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Introduction: As preterm infants are susceptible to hyperbilirubinemia, they require frequent close monitoring. Prior to initiation of phototherapy, hour-specific total serum bilirubin (TSB) percentile cut-points are lacking in these infants, which led to the current study. Methods: A multi-site retrospective cohort study of preterm infants born between January 2013 and June 2017 was completed at 3 NICUs in Ontario, Canada. A total of 2,549 infants born at 290/7–356/7 weeks' gestation contributed 6,143 pre-treatment TSB levels. Hour-specific TSB percentiles were generated using quantile regression, further described by degree of prematurity, and among those who subsequently received phototherapy. Results: Among all infants, at birth, hour-specific pre-treatment, TSB percentiles were 36.1 µmol/L (95% confidence interval [CI]: 34.3–39.3) at the 40th, 52.3 µmol/L (49.4–55.1) at the 75th, and 79.5 µmol/L (72.1–89.6) at the 95th percentiles. The corresponding percentiles were 39.3 μmol/L (35.9–43.2), 55.4 μmol/L (52.1–60.2), and 87.1 μmol/L (CI 70.5–102.4) prior to initiating phototherapy and 24.4 μmol/L (20.4–28.8), 35.3 μmol/L (31.1–41.5), and 52.0 μmol/L (46.1–62.4) among those who did not receive phototherapy. Among infants born at 29–32 weeks, pre-treatment TSB percentiles were 53.9 µmol/L (49.4–61.0) and 95.5 µmol/L (77.5–105.0) at the 75th and 95th percentiles, with respective values of 48.7 µmol/L (43.0–52.3), and 74.1 µmol/L (64.8–83.2) for those born at 33–35 weeks' gestation. Conclusion: Hour-specific TSB percentiles, derived from a novel nomogram, may inform how bilirubin is described in preterm newborns. Further research of pre-treatment TSB levels is required before clinical consideration. [ABSTRACT FROM AUTHOR]

Introduction: Transcutaneous bilirubin (TcB) measurement offers a noninvasive approach for bilirubin screening; however, its accuracy in preterm infants is unclear. This study determined the agreement between TcB and total serum bilirubin (TSB) among preterm infants. Methods: A multisite prospective cohort study was conducted at 3 NICUs in Ontario, Canada, September 2016 to June 2018. Among 296 preterm infants born at 240/7 to 356/7 weeks, 856 TcB levels were taken at the forehead, sternum, and before and after the initiation of phototherapy with TSB measurements. Bland-Altman plots and 95% limits of agreement (LOA) expressed agreement between TcB and TSB. Results: The overall mean TcB-TSB difference was −24.5 μmol/L (95% LOA −103.3 to 54.3), 1.6 μmol/L (95% LOA −73.4 to 76.5) before phototherapy, and −31.1 μmol/L (95% LOA −105.5 to 43.4) after the initiation of phototherapy. The overall mean TcB-TSB difference was −15.2 μmol/L (95% LOA −86.8 to 56.3) at the forehead and −24.4 μmol/L (95% LOA −112.9 to 64.0) at the sternum. The mean TcB-TSB difference was −31.4 μmol/L (95% LOA −95.3 to 32.4) among infants born 24–28 weeks, −25.5 μmol/L (95% LOA −102.7 to 51.8) at 29–32 weeks, and −15.9 μmol/L (95% LOA −107.4 to 75.6) at 33–35 weeks. Measures did not differ by maternal ethnicity. Conclusion: Among preterm infants, TcB may offer a noninvasive, immediate approach to screening for hyperbilirubinemia with more careful use in preterm infants born at <33 weeks' gestation, as TcB approaches treatment thresholds. Its underestimation of TSB after the initiation of phototherapy warrants the use of TSB for clinical decision-making after the initiation of phototherapy. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Evidence is mixed regarding the impact of false-positive (FP) newborn bloodspot screening (NBS) results on health care use. Using cystic fibrosis (CF) as an example, we determined the association of FP NBS results with health care use in infants and their mothers in Ontario, Canada. METHODS: We conducted a population-based cohort study of all infants with FP CF results (N = 1564) and screen-negative matched controls (N = 6256) born between April 2008 and November 2012 using linked health administrative data. Outcomes included maternal and infant physician and emergency visits and inpatient hospitalizations from the infant's third to 15th month of age. Negative binomial regression tested associations of NBS status with outcomes, adjusting for infant and maternal characteristics. RESULTS: A greater proportion of infants with FP results had >2 outpatient visits (16.2% vs 13.2%) and >2 hospital admissions (1.5% vs 0.7%) compared with controls; CF-related admissions and emergency department visits were not different from controls. Differences persisted after adjustment, with higher rates of outpatient visits (relative risk 1.39; 95% confidence interval 1.20-1.60) and hospital admissions (relative risk 1.67; 95% confidence interval 1.21-2.31) for FP infants. Stratified models indicated the effect of FP status was greater among those whose primary care provider was a pediatrician. No differences in health care use among mothers were detected. CONCLUSIONS: Higher use of outpatient services among FP infants may relate to a lengthy confirmatory testing process or follow-up carrier testing. However, increased rates of hospitalization might signal heightened perceptions of vulnerability among healthy infants. [ABSTRACT FROM AUTHOR]

