{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T13:49:43Z","timestamp":1792763383133,"version":"4.5.0"},"reference-count":193,"publisher":"National Institute for Health and Care Research","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000664","name":"Health Technology Assessment programme","doi-asserted-by":"publisher","award":["NIHR159928"],"award-info":[{"award-number":["NIHR159928"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journalslibrary.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["Health Technol Assess"],"abstract":"<jats:sec id=\"abs1-1\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Newborn screening using whole genome sequencing is being evaluated in numerous projects across the world, including Genomics England Limited\u2019s 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 \u2018genotype-first\u2019 approach has the potential for harms through overdiagnosis, and benefits are uncertain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-2\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-3\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-4\">\n                    <jats:title>Data sources<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>Actionability reports and scores from the Clinical Genome Resource website (downloaded 30 April 2024).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-5\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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 \u2018actionability\u2019 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-6\">\n                    <jats:title>Limitations<\/jats:title>\n                    <jats:p>Although we only examined five conditions in depth, the consistency in lack of data suggests that our conclusions are robust.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-7\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-8\">\n                    <jats:title>Future work<\/jats:title>\n                    <jats:p>Large-scale collaborative research is required to evaluate the short- and long-term harms, benefits and economic implications of whole genome sequencing for screening newborns. We propose a staged approach to evaluation, considering only conditions with pathogenic variants with high penetrance to minimise harm from overdiagnosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-9\">\n                    <jats:title>Study registration<\/jats:title>\n                    <jats:p>This study is registered as PROSPERO CRD42023475529.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs1-10\">\n                    <jats:title>Funding<\/jats:title>\n                    <jats:p>\n                      This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR159928) and is published in full in\n                      <jats:italic>Health Technology Assessment<\/jats:italic>\n                      ; Vol. 29, No. 65. See the NIHR Funding and Awards website for further award information.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3310\/djrf1124","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T08:57:11Z","timestamp":1739264231000},"page":"1-172","update-policy":"https:\/\/doi.org\/10.3310\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Evaluating whole genome sequencing for rare diseases in newborn screening: evidence synthesis from a series of systematic reviews"],"prefix":"10.3310","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9963-2918","authenticated-orcid":true,"given":"Karoline","family":"Freeman","sequence":"first","affiliation":[{"name":"Warwick Medical School, University of Warwick, Coventry, 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