Understanding the Impact of Different Modes of Information Provision on Preferences for a Newborn Bloodspot Screening Program in the United Kingdom.

Introduction. This study aimed to understand the impact of alternative modes of information provision on the stated preferences of a sample of the public for attributes of newborn bloodspot screening (NBS) in the United Kingdom. Methods. An online discrete choice experiment survey was designed using 4 attributes to describe NBS (effect of treatment on the condition, time to receive results, whether the bloodspot is stored, false-positive rate). Survey respondents were randomized to 1 of 2 survey versions presenting the background training materials using text from a leaflet (leaflet version) or an animation (animation version). Heteroskedastic conditional logistic regression was used to estimate the effect of mode of information provision on error variance. Results. The survey was completed by 1,000 respondents (leaflet = 525; animation = 475). Preferences for the attributes in the DCE were the same in both groups, but the group receiving the animation version had 9% less error variance in their responses. Respondents completing the animation version gave higher ratings compared with the leaflet version in terms of ease of perceived understanding. Subgroup analysis suggested that the animation was particularly effective at reducing error variance for women (20%), people with previous children (16.5%), and people between the ages of 35 and 45 y (11.8%). Limitations. This study used simple DCE with 4 attributes, and the results may vary for more complex choice questions. Conclusion. This study provides evidence that that supplementing the information package offered to parents choosing to take part in NBS with an animation may aid them their decision making. Further research would be needed to test the animation in the health system. Implications. Researchers designing DCE should carefully consider the design of their training materials to improve the quality of data collected. Highlights: Prior to completing a discrete choice experiment about newborn bloodspot screening, respondents were shown information using either a leaflet-based or animated format.Respondents receiving information using an animation version reported that the information was slightly easier to understand and exhibited 9% less error variance in expressing their preferences for a newborn screening program.Using the animation version to present information appeared to have a larger impact in reducing the error variance of responses for specific respondents including women, individuals with children, individuals between the ages of 35 and 45 y, and individuals educated to degree level.

Standards for the care of people with cystic fibrosis (CF): A timely and accurate diagnosis.

There is considerable activity with respect to diagnosis in the field of cystic fibrosis (CF). This relates primarily to developments in newborn bloodspot screening (NBS), more extensive gene analysis and improved characterisation of CFTR-related disorder (CFTR-RD). This is particularly pertinent with respect to accessibility to variant-specific therapy (VST), a transformational intervention for people with CF with eligible CFTR gene variants. This advance reinforces the need for a timely and accurate diagnosis. In the future, there is potential for trials to assess effectiveness of variant-specific therapy for CFTR-RD. The guidance in this paper reaffirms previous standards, clarifies a number of issues, and integrates emerging evidence. Timely and accurate diagnosis has never been more important for people with CF.

Genotyping in patients with congenital adrenal hyperplasia by sequencing of newborn bloodspot samples.

OBJECTIVES: Genotype-phenotype correlation in congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency ranges from 45 to 97 %. We performed massively parallel sequencing of CYP21A2 on stored newborn bloodspot samples to catalogue the genotypes present in our patients with CAH and enable genotype-phenotype comparison. METHODS: Participants ≤15 years old with clinically diagnosed CAH were recruited from The Sydney Children's Hospitals Network. Phenotype was classified from clinical and biochemical details in the medical record as salt wasting (SW), simple virilising (SV), non-classic (NC) or an intermediate phenotype (SW/SV; SV/NC). Amplicon-based sequencing for CYP21A2 was performed on stored newborn bloodspot samples by the New South Wales Newborn Bloodspot Screening Laboratory on MiSeq™Dx (Illumina, California). Available genetic test results were also obtained from the medical records. RESULTS: Samples from 67 participants (43 % female, age 0.3-15 years) were sequenced, including 9 sibships. SW phenotype was present in 33/67 participants (49 %), SV in 9 (13 %) and NC in 16 (24 %). Intermediate phenotypes included SW/SV in seven participants (10 %) and SV/NC in two (3 %). Variants were identified in 90/116 alleles (78 %). A complete genotype was available in 47/67 participants (70 %). The most common genotype was homozygous c.293-13A/C>G (I2G) in 7/47 participants (15 %). Genotype correlated with the most commonly reported phenotype in 36/44 cases (82 %). Correlation was higher in SW and NC phenotypes. CONCLUSIONS: This study uses genetic testing of newborn bloodspots to identify and characterise the genotypes present in an ethnically diverse Australian population with CAH. It further strengthens our knowledge of genotype-phenotype correlations in CAH.

