Newborn Screening Today and Tomorrow: A Brief Report from the International Primary Immunodeficiencies Congress.

This article presents the report of the session on "Newborn Screening for Primary Immunodeficiencies-Now What?" organised during the International Primary Immunodeficiency Congress (IPIC) held in November 2023. This clinical conference was organised by the International Patient Organisation for Primary Immunodeficiencies (IPOPI), the global patient organisation advocating for primary immunodeficiencies (PIDs) in patients. The session aimed at exploring the advances in newborn screening (NBS) for severe combined immunodeficiency, starting with the common practice and inserting the discussion into the wider perspective of genomics whilst taking into consideration the ethical aspects of screening as well as incorporating families and the public into the discussions, so as to ensure that NBS for treatable rare disorders continues to be one of the major public health advances of the 20th century.

International Perspectives of Extended Genetic Sequencing When Used as Part of Newborn Screening to Identify Cystic Fibrosis.

There is increasing interest in using extended genetic sequencing (EGS) in newborn screening (NBS) for cystic fibrosis (CF). How this is implemented will change the number of children being given an uncertain outcome of CRMS/CFSPID (cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome/CF Screen Positive Inconclusive Diagnosis), probable carrier results, and the number of missed CF diagnoses. An international survey of CF health professionals was used to gather views on two approaches to EGS-specific (may reduce detection of CRMS/CFSID but miss some CF cases) versus sensitive (may increase detection of CRMS/CFSPID but avoid missing more CF cases). Health professionals acknowledged the anxiety caused to parents (and health professionals) from the uncertainty surrounding the prognosis and management of CRMS/CFSPID. However, most preferred the sensitive approach, as overall, identifying more cases of CRMS/CFSPID was viewed as less physically and psychologically damaging than a missed case of CF. The importance of early diagnosis and treatment for CF to ensure better health outcomes and reducing diagnostic odysseys for parents were highlighted. A potential benefit to identifying more children with CRMS/CFSPID included increasing knowledge to obtain a better understanding of how these children should best be managed in the future.

Retrospective Review of Positive Newborn Screening Results for Isovaleric Acidemia and Development of a Strategy to Improve the Efficacy of Newborn Screening in the UK.

Since the UK commenced newborn screening for isovaleric acidemia in 2015, changes in prescribing have increased the incidence of false positive (FP) results due to pivaloylcarnitine. A review of screening results between 2015 and 2022 identified 24 true positive (TP) and 84 FP cases, with pivalate interference confirmed in 76/84. Initial C5 carnitine (C5C) did not discriminate between FP and TP with median (range) C5C of 2.9 (2.0-9.6) and 4.0 (1.8->70) µmol/L, respectively, and neither did Precision Newborn Screening via Collaborative Laboratory Integrated Reports (CLIR), which identified only 1/47 FP cases. However, among the TP cases, disease severity showed a correlation with initial C5C in 'asymptomatic' individuals (n = 17), demonstrating a median (range) C5C of 3.0 (1.8-7.1) whilst 'clinically affected' patients (n = 7), showed a median (range) C5C of 13.9 (7.7-70) µmol/L. These findings allowed the introduction of dual cut-off values into the screening algorithm to reduce the incidence of FPs, with initial C5C results ≥ 5 µmol/L triggering urgent referral, and those >2.0 and <5.0 µmol/L prompting second-tier C5-isobar testing. This will avoid delayed referral in babies at particular risk whilst reducing the FP rate for the remainder.

Stakeholder Views of the Proposed Introduction of Next Generation Sequencing into the Cystic Fibrosis Screening Protocol in England.

