The United Kingdom National screening committee and the evolution of the UK screening criteria

Established in 1996, the UKNSC serves to advise the NHS and ministers in all four countries of the UK with regards to all aspects of population screening and has responsibility for making recommendations with respect to which conditions are included in the screening programme. The UKNSC is accountable to the four CMOs, and currently recommends screening for 10 conditions via dried blood spots collected by a nurse, midwife or health visitor, five days following birth and sent to one of thirteen laboratories in the UK for testing (United Kindgom Government 2022b).

The conditions included in the UK NBS programme have been determined based on a set of criteria, derived from the principles originally developed by Wilson and Jungner in 1966 for general population screening (Table 1) (United Kingdom National Screening Committee 2022; Jungner G and Wilson JMG, 1966). The criteria have evolved since the establishment of the UKNSC in 1996, with a revised list of 20 criteria published two years later by the UKNSC in their first report (Table 1) (United Kingdom National Screening Committee 1998). Whilst the same set of screening criteria is currently in use, the process shifted in 2015, with annual calls put out for proposals to screen specific diseases (United Kingdom National Screening Committee 2023a). Valid proposals are taken forward by commissioning an evidence map from an external consultant (e.g. Costello Medical), whereby published research related to a particular proposed disease is reviewed against the 20 criteria set by the UKNSC to recommend screening. There is also public consultation, and anyone can submit a response to the call, including learned scientific or medical societies and individuals such as medical experts, scientists, patients, carers, and parents.

Table 1 Comparison of National screening committee criteria for population screening programme with original Wilson and Jungner principles of disease screening

Our analysis of meeting minutes and evidence maps of the 20 diseases put forward to the UKNSC reveals that none were recommended for NBS between 2015 and 2022. Tyrisonaemia Type 1 was recommended in early 2023 and only Severe Combined Immunodeficiency Disorder (SCID) has progressed to a pilot screen (Mackie 2023). Table 2 provides the list of the UKNSC criteria (from those cited in Table 1) not met for each of these 20 diseases. The three most common reasons for the UKNSC not recommending NBS for a specific disease are lack of a specific test (cited in seven cases), lack of high-quality randomised-controlled trials showing that the screening programme is effective in reducing mortality or morbidity (cited in five cases), and lack of UK-specific prevalence data (cited in five cases).

Table 2 Diseases reviewed for newborn screening in the UK since 2015Comparison of newborn screening criteria in the United States, the United Kingdom, and other European countries

In 2003, the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) was formed to advise the Secretary of Health and Human Services (SHHS) about newborn and childhood screening. In 2004, the ACHDNC reviewed the panel of conditions recommended for national implementation. The American College of Medical Genetics (ACMG, now the American College of Medical Genetics and Genomics) was tasked with collecting expert opinions and analysing scientific literature on NBS (Health Resources and Services Administration - Advisory Committee on Heritable Disorders in Newborns and Children, 2023). These findings were intended to inform recommendations, including the establishment of a standardised panel of conditions. The panel was finalised in 2005 and subsequently recommended to the SHHS, which officially approved it in 2008 (Health Resources and Services Administration - Advisory Committee on Heritable Disorders in Newborns and Children, 2023). The initial Recommended Uniform Screening Panel (RUSP) included 29 core conditions and 25 secondary conditions. Core conditions were those deemed suitable for immediate implementation, while secondary conditions were those that could be detected during screening for a core condition but required further research due to insufficient scoring. In 2010, severe combined immunodeficiency (SCID) was added, and by 2016, the panel had expanded to 35 core conditions and 26 secondary conditions (Health Resources and Services Administration - Advisory Committee on Heritable Disorders in Newborns and Children, 2023).

