In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease.

Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.

Implementing evidence-based assertions of clinical actionability in the context of secondary findings: Updates from the ClinGen Actionability Working Group.

PURPOSE: The ClinGen Actionability Working Group (AWG) developed an evidence-based framework to generate actionability reports and scores of gene-condition pairs in the context of secondary findings from genome sequencing. Here we describe the expansion of the framework to include actionability assertions. METHODS: Initial development of the actionability rubric was based on previously scored adult gene-condition pairs and individual expert evaluation. Rubric refinement was iterative and based on evaluation, feedback, and discussion. The final rubric was pragmatically evaluated via integration into actionability assessments for 27 gene-condition pairs. RESULTS: The resulting rubric has a 4-point scale (limited, moderate, strong, and definitive) and uses the highest-scoring outcome-intervention pair of each gene-condition pair to generate a preliminary assertion. During AWG discussions, predefined criteria and factors guide discussion to produce a consensus assertion for a gene-condition pair, which may differ from the preliminary assertion. The AWG has retrospectively generated assertions for all previously scored gene-condition pairs and are prospectively asserting on gene-condition pairs under assessment, having completed over 170 adult and 188 pediatric gene-condition pairs. CONCLUSION: The AWG expanded its framework to provide actionability assertions to enhance the clinical value of their resources and increase their utility as decision aids regarding return of secondary findings.

Variability in Newborn Screening Across Canada: Spinal Muscular Atrophy and Beyond.

BACKGROUND: Newborn screening (NBS) identifies infants with severe, early-onset diseases, enabling early diagnosis and treatment. In Canada, decisions regarding disease inclusion in NBS programs occur at the provincial level, which leads to variability in patient care. We aimed to determine whether important differences exist in NBS programs across provinces and territories. Given that spinal muscular atrophy (SMA) is the most recent disease added to NBS programs, we hypothesized that its inclusion would show interprovincial variability and be more likely in provinces already screening for a greater number of diseases. METHODS: We conducted a cross-sectional survey of all NBS labs in Canada to understand: 1) what conditions were included in their program; 2) what genetic-based testing was performed and; 3) if SMA was included. RESULTS: All NBS programs (N = 8) responded to this survey by June 2022. There was a 2.5-fold difference in the number of conditions screened (N = 14 vs N = 36) and a 9-fold difference in the number of conditions screened by gene-based testing. Only nine conditions were common to all provincial NBS programs. NBS for SMA was performed in four provinces at the time of our survey, with BC recently becoming the fifth province to add SMA to their NBS on October 1, 2022. Currently, 72% of Canadian newborns are screened for SMA at birth. CONCLUSION: Although healthcare in Canada is universal, its decentralization gives rise to regional differences in NBS programs which creates inequity in the treatment, care, and potential outcomes of affected children across provincial jurisdictions.

Assessing the quality and value of metabolic chart data for capturing core outcomes for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

BACKGROUND: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits. METHODS: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death. RESULTS: The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3-3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9-1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients' metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated. CONCLUSIONS: Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented.

The mitochondrial tRNA MT-TW m.5537_5538insT variant presents with significant intra-familial clinical variability.

Mitochondrial disorders can present with a wide range of clinical and biochemical phenotypes. Mitochondrial DNA variants may be influenced by factors such as degree of heteroplasmy and tissue distribution. We present a four-generation family in which 10 individuals carry a pathogenic mitochondrial variant (m.5537_5538insT, MT-TW gene) with differing levels of heteroplasmy and clinical features. This genetic variant has been documented in two prior reports, both in individuals with Leigh syndrome. In the current family, three individuals have severe mitochondrial symptoms including Leigh syndrome (patient 1, 100% in blood), MELAS (patient 2, 97% heteroplasmy in muscle), and MELAS-like syndrome (patient 3, 50% heteroplasmy in blood and 100% in urine). Two individuals have mild mitochondrial symptoms (patient 4, 50% in blood and 67% in urine and patient 5, 50% heteroplasmy in blood and 30% in urine). We observe that this variant is associated with multiple mitochondrial presentations and phenotypes, including MELAS syndrome for which this variant has not previously been reported. We also demonstrate that the level of heteroplasmy of the mitochondrial DNA variant correlates with the severity of clinical presentation; however, not with the specific mitochondrial syndrome.

