TY - JOUR
T1 - Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature
AU - Jackson, Heather R.
AU - Miglietta, Luca
AU - Habgood-Coote, Dominic
AU - D'souza, Giselle
AU - Shah, Priyen
AU - Nichols, Samuel
AU - Vito, Ortensia
AU - Powell, Oliver
AU - Davidson, Maisey Salina
AU - Shimizu, Chisato
AU - Agyeman, Philipp K.A.
AU - Beudeker, Coco R.
AU - Brengel-Pesce, Karen
AU - Carrol, Enitan D.
AU - Carter, Michael J.
AU - De, Tisham
AU - Eleftheriou, Irini
AU - Emonts, Marieke
AU - Epalza, Cristina
AU - Georgiou, Pantelis
AU - De Groot, Ronald
AU - Fidler, Katy
AU - Fink, Colin
AU - Van Keulen, Daniëlle
AU - Kuijpers, Taco
AU - Moll, Henriette
AU - Papatheodorou, Irene
AU - Paulus, Stephane
AU - Pokorn, Marko
AU - Pollard, Andrew J.
AU - Rivero-Calle, Irene
AU - Rojo, Pablo
AU - Secka, Fatou
AU - Schlapbach, Luregn J.
AU - Tremoulet, Adriana H.
AU - Tsolia, Maria
AU - Usuf, Effua
AU - Van Der Flier, Michiel
AU - Von Both, Ulrich
AU - Vermont, Clementien
AU - Yeung, Shunmay
AU - Zavadska, Dace
AU - Zenz, Werner
AU - Coin, Lachlan J.M.
AU - Cunnington, Aubrey
AU - Burns, Jane C.
AU - Wright, Victoria
AU - Martinon-Torres, Federico
AU - Herberg, Jethro A.
AU - Rodriguez-Manzano, Jesus
AU - Levin, Michael
AU - PERFORM consortium
N1 - Funding Information:
Financial support. This work was supported by the European Union’s Horizon 2020 Program under grants (848196 DIAMONDS, 668303 PERFORM, 279185 EUCLIDS, Prof Levin), by the Imperial Biomedical Research Centre (BRC) of the National Institute for Health Research (NIHR), grants (206508/Z/17/Z and MRF-160-0008-ELP-KAFO-C0801 to Dr Kaforou) from the Wellcome Trust and the Medical Research Foundation, a grant (215214/Z/19/Z to Dr Jackson) from the Wellcome Trust, a grant (R61HD105590-01 PreVAIL kIds to Dr. Burns) from the National Institutes of Health, and grants (WDPI_G28062 and WDPI_P89720 to Drs Herberg and Georgiou) from the Community Jameel Imperial College COVID-19 Excellence Fund and the Rosetrees Trust. This work has been supported by the Imperial Confidence in Concept Scheme, funded by MRC Confidence in Concept, Wellcome Trust Institutional Strategic Support Fund, NIHR Imperial BRC, and Rosetrees Trust (to Rodriguez-Manzano and Kaforou).
Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - Background: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. Methods: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). Results: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. Conclusions: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.
AB - Background: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. Methods: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). Results: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. Conclusions: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.
KW - COVID-19
KW - diagnostic signature
KW - host diagnostics
KW - host response
KW - MIS-C
KW - pediatric infectious diseases
KW - rapid diagnostics
KW - transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85164231285&partnerID=8YFLogxK
U2 - 10.1093/jpids/piad035
DO - 10.1093/jpids/piad035
M3 - Article
C2 - 37255317
AN - SCOPUS:85164231285
SN - 2048-7193
VL - 12
SP - 322
EP - 331
JO - Journal of the Pediatric Infectious Diseases Society
JF - Journal of the Pediatric Infectious Diseases Society
IS - 6
ER -