The ACHDNC follows a structured, evidence-based approach for evaluating conditions nominated for inclusion in the RUSP. After a condition gets nominated by researchers or advocacy groups, an external group compiles and analyses data for the ACHDNC, drawing from systematic literature reviews, decision-analytic modelling, and stakeholder input (Goldenberg et al. 2016). This process is structured around the chain of evidence, encompassing newborn screening, follow-up diagnostics, and treatment outcomes (Goldenberg et al. 2016). The ACHDNC then evaluates the net benefit of screening based on health outcomes, benefits, harms, and screening effectiveness, assigning a rating from A (high benefit) to L (low certainty of benefit) (Kemper et al. 2014). In 2013, the decision-making process was revised to include an assessment of the capability of newborn screening programmes to implement the test, evaluating feasibility and readiness (Kemper et al. 2014). The Decision Matrix integrates these ratings to guide recommendations, with conditions rated A1 or A2 being strongly recommended, while others may require further research or system improvements (Kemper et al. 2014). The final decision is submitted to the SHHS, who provides guidance for state-level implementation (Table 3).

Table 3 Decision-Making process for conditions nominated to the recommended uniform screening panel (RUSP)

Unlike a nationally mandated screening programme, the RUSP serves as a federal guideline for NBS. Individual states retain the authority to determine which conditions to include in their programmes. However, several states have enacted laws that align their NBS programmes with the RUSP, ensuring that any condition added to the federal panel is promptly included at the state level (Salova 2025).

Of note, in seven cases noted in Table 2, where the UKNSC did not recommend screening due to lack of a specific test, these diseases are currently screened for in the US programme (Biotinidase deficiency, Congenital Adrenal Hyperplasia, Galactosaemia, Long-chain 3-hydroxyacyl dehydrogenase deficiency, Mitochondrial Trifunctional Protein, Mucopolysaccharidosis I) (Health Resources and Services Administration - Advisory Committee on Heritable Disroders in Newborns and Children 2023). Indeed, eleven of the diseases not recommended by the UKNSC for newborns in UK are part of the NBS programme in the US, which highlights the dramatic difference in the approval process between the US and the UK. The UKNSC utilises this difference to claim that the UK process is more rigorous, whereas others argue that the UK screening criteria are not appropriate for all diseases, specifically rare genetic diseases (Genetic Alliance 2019; Page 2023; Downing and Pollitt 2008). It could be argued that the difference in the scope of the NBS programme between the US and the UK may be explained by variations in health economics and the contrast between public and private healthcare systems. However, the argument of cost versus benefit is not part of the criteria used by the UKNSC to make its initial recommendations to ministers and CMOs.

NBS programmes across European countries exhibit significant variability in both the number of conditions screened and the decision-making processes governing their inclusion. While some countries, such as the Netherlands (23 conditions) and Poland (29 conditions), have extensive screening panels, others, such as Greece (5 conditions) have more limited programmes (Therrell et al. 2024; Loeber et al. 2021). The governance over the screening policy also differs, with centralised bodies similar to the UKNSC such as Germany’s Federal Joint Committee and Netherland’s Centre for Population Screening of the National Institute for Public Health and the Environment overseeing inclusion based on predefined criteria, whereas countries like Italy and Spain allow regional health authorities to determine screening policies. Despite these differences, many countries in Europe still screen for considerably more conditions than the UK. For example, Sweden, Portugal and Austria screens for 24 conditions (Therrell et al. 2024; Loeber et al. 2021).

Case study – biotinidase deficiency

Biotinidase deficiency (BD) is an autosomal recessive metabolic disorder that affects the BTD gene; this gene is responsible for producing an enzyme called biotinidase (Online Mendelian Inheritance in Man (OMIM), 2023). The disorder occurs due to an absence of biotinidase activity, which results in the body’s inability to breakdown and recycle biotin, a B vitamin (Online Mendelian Inheritance in Man (OMIM), 2023). In the absence of normal biotinidase activity, babies tend to develop primary neurologic symptoms such as seizures, hypotonia, vision problems and hearing loss, along with cutaneous abnormalities, including skin rashes, alopecia and recurrent viral or fungal infections (Chedrawi et al. 2008; Yang et al. 2020). Treatment consists of lifelong oral supplementation with unbound (free) biotin (Dahiphale et al. 2008). Children diagnosed before symptom manifestation generally remain asymptomatic and appear to have a normal development if adequate adherence to biotin supplementation is maintained (Dahiphale et al. 2008; Szymanska et al. 2015). If babies are not diagnosed and treatment is delayed, children suffer different degrees of irreversible neurologic symptoms such as hearing loss, visual abnormalities, and developmental delays (Liu et al. 2023).