Ethical and practical considerations related to data sharing when collecting patient-reported outcomes in care-based child health research.

PURPOSE: The collection and use of patient reported outcomes (PROs) in care-based child health research raises challenging ethical and logistical questions. This paper offers an analysis of two questions related to PROs in child health research: (1) Is it ethically obligatory, desirable or preferable to share PRO data collected for research with children, families, and health care providers? And if so, (2) What are the characteristics of a model best suited to guide the collection, monitoring, and sharing of these data? METHODS: A multidisciplinary team of researchers, providers, patient and family partners, and ethicists examined the literature and identified a need for focus on PRO sharing in pediatric care-based research. We constructed and analyzed three models for managing pediatric PRO data in care-based research, drawing on ethical principles, logistics, and opportunities to engage with children and families. RESULTS: We argue that it is preferable to share pediatric PRO data with providers, but to manage expectations and balance the risks and benefits of research, this requires a justifiable data sharing model. We argue that a successful PRO data sharing model will allow children and families to have access to and control over their own PRO data and be engaged in decision-making around how PROs collected for research may be integrated into care, but require support from providers. CONCLUSION: We propose a PRO data sharing model that can be used across diverse research settings and contributes to improved transparency, communication, and patient-centered care and research.

Intrauterine enzyme replacement therapies for lysosomal storage disorders: Current developments and promising future prospects.

Lysosomal storage disorders (LSDs) are a group of monogenic condition, with many characterized by an enzyme deficiency leading to the accumulation of an undegraded substrate within the lysosomes. For those LSDs, postnatal enzyme replacement therapy (ERT) represents the standard of care, but this treatment has limitations when administered only postnatally because, at that point, prenatal disease sequelae may be irreversible. Furthermore, most forms of ERT, specifically those administered systemically, are currently unable to access certain tissues, such as the central nervous system (CNS), and furthermore, may initiate an immune response. In utero enzyme replacement therapy (IUERT) is a novel approach to address these challenges evaluated in a first-in-human clinical trial for IUERT in LSDs (NCT04532047). IUERT has numerous advantages: in-utero intervention may prevent early pathology; the CNS can be accessed before the blood-brain barrier forms; and the unique fetal immune system enables exposure to new proteins with the potential to prevent an immune response and may induce sustained tolerance. However, there are challenges and limitations for any fetal procedure that involves two patients. This article reviews the current state of IUERT for LSDs, including its advantages, limitations, and potential future directions for definitive therapies.

The Ontario Newborn Screening Program: A novel referral center model.

Newborn screening (NBS) for inherited and congenital disorders is a form of secondary disease prevention and a public health responsibility. The development of NBS programs is one of the most important achievements in health care. While the scope of the screening targets has expanded and methods have evolved, the screening process has remained essentially unchanged.In 2006, the Canadian province of Ontario implemented a new provincial NBS program that differs from conventional programs. One of the key differences is the structured and fully funded partnership between the ministry of health, the NBS laboratory, and the treatment centers in the province. Each one of these partners has defined roles and accountability. Another difference is the move away from the conventional recall process to an immediate referral system to selected treatment centers.In this article, we report our experience with the new screening structure and discuss it as a model for future NBS programs.

Quantitation of phosphatidylethanols in dried blood spots to determine rates of prenatal alcohol exposure in Ontario.