European survey of newborn bloodspot screening for CF: opportunity to address challenges and improve performance.

BACKGROUND: The aim of this study was to record the current status of newborn bloodspot screening (NBS) for CF across Europe and assess performance. METHODS: Survey of representatives of NBS for CF programmes across Europe. Performance was assessed through a framework developed in a previous exercise. RESULTS: In 2022, we identified 22 national and 34 regional programmes in Europe. Barriers to establishing NBS included cost and political inertia. Performance was assessed from 2019 data reported by 21 national and 21 regional programmes. All programmes employed different protocols, with IRT-DNA the most common strategy. Six national and 11 regional programmes did not use DNA analysis. CONCLUSIONS: Integrating DNA analysis into the NBS protocol improves PPV, but at the expense of increased carrier and CFSPID recognition. Some programmes employ strategies to mitigate these outcomes. Programmes should constantly strive to improve performance but large datasets are needed to assess outcomes reliably.

International Approaches to Management of CFTR-Related Metabolic Syndrome/Cystic Fibrosis Screen Positive, Inconclusive Diagnosis.

The main aim of the present study was to explore health professionals' reported experiences and approaches to managing children who receive a designation of cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive inconclusive diagnosis following a positive NBS result for cystic fibrosis. An online questionnaire was distributed via Qualtrics Survey Software and circulated to a purposive, international sample of health professionals involved in managing children with this designation. In total, 101 clinicians completed the online survey: 39 from the US, six from Canada, and 56 from Europe (including the UK). Results indicated that while respondents reported minor deviations in practice, they were cognizant of recommendations in the updated guidance and for the most part, attempted to implement these into practice consistently internationally. Where variation was reported, the purpose of this appeared to be to enable clinicians to respond to either clinical assessments or parental anxiety in order to improve outcomes for the child and family. Further research is needed to determine if these findings are reflective of both a wider audience of clinicians and actual (rather than reported) practice.

Processing of Positive Newborn Screening Results for Congenital Hypothyroidism: A Qualitative Exploration of Current Practice in England.

The objective of this research was to explore current communication practices for positive newborn bloodspot screening results for congenital hypothyroidism from the newborn bloodspot screening laboratory to clinicians and then families, in order to (i) understand how the pathway is implemented in practice, (ii) highlight regional differences and (iii) identify barriers and facilitators. A qualitative exploratory design was employed using semi-structured interviews across 13 newborn bloodspot screening laboratories in England. Participants included 35 clinicians and 17 NBS laboratory staff across the 13 laboratories and 18 members of relevant clinical teams. Findings illuminated variations in how positive newborn bloodspot screening results for congenital hypothyroidism are communicated in practice. This included regional variations due to historical arrangements and local resources. Contacting the appropriate person could be challenging and obtaining feedback from clinical teams to the laboratory after the child has been seen could be time consuming for those involved. Standardised communication model(s) for positive newborn bloodspot screening results for congenital hypothyroidism, which include named contact individuals, defined pathways of care and processes for feeding back to laboratories, may help to ensure the process is less labour intensive, particularly from a laboratory perspective.

Establishment of a sustainable newborn TSH-screening program in the People's Democratic Republic of Laos.

BACKGROUND: Neonatal screening programs have been established and are in use in most countries worldwide. Laos belongs to the few countries which still have not established any kind of newborn screening. METHODS: Basis for the current screening was an initial pilot project between 2008 and 2010. Then 11.362 samples of newborn infants were screened, samples were weekly air-shipped to a German screening laboratory. During the current project TSH-measurements take place at the laboratory of the largest delivery hospital in Laos, the Mother & Newborn Hospital in Vientiane. RESULTS: Teaching regarding taking samples and doing measurements started in January 2019, until end of July 2020 altogether 3214 samples were measured. None of the samples was above the predefined cutoff of 20µU/l. CONCLUSIONS: Newborn screening for congenital hypothyroidism with measurements of samples within Laos is feasible. Plausibility control is achieved by regular checks of screening results sent by email to Germany. The most challenging task is to cover all newborns born at participating hospitals and finally to expand the screening beyond the capital to other areas in the country.

