Evidence map›Paper›PMID 42343115›Full record

ArticleNature medicine2026

Automated reanalysis of genomic data for rare disease diagnostics at scale.

Matthew J Welland, K D Ahlquist, Paul De Fazio, Christina Austin-Tse, Lynn Pais, Laura Wedd, Samantha Bryen, Rocio Rius, Michael Franklin, Caitlin Morrison and 27 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Review
  3. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

37 authors.

Matthew J Welland *Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.
K D Ahlquist *Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Paul De Fazio *Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Christina Austin-TseCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Lynn PaisProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Laura WeddCentre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.
Samantha BryenCentre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.
Rocio RiusCentre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-9871-3126
Michael FranklinCentre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.
Caitlin MorrisonCentre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.
Giles HallData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0009-0003-5984-0071
Laura GauthierCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Alex BloemendalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
David I FrancisVictorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Andrew J MallettTownsville Hospital and Health Service, Townsville, Queensland, Australia.ORCID http://orcid.org/0000-0002-8752-2551
Amali MallawaarachchiClinical Genetics Service, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
Paul J LockhartMurdoch Children's Research Institute, Melbourne, Victoria, Australia.ORCID http://orcid.org/0000-0003-2531-8413
Richard LeventerMurdoch Children's Research Institute, Melbourne, Victoria, Australia.ORCID http://orcid.org/0000-0003-0362-5607
Ingrid E SchefferUniversity of Melbourne, Melbourne, Victoria, Australia.
Katherine B HowellMurdoch Children's Research Institute, Melbourne, Victoria, Australia.ORCID http://orcid.org/0000-0002-5469-8411
Karin S KassahnDepartment of Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia.ORCID http://orcid.org/0000-0002-1662-3355
Hamish S ScottDepartment of Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia.ORCID http://orcid.org/0000-0002-5813-631X
Julie McGaughranGenetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
John ChristodoulouMurdoch Children's Research Institute, Melbourne, Victoria, Australia.ORCID http://orcid.org/0000-0002-8431-0641
David R ThorburnVictorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.ORCID http://orcid.org/0000-0002-7725-9470
Bryony A ThompsonDepartment of Pathology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
Chirag V PatelGenetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
Greg SmithMicrosoft Research, Redmond, WA, USA.
Anne O'Donnell-LuriaCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0001-6418-9592
Simon SadedinVictorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Heidi L RehmCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Sebastian LunkeVictorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.ORCID http://orcid.org/0000-0002-7168-0723
Jeremiah WanderMicrosoft Research, Redmond, WA, USA.
Kaitlin E SamochaCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-1704-3352
Cas SimonsCentre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0003-3147-8042
Daniel G MacArthurCentre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-5771-2290
Zornitza StarkVictorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia. zornitza.stark@vcgs.org.au.ORCID http://orcid.org/0000-0001-8640-1371

Funding

Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5M
Broad Institute Mendelian Genomic Research CenterU01HG011755 · NHGRI · BROAD INSTITUTE, INC. · PI Anne O'Donnell-Luria, MICHAEL E TALKOWSKI · 2021 to 2026
$14.6M
A powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9M
Department of Health | National Health and Medical Research Council (NHMRC) GNT1113531Department of Health | National Health and Medical Research Council (NHMRC) GNT2000001NHGRI NIH HHS R01 HG009141NHGRI NIH HHS U01 HG011755NHGRI NIH HHS UM1 HG008900U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) R01HG009141U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) U01HG011755U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) UM1HG008900
6 · The paper itself

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.

Indexed as

GenomicsRare DiseasesAutomationHumansSoftware

Identifiers

PMID42343115
PMCPMC13472938

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.