BACKGROUND: Estimating rates of prenatal alcohol exposure (PAE) in a population is necessary to ensure that proper medical and social supports and interventions are in place. This study sought to estimate PAE in Ontario, Canada by quantifying phosphatidylethanol (PEth) homologues in over 2000 residual neonatal dried blood spots (DBS). METHODS: A random selection of 2011 residual DBS collected over a 1-week time period were anonymized and extracted. A targeted liquid chromatography-mass spectrometry method was used to quantify 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanol (PEth (16:0/18:1) or POPEth), the clinically accepted biomarker, and six additional PEth homologues. A POPEth level above the United States Drug Testing Laboratories (USDTL) cutoff up to 4 weeks predelivery was indicative of PAE. All PEth homologues were correlated to one another and logistic regression was used to determine the association between PAE status and infant characteristics. RESULTS: The estimated rate of PAE in Ontario, up to the last 4 weeks of gestation, was 15.5% (POPEth >28.5 nM). Most PEth homologues were moderately to strongly correlated to one another. A low birth weight and preterm birth were both associated with PAE, while being small for gestational age had lower odds of PAE. CONCLUSIONS: The results of this study suggest that PAE may be more prevalent in Ontario than previous estimates by self-report or meconium testing. These findings support the need to consider the effectiveness of current interventions and the design of new interventions to address this significant public health issue.

Patient Engagement in a Multi-Stakeholder Workshop to Plan the Collection of Patient-Oriented Outcomes for Children with Inherited Metabolic Diseases.

Building on a study to develop core outcome sets for children with rare inherited metabolic diseases, the purpose of this workshop was to inform the design of longitudinal pediatric registries that support registry-based clinical trials. This workshop was co-designed by two patient/family partner investigators and attended by two family advisors who received preparatory training. Patient partners and advisors recommended integrating the collection of registry data into everyday life and highlighted the importance of transparent communication and attention to the issue of integration of patient-reported data into clinical care. We propose a need to explore strategies for engaging patients in post-project knowledge translation.

Ultrasound findings of finger, wrist and knee joints in Mucopolysaccharidosis Type I.

INTRODUCTION: Musculoskeletal findings in MPS can progress after enzyme replacement. Our aim was to examine synovial recesses, tendons, retinacula and pulleys using ultrasonography for structural and inflammatory changes. MATERIAL AND METHODS: The wrist, metacarpophalangeal (MCP), proximal and distal interphalangeal (PIP and DIP) joints, the finger flexor tendons and the knee including entheses of quadriceps and patella tendons were assessed clinically. Ultrasonography of the various synovial recesses of the wrist as well as the extensor retinaculum, carpal tunnel, MCP, PIP and DIP joints of the second finger, extensor and flexor tendons, A1-5 pulleys and the knee joint including relevant entheses followed. Significance of differences between patient values and available normative data were assessed using t-tests. RESULTS: Ultrasonography showed significant abnormal intraarticular material in the wrist without a clear distribution to synovial recesses and without effusions. Doppler signals were found in a perisynovial distribution and not intrasynovial as expected in in inflammatory arthritis. Findings were similar in the knee but not the fingers. Flexor and extensor tendons were also mostly normal in their structure but significant thickening of retinaculae and the flexor tendon pulleys was seen (p<0.0001 compared to normal). CONCLUSION: MPS I patients showed intraarticular deposition of abnormal material in the wrist and knee but not in the finger joints where significant thickening of retinaculae/pulleys controlling tendon position was dominant. No ultrasound findings of inflammatory pathology were demonstrated but rather a secondary reaction to abnormal deposition and direct damage of GAG.

Whole genome sequencing identifies pathogenic RNU4ATAC variants in a child with recurrent encephalitis, microcephaly, and normal stature.

Biallelic pathogenic variants in RNU4ATAC have been linked to microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). Although children with MOPD1 have been reported to show profound, life-limiting clinical decompensation at the time of a febrile illness, these episodes including magnetic resonance imaging (MRI) findings have not been well characterized. We present acute MRI brain findings for a 10-year-old girl with homozygous variants in RNU4ATAC (NR_023343.1) n.55G>A, who presented with two episodes of clinical decompensation associated with a febrile illness in early childhood. The pathogenic variants were identified by whole genome sequencing as RNU4ATAC is not captured in most exome products. Her MRI of the brain revealed symmetric, diffusion restriction of the deep gray nuclei that initially pointed to a mitochondrial disease or acute necrotizing encephalopathy. Her phenotype included microcephaly and profound cognitive impairment that can be seen with MOPD1. However, she did not demonstrate clinical or radiographic evidence of a spondyloepimetaphyseal dysplasia or "primordial dwarfism" that is characteristic of this disease. As such, the predominant neurological presentation of this child represents an atypical variant of RNU4ATAC-associated disease and should be a diagnostic consideration for geneticists and neurologists caring for children, particularly in the event of an acute clinical decline.