The project aimed to gather, analyse, and compare the views of stakeholders about the proposed UK cystic fibrosis (CF) screening protocol incorporating next generation sequencing (NGS). The study design was based on principles of Q-methodology with a willingness-to-pay exercise. Participants were recruited from 12 CF centres in the UK. The study contained twenty-eight adults who have experience with CF (parents of children with CF (n = 21), including parents of children with CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS)/CF screen positive-inconclusive diagnosis (CFSPID), an uncertain outcome (n = 3), and adults with CF (n = 4)), and nine health professionals involved in caring for children with CF. Parents and health professionals expressed a preference for a sensitive approach to NGS. This was influenced by the importance participants placed on not missing any children with CF via screening and the balance of harm between missing a case of CF compared to picking up more children with an uncertain outcome (CRMS/CFSPID). Given the preference for a sensitive approach, the need for adequate explanations about potential outcomes including uncertainty (CFSPID) at the time of screening was emphasized. More research is needed to inform definitive guidelines for managing children with an uncertain outcome following CF screening.

2023 APHL/ISNS Newborn Screening Symposium.

Introduction and Abstracts of the 2023 APHL/ISNS Newborn Screening Symposium in Sacramento, CA, USA from 15-19 October 2023.

Genomic newborn screening: Are we entering a new era of screening?

Population newborn screening (NBS) for phenylketonuria began in the United States in 1963. In the 1990s electrospray ionization mass spectrometry permitted an array of pathognomonic metabolites to be identified simultaneously, enabling up to 60 disorders to be recognized with a single test. In response, differing approaches to the assessment of the harms and benefits of screening have resulted in variable screening panels worldwide. Thirty years on and another screening revolution has emerged with the potential for first line genomic testing extending the range of screening conditions recognized after birth to many hundreds. At the annual SSIEM conference in 2022 in Freiburg, Germany, an interactive plenary discussion on genomic screening strategies and their challenges and opportunities was conducted. The Genomics England Research project proposes the use of Whole Genome Sequencing to offer extended NBS to 100 000 babies for defined conditions with a clear benefit for the child. The European Organization for Rare Diseases seeks to include "actionable" conditions considering also other types of benefits. Hopkins Van Mil, a private UK research institute, determined the views of citizens and revealed as a precondition that families are provided with adequate information, qualified support, and that autonomy and data are protected. From an ethical standpoint, the benefits ascribed to screening and early treatment need to be considered in relation to asymptomatic, phenotypically mild or late-onset presentations, where presymptomatic treatment may not be required. The different perspectives and arguments demonstrate the unique burden of responsibility on those proposing new and far-reaching developments in NBS programs and the need to carefully consider both harms and benefits.

Newborn Screening in a Pandemic-Lessons Learned.

The COVID-19 pandemic affected many essential aspects of public health, including newborn screening programs (NBS). Centers reported missing cases of inherited metabolic disease as a consequence of decreased diagnostic process quality during the pandemic. A number of problems emerged at the start of the pandemic, but from the beginning, solutions began to be proposed and implemented. Contingency plans were arranged, and these are reviewed and described in this article. Staff shortage emerged as an important issue, and as a result, new work schedules had to be implemented. The importance of personal protective equipment and social distancing also helped avoid disruption. Staff became stressed, and this needed to be addressed. The timeframe for collecting bloodspot samples was adapted in some cases, requiring reference ranges to be modified. A shortage of essential supplies and protective equipment was evident, and laboratories described sharing resources in some situations. The courier system had to be adapted to make timely and safe transport possible. Telemedicine became an essential tool to enable communication with patients, parents, and medical staff. Despite these difficulties, with adaptations and modifications, some centers evaluated candidate conditions, continued developments, or began new NBS. The pandemic can be regarded as a stress test of the NBS under real-world conditions, highlighting critical aspects of this multidisciplinary system and the need for establishing local, national, and global strategies to improve its robustness and reliability in times of shortage and overloaded national healthcare systems.

Current State and Innovations in Newborn Screening: Continuing to Do Good and Avoid Harm.