BACKGROUND: The risk of psychosocial harm in families of infants with false-positive (FP) newborn bloodspot screening (NBS) results for cystic fibrosis (CF) is a longstanding concern. Whether well designed retrieval and confirmatory testing systems can mitigate risks remains unknown. METHODS: Using a mixed-methods cohort design, we obtained prospective self-report data from mothers of infants with FP CF NBS results 2 to 3 months after confirmatory testing at Ontario's largest follow-up center, and from a randomly selected control sample of mothers of screen negative infants from the same region. Mothers completed a questionnaire assessing experience and psychosocial response. A sample of mothers of FP infants completed qualitative interviews. RESULTS: One hundred thirty-four mothers of FP infants (response rate, 55%) and 411 controls (response rate, 47%) completed questionnaires; 54 mothers of FP infants were interviewed. Selected psychosocial response measures did not detect psychosocial distress in newborns or 1 year later (P > .05). Mothers recalled distress during notification of the positive result and in the follow-up testing period related to fear of chronic illness, but valued the screening system of care in mitigating concerns. CONCLUSIONS: Although immediate distress was reported among mothers of FP infants, selected psychometric tools did not detect these concerns. The NBS center from which mothers were recruited minimizes delay between notification and confirmatory testing and ensures trained professionals are communicating results and facilitating follow-up. These factors may explain the presence of minimal psychosocial burden. The screening system reflected herein may be a model for NBS programs working to minimize FP-related psychosocial harm. [ABSTRACT FROM AUTHOR]

Background: It is recommended that all pregnant women be offered screening for Down syndrome and open neural tube defects, but emerging prenatal tests that are not publicly insured may compromise access. We evaluated screening rates for publicly insured screening tests across health care regions in the province of Ontario and determined whether maternal, provider or regional characteristics are associated with screening uptake. Methods: We conducted a population-based retrospective cohort study involving pregnant women in Ontario who were at or beyond 16 weeks' gestation in 2007-2009. We ascertained prenatal screening rates using linked health administrative and prenatal screening datasets. We examined maternal, provider and regional characteristics associated with screening uptake. Rate ratios (RRs) were estimated. Results: Of the 264 737 women included in the study, 62.2% received prenatal screening; uptake varied considerably by region (range 27.8%-80.3%). A greater proportion of women initiated screening in the first rather than the second trimester (50.0% v. 12.2%). Factors associated with lower screening rates included living in a rural area versus an urban area (adjusted rate ratio 0.64, 95% confidence interval [CI] 0.63-0.66), receiving first-trimester care from a family physician or midwife versus an obstetrician (adjusted rate ratio 0.91, 95% CI 0.90-0.92, and 0.40, 95% CI 0.38-0.43, respectively) and being in a lower income quintile (adjusted RR for lowest v. highest 0.95, 95% CI 0.94-0.96). Being an immigrant or a refugee was associated with higher screening rates. Interpretation: There were significant maternal, provider and regional differences in the uptake of prenatal screening across the province. With discrepancies expected to increase with the emergence of noninvasive prenatal tests paid for out of pocket by many women, policy efforts to reduce barriers to prenatal screening and optimize its availability are warranted. [ABSTRACT FROM AUTHOR]