Newborn Screening for Spinal Muscular Atrophy: Ontario Testing and Follow-up Recommendations.

BACKGROUND: Spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons causing muscle atrophy and weakness. Nusinersen, the first effective SMA therapy was approved by Health Canada in June 2017 and has been added to the provincial formulary of all but one Canadian province. Access to this effective therapy has triggered the inclusion of SMA in an increasing number of Newborn Screening (NBS) programs. However, the range of disease-modifying SMN2 gene copy numbers encountered in survival motor neuron 1 (SMN1)-null individuals means that neither screen-positive definition nor resulting treatment decisions can be determined by SMN1 genotype alone. We outline an approach to this challenge, one that specifically addresses the case of SMA newborns with four copies of SMN2. OBJECTIVES: To develop a standardized post-referral evaluation pathway for babies with a positive SMA NBS screen result. METHODS: An SMA NBS pilot trial in Ontario using first-tier MassARRAY and second-tier multi-ligand probe amplification (MLPA) was launched in January 2020. Prior to this, Ontario pediatric neuromuscular disease and NBS experts met to review the evidence regarding the diagnosis and treatment of children with SMA as it pertained to NBS. A post-referral evaluation algorithm was developed, outlining timelines for patient retrieval and management. CONCLUSIONS: Ontario's pilot NBS program has created a standardized path to facilitate early diagnosis of SMA and initiation of treatment. The goal is to provide timely access to those SMA infants in need of therapy to optimize motor function and prolong survival.

Health services use by children identified as heterozygous hemoglobinopathy mutation carriers via newborn screening.

BACKGROUND: Newborn screening (NBS) for sickle cell disease incidentally identifies heterozygous carriers of hemoglobinopathy mutations. In Ontario, Canada, these carrier results are not routinely disclosed, presenting an opportunity to investigate the potential health implications of carrier status. We aimed to compare rates of health services use among children identified as carriers of hemoglobinopathy mutations and those who received negative NBS results. METHODS: Eligible children underwent NBS in Ontario from October 2006 to March 2010 and were identified as carriers or as screen-negative controls, matched to carriers 5:1 based on neighbourhood and timing of birth. We used health care administrative data to determine frequencies of inpatient hospitalizations, emergency department (ED) visits, and physician encounters through March 2012, using multivariable negative binomial regression to compare rates of service use in the two cohorts. We analyzed data from 4987 carriers and 24,935 controls. RESULTS: Adjusted incidence rate ratios (95% CI) for service use in carriers versus controls among children < 1 year of age were: 1.11 (1.06-1.17) for ED visits; 0.97 (0.89-1.06) for inpatient hospitalization; and 1.02 (1.00-1.04) for physician encounters. Among children ≥1 year of age, adjusted rate ratios were: 1.03 (0.98-1.07) for ED visits; 1.14 (1.03-1.25) for inpatient hospitalization and 0.92 (0.90-0.94) for physician encounters. CONCLUSIONS: While we identified statistically significant differences in health services use among carriers of hemoglobinopathy mutations relative to controls, effect sizes were small and directions of association inconsistent across age groups and health service types. Our findings are consistent with the assumption that carrier status is likely benign in early childhood.

Primary care providers' role in newborn screening result notification for cystic fibrosis.