In 1963, Robert Guthrie's pioneering work developing a bacterial inhibition assay to measure phenylalanine in dried blood spots, provided the means for whole-population screening to detect phenylketonuria in the USA. In the following decades, NBS became firmly established as a part of public health in developed countries. Technological advances allowed for the addition of new disorders into routine programmes and thereby resulted in a paradigm shift. Today, technological advances in immunological methods, tandem mass spectrometry, PCR techniques, DNA sequencing for mutational variant analysis, ultra-high performance liquid chromatography (UPLC), iso-electric focusing, and digital microfluidics are employed in the NBS laboratory to detect more than 60 disorders. In this review, we will provide the current state of methodological advances that have been introduced into NBS. Particularly, 'second-tier' methods have significantly improved both the specificity and sensitivity of testing. We will also present how proteomic and metabolomic techniques can potentially improve screening strategies to reduce the number of false-positive results and improve the prediction of pathogenicity. Additionally, we discuss the application of complex, multiparameter statistical procedures that use large datasets and statistical algorithms to improve the predictive outcomes of tests. Future developments, utilizing genomic techniques, are also likely to play an increasingly important role, possibly combined with artificial intelligence (AI)-driven software. We will consider the balance required to harness the potential of these new advances whilst maintaining the benefits and reducing the risks for harm associated with all screening.

Impact of COVID-19 on Pediatric Laboratory Medicine: An IFCC C-ETPLM, SSIEM, ISNS Global Survey.

Objective: Pediatric laboratory medicine is a unique practice serving a vulnerable group of patients including highly specialized testing aiming to detect and treat inherited conditions early to avoid adverse outcomes. Data on the actual impact of COVID-19 pandemic on this speciality is lacking. Methods: A survey was conducted by the IFCC Committee on Emerging Technologies in Pediatric Laboratory Medicine in partnership with the Society for the Study of Inborn Errors of Metabolism and International Society for Neonatal Screening, to assess the impact on the clinical service provision during the initial wave (January to July 2020) of the COVID-19 pandemic and to gather experiences learned in order to improve laboratory preparedness for future outbreaks. Results: 217 survey responses were received from 69 regions. Sixty-three laboratories (29%) reported a restriction or suspension of service for a median period of four months. The common tests/ services suspended were new-born screening program, body fluids and sweat testing. The reasons for the suspension were related to bio-safety risks of COVID-19 transmission, manpower constraints and supplies disruption. A minority (9-10%) of laboratories did observe delayed/missed diagnoses or a more severe presentation of a clinical disorder. The critical operational decisions that helped manage the initial wave of COVID-19 included modifying work shift patterns, split-teams arrangement, use of personal protection equipment and social distancing. Conclusion: The provision and delivery of pediatric laboratories services were affected during the initial wave of the COVID-19 pandemic. Manpower preparedness for future potential disruptions to pediatric laboratory services is a key finding and recommendation from this survey.

Co-designing Improved Communication of Newborn Bloodspot Screening Results to Parents: Mixed Methods Study.

BACKGROUND: Each year in England, almost 10,000 parents are informed of their child's positive newborn bloodspot screening (NBS) results. This occurs approximately 2 to 8 weeks after birth depending on the condition. Communication of positive NBS results is a subtle and skillful task, demanding thought, preparation, and evidence to minimize potentially harmful negative sequelae. Evidence of variability in the content and the way the result is currently communicated has the potential to lead to increased parental anxiety and distress. OBJECTIVE: This study focused on the development of co-designed interventions to improve the experiences of parents receiving positive NBS results for their children and enhance communication between health care professionals and parents. METHODS: An experience-based co-design approach was used to explore experiences and co-design solutions with 17 health professionals employed in 3 National Health Service Trusts in England and 21 parents (13/21, 62% mothers and 8/21, 38% fathers) of 14 children recruited from the same 3 National Health Service Trusts. Experiences with existing services were gathered via semistructured interviews with health professionals. Filmed narrative interviews with parents were developed into a composite film. The co-design process identified priorities for improving communication of positive NBS results through separate parent and health professional feedback events followed by joint feedback events. In total, 4 interventions were then co-designed between the participants through a web-based platform. RESULTS: Parents and health professionals provided positive feedback regarding the process of gathering experiences and identifying priorities. Themes identified from the parent interviews included impact of initial communication, parental reactions, attending the first clinic appointment, impact of health professionals' communication strategies and skills, impact of diagnosis on family and friends, improvements to the communication of positive NBS results, and parents' views on NBS. Themes identified from the health professional interviews included communication between health professionals, process of communicating with the family, parent- and family-centered care, and availability of resources and challenges to effective communication. In response to these themes, 4 interventions were co-designed: changes to the NBS card; standardized laboratory proformas; standardized communication checklists; and an email or letter for providing reliable, up-to-date, condition-specific information for parents following the communication of positive NBS results. CONCLUSIONS: Parents and health professionals were able to successfully work together to identify priorities and develop co-designed interventions to improve communication of positive NBS results to parents. The resulting co-designed interventions address communication at different stages of the communication pathway to improve the experiences of parents receiving positive NBS results for their children. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s40814-019-0487-5.

