Authors' objectives: Newborn screening using whole genome sequencing is being evaluated in numerous projects across the world, including Genomics England Limited’s Generation Study. It presents considerable challenges for policy advisors, not least, given the logistics of simultaneously evaluating the evidence for the suggested 200 rare genetic conditions. The ‘genotype-first’ approach has the potential for harms through overdiagnosis, and benefits are uncertain. To assess different approaches to evaluating whole genome sequencing for newborn screening to inform the development of a robust method of evaluation for informing policy decisions. In 2021, Genomics England Limited (GEL) launched its Generation Study of whole genome sequencing (WGS) to screen for over 200 rare diseases in 100,000 newborns to explore its potential for an expanded UK newborn screening programme. This presents a number of new challenges for policy advisors. Multiplex testing has been available for years. Tandem mass spectrometry, currently used in the newborn blood spot (NBS) screening programme, can detect dozens of statistical abnormalities in the blood spot. Each condition included on the NBS programme and any potential candidate conditions have been assessed in turn. However, there is pressure to assess all the conditions that might be found with WGS at once. The genotype-first approach has the potential for harms, and in some cases, may be more uncertain than more traditional methods. Not everyone with a pathogenic variant will develop symptomatic disease (incomplete penetrance), and symptoms caused by the same genetic variant can vary in severity among affected people (expressivity). A cost-effectiveness analysis of WGS in newborn screening will be needed for a policy decision, but screening for potentially hundreds of conditions with a single test will require a different methodological approach than one that focuses on a single condition. Finally, the use of WGS for newborn screening presents several ethical challenges. The majority are common to all screening programmes (anxiety, informed choice and penetrance), but there are some that are more pressing or likely in this programme. For example, some of the genetic variants might only be of significance later in life, and there are implications for the relatives if a variant is found and there is considerable commercial interest in secondary uses of the data which will not benefit participants directly. We, therefore, aimed to (1) assess different evidence sources and approaches to evidence synthesis, (2) review methods for evaluating cost-effectiveness and (3) collate views of the public on the main challenges of WGS to inform an approach to assessing WGS for newborn screening in the future. To undertake a series of five systematic reviews covering a stratified (by burden and cost of the intervention) random sample of rare diseases to establish the evidence base per condition and to provide a reference case for comparison with alternative review approaches. The reviews addressed six questions mapped to the UK National Screening Committee (NSC) criteria on penetrance and expressivity, the proportion of children with disease who carry gene variants, test accuracy, effectiveness of earlier treatment, effectiveness and benefits and harms of WGS. To explore the utility of the existing online resource Clinical Genome Resource (ClinGen) to provide evidence on the actionability of rare paediatric genetic diseases in order to evaluate it as a potential evidence source for the UK NSC. To undertake a review of genomic studies of newborn screening cohorts reporting penetrance of pathogenic variants to explore the feasibility of identifying highly penetrant pathogenic variants that could be considered for a screening programme. To produce a methodological overview of existing published economic evaluations and costing studies of WGS or whole exome sequencing (WES). To explore patient and public views about the introduction of WGS for newborn screening.