Psychological Impact of NBS for CF.

Newborn screening for cystic fibrosis has resulted in diagnosis often before symptoms are recognised, leading to benefits including reduced disease severity, decreased burden of care, and lower costs. The psychological impact of this often unsought diagnosis on the parents of seemingly well children is less well understood. The time during which the screening result is communicated to families but before the confirmatory test results are available is recognised as a period of uncertainty and it is this uncertainty that can impact most on parents. Evidence suggests this may be mitigated against by ensuring the time between communication and confirmatory testing is minimized and health professionals involved in communicating positive newborn screening results and diagnostic results for cystic fibrosis to families are knowledgeable and able to provide appropriate reassurance. This is particularly important in the case of false positive results or when the child is given a Cystic Fibrosis Screen Positive, Inconclusive Diagnosis designation. However, to date, there are no formal mechanisms in place to support health professionals undertaking this challenging role, which would enable them to meet the expectations set out in specific guidance.

Constructing a Bioethical Framework to Evaluate and Optimise Newborn Bloodspot Screening for Cystic Fibrosis.

Newborn bloodspot screening for cystic fibrosis is a valid public health strategy for populations with a high incidence of this inherited condition. There are a wide variety of approaches to screening and in this paper, we propose that a bioethical framework is required to determine the most appropriate screening protocol for a population. This framework depends on the detailed evaluation of the ethical consequences of all screening outcomes and placing these in the context of the genetic profile of the population screened, the geography of the region and the healthcare resources available.

Rethinking Strategies for Positive Newborn Screening Result (NBS+) Delivery (ReSPoND): a process evaluation of co-designing interventions to minimise impact on parental emotional well-being and stress.

BACKGROUND: Newborn blood spot (NBS) screening seeks to prevent ill health, disability and death through early diagnosis and effective intervention. Each year, around 10,000 parents of babies born in England are given a positive NBS result indicating their child may be affected or carriers of one of the nine conditions currently screened for. Despite guidance, these results are inconsistently delivered to parents across geographical regions. There is evidence that many parents are dissatisfied with how NBS results are communicated to them and that poor communication practices can lead to various negative sequelae. The purpose of this study is to co-design, implement and undertake a process evaluation of new, co-designed interventions to improve delivery of initial positive NBS results to parents. METHODS: This mixed-methods study will use four phases with defined outputs. Family Systems Theory will form the theoretical basis for the study. The principles and methods of experience-based co-design will underpin intervention development. Normalisation Process Theory will underpin the process evaluation of the interventions co-designed to improve the delivery of positive NBS results to parents. An economic analysis will determine resource use and costs of current practice and of implementing the new co-designed interventions. The nominal group technique will be used to inform the selection of suitable outcome measures for a future evaluation study. DISCUSSION: The main output of the proposed study will be co-designed interventions for initial communication of positive NBS results to parents ready to be evaluated in a definitive evaluation study.The interventions, co-designed with parents, will help to minimise potential negative sequelae associated with poor communication practices by considering parental and staff experiences as well as healthcare challenges such as finite resources. In addition, information about indicative costs associated with different communication strategies will be determined.It is anticipated it may also be possible to extrapolate principles of good communication practices from the present study for the delivery of bad news to parents for children newly diagnosed with other conditions including cancer and other chronic conditions such as diabetes or epilepsy. TRIAL REGISTRATION: ISRCTN 15330120 date of registration 17/01/2018.

International approaches for delivery of positive newborn bloodspot screening results for CF.

BACKGROUND: Newborn bloodspot screening (NBS) for cystic fibrosis (CF) is a well-established public health strategy with international standards. A European survey demonstrated considerable variability in approach to delivering a positive NBS result. We used a mixed methods approach to explore healthcare systems and beliefs around this process. METHODS: We used semi-structured interviews and online questionnaires with a purposive, international sample of health professionals involved in communicating positive NBS results to parents. Data were analysed using thematic analysis and Qualtrics Survey Software. RESULTS: In total, 63 healthcare professionals were approached; 25 interviews were conducted with delegates at the 2017 ECFS conference, 4 online questionnaires were subsequently completed by participants in the EU, 1 from Australia and 33 from the US. Methods used to communicate positive NBS results to families varied considerably. This influenced the quality and quantity of information provided which had the potential to heighten anxiety and affect timely diagnostic testing. Participants identified positive practices including systems to improve the timeliness of screening and processing of results, as well as areas for improvement. Respondents stated that knowledge of CF and familiarity with the family were both important when deciding who should communicate positive NBS results. CONCLUSIONS: Guidance and practice regarding communication of positive NBS results for CF to families varies considerably internationally. Further research is needed to ensure information received is accurate, up-to-date and from the most appropriate person. Also, that all children are followed up in a timely manner to minimise potential negative outcomes for the child and family.

The expansion and performance of national newborn screening programmes for cystic fibrosis in Europe.

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) is a well-established public health strategy with international standards. The aim of this study was to provide an update on NBS for CF in Europe and assess performance against the standards. METHODS: Questionnaires were sent to key workers in each European country. RESULTS: In 2016, there were 17 national programmes, 4 countries with regional programmes and 25 countries not screening in Europe. All national programmes employed different protocols, with IRT-DNA the most common strategy. Five countries were not using DNA analysis. In addition, the processing and structure of programmes varied considerably. Most programmes were achieving the ECFS standards with respect to timeliness, but were less successful with respect to sensitivity and specificity. CONCLUSIONS: There has been a steady increase in national CF NBS programmes across Europe with variable strategies and outcomes that reflect the different approaches.

An evaluation of pregnant women's knowledge and attitudes about newborn bloodspot screening.

OBJECTIVES: research suggests that information provided to parents about newborn bloodspot screening (NBS) can be inconsistent. The majority of international NBS programmes recommend that parents should receive information about NBS in the antenatal period, however prior studies have mostly focused on postnatal women's knowledge, with no quantitative study of women's knowledge in the antenatal period conducted to date. Thus, the aim of this study was to determine if antenatal women received information about NBS in the antenatal period and to evaluate their knowledge and attitudes about NBS. DESIGN/PARTICIPANTS: we conducted a cross-sectional study among antenatal attendees at three maternity hospitals in Ireland. A total of 662 antenatal women (≥36 weeks gestation) were recruited into the study (279 primiparous, 368 multiparous). Women were asked to complete a self reported knowledge and attitude questionnaire about NBS. FINDINGS: primiparity (OR 2.75; 95% CI 1.65, 4.59) lower educational status (OR 1.79; 95% CI 1.02, 3.15) and not having private health insurance (OR 1.84; 95% CI 1.19, 2.85) were independently associated with poor NBS knowledge. Fourteen per cent of antenatal women recalled receiving an information leaflet about NBS, yet over 87 % reported that they would like more information. Thirty four per cent of women agreed that they understand everything they need to know about NBS. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: the process of providing women with information about NBS in the antenatal period is inconsistent; consequently their awareness about NBS is limited. To make an informed choice about NBS women require information to be provided in a more structured format. There are many missed opportunities in the antenatal period for maternity care providers to provide women with information about NBS. Our study recommends that healthcare providers should have a more formal and structured approach with regard to the provision of information about NBS in the antenatal period. This could be achieved by incorporating NBS education into antenatal education classes or through multimedia while women are waiting in the antenatal clinic. Healthcare providers may need education about the importance and benefits of providing women with information about NBS in the antenatal period.

Newborn bloodspot screening for cystic fibrosis: What do antenatal and postnatal women know about cystic fibrosis?

BACKGROUND: The Republic of Ireland has one of the highest reported incidences of cystic fibrosis (CF) in the world (1/1353) with an estimated carrier rate of 1/20. No cure exists, however there have been significant advances in available treatments. Newborn bloodspot screening (NBS) for CF was added to the NBS programme in Ireland in July 2011. Little is known about antenatal or postnatal women's knowledge about CF. METHODS: This was a cross-sectional study of 662 antenatal (≥36weeks gestation) and 480 postnatal women (post NBS). Women were asked to self-complete a questionnaire including 14 CF knowledge questions. RESULTS: Among the respondents significantly more postnatal than antenatal women were aware that CF is included on the NBS (81.8% vs 63.5%; p<0.001). 92.7% believe that there are health consequences to being a carrier and 33.6% believe there is a cure for CF. In the multivariate analysis, lower educational status (OR 2.13; 95% CI 1.31, 3.46) being an antenatal mother (OR 1.51; 95% CI 1.04, 2.18), having no family history of CF (OR 5.82; 95% CI 1.62, 20.90) were associated with poor CF knowledge, while increasing age was found to be protective against poor CF knowledge (OR 0.96; 95% CI 0.92, 0.99). CONCLUSIONS: Results from this study provide a useful insight into women's preexisting knowledge about CF, which could be used to inform initial discussions with parents about their child's diagnosis.

