{
  "abstract": "Reanalysis of genomic data in rare disease is highly effective in increasing diagnostic yields but remains limited by manual approaches. Automation and optimization for high specificity will be necessary to ensure scalability, adoption and sustainability of iterative reanalysis. We developed Talos, an open-source tool that automates variant prioritization by integrating dynamically updated gene-disease and variant-level evidence with inheritance-aware filtering and validated its performance using data from 1,089 individuals with rare disease. Trio-based analysis identified 90% of known diagnoses, returning 1.3 variants per case on average. Variant burden reduced to one variant per 200 cases on iterative monthly reanalysis. Application to an unselected cohort of 4,735 undiagnosed individuals identified 241 diagnoses (5.1% yield): 78 (32%) due to new gene-disease relationships, 54 (22%) due to new variant-level evidence and 109 (45%) due to improved analysis strategies. Our automated, iterative reanalysis model demonstrates the feasibility of delivering frequent, systematic reanalysis at scale.",
  "abstract_shown": true,
  "affiliations": [
    "Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia",
    "Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia",
    "Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA",
    "Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia",
    "Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia",
    "Institute for Molecular Bioscience and Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia",
    "Townsville Hospital and Health Service, Townsville, Queensland, Australia",
    "Clinical Genetics Service, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia",
    "Garvan Institute of Medical Research, Sydney, New South Wales, Australia",
    "Murdoch Children's Research Institute, Melbourne, Victoria, Australia",
    "University of Melbourne, Melbourne, Victoria, Australia",
    "Royal Children's Hospital, Melbourne, Victoria, Australia",
    "Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia",
    "Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia",
    "Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia",
    "Centre for Cancer Biology, an alliance between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia",
    "UniSA Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia",
    "Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia",
    "Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia",
    "Department of Pathology, Royal Melbourne Hospital, Melbourne, Victoria, Australia",
    "Microsoft Research, Redmond, WA, USA",
    "Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA",
    "Australian Genomics, Melbourne, Victoria, Australia. zornitza.stark@vcgs.org.au",
    "University of Melbourne, Melbourne, Victoria, Australia. zornitza.stark@vcgs.org.au",
    "Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia. zornitza.stark@vcgs.org.au"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 37,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Matthew J. Welland",
      "orcid": "0000-0001-5963-863X"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "K. D. Ahlquist",
      "orcid": "0000-0001-6812-9458"
    },
    {
      "affs": [
        4
      ],
      "name": "Paul De Fazio"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Christina Anne Austin-Tse",
      "orcid": "0000-0001-6492-6716"
    },
    {
      "affs": [
        3
      ],
      "name": "Lynn S. Pais",
      "orcid": "0000-0001-9673-4305"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Laura Wedd"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Samantha Bryen"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Rocío Rius",
      "orcid": "0000-0002-9871-3126"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Michael Franklin"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Caitlin Morrison"
    },
    {
      "affs": [
        5
      ],
      "name": "Giles Hall",
      "orcid": "0009-0003-5984-0071"
    },
    {
      "affs": [
        2,
        5
      ],
      "name": "Laura Gauthier"
    },
    {
      "affs": [
        5,
        3
      ],
      "name": "Alex Bloemendal"
    },
    {
      "affs": [
        4
      ],
      "name": "David I. Francis",
      "orcid": "0000-0002-4620-9315"
    },
    {
      "affs": [
        6,
        7,
        8
      ],
      "name": "Andrew John Mallett",
      "orcid": "0000-0002-8752-2551"
    },
    {
      "affs": [
        9,
        10
      ],
      "name": "Amali C. Mallawaarachchi",
      "orcid": "0000-0002-1229-1701"
    },
    {
      "affs": [
        11,
        12
      ],
      "name": "Paul J. Lockhart",
      "orcid": "0000-0003-2531-8413"
    },
    {
      "affs": [
        11,
        13,
        12
      ],
      "name": "Richard Jacob Leventer",
      "orcid": "0000-0003-0362-5607"
    },
    {
      "affs": [
        14,
        13,
        12
      ],
      "name": "Ingrid Eileen Scheffer",
      "orcid": "0000-0002-2311-2174"
    },
    {
      "affs": [
        11,
        13,
        12
      ],
      "name": "Katherine B. Howell",
      "orcid": "0000-0002-5469-8411"
    },
    {
      "affs": [
        15,
        16
      ],
      "name": "Karin S. Kassahn",
      "orcid": "0000-0002-1662-3355"
    },
    {
      "affs": [
        15,
        17,
        16,
        18
      ],
      "name": "Hamish S. Scott",
      "orcid": "0000-0002-5813-631X"
    },
    {
      "affs": [
        19,
        20
      ],
      "name": "Julie M. McGaughran",
      "orcid": "0000-0002-0926-7858"
    },
    {
      "affs": [
        11,
        12
      ],
      "name": "John Christodoulou",
      "orcid": "0000-0002-8431-0641"
    },
    {
      "affs": [
        11,
        12,
        4
      ],
      "name": "David Ross Thorburn",
      "orcid": "0000-0002-7725-9470"
    },
    {
      "affs": [
        21
      ],
      "name": "Bryony A. Thompson",
      "orcid": "0000-0001-8655-1839"
    },
    {
      "affs": [
        20
      ],
      "name": "Chirag Patel",
      "orcid": "0000-0002-6374-5224"
    },
    {
      "affs": [
        22
      ],
      "name": "Greg Smith"
    },
    {
      "affs": [
        2,
        23,
        3
      ],
      "name": "Anne O’Donnell‐Luria",
      "orcid": "0000-0001-6418-9592"
    },
    {
      "affs": [
        11,
        4
      ],
      "name": "Simon Sadedin",
      "orcid": "0000-0002-2144-7894"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Heidi L. Rehm",
      "orcid": "0000-0002-6025-0015"
    },
    {
      "affs": [
        11,
        12,
        4
      ],
      "name": "Sebastian Lunke",
      "orcid": "0000-0002-7168-0723"
    },
    {
      "affs": [
        22
      ],
      "name": "Jeremiah D. Wander",
      "orcid": "0000-0003-4125-8983"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Kaitlin E. Samocha",
      "orcid": "0000-0002-1704-3352"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Cas Simons",
      "orcid": "0000-0003-3147-8042"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Daniel G. MacArthur",
      "orcid": "0000-0002-5771-2290"
    },
    {
      "affs": [
        24,
        25,
        26
      ],
      "name": "Zornitza Stark",
      "orcid": "0000-0001-8640-1371"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9gmhgebew2fba.bib",
  "cited_by": 21,
  "doi": "10.1038/s41591-026-04477-5",
  "fulltext_url": null,
  "id": "9gmhgebew2fba",
  "issns": [
    "1078-8956",
    "1546-170X",
    "1744-7933"
  ],
  "landing_url": "https://doi.org/10.1038/s41591-026-04477-5",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1311|Genomics and Rare Diseases"
    ]
  ],
  "openalex": "W7165748861",
  "pdf_url": "https://www.nature.com/articles/s41591-026-04477-5.pdf",
  "pmcid": "PMC13472938",
  "pmid": "42343115",
  "published": "2026-06-24",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/9gmhgebew2fba.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:48Z",
      "native_id": "W7165748861",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41591-026-04477-5"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Genomics and Rare Diseases",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Automated reanalysis of genomic data for rare disease diagnostics at scale",
  "title_text": "Automated reanalysis of genomic data for rare disease diagnostics at scale",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T13:20:47Z",
  "url": "https://research.draconitic.com/paper/9gmhgebew2fba",
  "venue": "Nature Medicine",
  "versions": []
}