Shivashri Chockalingam

Background: 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. Objective: 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. 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. Data sources: 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). Results: 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. Limitations: Although we only examined five conditions in depth, the consistency in lack of data suggests that our conclusions are robust. Conclusions: 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. Future work: 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. Study registration: This study is registered as PROSPERO CRD42023475529. Funding: 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 Health Technology Assessment ; Vol. 29, No. 65. See the NIHR Funding and Awards website for further award information.

Background: Assessment of newborn screening using whole genome sequencing (WGS) presents considerable challenges for policy advisors, not least given the logistics of simultaneously evaluating the evidence for 200 rare genetic conditions. The ‘genotype first’ approach has the potential for harms, and benefits are uncertain. Objective: To assess different approaches to evaluating WGS for newborn screening to inform the development of a robust method for informing policy decisions. Methods: We undertook ‘traditional’ reviews of five conditions using standard systematic review methods (considering gene penetrance, expressivity, and prevalence, the accuracy and effectiveness of WGS, and effect of earlier treatment) (search inception to November 2023), evaluated the NIH Clinical Genome Resource (ClinGen) for evidence on the five conditions, reviewed genomic studies of paediatric screening cohorts reporting penetrance for pathogenic variants (search inception to February 2024) and undertook a methodological review of economic evaluations of WGS/ whole exome sequencing (WES) (search inception to January 2024). We explored public views on evaluating WGS. Data sources: MEDLINE (Ovid), Embase (Ovid), Web of Science, Science Citation Index (via Clarivate), the Cochrane Library (via Wiley), CEA registry and Econlit. Actionability reports and scores were downloaded from the ClinGen website on 30 ^th April 2024. Results: The traditional review approach identified 221 studies that either reported on the genetic spectrum of individuals with the five conditions or provided limited evidence about the benefits of earlier treatment. No evidence about penetrance and expressivity or the accuracy or effectiveness of WGS in newborns was identified. ClinGen reviews were available for four of the five conditions. The ClinGen ‘actionability’ ratings for all four conditions disagreed with the findings of our traditional 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 for consideration in a screening programme. None of the 86 economic evaluations of WGS or WES were set in a screening context. Some micro-costing studies are available that could help understand the resource use and costs associated with WGS. Following a series of PPI meetings, attendees appreciated the uncertainties of WGS and suggested that a wider stakeholder perspective was needed to inform policy decisions. Limitations: Although we only examined five conditions in depth, the consistency in lack of data suggests our conclusions are robust. Conclusions: The traditional systematic review approach for evaluating WGS of newborns identified a paucity of high-quality evidence. Extending the review to all 200 conditions is not feasible and is unlikely to yield the level of evidence required by policy advisors. The use of existing genome resources and review of genomic studies of newborn screening cohorts were not found to be viable alternatives. The cost-effectiveness of WGS in a newborn screening context is unknown. Future work: Large-scale collaborative research is required to evaluate the short- and long-term harms, benefits and economic implications of WGS for screening newborns. We propose a staged approach to evaluation considering only conditions with pathogenic variants with very high penetrance to minimise harm from overdiagnosis. Study registration: The protocol for this study is registered on PROSPERO: CRD42023475529 Funding details: This study/project is funded by the NIHR Evidence Synthesis Programme (ESG_HTA_NIHR159928). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.