Review of Current International Decision-Making Processes for Newborn Screening: Lessons for Australia.

Newborn bloodspot screening has been operating successfully in Australia for almost 50 years. Recently, the development of new technologies and treatments has led to calls for the addition of new conditions to the screening programs. Internationally, it is recognized by governments that national policies for newborn screening should support transparent and evidence-based decision making, and promote consistency between states within a country. Australia is lagging behind the international community, and currently has no national policies or decision-making processes, agreed by government, to support its newborn screening programs. In contrast, New Zealand (NZ), the United Kingdom (UK), and the United States of America (US) have robust and transparent processes to assess conditions for screening, which have been developed by, and have pathways to, government. This review provides detail on the current policy environment for newborn screening in Australia, highlighting that there are a number of risks to the programs resulting from the lack of a decision-making process. It also describes the processes used to assess conditions for newborn screening in the US, UK, and NZ. These examples highlight the benefits of developing a national decision-making process, including ensuring that screening is evidence based and effective. These examples also provide models that might be considered for Australia, as well as other countries currently seeking to introduce or expand newborn bloodspot screening.

Comparative evaluation of newborn bloodspot specimen cards by experienced laboratory personnel and by an optical scanning instrument.

A major factor in determining the suitability of a dried blood spot (DBS) specimen is the subjective nature of evaluation by laboratory personnel. Using newborn screening DBS specimen cards as they were submitted to a public health NBS program, we conducted a systematic pilot study of DBS evaluation by multiple experienced laboratory personnel (ELP) and by an automated optical scanning instrument (OSI) (CardScan (tm), BSD Robotics). OSI confirmed the satisfactory status of all newborn DBS specimen cards that passed initial review by the first ELP. Among the questionable cards selected for further review, 58% passed multiple ELP consensus assessment, and 62% passed OSI evaluation. The overall agreement between ELP and OSI was 86%. Among questionable specimen cards, ELP and OSI were more strongly correlated when multiple ELP assessment was unanimous. We conclude that subjective assessment by ELP is essential and that OSI evaluation is a useful adjunct when ELP assessment does not reach consensus. OSI further allows the selection of optimal locations for punching DBS from unsatisfactory or questionable specimens, optimizing the quality of interim analyses that may be conducted while repeat specimens are being collected. Instrument evaluation of specimen cards would also be valuable as an independent reference method for training laboratory and specimen collection personnel. OSI technology merits further studies to confirm and extend our findings.

Novel application of digital microfluidics for the detection of biotinidase deficiency in newborns.

OBJECTIVE: Newborn screening for biotinidase deficiency can be performed using a fluorometric enzyme assay on dried blood spot specimens. As a pre-requisite to the consolidation of different enzymatic assays onto a single platform, we describe here a novel analytical method for detecting biotinidase deficiency using the same digital microfluidic cartridge that has already been demonstrated to screen for five lysosomal storage diseases (Pompe, Fabry, Gaucher, Hurler and Hunter) in a multiplex format. METHODS: A novel assay to quantify biotinidase concentration in dried blood spots (DBS) was developed and optimized on the digital microfluidic platform using proficiency testing samples from the Centers for Disease Control and Prevention. The enzymatic assay uses 4-methylumbelliferyl biotin as the fluorogenic substrate. Biotinidase deficiency assays were performed on normal (n=200) and deficient (n=7) newborn DBS specimens. RESULTS: Enzymatic activity analysis of biotinidase deficiency revealed distinct separation between normal and affected DBS specimens using digital microfluidics and these results matched the expected activity. CONCLUSIONS: This study has demonstrated performance of biotinidase deficiency assays by measurement of 4-methylumbelliferyl product on a digital microfluidic platform. Due to the inherent ease in multiplexing on such a platform, consolidation of other fluorometric assays onto a single cartridge may be realized.