OBJECTIVE: To explore primary care providers' (PCPs') role in result notification for newborn screening (NBS) for cystic fibrosis (CF), given that expanded NBS has increased the number of positive screening test results, drawing attention to the role of PCPs in supporting families. DESIGN: Cross-sectional survey and qualitative interviews. SETTING: Ontario. PARTICIPANTS: Primary care providers (FPs, pediatricians, and midwives) who received a positive CF NBS result for an infant in their practice in the 6 months before the study. MAIN OUTCOME MEASURES: Whether the PCP notified the family of the initial positive CF screening result. RESULTS: Data from 321 PCP surveys (response rate of 51%) are reported, including 208 FPs, 68 pediatricians, and 45 midwives. Interviews were completed with 34 PCPs. Most (65%) surveyed PCPs reported notifying the infant's family of the initial positive screening result; 81% agreed that they have an important role to play in NBS; and 88% said it was important for PCPs, rather than the NBS centre, to notify families of initial positive results. With support and information from NBS centres, 68% would be extremely or very confident in doing so; this dropped to 54% when reflecting on their recent reporting experience. More than half (58%) of all PCPs said written point-of-care information from the NBS centre was the most helpful format. Adjusted for relevant factors, written educational information was associated with a lower rate of notifying families than written plus verbal information (risk ratio of 0.79; 95% CI 0.69 to 0.92). In the interviews, PCPs emphasized the challenge of balancing required content knowledge with the desire for the news to come from a familiar provider. CONCLUSION: Most PCPs notify families of NBS results and value this role. These data are relevant as NBS programs and other genomic services expand and consider ways of keeping PCPs confident and actively involved.

Newborn screening for cystic fibrosis: Role of primary care providers in caring for infants with positive screening results.

OBJECTIVE: To explore primary care providers' (PCPs') preferred roles and confidence in caring for infants receiving a positive cystic fibrosis (CF) newborn screening (NBS) result, as well as management of CF family planning issues, given that expanded NBS has resulted in an increase in positive results. DESIGN: Mailed questionnaire. SETTING: Ontario. PARTICIPANTS: Ontario FPs, pediatricians, and midwives identified by Newborn Screening Ontario as having had an infant with a positive CF NBS result in their practice in the previous 6 months. MAIN OUTCOME MEASURE: Primary care providers' preferred roles in providing well-baby care for infants with positive CF screening results. RESULTS: Overall, 321 of 628 (51%) completed surveys (208 FPs, 68 pediatricians, 45 midwives). For well-baby care for infants confirmed to have CF, 77% of PCPs indicated they would not provide total care (ie, 68% would share care with other specialists and 9% would refer to specialists completely); for infants with an inconclusive CF diagnosis, 50% of PCPs would provide total care, 45% would provide shared care, and 5% would refer to a specialist; for CF carriers, 89% of PCPs would provide total care, 9% would provide shared care, and 2% would refer. Half (54%) of PCPs were extremely or very confident in providing reassurance about CF carriers' health. Only 25% knew how to order parents' CF carrier testing; 67% knew how to refer for prenatal diagnosis. Confidence in reassuring parents about the health of CF carrier children was associated with providing total well-baby care for CF carriers (risk ratio of 1.50; 95% CI 1.14 to 1.97) and infants with an inconclusive diagnosis (risk ratio of 3.30; 95% CI 1.34 to 8.16). CONCLUSION: Most PCPs indicated willingness to treat infants with a range of CF NBS results in some capacity. It is concerning that some indicated CF carriers should have specialist involvement and only half were extremely or very confident about reassuring families about carrier status. This raises issues about possible medicalization of those with carrier status, prompting the need for PCP education about genetic disorders and the meaning of genetic test results.

Health-care providers' perspectives on uncertainty generated by variant forms of newborn screening targets.

PURPOSE: Despite the public health successes of newborn bloodspot screening, uncertainty associated with variant forms of primary screening targets has led to discrepancies in medical management. This study explored health-care providers' approaches to managing atypical forms of inherited metabolic diseases (IMDs) in the absence of evidence-based guidelines. METHODS: Semistructured telephone interviews were conducted with metabolic specialists. 3-Methylcrotonyl CoA deficiency and variant forms of phenylketonuria, biotinidase deficiency, and fatty acid oxidation disorders were considered. Data were analyzed inductively and deductively using a novel taxonomy of uncertainty. RESULTS: Health-care providers (n = 12) navigate diagnostic, prognostic, and therapeutic challenges of uncertainty while interpreting patient and family attitudes, preferences, and ideas in the care of children with these result types. Participants explained the limits of classifying mild and atypical metabolic phenotypes. Participants also described the challenge of finding balance between cautious care and overmedicalization. Developing consistent care plans and honest communication with families were perceived as effective strategies when navigating uncertainty. CONCLUSION: Providers' experiences suggest a need for transparent and accessible guidelines that account for challenges associated with uncertainty generated by screening. Timely consideration of this challenge is warranted with increasing emergence of genotype-first approaches to screening.

