Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature

Diamonds Search Study; Heather R Jackson; Luca Miglietta; Dominic Habgood-Coote; Giselle D'Souza; Priyen Shah; Samuel Nichols; Ortensia Vito; Oliver Powell; Maisey Salina Davidson; Chisato Shimizu; Philipp K A Agyeman; Coco R Beudeker; Karen Brengel-Pesce; Enitan D Carrol; Michael J Carter; Tisham De; Irini Eleftheriou; Marieke Emonts; Cristina Epalza; Pantelis Georgiou; Ronald De Groot; Katy Fidler; Colin Fink; Daniëlle van Keulen; Taco Kuijpers; Henriette Moll; Irene Papatheodorou; Stephane Paulus; Marko Pokorn; Andrew J Pollard; Irene Rivero-Calle; Pablo Rojo; Fatou Secka; Luregn J Schlapbach; Adriana H Tremoulet; Maria Tsolia; Effua Usuf; Michiel Van Der Flier; Ulrich Von Both; Clementien Vermont; Shunmay Yeung; Dace Zavadska; Werner Zenz; Lachlan J M Coin; Aubrey Cunnington; Jane C Burns; Victoria Wright; Federico Martinon-Torres; Jethro A Herberg; Jesus Rodriguez-Manzano

doi:10.1093/jpids/piad035

Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature

Diamonds Search Study, Heather R Jackson, Luca Miglietta, Dominic Habgood-Coote, Giselle D'Souza, Priyen Shah, Samuel Nichols, Ortensia Vito, Oliver Powell, Maisey Salina Davidson, Chisato Shimizu, Philipp K A Agyeman, Coco R Beudeker, Karen Brengel-Pesce, Enitan D Carrol, Michael J Carter, Tisham De, Irini Eleftheriou, Marieke Emonts, Cristina EpalzaPantelis Georgiou, Ronald De Groot, Katy Fidler, Colin Fink, Daniëlle van Keulen, Taco Kuijpers, Henriette Moll, Irene Papatheodorou, Stephane Paulus, Marko Pokorn, Andrew J Pollard, Irene Rivero-Calle, Pablo Rojo, Fatou Secka, Luregn J Schlapbach, Adriana H Tremoulet, Maria Tsolia, Effua Usuf, Michiel Van Der Flier, Ulrich Von Both, Clementien Vermont, Shunmay Yeung, Dace Zavadska, Werner Zenz, Lachlan J M Coin, Aubrey Cunnington, Jane C Burns, Victoria Wright, Federico Martinon-Torres, Jethro A Herberg, Jesus Rodriguez-Manzano

Women & Children's Health

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	322-331
Number of pages	10
Journal	Journal of the Pediatric Infectious Diseases Society
Volume	12
Issue number	6
Early online date	31 May 2023
DOIs	https://doi.org/10.1093/jpids/piad035
Publication status	Published - 30 Jun 2023

Keywords

Child
Humans
COVID-19/diagnosis
Systemic Inflammatory Response Syndrome/diagnosis
Hospitals
Mucocutaneous Lymph Node Syndrome/diagnosis
COVID-19 Testing

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Diamonds Search Study, Jackson, H. R., Miglietta, L., Habgood-Coote, D., D'Souza, G., Shah, P., Nichols, S., Vito, O., Powell, O., Davidson, M. S., Shimizu, C., Agyeman, P. K. A., Beudeker, C. R., Brengel-Pesce, K., Carrol, E. D., Carter, M. J., De, T., Eleftheriou, I., Emonts, M., ... Rodriguez-Manzano, J. (2023). Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature. Journal of the Pediatric Infectious Diseases Society, 12(6), 322-331. https://doi.org/10.1093/jpids/piad035

@article{bb0cf3ead0cf4e9cb94d8863962a2766,

title = "Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature",

abstract = "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.",

keywords = "Child, Humans, COVID-19/diagnosis, Systemic Inflammatory Response Syndrome/diagnosis, Hospitals, Mucocutaneous Lymph Node Syndrome/diagnosis, COVID-19 Testing",

author = "{Diamonds Search Study} and Jackson, {Heather R} and Luca Miglietta and Dominic Habgood-Coote and Giselle D'Souza and Priyen Shah and Samuel Nichols and Ortensia Vito and Oliver Powell and Davidson, {Maisey Salina} and Chisato Shimizu and Agyeman, {Philipp K A} and Beudeker, {Coco R} and Karen Brengel-Pesce and Carrol, {Enitan D} and Carter, {Michael J} and Tisham De and Irini Eleftheriou and Marieke Emonts and Cristina Epalza and Pantelis Georgiou and {De Groot}, Ronald and Katy Fidler and Colin Fink and {van Keulen}, Dani{\"e}lle and Taco Kuijpers and Henriette Moll and Irene Papatheodorou and Stephane Paulus and Marko Pokorn and Pollard, {Andrew J} and Irene Rivero-Calle and Pablo Rojo and Fatou Secka and Schlapbach, {Luregn J} and Tremoulet, {Adriana H} and Maria Tsolia and Effua Usuf and {Van Der Flier}, Michiel and {Von Both}, Ulrich and Clementien Vermont and Shunmay Yeung and Dace Zavadska and Werner Zenz and Coin, {Lachlan J M} and Aubrey Cunnington and Burns, {Jane C} and Victoria Wright and Federico Martinon-Torres and Herberg, {Jethro A} and Jesus Rodriguez-Manzano",

note = "Funding Information: Financial support. This work was supported by the European Union{\textquoteright}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: {\textcopyright} 2023 The Author(s). Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.",

year = "2023",

month = jun,

day = "30",

doi = "10.1093/jpids/piad035",

language = "English",

volume = "12",

pages = "322--331",

journal = "Journal of the Pediatric Infectious Diseases Society",

issn = "2048-7207",

publisher = "Oxford University Press",

number = "6",

}

Diamonds Search Study, Jackson, HR, Miglietta, L, Habgood-Coote, D, D'Souza, G, Shah, P, Nichols, S, Vito, O, Powell, O, Davidson, MS, Shimizu, C, Agyeman, PKA, Beudeker, CR, Brengel-Pesce, K, Carrol, ED, Carter, MJ, De, T, Eleftheriou, I, Emonts, M, Epalza, C, Georgiou, P, De Groot, R, Fidler, K, Fink, C, van Keulen, D, Kuijpers, T, Moll, H, Papatheodorou, I, Paulus, S, Pokorn, M, Pollard, AJ, Rivero-Calle, I, Rojo, P, Secka, F, Schlapbach, LJ, Tremoulet, AH, Tsolia, M, Usuf, E, Van Der Flier, M, Von Both, U, Vermont, C, Yeung, S, Zavadska, D, Zenz, W, Coin, LJM, Cunnington, A, Burns, JC, Wright, V, Martinon-Torres, F, Herberg, JA & Rodriguez-Manzano, J 2023, 'Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature', Journal of the Pediatric Infectious Diseases Society, vol. 12, no. 6, pp. 322-331. https://doi.org/10.1093/jpids/piad035

TY - JOUR

T1 - Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature

AU - Diamonds Search Study

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

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 - 2023/6/30

Y1 - 2023/6/30

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 - Child

KW - Humans

KW - COVID-19/diagnosis

KW - Systemic Inflammatory Response Syndrome/diagnosis

KW - Hospitals

KW - Mucocutaneous Lymph Node Syndrome/diagnosis

KW - COVID-19 Testing

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

SN - 2048-7207

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 -

Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature

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