Introduction: Genetic testing is used across medical disciplines leading to unprecedented demand for genetic services. This has resulted in excessive waitlists and unsustainable pressure on the standard model of genetic healthcare. Alternative models are needed; e-health tools represent scalable and evidence-based solution. We aim to evaluate the effectiveness of the Genetics Navigator, an interactive patient-centred digital platform that supports the collection of medical and family history, provision of pregenetic and postgenetic counselling and return of genetic testing results across paediatric and adult settings., Methods and Analysis: We will evaluate the effectiveness of the Genetics Navigator combined with usual care by a genetics clinician (physician or counsellor) to usual care alone in a randomised controlled trial. One hundred and thirty participants (adults patients or parents of paediatric patients) eligible for genetic testing through standard of care will be recruited across Ontario genetics clinics. Participants randomised into the intervention arm will use the Genetics Navigator for pretest and post-test genetic counselling and results disclosure in conjunction with their clinician. Participants randomised into the control arm will receive usual care, that is, clinician-delivered pretest and post-test genetic counselling, and results disclosure. The primary outcome is participant distress 2 weeks after test results disclosure. Secondary outcomes include knowledge, decisional conflict, anxiety, empowerment, quality of life, satisfaction, acceptability, digital health literacy and health resource use. Quantitative data will be analysed using statistical hypothesis tests and regression models. A subset of participants will be interviewed to explore user experience; data will be analysed using interpretive description. A cost-effectiveness analysis will examine the incremental cost of the Navigator compared with usual care per unit reduction in distress or unit improvement in quality of life from public payer and societal perspectives., Ethics and Dissemination: This study was approved by Clinical Trials Ontario. Results will be shared through stakeholder workshops, national and international conferences and peer-reviewed journals., Trial Registration Number: NCT06455384., Competing Interests: Competing interests: YB and MC are cofounders of Genetics Adviser., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population., Methods: We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing., Findings: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset (14 [74%] of 19 vs 29 [36%] of 81; p=0·0027), referral setting (12 [71%] of 17 for intensive care, 19 [44%] of 43 non-intensive care inpatient, and 12 [28%] of 40 outpatient; p=0·0178), and epilepsy syndrome (13 [87%] of 15 for self-limited epilepsies, 18 [35%] of 51 for developmental and epileptic encephalopathies, 12 [35%] of 34 for other syndromes; p=0·001). Rapid genome sequencing revealed genetic heterogeneity, with 34 unique genes or genomic regions implicated. Genetic diagnoses had immediate clinical utility, informing treatment (24 [56%] of 43), additional evaluation (28 [65%]), prognosis (37 [86%]), and recurrence risk counselling (all cases)., Interpretation: Our findings support the feasibility of implementation of rapid genome sequencing in the clinical care of infants with new-onset epilepsy. Longitudinal follow-up is needed to further assess the role of rapid genetic diagnosis in improving clinical, quality-of-life, and economic outcomes., Funding: American Academy of Pediatrics, Boston Children's Hospital Children's Rare Disease Cohorts Initiative, Canadian Institutes of Health Research, Epilepsy Canada, Feiga Bresver Academic Foundation, Great Ormond Street Hospital Charity, Medical Research Council, Murdoch Children's Research Institute, National Institute of Child Health and Human Development, National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, University of Toronto McLaughlin Centre., Competing Interests: Declaration of interests APa is a current member of the National Institute of Health and Clinical excellence (NICE) technology appraisal committee B and has a financial interest in Genedrive PLC. KW has consulted for Stoke Therapeutics. JHC has received renumeration for lectures by GW pharma/Jazz, UCB/Zogenix, Biocodex, and Biogen; is a member of the Data Monitoring and Safety Committee for Admiral Trial (Stroke Therapeutics); and is Chair of the Medical Advisory Board for Matthews Friends, Dravet UK, and Hope for Hypothalamic Hamartoma. IES has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Rogcon, Takeda Pharmaceuticals, UCB, and Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova, Nutricia, Zuellig Pharma, and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin, Encoded Therapeutics, and Eisai; has served as an investigator for Anavex Life Sciences, Cerecin, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder, Epygenyx, ES-Therapeutics, GW Pharma, Marinus, Neurocrine BioSciences, Ovid Therapeutics, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix, and Zynerba; and has consulted for Care Beyond Diagnosis, Epilepsy Consortium, Atheneum Partners, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, BioMarin, Encoded Therapeutics, and Biohaven Pharmaceuticals; and is a Non-Executive Director of Bellberry and a Director of the Australian Academy of Health and Medical Sciences and the Australian Council of Learned Academies. IES might accrue future revenue on pending patent WO61/010176 (filed in 2008; therapeutic compound); has a patent for SCN1A testing held by Bionomics and licensed to various diagnostic companies; has a patent molecular diagnostic or theranostic target for benign familial infantile epilepsy (PRRT2; 2011904493, 2012900190, and PCT/AU2012/001321 [TECH ID:2012-009]). GC has received honorarium from CADTH and serves as the Co-Lead of the Can-GARD Initiative and on the SickKids Precision Child Health steering committee. APo serves on the scientific advisory boards for TevardBio and Syngap Research Fund, and on the American Epilepsy Society Board of Directors. KBH has received support from RogCon Biosciences and Praxis Precision Medicines. AM has received consulting fees from Rocket Pharmaceuticals; honorarium from Jazz Pharmaceuticals; support for attending conferences from Jazz Pharmaceuticals and European Paediatric Neurology Society; fees for participating on boards for Biogen and Biocodex; and serves unpaid roles on the ILAE Genetic Literacy Task Force, EPICARE, and Great Ormond Street Hospital National Institute for Health and Care Research Biomedical Research Centre Chair of Junior Faculty. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