Metabolic Signatures of Cystic Fibrosis Identified in Dried Blood Spots For Newborn Screening Without Carrier Identification.

Cystic fibrosis (CF) is a complex multiorgan disorder that is among the most common fatal genetic diseases benefiting from therapeutic interventions early in life. Newborn screening (NBS) for presymptomatic detection of CF currently relies on a two-stage immunoreactive trypsinogen (IRT) and cystic fibrosis transmembrane conductance regulator (CFTR) mutation panel algorithm that is sensitive but not specific for identifying affected neonates with a low positive predictive value. For the first time, we report the discovery of a panel of CF-specific metabolites from a single 3.2 mm diameter dried blood spot (DBS) punch when using multisegment injection-capillary electrophoresis-mass spectrometry (MS) as a high-throughput platform for nontargeted metabolite profiling from volume-restricted/biobanked specimens with quality control. This retrospective case-control study design identified 32 metabolites, including a series of N-glycated amino acids, oxidized glutathione disulfide, and nicotinamide that were differentially expressed in normal birth weight CF neonates without meconium ileus ( n = 36) as compared to gestational age/sex-matched screen-negative controls ( n = 44) after a false discovery rate adjustment ( q < 0.05). Also, 16 metabolites from DBS extracts allowed for discrimination of true CF cases from presumptive screen-positive carriers with one identified CFTR mutation and transient neonatal hypertrypsinogenemic neonates ( n = 72), who were later confirmed as unaffected due to a low sweat chloride (<29 mM) test result. Importantly, six CF-specific biomarker candidates satisfying a Bonferroni adjustment ( p < 7.25 × 10-5) from three independent batches of DBS specimens included several amino acids depleted in circulation (Tyr, Ser, Thr, Pro, Gly) likely reflecting protein maldigestion/malabsorption. Additionally, CF neonates had lower ophthalmic acid as an indicator of oxidative stress due to impaired glutathione efflux from exocrine/epithelial tissue and elevation of an unknown trivalent peptide that was directly correlated with IRT (ρ = 0.332, p = 4.55 × 10-4). Structural elucidation of unknown metabolites was performed by high-resolution MS/MS, whereas biomarker validation was realized when comparing a subset of metabolites from matching neonatal DBS specimens independently analyzed by direct infusion-MS/MS at an accredited NBS facility. This work sheds new light into the metabolic phenotype of CF early in life, which is required for better functional understanding of CFTR mutations of unknown clinical consequence and the development of more accurate yet cost-effective strategies for CF screening.

Postnatal gestational age estimation via newborn screening analysis: application and potential.

Introduction: Preterm birth is a major global health concern, contributing to 35% of all neonatal deaths in 2016. Given the importance of accurately ascertaining estimates of preterm birth and in light of current limitations in postnatal gestational age (GA) estimation, novel methods of estimating GA postnatally in the absence of prenatal ultrasound are needed. Previous work has demonstrated the potential for metabolomics to estimate GA by analyzing data captured through routine newborn screening. Areas covered: Circulating analytes found in newborn blood samples vary by GA. Leveraging newborn screening and demographic data, our group developed an algorithm capable of estimating GA postnatally to within approximately 1 week of ultrasound-validated GA. Since then, we have built on the model by including additional analytes and validating the model's performance through internal and external validation studies, and through implementation of the model internationally. Expert opinion: Currently, using metabolomics to estimate GA postnatally holds considerable promise but is limited by issues of cost-effectiveness and resource access in low-income settings. Future work will focus on enhancing the precision of this approach while prioritizing point-of-care testing that is both accessible and acceptable to individuals in low-resource settings.