PMID- 31019026
OWN - NLM
STAT- MEDLINE
DCOM- 20200518
LR  - 20220928
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 11
IP  - 489
DP  - 2019 Apr 24
TI  - Diagnosis of genetic diseases in seriously ill children by rapid whole-genome 
      sequencing and automated phenotyping and interpretation.
LID - 10.1126/scitranslmed.aat6177 [doi]
LID - eaat6177
AB  - 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.
CI  - Copyright (c) 2019 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works.
FAU - Clark, Michelle M
AU  - Clark MM
AUID- ORCID: 0000-0001-6828-8934
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Hildreth, Amber
AU  - Hildreth A
AUID- ORCID: 0000-0003-1412-3442
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
AD  - Department of Pediatrics, University of California San Diego, San Diego, CA 
      92093, USA.
AD  - Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
FAU - Batalov, Sergey
AU  - Batalov S
AUID- ORCID: 0000-0002-0925-0554
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Ding, Yan
AU  - Ding Y
AUID- ORCID: 0000-0002-9914-9352
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Chowdhury, Shimul
AU  - Chowdhury S
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Watkins, Kelly
AU  - Watkins K
AUID- ORCID: 0000-0002-7747-9967
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Ellsworth, Katarzyna
AU  - Ellsworth K
AUID- ORCID: 0000-0001-6269-4771
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Camp, Brandon
AU  - Camp B
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Kint, Cyrielle I
AU  - Kint CI
AD  - Diploid, 3001 Leuven, Belgium.
FAU - Yacoubian, Calum
AU  - Yacoubian C
AD  - Clinithink Ltd., London N1 6DR, UK.
FAU - Farnaes, Lauge
AU  - Farnaes L
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
AD  - Department of Pediatrics, University of California San Diego, San Diego, CA 
      92093, USA.
FAU - Bainbridge, Matthew N
AU  - Bainbridge MN
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
AD  - Codified Genomics, LLC, Houston, TX 77033, USA.
FAU - Beebe, Curtis
AU  - Beebe C
AD  - Rady Children's Hospital, San Diego, CA 92123, USA.
FAU - Braun, Joshua J A
AU  - Braun JJA
AUID- ORCID: 0000-0002-9601-3185
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Bray, Margaret
AU  - Bray M
AUID- ORCID: 0000-0003-2475-730X
AD  - Alexion Pharmaceuticals Inc., New Haven, CT 06510, USA.
FAU - Carroll, Jeanne
AU  - Carroll J
AUID- ORCID: 0000-0003-3673-0323
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
AD  - Department of Pediatrics, University of California San Diego, San Diego, CA 
      92093, USA.
FAU - Cakici, Julie A
AU  - Cakici JA
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Caylor, Sara A
AU  - Caylor SA
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Clarke, Christina
AU  - Clarke C
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Creed, Mitchell P
AU  - Creed MP
AUID- ORCID: 0000-0002-8388-7078
AD  - University of Kansas School of Medicine, Kansas City, MO 66160, USA.
FAU - Friedman, Jennifer
AU  - Friedman J
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
AD  - Department of Neurosciences, University of California San Diego, San Diego, CA 
      92093, USA.
FAU - Frith, Alison
AU  - Frith A
AD  - Clinithink Ltd., London N1 6DR, UK.
FAU - Gain, Richard
AU  - Gain R
AD  - Clinithink Ltd., London N1 6DR, UK.
FAU - Gaughran, Mary
AU  - Gaughran M
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - George, Shauna
AU  - George S
AUID- ORCID: 0000-0003-2312-6098
AD  - Rady Children's Hospital, San Diego, CA 92123, USA.
FAU - Gilmer, Sheldon
AU  - Gilmer S
AUID- ORCID: 0000-0002-5295-1065
AD  - Rady Children's Hospital, San Diego, CA 92123, USA.
FAU - Gleeson, Joseph
AU  - Gleeson J
AUID- ORCID: 0000-0002-0889-9220
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
AD  - Department of Neurosciences, University of California San Diego, San Diego, CA 
      92093, USA.
FAU - Gore, Jeremy
AU  - Gore J
AUID- ORCID: 0000-0001-5011-3933
AD  - Tessella, Needham, MA 02494, USA.
FAU - Grunenwald, Haiying
AU  - Grunenwald H
AUID- ORCID: 0000-0002-5064-3149
AD  - Illumina Inc., San Diego, CA 92122, USA.
FAU - Hovey, Raymond L
AU  - Hovey RL
AUID- ORCID: 0000-0001-6099-2871
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Janes, Marie L
AU  - Janes ML
AUID- ORCID: 0000-0001-6646-3831
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Lin, Kejia
AU  - Lin K
AUID- ORCID: 0000-0001-8059-8214
AD  - Rady Children's Hospital, San Diego, CA 92123, USA.
FAU - McDonagh, Paul D
AU  - McDonagh PD
AD  - Alexion Pharmaceuticals Inc., New Haven, CT 06510, USA.