A Public Dialogue to Inform the Use of Wider Genomic Testing When Used as Part of Newborn Screening to Identify Cystic Fibrosis.

Cystic fibrosis (CF) has been included within the UK national newborn screening programme since 2007. The approach uses measures of immunoreactive trypsin (IRT) in dried blood spot samples obtained at day 5 of life. Samples which reveal IRT results >99.5th centile go on to be tested for a limited panel of CF mutations. While the programme works well and achieves a high level of sensitivity and specificity, it relies upon repeat testing in some cases and identifies probable carriers, both potentially provoking parental anxiety. In addition, the limited CF mutation panel may not fully reflect the ethnic diversity within the UK population. The use of wider genomic screening, made possible by next-generation sequencing to replace more limited panels, can be used to avoid these shortcomings. However, the way in which this approach is employed can either be designed to maximise specificity by limiting reporting to combinations of known pathogenic mutations or can maximise sensitivity by also reporting combinations of pathogenic mutations together with variants of uncertain significance. The latter approach also increases the number of Cystic Fibrosis Screen-Positive Inconclusive Diagnosis (CFSPID) designations reported, resulting in uncertainty for parents. To help consider the design of the programme, a dialogue was commissioned by the UK National Screening Committee (UKNSC) to elicit the views of members of the public without direct experience of CF, to determine if there was a preference for maximising the sensitivity or the specificity of CF screening. The participants initially expressed a clear preference to maximise sensitivity and avoid missing CF cases, but after time to reflect and consider the implications of their choice, a number changed their views so as to tolerate some missed cases if this resulted in greater certainty of outcome; this became the majority view. It is proposed that it may be a generalisable finding that the public, when facing whole-population screening programmes, may require significant time and information to inform and make their choices and may attach great importance to clarity and certainty of outcome in the screening process.

Towards Achieving Equity and Innovation in Newborn Screening across Europe.

Although individual rare disorders are uncommon, it is estimated that, together, 6000+ known rare diseases affect more than 30 million people in Europe, and present a substantial public health burden. Together with the psychosocial burden on affected families, rare disorders frequently, if untreated, result in a low quality of life, disability and even premature death. Newborn screening (NBS) has the potential to detect a number of rare conditions in asymptomatic children, providing the possibility of early treatment and a significantly improved long-term outcome. Despite these clear benefits, the availability and conduct of NBS programmes varies considerably across Europe and, with the increasing potential of genomic testing, it is likely that these differences may become even more pronounced. To help improve the equity of provision of NBS and ensure that all children can be offered high-quality screening regardless of race, nationality and socio-economic status, a technical meeting, endorsed by the Slovenian Presidency of the Council of the European Union, was held in October 2021. In this article, we present experiences from individual EU countries, stakeholder initiatives and the meeting's final conclusions, which can help countries attempting to establish new NBS programmes or expand existing provision.

Delivering Positive Newborn Screening Results: Cost Analysis of Existing Practice versus Innovative, Co-Designed Strategies from the ReSPoND Study.