The 2021 evidence map concludes that whole population screening for BD in newborns should not be introduced in the UK and that the current recommendation should be retained (Costello Medical., 2021). The justification for this decision was based on two observations; firstly, while some evidence on the prevalence and incidence of BD in high-income countries exists, currently there is no evidence on the prevalence and incidence rates of BD in the UK (Costello Medical., 2021). Secondly, while evidence is available on the accuracy of current screening tests using the dried blood spots for BD in high-income countries, no UK-specific evidence was found (Costello Medical., 2021). It was then established that the limited number of studies currently available, the heterogeneity in the index tests examined, and the lack of consistency in the outcomes reported limited the comparability of the evidence available (Costello Medical., 2021).

On the basis of this evidence map, the UKNSC concluded that the volume and type of evidence related to screening for BD is currently insufficient to justify an update review at this stage and should be reconsidered in three-years time. Thus, while the UK still does not screen for BD, it is screened for in over 30 other countries, including the US.

(Wolf et al. 1985; Costello Medical., 2021; Therrell et al. 2024). Importantly the decision, not to recommend screening for BD, moved forward despite consultation responses from the Royal College of Paediatrics and Child Health and University College London Great Ormond Street Institute of Child Health urging for early screening for BD and citing evidence on improved outcomes when early treatment is initiated (Wolf 1993; Costello Medical., 2021). Barry Wolf, the pioneer of BD newborn screening, published in 2017 on the successful long-term outcomes of adolescents and adults with profound BD who were identified through newborn screening, showing normal cognitive development, academic achievement, and healthy pregnancies in treated individuals (Wolf 2017). Interestingly, BD is in the recently published list of diseases to be included in the upcoming NGP, despite being rejected for NBS by the UKNSC in 2012, 2018 and 2022.

Rare diseases and the voice of patients and parents

Rare diseases, though individually affecting only a limited number of patients, collectively impact a substantial portion of the global population. It is estimated that between three to six% of the global population suffer from a rare disease (Nguengang Wakap et al. 2020). Living with a rare disease presents a lifelong challenge, encompassing complex care needs that can significantly impact people’s quality of life (Ferreira 2019). Early diagnosis plays a pivotal role in providing individuals with rare diseases an opportunity to be involved in clinical trials and other research studies (United Kingdom Government Department of Health 2013; United Kingdom Government Department of Health 2023). Additionally, early diagnosis alleviates the emotional distress of families grappling with uncertainty, reduces the financial burden on the NHS by shortening an often-prolonged diagnostic odyssey, and facilitates the engagement of caregivers with patient support groups, offering invaluable enhancements to the quality of life for both the patients and their caregivers (Genetic Alliance 2019; European Organisation for Rare Diseases 2021). It is therefore vital that the voice of rare disease patients and that of their carers and family members is taken into consideration when developing wider national policy.

The report published in 2018 by GAUK was critical of the UKNSC with regards to how they had modified the original Wilson and Jungner criteria in a way that would make it highly unlikely to gain approval for NBS of a rare genetic disease (Genetic Alliance 2019). They noted that this had been done by re-wording of the original Wilson and Jungner criteria, for example “suitable test” had been changed to “validated test”, and “acceptable” treatment had been changed to “effective treatment” (Genetic Alliance 2019). Moreover, the inclusion of new criteria, such as the requirement for a high quality randomised controlled trial, created an additional barrier to the addition of rare genetic diseases to the UK NBS programme (Genetic Alliance 2019). In the UKNSC minutes published in 2020, it is noted that the committee reviewed the 2018 GAUK report and sent a response to the authors, but did not make any changes to the criteria with regards to NBS screening for rare genetic diseases (United Kingdom National Screening Committee, 2020). Similarly, no changes were made following the publication of EURORDIS recommendations in 2021 which promote screening that is proportionate to the reality of evidence challenges with rare diseases, and should not be unreasonable or impossible (European Organisation for Rare Diseases 2021). Nevertheless, in a blog on the website that celebrated 25 years of the UKNSC, the committee contended that the UK has “the most robust screening process in the world” (United Kingdom National Screening Committee 2021) (Table 4).

