Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation.
Journal
Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086
Informations de publication
Date de publication:
24 04 2019
24 04 2019
Historique:
received:
17
03
2018
revised:
24
10
2018
accepted:
01
04
2019
entrez:
26
4
2019
pubmed:
26
4
2019
medline:
19
5
2020
Statut:
ppublish
Résumé
By informing timely targeted treatments, rapid whole-genome sequencing can improve the outcomes of seriously ill children with genetic diseases, particularly infants in neonatal and pediatric intensive care units (ICUs). The need for highly qualified professionals to decipher results, however, precludes widespread implementation. We describe a platform for population-scale, provisional diagnosis of genetic diseases with automated phenotyping and interpretation. Genome sequencing was expedited by bead-based genome library preparation directly from blood samples and sequencing of paired 100-nt reads in 15.5 hours. Clinical natural language processing (CNLP) automatically extracted children's deep phenomes from electronic health records with 80% precision and 93% recall. In 101 children with 105 genetic diseases, a mean of 4.3 CNLP-extracted phenotypic features matched the expected phenotypic features of those diseases, compared with a match of 0.9 phenotypic features used in manual interpretation. We automated provisional diagnosis by combining the ranking of the similarity of a patient's CNLP phenome with respect to the expected phenotypic features of all genetic diseases, together with the ranking of the pathogenicity of all of the patient's genomic variants. Automated, retrospective diagnoses concurred well with expert manual interpretation (97% recall and 99% precision in 95 children with 97 genetic diseases). Prospectively, our platform correctly diagnosed three of seven seriously ill ICU infants (100% precision and recall) with a mean time saving of 22:19 hours. In each case, the diagnosis affected treatment. Genome sequencing with automated phenotyping and interpretation in a median of 20:10 hours may increase adoption in ICUs and, thereby, timely implementation of precise treatments.
Identifiants
pubmed: 31019026
pii: 11/489/eaat6177
doi: 10.1126/scitranslmed.aat6177
pmc: PMC9512059
mid: NIHMS1659831
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCATS NIH HHS
ID : U01 TR002271
Pays : United States
Organisme : NICHD NIH HHS
ID : U19 HD077693
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002550
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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