared to 3-OHGA (R = 0.7242). Mean differences between the reinjection and initial methods for 2-OHGA and 3-OHGA were -8.5% and -61.1% respectively. The large decrease in 3-OHGA concentration for many specimens using the reinjection method was primarily attributable to separation from unknown variable interference(s) that were falsely elevating 3-OHGA in the initial analysis despite the use of a more unique quantifier ion. Overall, the reinjection approach increased analytical specificity in evaluating for the presence of increased urinary 3-OHGA. This second-tier approach, using a GC isothermal hold, could easily be implemented or adapted by other clinical laboratories experiencing related diagnostic challenges., (Copyright © 2022 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Inborn errors of propionate, cobalamin and methionine metabolism are targets for Newborn Screening (NBS) in most programs world-wide, and are primarily screened by analyzing for propionyl carnitine (C3) and methionine in dried blood spot (DBS) cards using tandem mass spectrometry (MS/MS). Single-tier NBS approaches using C3 and methionine alone lack specificity, which can lead to an increased false-positive rate if conservative cut-offs are applied to minimize the risk of missing cases. Implementation of liquid chromatography tandem mass spectrometry (LC-MS/MS) second-tier testing for 2-methylcitric acid (MCA), methylmalonic acid (MMA), and homocysteine (HCY) from the same DBS card can improve disease screening performance by reducing the false-positive rate and eliminating the need for repeat specimen collection. However, DBS analysis of MCA, MMA, and HCY by LC-MS/MS is challenging due to limited specimen size and analyte characteristics leading to a combination of low MS/MS sensitivity and poor reverse-phase chromatographic retention. Sufficient MS response and analytical performance can be achieved for MCA by amidation using DAABD-AE and by butylation for MMA and HCY. Herein we describe the validation of a second-tier dual derivatization LC-MS/MS approach to detect elevated MCA, MMA, and HCY in DBS cards for NBS. Clinical utility was demonstrated by retrospective analysis of specimens, an interlaboratory method comparison, and assessment of external proficiency samples. Imprecision was <10.8% CV, with analyte recoveries between 90.2 and 109.4%. Workflows and analytical performance characteristics of this second-tier LC-MS/MS approach are amenable to implementation in the NBS laboratory., Competing Interests: 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., (© 2021 THE AUTHORS. Publishing services by ELSEVIER B.V. on behalf of MSACL.)

Head and neck cancer patients present unique airway challenges, and oropharyngeal, laryngeal, and hypopharyngeal tumours considerably distort and narrow the anatomy of the airway. We describe the use of 3D augmented reality software combined with 3D printed models to assess the anatomy of difficult airways and to assist in the formulation of the most optimal airway management strategy in such patients. The reported patients had computed tomograms (CT) of the neck prior to their anaesthetic and surgical management. DICOM files of the respective scans were imported to 3D rendering software (OsiriX, Pixmeo). We constructed volume rendered models for initial assessment of the airway then generated serial surface rendered models to create a virtual endoscopic path of the airway to simulate the fibreoptic approach. To further facilitate the study of difficult airways we have subsequently printed 3D models of those that were most difficult using rapid prototyping. Head and neck tumours significantly distort the airway. Thorough study of the relevant anatomy prior to airway management for operating reasons enhances communication between the surgeon and anaesthetist, and aids selection of the most appropriate intubation approach. In conclusion, this paper highlights a useful and novel pre-assessment strategy that allows a virtual, visual, 3-dimensional assessment of the airway anatomy combined with 3D modelling and 3D printing. This enables the airway specialist, anaesthetist, and head and neck surgeon to anticipate any critical steps and adjust the plan accordingly., (Copyright © 2020 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Global developmental delay and intellectual disability (GDD/ID) affect 3% of the paediatric population. Although inborn errors of metabolism (IEM) are not a common cause of GDD/ID, early therapeutic intervention can improve neurodevelopmental manifestations. In 2012, a first-tier test panel, including specialized metabolic and routine chemistry tests, was piloted to community-based paediatricians in British Columbia with aims to achieve earlier diagnosis of treatable IEM., Objective: The aim of this retrospective review was to evaluate the diagnostic yield from these first-tier tests in the 7 years before (2006 to 2012) and after (2013 to 2019) implementation at the community paediatrician level., Results: Prior and postimplementation diagnostic yield of an IEM from first-tier metabolic testing was 9 out of 986 (0.91%) and 11 out of 4,345 children (0.25%), respectively. Disorders of creatine metabolism and organic acidurias were the most frequently established diagnoses in both time periods. No diagnoses were established through acylcarnitine copper/ceruloplasmin, lactate, or ammonia testing. Twenty out of 24 patients had specific neurological or other red flag signs in addition to GDD/ID. Four boys diagnosed with an x-linked creatine transporter defect (CTD) had speech-language delay as the most prominent finding., Conclusions: The expansion of first-tier metabolic testing to community-based paediatricians in BC did not yield an increase in IEM diagnoses. A modified first-tier test panel should be offered to patients with GDD/ID, neurologic, and/or red flag signs. Urine creatine testing in boys with speech-language delay warrants consideration to detect CTD., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Newborn screening for Cystic Fibrosis has been implemented in most programs worldwide, but the approach used varies, including combinations of immunoreactive trypsinogen (IRT) and CFTR mutation analysis on one or more specimens. The British Columbia (BC) newborn screening program tests ~45,000 infants per year in BC and the Yukon Territory, covering almost 1.5 million km 2 in western Canada. CF screening was initiated using an IRT-DNA-IRT approach with a second bloodspot card at 21 days of age for all CFTR mutation heterozygotes and any non-carriers in the top 0.1% for IRT. This second IRT was implemented to avoid sweat testing of infants without persistent hypertrypsinemia, reducing the burden of travel for families. Over nine years (2010-2018), 401,977 infants were screened and CF was confirmed in 76, and a further 28 were deemed CF screen positive inconclusive diagnosis (CFSPID). Day 21 IRT was normal in 880 CFTR mutation carriers who were quoted a very low CF risk and offered optional sweat testing. Only 13% of families opted for sweat testing and a total of 1036 sweat tests were avoided. There were six false negative CF cases (and three CFSPID) due to a low initial IRT or no CFTR mutations. Although one CFSPID case had a normal repeat IRT result, the addition of the day 21 IRT did not contribute to any CF false negatives., Competing Interests: Conflicts of InterestThe authors declare no conflict of interest., (© 2020 by the authors.)