Table 4 The UK National screening committee four principles of ethical evaluationReform of the United Kingdom National screening committee

With the reorganisation of the UKNSC, a Blood Spot Task Group (BSTG) was established in 2022 consisting of paediatricians, academics, ethicists, quality assurance professionals, geneticists, as well as patient and public voice representatives (United Kingdom Government 2022). The task group’s first aims are to compare the UK screening and implementation practices with the EURODIS key principles in NBS, develop recommendations that meet the challenges of finding good quality evidence on the accuracy of different tests for rare genetic diseases, and develop a publication on the challenges and solutions in economic models relating to NBS (Seedat F., 2022).

Review of the BSTG meeting minutes in July 2023 reveals that a manuscript comparing the EURORDIS principles with UK practices was submitted for peer review, taking into consideration feedback received from patient and public voice members (United Kingdom National Screening Committee 2023b). In the paper, which was published two months later (Lombardo et al. 2023), the UKNSC concluded that UK practices are only partially aligned with the EURORDIS first principle, which recommends identifying opportunities to support the newborn and their family as broadly as possible, including making recommendations for screening of actionable conditions - defined by EURORDIS as conditions where early intervention leads to health benefits for the newborn, conditions where facilitation of early diagnosis avoids a prolonged diagnostic odyssey, or where there are improved outcomes for the family such as access to patient groups and informed reproductive rights (European Organisation for Rare Diseases 2021).The UKNSC maintains that NBS should only be recommended when a disease is treatable (Lombardo et al. 2023), which is in contrast to the approach of EUDORIS. It is surprising, therefore, that Genomics England has taken the decision to identify 223 rare genetic diseases in babies, most of which are not treatable, but are considered actionable diseases (Genomics England 2023c).

During 2020 and 2021, the UKNSC worked with a representative of the Nuffield Council on Bioethics to review the way the committee considers the ethical aspects of the current screening programme, and new members with expertise in ethics and social science were recruited (Joynson 2021). This resulted in the suggestion of four new core ethical principles that should be considered in the decision-making process of the UKNSC when examining new cases for NBS (Table 5) (Joynson 2021). However, it is not clear from the UKNSC minutes whether consideration of these four new ethical principles has had any influence on the committee’s current decision-making process.

In summary, the minutes of the UKNSC between 2015 and 2022 show that the UKNSC has rigidly adhered to an algorithmic decision-making process, which requires each of the 20 screening criteria (Table 1) to be met before recommending a new disease for NBS. As a result, between 2015 and 2022 no new disease has been added to the UK NBS programme, despite the voice of parents, and medical and scientific experts. By contrast, other countries have expanded their screening programmes considerably during this time by using low-cost biochemical assays and adopting a more pragmatic approach to their screening criteria.

Table 5 Ethical principles guiding the selection of conditions included in the newborn genomes programmeGenomics England and the introduction of the newborn genomes programme

In 2016, CMO Dame Sally Davies entitled her annual report ‘Generation Genome’, setting the stage for establishing Genomics England and the 500,000 Genome Project, Genomic England’s first initiative to sequence adult patients affected by rare diseases or cancer (Davies C. S., 2016). The main argument put forward for this work is the potential of personalised medicine and prevention over cure, which is predicted to increase population health and reduce healthcare costs. The project was funded by the Wellcome Trust (an independent medical charity), UK Research and Innovation (UKRI) with four Biopharmaceutical companies (Amgen, Astra Zeneca, GSK, and Johnson & Johnson), each contributing £120,000 million to the project (Bell 2019). Of note, the genomic data of individuals participating in the project was linked to their healthcare data, which was provided by the NHS. The full anonymised data (genomic and healthcare) from the 500,000 genomes project was released by the UK Biobank in 2023 with the four BioPharmaceutical companies given early access to the data, nine months before it was made public (Bell 2019). The value of this resource to the scientific community and businesses (eg Biopharma, healthcare and health insurance) is immeasurable and data from the BioBank has already contributed to over 9000 scientific research papers (Callaway 2023).