Authors' results and conclusions: The traditional review approach identified 268 studies reporting the genetic spectrum of individuals with the five conditions or benefits of earlier, symptomatic treatment. No evidence on the penetrance and expressivity or the accuracy or effectiveness of whole genome sequencing in newborns was identified. A review of 200 conditions would take a team of five reviewers 23 years to complete. Clinical Genome Resource reviews were available for four or five conditions. All four ‘actionability’ ratings disagreed with the findings of our reviews. Our review of 14 genomic studies of newborn screening cohorts found insufficient information to allow individual highly penetrant pathogenic variants for any condition to be identified. None of the 86 economic evaluations of whole genome sequencing or whole exome sequencing were set in a screening context. Some micro-costing studies are available that could help understand the resource use and costs associated with whole genome sequencing. Following a series of patient and public involvement meetings, attendees appreciated the uncertainties of whole genome sequencing. A wider stakeholder perspective is needed to inform policy decisions. The systematic review approach for evaluating whole genome sequencing of newborns identified a paucity of high-quality evidence. Extending the review to all 200 conditions is not feasible. Currently, the use of existing genome resources and review of genomic studies of newborn screening cohorts are not viable alternatives. The cost-effectiveness of whole genome sequencing in a newborn screening context is unknown. Review of five conditions Extrapolating the traditional approach to 200 conditions We screened 19,689 titles and abstracts for the 5 traditional reviews, of which 1348 were selected for full-text assessment (range 55–449 per condition). A total of 268 studies were eligible for inclusion across the 5 reviews (range 31–78). No evidence was identified for the four review questions that required studies to be conducted in newborns. Overall, the five traditional reviews yielded very little of the evidence required by the UK NSC. Considering the time taken to identify and select the evidence, and extrapolating to a review of 200 conditions, we could expect as many as 787,560 unique records, 53,920 full texts to be screened and 8840 studies to be reviewed and synthesised, which is estimated to take a team of 5 reviewers 23 years to complete. A traditional systematic review approach to evaluating WGS of newborns is unfeasible, and we were unable to identify an acceptable alternative way to evaluate WGS for newborn screening in a single mechanism. Cost-effectiveness evidence for WGS has only focused on symptomatic populations to date. Our review highlights the main evidence gaps and informs the direction of future research efforts. We propose research undertaken in large joined-up collaborations to produce the evidence that is needed for policy advisors before an evaluation of WGS is feasible. This may include a co-ordinated international approach to collecting penetrance data for pathogenic variants with a clear treatment plan. This could be followed by a staged approach of evaluation considering only those of the 200 conditions for screening that have pathogenic variants with very high penetrance.

Authors' methods: We approached the objective with systematic review methods for a sample of five conditions (considering gene penetrance, expressivity, accuracy and effectiveness of whole genome sequencing and effect of earlier treatment) (search inception to November 2023), evaluated the National Institutes of Health [US] Clinical Genome Resource (ClinGen) as an alternative evidence source for the five conditions and we compared this to a review of genomic studies of newborn screening cohorts reporting penetrance for pathogenic variants of any paediatric condition (search inception to February 2024). We undertook a methodological review of economic evaluations of whole genome sequencing/whole exome sequencing (search inception to January 2024) and explored public views on evaluating whole genome sequencing. MEDLINE (Ovid), EMBASE (Ovid), Web of Science, Science Citation Index (via Clarivate), the Cochrane Library (via Wiley), cost-effectiveness analysis registry and American Economic Association electronic bibliography. Actionability reports and scores from the Clinical Genome Resource website (downloaded 30 April 2024). Although we only examined five conditions in depth, the consistency in lack of data suggests that our conclusions are robust. Review of five conditions A stratified random sample of five conditions was reviewed. Stratification was based on a range of scenarios that might reasonably have an impact on the UK NSC’s recommendations relating to WGS for newborn screening. The five conditions were: pyridoxine-dependent epilepsy (PDE) heritable retinoblastoma (hRB) X-linked hypophosphataemic rickets (XLHR) familial haemophagocytic lymphohistiocytosis medium-chain acyl-CoA dehydrogenase deficiency (MCADD). Data sources MEDLINE (via Ovid), EMBASE (via Ovid), Science Citation Index (SCI) (via Clarivate) and the Cochrane Library (via Wiley) from inception to November 2023. Study eligibility criteria were defined for each review question and included the following: Population This included the below: studies of newborn screening cohorts, or studies of newborns and children (≤ 18 years) with clinical, or biochemical and clinical features of the five conditions. Exposure/intervention This included the below: presence of pathogenic variants in the relevant gene(s) detected by sequencing eligible interventions relevant to the screening context, with ‘early’ intervention defined separately for each condition. Target condition This included the below: clinically or clinically and biochemically defined disease. Outcomes These included the below: measures of disease-specific morbidity and mortality any health-related health outcomes that could be measured across conditions any harms or other benefits from WGS. We produced a narrative synthesis of studies. Data source: MEDLINE (Ovid), EMBASE (Ovid), cost-effectiveness analysis registry, Web of Science (WoS) and American Economic Association electronic bibliography (EconLit) from inception to February 2024 and hand searches of identified systematic reviews. Study eligibility criteria: Economic evaluations, clinical trials and Health Technology Assessments reporting costs of WGS or WES in human health care. Evidence synthesis: a general narrative synthesis of the methodological approaches adopted will be reported. We will also focus on two specific methodological questions: How were the costs associated with WGS and WES estimated? What comparators were included in each study?

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/NIHR159928

Year Published: 2025

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/DJRF1124

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/DJRF1124

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk