Biotinidase activity is affected by both seasonal temperature and filter collection cards.

This study set out to examine pre-analytical factors affecting the frequency of positive results in newborn screening for biotinidase deficiency. This investigation was prompted by an increase in the annual screen positive rate for biotinidase deficiency in Ontario from 2.65x10-4 in 2016 to 6.57x10-4 in 2017. Season and trend decomposition was used to separate seasonality from an underlying trend in the time series of biotindase activity measurements for the period 2014-01-12 to 2019-07-27 (n = 798,770). This analysis revealed a marked seasonal effect (winter = median + ⩽ 17 MRU, summer = mean - ⩽20 MRU) and a non-linear negative trend. Seasonal temperature was correlated with biotinidase results (Pearson's r = 0.79) but not with the observed negative trend (Pearson's r = 0.0025). Time series analysis of biotinidase results grouped by print lot of filter paper revealed that recently printed filter paper cards inhibit biotinidase and that this inhibition resolved over time. This study demonstrates that biotindase activity is inhibited by both increased seasonal temperature and collection on newly printed filter cards.

Cross-sectional prospective feasibility study of newborn screening for sickle cell anaemia and congenital hypothyroidism in Guyana.

INTRODUCTION: Newborn screening (NBS) is a test done shortly after birth to detect conditions that cause severe health problems if not treated early. An estimated 71% of babies worldwide are born in jurisdictions that do not have an established NBS programme. Guyana currently has no NBS programme and has established a partnership with Newborn Screening Ontario (NSO) to initiate screening. OBJECTIVES: To assess the feasibility of implementing a NBS programme in Guyana for congenital hypothyroidism (CH) and haemoglobinopathies (HBG) and to report on screen positive rates and prevalence (Hardy-Weinberg equilibrium (HWE)) for CH and HBG. METHODS: Term, healthy Guyanese infants were evaluated (with consent) using heel prick dried blood spots (DBS) shortly after birth (closer to 24 hours of life). DBS samples were analysed at NSO. Screening test for CH was done using a human thyroid-stimulating hormone (hTSH) assay. Mean hTSH levels between the Guyanese sample and the Ontarian population were compared using Student's t-test with an alpha of 0.05. Screening test for HBG was performed with a cation-exchange high-performance liquid chromatography. RESULTS: The pilot was conducted from 6 June 2016 to 22 September 2017. Georgetown Public Hospital Corporation recruited 2294 mothers/infants. Screen positive rate for CH in our sample was 0.0% (0/2038 infants). Mean TSH levels in Guyanese samples (1.7 µU/mL blood) was noticed to be significantly different than in the Ontarian population (4.3 µU/mL blood) (p<0.05). Screen positive rate for sickle cell anaemia (SCA) in our sample was 0.3% (7/2039 patients), and the carrier rate was 8.4% (172/2039 patients). Using the HWE, the SCA frequency (S allele frequency)2 is 0.0492=0.002 CONCLUSION: NBS for CH and SCA in Guyana could be beneficial. Future work should focus on conducting larger pilots which could be used to inform diagnosis and treatment guidelines for Guyanese people.

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.

What is in a Name? Parent, Professional and Policy-Maker Conceptions of Consent-Related Language in the Context of Newborn Screening.

Newborn bloodspot screening programs are some of the longest running population screening programs internationally. Debate continues regarding the need for parents to give consent to having their child screened. Little attention has been paid to how meanings of consent-related terminology vary among stakeholders and the implications of this for practice. We undertook semi-structured interviews with parents (n = 32), healthcare professionals (n = 19) and policy decision makers (n = 17) in two Canadian provinces. Conceptions of consent-related terms revolved around seven factors within two broad domains, decision-making and information attainment. Decision-making comprised: parent decision authority; voluntariness; parent engagement with decision-making; and the process of enacting choice. Information ascertainment comprised: professional responsibilities (including disclosure of information and time to review); parent responsibilities; and the need for discussion and understanding prior to a decision. Our findings indicate that consent-related terms are variously understood, with substantive implications for practice. We suggest that consent procedures should be explained descriptively, regardless of approach, so there are clear indications of what is expected of parents and healthcare professionals. Support systems are required both to meet the educational needs of parents and families and to support healthcare professionals in delivering information in a manner in keeping with parent needs.

Building a Newborn Screening Information Management System from Theory to Practice.

Information Management Systems are the central process management and communication hub for many newborn screening programs. In late 2014, Newborn Screening Ontario (NSO) undertook an end to end assessment of its information management needs which resulted in a project to develop a flexible IS Information Systems (IS) ecosystem and related process changes. This enabled NSO to better manage its current and future work-flows and communication needs. An idealized vision of a Screening Information Management System (SIMS) was developed that was refined into enterprise and functional architectures. This was followed by the development of technical specifications, user requirements and procurement. In undertaking a holistic full product lifecycle redesign approach, a number of change management challenges were faced by NSO across the entire program. Strong leadership support and full program engagement are key for overall project success. It is anticipated that improvements in program flexibility and the ability to innovate will outweigh the efforts and costs.

Postnatal gestational age estimation using newborn screening blood spots: a proposed validation protocol.

BACKGROUND: Knowledge of gestational age (GA) is critical for guiding neonatal care and quantifying regional burdens of preterm birth. In settings where access to ultrasound dating is limited, postnatal estimates are frequently used despite the issues of accuracy associated with postnatal approaches. Newborn metabolic profiles are known to vary by severity of preterm birth. Recent work by our group and others has highlighted the accuracy of postnatal GA estimation algorithms derived from routinely collected newborn screening profiles. This protocol outlines the validation of a GA model originally developed in a North American cohort among international newborn cohorts. METHODS: Our primary objective is to use blood spot samples collected from infants born in Zambia and Bangladesh to evaluate our algorithm's capacity to correctly classify GA within 1, 2, 3 and 4 weeks. Secondary objectives are to 1) determine the algorithm's accuracy in small-for-gestational-age and large-for-gestational-age infants, 2) determine its ability to correctly discriminate GA of newborns across dichotomous thresholds of preterm birth (≤34 weeks, <37 weeks GA) and 3) compare the relative performance of algorithms derived from newborn screening panels including all available analytes and those restricted to analyte subsets. The study population will consist of infants born to mothers already enrolled in one of two preterm birth cohorts in Lusaka, Zambia, and Matlab, Bangladesh. Dried blood spot samples will be collected and sent for analysis in Ontario, Canada, for model validation. DISCUSSION: This study will determine the validity of a GA estimation algorithm across ethnically diverse infant populations and assess population specific variations in newborn metabolic profiles.

Psychosocial Response to Uncertain Newborn Screening Results for Cystic Fibrosis.

OBJECTIVE: To explore the psychosocial implications of diagnostic uncertainty that result from inconclusive results generated by newborn bloodspot screening (NBS) for cystic fibrosis (CF). STUDY DESIGN: Using a mixed methods prospective cohort study of children who received NBS for CF, we compared psychosocial outcomes of parents whose children who received persistently inconclusive results with those whose children received true positive or screen-negative results. RESULTS: Mothers of infants who received inconclusive results (n = 17), diagnoses of CF (n = 15), and screen-negative results (n = 411) were surveyed; 23 parent interviews were completed. Compared with mothers of infants with true positive/screen-negative results, mothers of infants with inconclusive results reported greater perceived uncertainty (P < .006) but no differences in anxiety or vulnerability (P > .05). Qualitatively, parents valued being connected to experts but struggled with the meaning of an uncertain diagnosis, worried about their infant's health-related vulnerability, and had mixed views about surveillance. CONCLUSION: Inconclusive CF NBS results were not associated with anxiety or vulnerability but led to health-related uncertainty and qualitative concerns. Findings should be considered alongside efforts to optimize protocols for CF screening and surveillance. Educational and psychosocial supports are warranted for these families.

A secondary benefit: the reproductive impact of carrier results from newborn screening for cystic fibrosis.

PURPOSE: Newborn screening (NBS) for cystic fibrosis (CF) can identify carriers, which is considered a benefit that enables reproductive planning. We examined the reproductive impact of carrier result disclosure of NBS for CF. METHODS: We surveyed mothers of carrier infants after NBS (Time 1) and 1 year later (Time 2) to ascertain intended and reported communication of their infants' carrier results to relatives, carrier testing for themselves/other children, and reproductive decisions. A sub-sample of mothers was also interviewed at Time 1 and Time 2. RESULTS: The response rate was 54%. A little more than half (55%) of mothers underwent carrier testing at Time 1; another 40% of those who intended to undergo testing at Time 1 underwent testing at Time 2. Carrier result communication to relatives was high (92%), but a majority of participants did not expect the results to influence family planning (65%). All interviewed mothers valued learning their infants' carrier results. Some underwent carrier testing and then shared results with family. Others did not use the results or used them in unintended ways. CONCLUSION: Although mothers valued learning carrier results from NBS, they reported moderate uptake of carrier testing and limited influence on family planning. Our study highlights the secondary nature of the benefit of disclosing carrier results of NBS.Genet Med 19 4, 403-411.

Parent Experience With False-Positive Newborn Screening Results for Cystic Fibrosis.

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.

Consent for newborn screening: parents' and health-care professionals' experiences of consent in practice.

