Healthcare professionals' and parents' experiences of the confirmatory testing period:A qualitative study of the UK expanded newborn screening pilot

Background: With further expansion of the number of conditions for which newborn screening can be undertaken, it is timely to consider the impact of positive screening results and the confirmatory testing period on the families involved. This study was undertaken as part of a larger programme of work to evaluate the Expanded Newborn Screening (ENBS) programme in the United Kingdom (UK). It was aimed to determine the views and experiences of healthcare professionals (HCPs) and parents on communication and interaction during the period of confirmatory testing following a positive screening result. Methods: Semi-structured interviews were undertaken with parents of children who had received a positive ENBS result and HCPs who had been involved with the diagnosis and support of parents. Ten parents and 11 healthcare professionals took part in the in-depth interviews. Questions considered the journey from the positive screening result through confirmatory testing to a confirmed diagnosis and the communication and interaction between the parents and HCPs that they had been experienced. Key themes were identified through thematic analysis. Results: The results point to a number of elements within the path through confirmatory testing that are difficult for parents and could be further developed to improve the experience. These include the way in which the results are communicated to parents, rapid turnaround of results, offering a consistent approach, exploring interventions to support family relationships and reviewing the workload and scheduling implications for healthcare professionals. Conclusions: As technology enables newborn screening of a larger number of conditions, there is an increasing need to consider and mediate the potentially negative effects on families. The findings from this study point to a number of elements within the path through confirmatory testing that are difficult for parents and could be further developed to benefit the family experience

Stakeholder views of the proposed introduction of next generation sequencing into the cystic fibrosis screening protocol in England

The project aimed to gather, analyze and compare views of stakeholders on 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. Par-ticipants were recruited from 12 CF centers in the UK. Twenty-eight adults with experience of CF (parents of children with CF [n=21], parents of children with CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS)/CF Screen Positive – Inconclusive Diag-nosis (CFSPID), an uncertain outcome [n=3] and adults with CF [n=4]), and nine health profes-sionals 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 explana-tions about potential outcomes including uncertainty (CFSPID) at the time of screening was em-phasized. More research is needed to inform definitive guidelines for managing children with an uncertain outcome following CF screening

3q26 Amplification is Rarely Present in Women Whose LSIL Cytology does not Represent CIN 2+ Disease

Comparative Medicine - OneHealth and Comparative Medicine Poster SessionObjective: 10-17% of women with LSIL cytology truly have CIN 2+ disease at colposcopically directed biopsy and 20% of the CIN 2+ lesions derive from women with LSIL cytology. No molecular marker has yet been able to triage LSIL cytology effectively. If possible, the triage would spare women the referral to colposcopy. Irreversible chromosomal damage occurs during oncogenesis. Increasing cervical dysplastic severity occurs with increasing amplification of the 3q26 chromosomal region. The purpose of this study is to evaluate the test characteristics of 3q26 amplification in women whose routine cytology is reported as LSIL with emphasis on the negative predictive value for reassurance. Methods: We conducted a retrospective study using the available SurePath™ liquid cytology LSIL archival samples from women 17-59 years old which were linked to colposcopically directed biopsy samples taken on average 36 days after cytology sampling (3-90 day range). Nuclei from the LSIL samples were hybridized with a single-copy probe for the chromosome 3q26 region and a control probe for the centromeric alpha repeat sequence of chromosome 7, using standard FISH methods. Amplification was defined as five or more signals present in at least 2 cells. Results: Of the 68 paired cytology/biopsy samples, 3q26 amplification occurred in 40% of the women with CIN 2+ disease (sensitivity 95% CI: 12, 74). There was no amplification in 91% of women with less than CIN 2 disease (specificity 95% CI: 81, 97); and the negative predictive value was 90% (79, 96). Conclusions: The lack of 3q26 amplification in women with screening cytology LSIL results offers reassurance that CIN 2+ disease has not developed. Future prospective studies are ongoing

Global impact of COVID-19 on newborn screening programmes.

peer reviewedINTRODUCTION: 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

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

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

A database of chlorophyll a in Australian waters

© The Author(s) 2018. Chlorophyll a is the most commonly used indicator of phytoplankton biomass in the marine environment. It is relatively simple and cost effective to measure when compared to phytoplankton abundance and is thus routinely included in many surveys. Here we collate 173, 333 records of chlorophyll a collected since 1965 from Australian waters gathered from researchers on regular coastal monitoring surveys and ocean voyages into a single repository. This dataset includes the chlorophyll a values as measured from samples analysed using spectrophotometry, fluorometry and high performance liquid chromatography (HPLC). The Australian Chlorophyll a database is freely available through the Australian Ocean Data Network portal (https://portal.aodn.org.au/). These data can be used in isolation as an index of phytoplankton biomass or in combination with other data to provide insight into water quality, ecosystem state, and relationships with other trophic levels such as zooplankton or fish

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

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