TY - JOUR
T1 - A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM)
T2 - a multi-cohort machine learning study
AU - Jackson, Heather R
AU - Zandstra, Judith
AU - Menikou, Stephanie
AU - Hamilton, Melissa Shea
AU - McArdle, Andrew J
AU - Fischer, Roman
AU - Thorne, Adam M
AU - Huang, Honglei
AU - Tanck, Michael W
AU - Jansen, Machiel H
AU - De, Tisham
AU - Agyeman, Philipp K A
AU - Von Both, Ulrich
AU - Carrol, Enitan D
AU - Emonts, Marieke
AU - Eleftheriou, Irini
AU - Van der Flier, Michiel
AU - Fink, Colin
AU - Gloerich, Jolein
AU - De Groot, Ronald
AU - Moll, Henriette A
AU - Pokorn, Marko
AU - Pollard, Andrew J
AU - Schlapbach, Luregn J
AU - Tsolia, Maria N
AU - Usuf, Effua
AU - Wright, Victoria J
AU - Yeung, Shunmay
AU - Zavadska, Dace
AU - Zenz, Werner
AU - Coin, Lachlan J M
AU - Casals-Pascual, Climent
AU - Cunnington, Aubrey J
AU - Martinon-Torres, Federico
AU - Herberg, Jethro A
AU - de Jonge, Marien I
AU - Levin, Michael
AU - Kuijpers, Taco W
AU - Kaforou, Myrsini
AU - PERFORM consortium
A2 - Balode, Anda
A2 - Bārzdiņa, Arta
A2 - Deksne, Dārta
A2 - Gardovska, Dace
A2 - Grāvele, Dagne
A2 - Grope, Ilze
A2 - Meiere, Anija
A2 - Nokalna, Ieva
A2 - Pavāre, Jana
A2 - Pučuka, Zanda
A2 - Selecka, Katrina
A2 - Sidorova, Aleksandra
A2 - Urbāne, Urzula Nora
N1 - Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
PY - 2023/11
Y1 - 2023/11
N2 - BACKGROUND: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h.METHODS: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores.FINDINGS: 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%.INTERPRETATION: This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics.FUNDING: European Union's Horizon 2020 research and innovation programme, the European Union's Seventh Framework Programme (EUCLIDS), Imperial Biomedical Research Centre of the National Institute for Health Research, the Wellcome Trust and Medical Research Foundation, Instituto de Salud Carlos III, Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Refeencia Competitiva, Swiss State Secretariat for Education, Research and Innovation.
AB - BACKGROUND: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h.METHODS: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores.FINDINGS: 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%.INTERPRETATION: This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics.FUNDING: European Union's Horizon 2020 research and innovation programme, the European Union's Seventh Framework Programme (EUCLIDS), Imperial Biomedical Research Centre of the National Institute for Health Research, the Wellcome Trust and Medical Research Foundation, Instituto de Salud Carlos III, Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Refeencia Competitiva, Swiss State Secretariat for Education, Research and Innovation.
KW - Humans
KW - Child
KW - Proteomics
KW - Bacterial Infections/diagnosis
KW - Biomarkers/metabolism
KW - Virus Diseases/diagnosis
KW - Anti-Bacterial Agents
UR - http://www.scopus.com/inward/record.url?scp=85175274641&partnerID=8YFLogxK
UR - https://www.thelancet.com/cms/10.1016/S2589-7500(23)00149-8/attachment/1e5799cf-b421-4914-ad9d-5a966585e13d/mmc1.pdf
U2 - 10.1016/S2589-7500(23)00149-8
DO - 10.1016/S2589-7500(23)00149-8
M3 - Article
C2 - 37890901
SN - 2589-7500
VL - 5
SP - e774-e785
JO - The Lancet Digital Health
JF - The Lancet Digital Health
IS - 11
ER -