Consent processes for newborn bloodspot screening (NBS) are variable, with a lack of descriptive research that depicts how the offer of NBS is made to parents. We explored the experience, in practice, of consent for NBS. Semistructured interviews in two Canadian provinces were held with: (1) parents of children offered NBS (n=32); and (2) health-care professionals involved in the NBS process (n=19). Data on recollections of NBS, including consent processes, were utilized to identify emerging themes using the method of constant comparison. Three themes were relevant to NBS consent: (1) The 'offer' of NBS; (2) content and timing of information provision; and (3) the importance of parental experiences for consent decisions. Recollections of consent for NBS were similar between jurisdictions. Excepting midwives and their patients, NBS was viewed as a routine part of giving birth, with little evidence of an informed consent process. Although most parents were satisfied, all respondents suggested information about NBS be provided long before the birth. Accounts of parents who declined screening highlight the influence of parental experiences with the heel prick process in screening decisions. Findings further our understanding of consent in practice and highlight areas for improvement in parent-provider interactions.

Benefits and burdens of newborn screening: public understanding and decision-making.

In this article we review the literature regarding the public understanding of the potential benefits and burdens of expanded newborn bloodspot screening. We draw attention to broadened notions of benefit that go beyond early identification of asymptomatic individuals and interventions to reduce morbidity or mortality, and include benefits gained by families through knowledge that may facilitate life choices, as well as gains generated by avoiding diagnostic delays. We also reflect on burdens such as increasing false-positive results and parental anxiety, together with risks of overdiagnosis when the natural history of a condition is poorly understood. We conclude that expanded notions of benefit and burden bring with them implications for parental consent and confidentiality and the secondary use of bloodspots.

Factors associated with knowledge of and satisfaction with newborn screening education: a survey of mothers.

PURPOSE: Effective parental education about newborn blood-spot screening may facilitate prompt follow-up, reduce psychosocial harms, and promote trust in screening programs. However, little is known about the aspects of education delivery and content that are of most importance for fostering understanding and meeting parental expectations. We aimed to identify elements of newborn blood-spot screening education and their associations with mothers' knowledge and satisfaction levels. METHODS: We conducted a survey (by mail) of 1,712 mothers who were residing in Ontario, Canada, and whose infants had recently undergone newborn blood-spot screening. RESULTS: We received 750 completed questionnaires (response rate 47%). Factors associated with respondents' higher knowledge of newborn blood-spot screening were higher level of education (odds ratio = 2.79), English being spoken at home (odds ratio = 1.96), receiving an information sheet at the time of newborn blood-spot screening (odds ratio = 1.57), and receiving information about how to interpret the results (odds ratio = 2.65). Factors associated with being satisfied were: receiving information prenatally (odds ratio = 2.35), from a health-care professional (odds ratio = 4.54), or from an information sheet at the time of newborn blood-spot screening (odds ratio = 1.72); and receiving messages about the purpose of screening (odds ratio = 3.78), the communication process (odds ratio = 2.57), the interpretation of the results (odds ratio = 4.19), and sample-handling methods (odds ratio = 3.13). CONCLUSION: Promoting mothers' understanding and meeting their expectations with respect to education about newborn blood-spot screening may require greater engagement with prenatal providers. It also calls for a greater emphasis on communicating with mothers about how blood samples are handled and about the meaning of the test results.

The first three years of screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) by newborn screening ontario.

BACKGROUND: Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a disorder of mitochondrial fatty acid oxidation and is one of the most common inborn errors of metabolism. Identification of MCADD via newborn screening permits the introduction of interventions that can significantly reduce associated morbidity and mortality. This study reports on the first three years of newborn screening for MCADD in Ontario, Canada. METHODS: Newborn Screening Ontario began screening for MCADD in April 2006, by quantification of acylcarnitines (primarily octanoylcarnitine, C8) in dried blood spots using tandem mass spectrometry. Babies with positive screening results were referred to physicians at one of five regional Newborn Screening Treatment Centres, who were responsible for diagnostic evaluation and follow-up care. RESULTS: From April 2006 through March 2009, approximately 439 000 infants were screened for MCADD in Ontario. Seventy-four infants screened positive, with a median C8 level of 0.68 uM (range 0.33-30.41 uM). Thirty-one of the screen positive infants have been confirmed to have MCADD, while 36 have been confirmed to be unaffected. Screening C8 levels were higher among infants with MCADD (median 8.93 uM) compared to those with false positive results (median 0.47 uM). Molecular testing was available for 29 confirmed cases of MCADD, 15 of whom were homozygous for the common c.985A > G mutation. Infants homozygous for the common mutation tended to have higher C8 levels (median 12.13 uM) relative to compound heterozygotes for c.985A > G and a second detectable mutation (median 2.01 uM). Eight confirmed mutation carriers were identified among infants in the false positive group. The positive predictive value of a screen positive for MCADD was 46%. The estimated birth prevalence of MCADD in Ontario is approximately 1 in 14 000. CONCLUSIONS: The birth prevalence of MCADD and positive predictive value of the screening test were similar to those identified by other newborn screening programs internationally. We observed some evidence of correlation between genotype and biochemical phenotype (C8 levels), and between C8 screening levels and eventual diagnosis. Current research priorities include further examining the relationships among genotype, biochemical phenotype, and clinical phenotype, with the ultimate goal of improving clinical risk prediction in order to provide tailored disease management advice and genetic counselling to families.