We examined the utility of clinical and research processes in the reanalysis of publicly-funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians. Reanalysis of clinically relevant genes identified diagnoses in 4% (13/287); four were missed by clinical testing. Translational research methods, including analysis of novel candidate genes, identified candidates in 21% (61/287). Of these, 24 families have additional evidence through data sharing to support likely diagnoses (8% of cohort). This study indicates few diagnoses are missed by clinical laboratories, the incremental gain from reanalysis of clinically-relevant genes is modest, and the highest yield comes from validation of novel disease-gene associations. Future implementation of translational research methods, including continued reporting of compelling genes of uncertain significance by clinical laboratories, should be considered to maximize diagnoses., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Despite the superior diagnostic performance of exome and genome sequencing compared with conventional genetic tests, evidence gaps related to clinical utility and cost effectiveness have limited their availability in routine clinical practice in many jurisdictions. To inform adoption and reimbursement policy, this protocol provides a chain of evidence approach to determining the diagnostic utility, clinical utility and cost-effectiveness of whole exome sequencing (WES) from seven medical genetic centres in two Canadian provinces., Methods and Analysis: Using a multicentre observational cohort design, we will extract data specific to the pre-WES diagnostic pathway and 1-year post-WES medical management from electronic medical records for 650 patients with rare disease of suspected genetic aetiology who receive WES. The date from the clinical record will be linked to provincial administrative health database to capture healthcare resource use and estimate costs. Our analysis will: (1) define and describe diagnostic testing pathways that occur prior to WES among patients with rare disease, (2) determine the diagnostic utility of WES, characterised as the proportion of patients for whom causative DNA variants are identified, (3) determine the clinical utility of WES, characterised as a change in medical management triggered by WES results, (4) determine the pattern and cost of health service utilisation prior and 1 year following WES among patients who receive a diagnosis, do not receive a diagnosis, or receive an uncertain diagnosis and (5) estimate the cost-effectiveness of WES compared with conventional diagnostic testing pathways, measured by the incremental cost per additional patient diagnosed by WES using simulation modelling., Ethics and Dissemination: This protocol was approved by Clinical Trials Ontario (CTO-1577) and research ethics boards at the University of Calgary (REB18-0744 and REB20-1449) and University of Alberta (Pro0009156). Findings will be disseminated through academic publications and policy reports., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Genome-wide sequencing has emerged as a promising strategy for the timely diagnosis of rare diseases, but it is not yet available as a clinical test performed in Canadian diagnostic laboratories. We describe the protocol for evaluating a 2-year pilot project, Genome-wide Sequencing Ontario, to offer high-quality clinical genome-wide sequencing in Ontario, Canada., Methods: The Genome-wide Sequencing Ontario protocol was codesigned by the Ontario Ministry of Health, the Hospital for Sick Children in Toronto and the Children's Hospital of Eastern Ontario in Ottawa. Enrolment of a prospective cohort of patients began on Apr. 1, 2021. Eligible cases with blood samples available for the index case and both parents (i.e., trios) are randomized to receive exome sequencing or genome sequencing. We will collect patient-level data and ascertain costs associated with the laboratory workflow for exome sequencing and genome sequencing. We will compare point estimates for the diagnostic utility and timeliness of exome sequencing and genome sequencing, and we will determine an incremental cost-effectiveness ratio (expressed as the incremental cost of genome sequencing versus exome sequencing per additional patient with a causal variant detected)., Interpretation: Findings from this work will provide robust evidence for the diagnostic utility, cost-effectiveness and timeliness of exome sequencing and genome sequencing, and will be disseminated via academic publications and policy briefs. Findings will inform provincial and cross-provincial policy related to the long-term organization, delivery and reimbursement of clinical-grade genome diagnostics for rare disease., Competing Interests: Competing interests: The authorship group has received funding from the Ontario Ministry of Health and Genome Canada to examine the implementation of genome-wide sequencing in Ontario. Dimitri Stavropoulos has equity in PhenoTips. Wendy Ungar chairs the Ontario Genetics Advisory Committee, is a member of the Ontario Health Technology Assessment Committee, and receives funding from the Pharmaceutical Research and Manufacturers of America Foundation and honoraria from the Taiwan Center for Drug Evaluation. Robin Hayeems is a member of the Ontario Genetics Advisory Committee. Robin Hayeems, Martin Somerville and Kym Boycott are members of the Provincial Genetics Advisory Committee., (© 2022 CMA Impact Inc. or its licensors.)