FAU - McBride, Kyle
AU  - McBride K
AD  - Rady Children's Hospital, San Diego, CA 92123, USA.
FAU - Mulrooney, Patrick
AU  - Mulrooney P
AUID- ORCID: 0000-0002-3315-0940
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Nahas, Shareef
AU  - Nahas S
AUID- ORCID: 0000-0003-4494-0320
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Oh, Daeheon
AU  - Oh D
AUID- ORCID: 0000-0003-0627-8153
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Oriol, Albert
AU  - Oriol A
AUID- ORCID: 0000-0002-5236-950X
AD  - Rady Children's Hospital, San Diego, CA 92123, USA.
FAU - Puckett, Laura
AU  - Puckett L
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Rady, Zia
AU  - Rady Z
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Reese, Martin G
AU  - Reese MG
AD  - Fabric Genomics Inc., Oakland, CA 94612, USA.
FAU - Ryu, Julie
AU  - Ryu J
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
AD  - Department of Pediatrics, University of California San Diego, San Diego, CA 
      92093, USA.
FAU - Salz, Lisa
AU  - Salz L
AUID- ORCID: 0000-0002-6380-4984
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Sanford, Erica
AU  - Sanford E
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
AD  - Department of Pediatrics, University of California San Diego, San Diego, CA 
      92093, USA.
FAU - Stewart, Lawrence
AU  - Stewart L
AUID- ORCID: 0000-0002-3671-7877
AD  - Rady Children's Hospital, San Diego, CA 92123, USA.
FAU - Sweeney, Nathaly
AU  - Sweeney N
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
AD  - Department of Pediatrics, University of California San Diego, San Diego, CA 
      92093, USA.
FAU - Tokita, Mari
AU  - Tokita M
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Van Der Kraan, Luca
AU  - Van Der Kraan L
AUID- ORCID: 0000-0002-2437-4125
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - White, Sarah
AU  - White S
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Wigby, Kristen
AU  - Wigby K
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
AD  - Department of Pediatrics, University of California San Diego, San Diego, CA 
      92093, USA.
FAU - Williams, Brett
AU  - Williams B
AUID- ORCID: 0000-0001-8880-5740
AD  - Clinithink Ltd., London N1 6DR, UK.
FAU - Wong, Terence
AU  - Wong T
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Wright, Meredith S
AU  - Wright MS
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Yamada, Catherine
AU  - Yamada C
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Schols, Peter
AU  - Schols P
AD  - Diploid, 3001 Leuven, Belgium.
FAU - Reynders, John
AU  - Reynders J
AUID- ORCID: 0000-0002-4067-9500
AD  - Alexion Pharmaceuticals Inc., New Haven, CT 06510, USA.
FAU - Hall, Kevin
AU  - Hall K
AUID- ORCID: 0000-0002-8420-7791
AD  - Illumina Inc., San Diego, CA 92122, USA.
FAU - Dimmock, David
AU  - Dimmock D
AUID- ORCID: 0000-0001-6690-2523
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Veeraraghavan, Narayanan
AU  - Veeraraghavan N
AUID- ORCID: 0000-0001-5986-4880
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
FAU - Defay, Thomas
AU  - Defay T
AD  - Alexion Pharmaceuticals Inc., New Haven, CT 06510, USA.
FAU - Kingsmore, Stephen F
AU  - Kingsmore SF
AUID- ORCID: 0000-0002-3758-4631
AD  - Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA. 
      skingsmore@rchsd.org.
LA  - eng
GR  - U01 TR002271/TR/NCATS NIH HHS/United States
GR  - U19 HD077693/HD/NICHD NIH HHS/United States
GR  - UL1 TR002550/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
SB  - IM
CIN - Nat Med. 2019 Jun;25(6):877. PMID: 31171871
MH  - Diabetic Ketoacidosis/*genetics
MH  - Electronic Health Records
MH  - Female
MH  - Genomics/*methods
MH  - Humans
MH  - Intensive Care Units/statistics & numerical data
MH  - Natural Language Processing
MH  - Retrospective Studies
PMC - PMC9512059
MID - NIHMS1659831
EDAT- 2019/04/26 06:00
MHDA- 2020/05/19 06:00
PMCR- 2022/09/26
CRDT- 2019/04/26 06:00
PHST- 2018/03/17 00:00 [received]
PHST- 2018/10/24 00:00 [revised]
PHST- 2019/04/01 00:00 [accepted]
PHST- 2019/04/26 06:00 [entrez]
PHST- 2019/04/26 06:00 [pubmed]
PHST- 2020/05/19 06:00 [medline]
PHST- 2022/09/26 00:00 [pmc-release]
AID - 11/489/eaat6177 [pii]
AID - 10.1126/scitranslmed.aat6177 [doi]
PST - ppublish
SO  - Sci Transl Med. 2019 Apr 24;11(489):eaat6177. doi: 10.1126/scitranslmed.aat6177.