Although the communication pathways of Newborn Bloodspot Screening (NBS) are a delicate task, these pathways vary across different conditions and are often not evidence-based. The ReSPoND interventions were co-designed by healthcare professionals alongside parents who had received a positive NBS result for their child. To calculate the cost of these co-designed strategies and the existing communication pathways, we interviewed 71 members of the clinical and laboratory staff of the 13 English NBS laboratories in the English National Health Service. Therefore, a scenario analysis was used to compare the cost of the existing communication pathways to the co-designed strategies delivered by (i) home-visits and (ii) telecommunications. On average, the existing communication pathway cost £447.08 per infant (range: £237.12 to £628.51) or £234,872.75 (£3635.99 to £1,932,986.23) nationally. Implementing the new interventions relying on home-visits exclusively would cost on average £521.62 (£312.84 to £646.39) per infant and £297,816.03 (£4506.37 to £2,550,284.64) nationally, or £447.19 (£235.79 to £552.03) and £231,342.40 (£3923.7 to £1,922,192.22) if implemented via teleconsultations, respectively. The new strategies delivered are not likely to require additional resources compared with current practice. Further research is needed to investigate whether this investment represents good value for money for the NHS budget.

Global impact of COVID-19 on newborn screening programmes.

INTRODUCTION: The global COVID-19 pandemic has presented extraordinary disruption to healthcare services and exposed them to numerous challenges. Newborn screening (NBS) programmes were also affected; however, scarce data exist on the impact of COVID-19 on NBS. METHODS: We conducted an international survey to assess the global impact of COVID-19 on NBS, with the main aim of gathering the experiences of the COVID-19 pandemic from a large and representative number of NBS centres worldwide. RESULTS: The results of our study showed that COVID-19 impacted the NBS programmes, at least partially, in 29 out of 38 responding countries. Majority of the screening centres experienced a broad spectrum of difficulties and most were affected more in the second wave of the pandemic. Delays and unreliability with the postal service as well as flight cancellations caused delays in samples arriving to screening centres and with the provision of laboratory equipment and reagents. The availability of laboratory staff was sometimes reduced due to infection, quarantine or reassignment within the healthcare facility. Sample collection at home, second-tier tests and follow-up were also affected. Social restrictions and interruptions in public transport added to these difficulties. Only a limited number of centres managed to retain a fully functioning NBS programme. CONCLUSION: As the pandemic might continue or could recur in future years, it would be useful to develop guidelines to protect these valuable services.

Process evaluation of co-designed interventions to improve communication of positive newborn bloodspot screening results.

OBJECTIVE: To implement and evaluate co-designed interventions to improve communication of positive newborn bloodspot screening results and make recommendations for future research and practice. DESIGN: A process evaluation underpinned by Normalisation Process Theory. SETTING: Three National Health Service provider organisations in England. PARTICIPANTS: Twenty-four healthcare professionals (7 newborn screening laboratory staff and 24 clinicians) and 18 parents were interviewed. INTERVENTIONS: Three co-designed interventions were implemented in practice: standardised laboratory proformas, communication checklists and an email/letter template. PRIMARY OUTCOME MEASURES: Acceptability and feasibility of the co-designed interventions. RESULTS: Auditing the implementation of these interventions revealed between 58%-76% of the items on the laboratory proforma and 43%-80% of items on the communication checklists were completed. Interviews with healthcare professionals who had used the interventions in practice provided positive feedback in relation to the purpose of the interventions and the ease of completion both of which were viewed as enhancing communication of positive newborn bloodspot screening results. Interviews with parents highlighted the perceived benefit of the co-designed interventions in terms of consistency, pacing and tailoring of information as well as providing reliable information to families following communication of the positive newborn bloodspot screening result. The process evaluation illuminated organisational and contextual barriers during implementation of the co-designed interventions in practice. CONCLUSION: Variations in communication practices for positive newborn bloodspot screening results continue to exist. The co-designed interventions could help to standardise communication of positive newborn screening results from laboratories to clinicians and from clinicians to parents which in turn could improve parents' experience of receiving a positive newborn bloodspot screening result. Implementation highlighted some organisational and contextual barriers to effective adoption of the co-designed interventions in practice. TRIAL REGISTRATION NUMBER: ISRCTN15330120.

Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010.