Objectives: To evaluate the clinical impact of a congenital adrenal hyperplasia (CAH) newborn screening program and incremental costs relative to benefits in screened vs unscreened infants. We hypothesized that screening would lead to clinical benefits and would be cost effective., Study Design: This was an ambispective cohort study at British Columbia Children's Hospital, including infants diagnosed with CAH from 1988-2008 and 2010-2018. Data were collected retrospectively (unscreened cohort) and prospectively (screened cohort). Outcome measures included hospitalization, medical transport, and resuscitation requirements. The economic analysis was performed using a public payer perspective., Results: Forty unscreened and 17 screened infants were diagnosed with CAH (47% vs 53% male). Median days to positive screen was 6 and age at diagnosis was 5 days (range, 0-30 days) and 6 days (range, 0-13 days) in unscreened and screened populations, respectively. In unscreened newborns, 55% required transport to a tertiary care hospital, 85% required hospitalization, and 35% required a fluid bolus compared with 29%, 29%, and 12% in screened infants, respectively. The cost of care was $33 770 per case in unscreened vs $17 726 in screened newborns. In the screened cohort, the incremental cost-effectiveness ratio was $290 in the best case analysis and $4786 in the base case analysis, per hospital day avoided., Conclusions: Compared with unscreened newborns, those screened for CAH were less likely to require medical transport and had shorter hospital stays. Screening led to a decrease in hospitalization costs. Although screening did not result in cost savings, it was assessed to be cost effective considering the clinical benefits and incremental cost-effectiveness ratio., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) is a pan-Canadian practice-based research network of 14 Hereditary Metabolic Disease Treatment Centres and over 50 investigators. CIMDRN aims to develop evidence to improve health outcomes for children with inherited metabolic diseases (IMD). We describe the development of our clinical data collection platform, discuss our data quality management plan, and present the findings to date from our data quality assessment, highlighting key lessons that can serve as a resource for future clinical research initiatives relating to rare diseases., Methods: At participating centres, children born from 2006 to 2015 who were diagnosed with one of 31 targeted IMD were eligible to participate in CIMDRN's clinical research stream. For all participants, we collected a minimum data set that includes information about demographics and diagnosis. For children with five prioritized IMD, we collected longitudinal data including interventions, clinical outcomes, and indicators of disease management. The data quality management plan included: design of user-friendly and intuitive clinical data collection forms; validation measures at point of data entry, designed to minimize data entry errors; regular communications with each CIMDRN site; and routine review of aggregate data., Results: As of June 2019, CIMDRN has enrolled 798 participants of whom 764 (96%) have complete minimum data set information. Results from our data quality assessment revealed that potential data quality issues were related to interpretation of definitions of some variables, participants who transferred care across institutions, and the organization of information within the patient charts (e.g., neuropsychological test results). Little information was missing regarding disease ascertainment and diagnosis (e.g., ascertainment method - 0% missing)., Discussion: Using several data quality management strategies, we have established a comprehensive clinical database that provides information about care and outcomes for Canadian children affected by IMD. We describe quality issues and lessons for consideration in future clinical research initiatives for rare diseases, including accurately accommodating different clinic workflows and balancing comprehensiveness of data collection with available resources. Integrating data collection within clinical care, leveraging electronic medical records, and implementing core outcome sets will be essential for achieving sustainability.