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., (Copyright © the College of Family Physicians of Canada.)

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., (Copyright © the College of Family Physicians of Canada.)

Importance: Pharmacogenomic (PGx) testing provides preemptive pharmacotherapeutic guidance regarding the lack of therapeutic benefit or adverse drug reactions of PGx targeted drugs. Pharmacogenomic information is of particular value among children with complex medical conditions who receive multiple medications and are at higher risk of developing adverse drug reactions., Objectives: To assess the implementation outcomes of a PGx testing program comprising both a point-of-care model that examined targeted drugs and a preemptive model informed by whole-genome sequencing that evaluated a broad range of drugs for potential therapy among children in a pediatric tertiary care setting., Design, Setting, and Participants: This cohort study was conducted at The Hospital for Sick Children in Toronto, Ontario, from January 2017 to September 2020. Pharmacogenomic analyses were performed among 172 children who were categorized into 2 groups: a point-of-care cohort and a preemptive cohort. The point-of-care cohort comprised 57 patients referred to the consultation clinic for planned therapy with PGx targeted drugs and/or for adverse drug reactions, including lack of therapeutic benefit, after the receipt of current or past medications. The preemptive cohort comprised 115 patients who received exploratory whole-genome sequencing-guided PGx testing for their heart conditions from the cardiac genome clinic at the Ted Rogers Centre for Heart Research., Exposures: Patients received PGx analysis of whole-genome sequencing data and/or multiplex genotyping of 6 pharmacogenes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, VKORC1, and TPMT) that have established PGx clinical guidelines., Main Outcomes and Measures: The number of patients for whom PGx test results warranted deviation from standard dosing regimens., Results: A total of 172 children (mean [SD] age, 8.5 [5.6] years; 108 boys [62.8%]) were enrolled in the study. In the point-of-care cohort, a median of 2 target genes (range, 1-5 genes) were investigated per individual, with CYP2C19 being the most frequently examined; genotypes in 21 of 57 children (36.8%) were incompatible with standard treatment regimens. As expected from population allelic frequencies, among the 115 children in the whole-genome sequencing-guided preemptive cohort, 92 children (80.0%) were recommended to receive nonstandard treatment regimens for potential drug therapies based on their 6-gene pharmacogenetic profile., Conclusions and Relevance: In this cohort study, among both the point-of-care and preemptive cohorts, the multiplex PGx testing program provided dosing recommendations that deviated from standard regimens at an overall rate that was similar to the population frequencies of relevant variants.

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.

Objective: To examine the role of primary care providers in informing and supporting families who receive positive screening results., Design: Cross-sectional survey., Setting: Ontario., Participants: Family physicians, pediatricians, and midwives involved in newborn care., Main Outcome Measures: Beliefs, practices, and barriers related to providing information to families who receive positive screening results for their newborns., Results: A total of 819 providers participated (adjusted response rate of 60.9%). Of the respondents, 67.4% to 81.0% agreed that it was their responsibility to provide care to families of newborns who received positive screening results, and 64.2% to 84.8% agreed they should provide brochures or engage in general discussions about the identified conditions. Of the pediatricians, 67.3% endorsed having detailed discussions with families, but only 24.1% of family physicians and 27.6% of midwives endorsed this practice. All provider groups reported less involvement in information provision than they believed they should have. This discrepancy was most evident for family physicians: most stated that they should provide brochures (64.2%) or engage in general discussions (73.5%), but only a minority did so (15.3% and 27.7%, respectively). Family physicians reported insufficient time (42.2%), compensation (52.2%), and training (72.3%) to play this role, and only a minority agreed they were up to date (18.5%) or confident (16.5%) regarding newborn screening., Conclusion: Providers of primary newborn care see an information-provision role for themselves in caring for families who receive positive newborn screening results. Efforts to further define the scope of this role combined with efforts to mitigate existing barriers are warranted.