{
  "abstract": "Objective To evaluate systematic review approaches to synthesising evidence for policy advisers who are considering whether to screen newborns for hundreds of rare diseases using whole genome sequencing.Design Series of systematic reviews and roadmap for evidence generation for policy advisers.Data sources Medline, Embase, Science Citation Index, Cochrane Library.Methods 200 conditions included in Genomics England's Generation Study were stratified into five groups and one condition randomly selected from each group using criteria designed to maximise variability and availability of data. 30 systematic reviews were undertaken (five conditions, six review questions) about penetrance, detection rate, accuracy, benefit of earlier treatment, and benefits and harms of screening for the five conditions (search from inception to November 2023). Results were synthesised and reviewer time recorded. Genomic studies of newborn screening cohorts that reported penetrance were systematically reviewed using a non-condition specific approach (search inception to January 2024). The conditions and genes selected for reporting by these studies were identified. ClinGen was explored for synthesising evidence. All approaches were assessed by considering review effort and level and quality of evidence.Results The five conditions selected for systematic review were pyridoxine dependent epilepsy, heritable retinoblastoma, X linked hypophosphataemic rickets, familial haemophagocytic lymphohistiocytosis, and medium chain acyl-CoA dehydrogenase deficiency. 19 689 titles were screened and 268 papers included that addressed two of six research questions (detection rate and treatment benefit). No studies were identified for the remaining four research questions. Total reviewer time for five conditions was seven months. A team of five reviewers would take over 20 years to conduct similar reviews for 200 conditions. 10 published genomic studies of newborn screening cohorts were identified with a total of 76 268 newborns. The number of conditions screened for varied from 74 to 903, with low concordance (two of 1453 genes were included in all 10 studies). Selection of conditions was primarily based on clinical opinion. All studies reported and acted on genetic findings considered clinically significant, preventing collection of penetrance data.Conclusions Current evidence synthesis methods are neither feasible nor fruitful to provide policy advisers like the UK National Screening Committee with the evidence needed to understand the benefits and harms of newborn screening for multiple conditions using whole genome sequencing because the evidence is not available to synthesise. Evidence should be created through studies that only report pathogenic variants to parents and clinicians where penetrance and expressivity have been established through empirical evidence rather than clinical opinion. A roadmap for future evidence generation is proposed to highlight the need for new evidence generation combined with a staged approach to evaluation, focusing on pathogenic variants with evidence of high penetrance and expressivity.Registration Review registration PROSPERO (CRD42023475529).",
  "authors": [
    {
      "affiliations": [
        "Warwick Medical School, University of Warwick, Coventry, UK"
      ],
      "name": "Karoline Freeman"
    },
    {
      "affiliations": [
        "Warwick Medical School, University of Warwick, Coventry, UK"
      ],
      "name": "Dylan Taylor"
    },
    {
      "affiliations": [
        "Department of Applied Health Sciences, University of Birmingham, Birmingham, UK",
        "National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK"
      ],
      "name": "Jacqueline Dinnes"
    },
    {
      "affiliations": [
        "Warwick Medical School, University of Warwick, Coventry, UK"
      ],
      "name": "Corinna C A Clark"
    },
    {
      "affiliations": [
        "Warwick Medical School, University of Warwick, Coventry, UK"
      ],
      "name": "Inès Kander"
    },
    {
      "affiliations": [
        "Department of Applied Health Sciences, University of Birmingham, Birmingham, UK"
      ],
      "name": "Katie Scandrett"
    },
    {
      "affiliations": [
        "Warwick Medical School, University of Warwick, Coventry, UK"
      ],
      "name": "Shivashri Chockalingam"
    },
    {
      "affiliations": [
        "Warwick Medical School, University of Warwick, Coventry, UK"
      ],
      "name": "Naila Dracup"
    },
    {
      "affiliations": [
        "Warwick Medical School, University of Warwick, Coventry, UK"
      ],
      "name": "Rachel Court"
    },
    {
      "affiliations": [
        "Warwick Medical School, University of Warwick, Coventry, UK"
      ],
      "name": "Furqan Butt"
    },
    {
      "affiliations": [
        "UK National Screening Committee, London, UK"
      ],
      "name": "Cristina Visintin"
    },
    {
      "affiliations": [
        "Sheffield Children’s NHS Foundation Trust, Sheffield, UK"
      ],
      "name": "James R Bonham"
    },
    {
      "affiliations": [
        "Great Ormond Street Hospital for Children, London, UK"
      ],
      "name": "David Elliman"
    },
    {
      "affiliations": [
        "UK National Screening Committee, London, UK"
      ],
      "name": "Graham Shortland"
    },
    {
      "affiliations": [
        "UK National Screening Committee, London, UK"
      ],
      "name": "Anne Mackie"
    },
    {
      "affiliations": [
        "Division of Applied Medicine, University of Aberdeen College of Life Sciences and Medicine, Aberdeen, UK"
      ],
      "name": "Zosia Helena Miedzybrodzka"
    },
    {
      "affiliations": [
        "All Wales Medical Genomics Service, Cardiff, UK"
      ],
      "name": "Sian Mair Morgan"
    },
    {
      "affiliations": [
        "Warwick Medical School, University of Warwick, Coventry, UK"
      ],
      "name": "Felicity Kate Boardman"
    },
    {
      "affiliations": [
        "Department of Applied Health Sciences, University of Birmingham, Birmingham, UK",
        "National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK"
      ],
      "name": "Yemisi Takwoingi"
    },
    {
      "affiliations": [
        "Warwick Medical School, University of Warwick, Coventry, UK"
      ],
      "name": "Bethany Shinkins"
    },
    {
      "affiliations": [
        "Warwick Medical School, University of Warwick, Coventry, UK"
      ],
      "name": "Aileen Clarke"
    },
    {
      "affiliations": [
        "Warwick Medical School, University of Warwick, Coventry, UK"
      ],
      "name": "Sian Taylor-Phillips"
    }
  ],
  "title": "Challenges in evaluating whole genome sequencing for newborn screening: series of systematic reviews and roadmap for evidence generation for policy advisers",
  "uid": "7785be10-5b97-557c-8ea8-2cf70f0e4d9a"
}