Purpose: The presentation and etiology of cerebral palsy (CP) are heterogeneous. Diagnostic evaluation can be a prolonged and expensive process that might remain inconclusive. This study aimed to determine the diagnostic yield and impact on management of next-generation sequencing (NGS) in 50 individuals with atypical CP (ACP)., Methods: Patient eligibility criteria included impaired motor function with onset at birth or within the first year of life, and one or more of the following: severe intellectual disability, progressive neurological deterioration, other abnormalities on neurological examination, multiorgan disease, congenital anomalies outside of the central nervous system, an abnormal neurotransmitter profile, family history, brain imaging findings not typical for cerebral palsy. Previous assessment by a neurologist and/or clinical geneticist, including biochemical testing, neuroimaging, and chromosomal microarray, did not yield an etiologic diagnosis., Results: A precise molecular diagnosis was established in 65% of the 50 patients. We also identified candidate disease genes without a current OMIM disease designation. Targeted intervention was enabled in eight families (~15%)., Conclusion: NGS enabled a molecular diagnosis in ACP cases, ending the diagnostic odyssey, improving genetic counseling and personalized management, all in all enhancing precision medicine practices.

Background: The hepatic carnitine palmitoyltransferase I ( CPT1A ) p.P479L variant is common in Aboriginal populations across coastal British Columbia, Alaska, the Canadian North, and Greenland. While the high frequency of this variant suggests positive selection, other studies have shown an association with sudden unexpected death in infancy and infection. We utilized administrative health data to evaluate hospitalizations for a single year cohort of children of First Nations descent genotyped for the variant and, matched for location of birth. Seven years of data were reviewed for 150 children split evenly between CPT1A genotypes (homozyous, heterozygous, and noncarrier of the p.P479L variant)., Results: Children homozygous for the p.P479L allele had a higher rate of hospital admissions at 2.6 per individual as compared to noncarriers at 0.86. Heterozygous children also showed a significant increase at 1.9 per person. Length of stay per admission was increased for both p.P479L homozygotes and heterozygotes. The odds ratio (OR) for at least one hospitalization for any reason was increased for p.P479L homozygotes relative to noncarriers (OR=10.2, confidence interval [CI] 3.5 to 30.0) as were admissions for dental caries (OR=3.4, CI 1.5 to 7.8), acute lower respiratory tract infections (OR=6.0, CI 1.6 to 22.4), and otitis media (OR=13.5, CI 1.7 to 109.4)., Conclusions: The CPT1A p.P479L variant is associated with an increased rate of hospitalization for those homozygous, primarily for infectious disease causes. Heterozygotes also showed a small but significant increase in hospitalization rates suggesting some dosage effect. Functional studies will be required to identify the underlying pathological mechanism.

Background: We describe early health services utilization for children diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency through newborn screening in Ontario, Canada, relative to a screen negative comparison cohort., Methods: Eligible children were identified via newborn screening between April 1, 2006 and March 31, 2010. Age-stratified rates of physician encounters, emergency department (ED) visits and inpatient hospitalizations to March 31, 2012 were compared using incidence rate ratios (IRR) and incidence rate differences (IRD). We used negative binomial regression to adjust IRRs for sex, gestational age, birth weight, socioeconomic status and rural/urban residence., Results: Throughout the first few years of life, children with MCAD deficiency (n = 40) experienced statistically significantly higher rates of physician encounters, ED visits, and hospital stays compared with the screen negative cohort. The highest rates of ED visits and hospitalizations in the MCAD deficiency cohort occurred from 6 months to 2 years of age (ED use: 2.1-2.5 visits per child per year; hospitalization: 0.5-0.6 visits per child per year), after which rates gradually declined., Conclusions: This study confirms that young children with MCAD deficiency use health services more frequently than the general population throughout the first few years of life. Rates of service use in this population gradually diminish after 24 months of age.

Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid biosynthesis in human physiology is well illustrated by the severe metabolic disorders in this pathway. However, the biological role of sialic acid catabolism in humans remains unclear. Here, we present evidence that sialic acid catabolism is important for heart and skeletal muscle function and development in humans and zebrafish. In two siblings, presenting with sialuria, exercise intolerance/muscle wasting, and cardiac symptoms in the brother, compound heterozygous mutations [chr1:182775324C>T (c.187C>T; p.Arg63Cys) and chr1:182772897A>G (c.133A>G; p.Asn45Asp)] were found in the N-acetylneuraminate pyruvate lyase gene (NPL). In vitro, NPL activity and sialic acid catabolism were affected, with a cell-type-specific reduction of N-acetyl mannosamine (ManNAc). A knockdown of NPL in zebrafish resulted in severe skeletal myopathy and cardiac edema, mimicking the human phenotype. The phenotype was rescued by expression of wild-type human NPL but not by the p.Arg63Cys or p.Asn45Asp mutants. Importantly, the myopathy phenotype in zebrafish embryos was rescued by treatment with the catabolic products of NPL: N-acetyl glucosamine (GlcNAc) and ManNAc; the latter also rescuing the cardiac phenotype. In conclusion, we provide the first report to our knowledge of a human defect in sialic acid catabolism, which implicates an important role of the sialic acid catabolic pathway in mammalian muscle physiology, and suggests opportunities for monosaccharide replacement therapy in human patients.