In 2020, Genomics England announced a public dialogue, jointly commissioned by the UKNSC, to assess whether the public would support whole genome sequencing of 100,000 newborns (Hopkins Van Mil., 2021; Pichini et al. 2022). A total of 133 participants took part in the public dialogue and the responses were reported to be ‘largely positive” (Hopkins Van Mil., 2021). This report has been used to evidence the public’s approval of genomic screening of newborns. However, participants’ demographics data such age, gender, religion, ethnicity, and educational level was not made available in the report. This information is important for assessing the validity of the study, and its absence limits the ability to evaluate the generalisability of the findings. Moreover, the small sample size did not allow for stratification of opinions according to different characteristics e.g. pregnant women, parents etc. Nevertheless, based on the “largely positive” response from the public consultation, an independent ethics committee was established to determine the criteria for inclusion of genetic diseases in the NGP (Genomics England 2023d). In 2022, a public survey with respect to these criteria was undertaken and four ethical principles were identified to guide the choice of conditions to be screened for as part of the NGP (Table 5) (Genomics England 2023b).

These principles diverge significantly from the criteria set by the UKNSC with respect to NBS. Firstly, the language used to describe these principles is open to interpretation, in particular when determining what is considered “strong evidence” or a “high proportion” of individuals. Secondly, the third principle set by Genomics England does not specify requirement for UK specific data or evidence from double-blind randomised clinical trials, which are conditions that need to be met for UKNSC to recommend screening. Moreover, whilst Genomics England published the list of conditions that will be included in the NGP, the evidence maps showing how these conditions meet the ethical criteria have not been made publicly available (Genomics England 2023a). It is clear that the ethical principles guiding the choice of conditions the NGP aims to identify through whole genome sequencing differ significantly from those of the UKNSC. While we would expect to see a change in ethical principles with time, it would not be ethically and morally acceptable to have the UKNSC NBS programme and the NGP operating at the same time, given that NGP is being promoted on the Genomics England website as ‘an extension of the NBS programme’, giving the impression that diseases screened for in the NGP could become part of the NBS in the future (Genomics England 2023c).

It could be argued that Genomics England does not have to strictly adhere to the UKNSC criteria. However, the NGP is a study involving 100,000 newborns and their families, and is imbedded in, and jointly run by, the NHS. Horton and Lucassen provide a critical examination of the complexities and challenges of newborn genome screening based on insights from the NC NEXUS and BabySeq projects – two studies conducted in the US that aimed to explore the use of genomic sequencing in newborns in identifying actionable conditions and assess its impact on health outcomes. The authors highlight that the findings from these projects often identified specific risks that were difficult to quantify and required resource-intensive monitoring, rather than offering straightforward diagnoses with actionable treatments (Horton and Lucassen 2023). The added costs of repeated investigations and regular reviews over the lifetime of these patients – who may never develop these conditions – will significantly impact the NHS and should be appropriately addressed prior to embarking on a study of this scale.

Another important aspect of the NGP is the nature of informed consent. Parents will have to sign a consent form on behalf of their baby. It is therefore vital to determine how information on the 223 genetic diseases will be presented to parents and at what point in time will it be presented to ensure consent is informed. Information of this significance should be delivered by trained professionals in the appropriate settings and at an appropriate time, with both parents being present for informed consent (Science Media Center 2022). Indeed, both UKNSC and EURORDIS agree that whenever new programmes are piloted in the UK, all stakeholders should be involved in the planning of and implementation of the project, including designing and field-testing information and educational materials about the conditions included in screening programmes, the tests, and the subsequent treatment pathways, with the relevant stakeholders, modifying this information based on their feedback (Genomics England 2021; European Organisation for Rare Diseases 2021). This is considered essential for efficient implementation of the programme and to enable parents to make informed decisions about NBS, or in this case, the NGP.