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders ("conditions") then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40-50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together.

Regulatory landscape of providing information on newborn screening to parents across Europe.

Newborn screening (NBS) is an important part of public healthcare systems in many countries. The provision of information to parents about NBS is now recognised as an integral part of the screening process. Informing parents on all aspects of screening helps to achieve the benefits, promote trust and foster support for NBS. Therefore, policies and guidelines should exist to govern how the information about NBS is provided to parents, taking into account evidence-based best practices. The purpose of our survey was to explore whether any legally binding provisions, guidelines or recommendations existed pertaining to the provision of information about NBS to parents across Europe. Questions were designed to determine the regulatory process of when, by whom and how parents should be informed about screening. Twenty-seven countries participated in the survey. The results indicated that most countries had some sort of legal framework or guidelines for the provision of information to parents. However, only 37% indicated that the provision of information was required prenatally. The majority of countries were verbally informing parents with the aid of written materials postnatally, just prior to sample collection. Information was provided by a neonatologist, midwife or nurse. A website dedicated to NBS was available for 67% of countries and 89% had written materials about NBS for parents. The survey showed that there is a lack of harmonisation among European countries in the provision of information about NBS and emphasised the need for more comprehensive guidelines at the European level.

Performance of laboratory tests used to measure blood phenylalanine for the monitoring of patients with phenylketonuria.

Analysis of blood phenylalanine is central to the monitoring of patients with phenylketonuria (PKU) and age-related phenylalanine target treatment-ranges (0-12 years; 120-360 µmol/L, and >12 years; 120-600 µmol/L) are recommended in order to prevent adverse neurological outcomes. These target treatment-ranges are based upon plasma phenylalanine concentrations. However, patients are routinely monitored using dried bloodspot (DBS) specimens due to the convenience of collection. Significant differences exist between phenylalanine concentrations in plasma and DBS, with phenylalanine concentrations in DBS specimens analyzed by flow-injection analysis tandem mass spectrometry reported to be 18% to 28% lower than paired plasma concentrations analyzed using ion-exchange chromatography. DBS specimens with phenylalanine concentrations of 360 and 600 µmol/L, at the critical upper-target treatment-range thresholds would be plasma equivalents of 461 and 768 µmol/L, respectively, when a reported difference of 28% is taken into account. Furthermore, analytical test imprecision and bias in conjunction with pre-analytical factors such as volume and quality of blood applied to filter paper collection devices to produce DBS specimens affect the final test results. Reporting of inaccurate patient results when comparing DBS results to target treatment-ranges based on plasma concentrations, together with inter-laboratory imprecision could have a significant impact on patient management resulting in inappropriate dietary change and potentially adverse patient outcomes. This review is intended to provide perspective on the issues related to the measurement of phenylalanine in blood specimens and to provide direction for the future needs of PKU patients to ensure reliable monitoring of metabolic control using the target treatment-ranges.

Next Generation Sequencing in Newborn Screening in the United Kingdom National Health Service.

Next generation DNA sequencing (NGS) has the potential to improve the diagnostic and prognostic utility of newborn screening programmes. This study assesses the feasibility of automating NGS on dried blood spot (DBS) DNA in a United Kingdom National Health Service (UK NHS) laboratory. An NGS panel targeting the entire coding sequence of five genes relevant to disorders currently screened for in newborns in the UK was validated on DBS DNA. An automated process for DNA extraction, NGS and bioinformatics analysis was developed. The process was tested on DBS to determine feasibility, turnaround time and cost. The analytical sensitivity of the assay was 100% and analytical specificity was 99.96%, with a mean 99.5% concordance of variant calls between DBS and venous blood samples in regions with ≥30× coverage (96.8% across all regions; all variant calls were single nucleotide variants (SNVs), with indel performance not assessed). The pipeline enabled processing of up to 1000 samples a week with a turnaround time of four days from receipt of sample to reporting. This study concluded that it is feasible to automate targeted NGS on routine DBS samples in a UK NHS laboratory setting, but it may not currently be cost effective as a first line test.