TY - JOUR
T1 - A Novel Framework for Phenotyping Children With Suspected or Confirmed Infection for Future Biomarker Studies
AU - Nijman, Ruud G.
AU - Oostenbrink, Rianne
AU - Moll, Henriette A.
AU - Casals-Pascual, Climent
AU - von Both, Ulrich
AU - Cunnington, Aubrey
AU - de, Tisham
AU - Eleftheriou, Irini
AU - Emonts, Marieke
AU - Fink, Colin
AU - van der Flier, Michiel
AU - de Groot, Ronald
AU - Kaforou, Myrsini
AU - Kohlmaier, Benno
AU - Kuijpers, Taco W.
AU - Lim, Emma
AU - Maconochie, Ian K.
AU - Paulus, Stephane
AU - Martinon-Torres, Federico
AU - Pokorn, Marko
AU - Romaine, Sam T.
AU - Calle, Irene Rivero
AU - Schlapbach, Luregn J.
AU - Smit, Frank J.
AU - Tsolia, Maria
AU - Usuf, Effua
AU - Wright, Victoria J.
AU - Yeung, Shunmay
AU - Zavadska, Dace
AU - Zenz, Werner
AU - Levin, Michael
AU - Herberg, Jethro A.
AU - The PERFORM consortium (Personalized Risk assessment in febrile children to optimize Real-life Management across the European Union)
AU - Carrol, Enitan D.
N1 - Funding Information:
We thank the medical and nursing staff at the Alder Hey Children's NHS foundation Trust ED and PICU, the Erasmus MC ED, the Maasstad hospital ED and the St. Mary's hospital for their help in recruiting patients, all the children studied, and their parents and carers. Funding. This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 668303. RN was awarded a National Institute of Health Research Academic Clinical Lectureship (CL-2018-21-007), enabling this work. The studies from Alder Hey were funded by National Institute of Health Research Liverpool Biomedical Research Centre in Microbial Diseases, the Alder Hey Charity (PICU) and National Institute for Health Research Research for Innovation, Speculation and Creativity Programme grant RC-PG-0309-10053 (EC). The study from St. Mary's hospital was supported by the Imperial College Comprehensive Biomedical Research Centre (DMPED P26077 to JH); the Wellcome Trust Centre for Respiratory Infection at Imperial College; and the Southampton NIHR Wellcome Trust Clinical Research Facility and NIHR Wessex Local Clinical Research Network. The studies from the Erasmus ED and Maasstad ED cohorts were funded by ZonMW, a Dutch organization for health research and development, and Erasmus MC Doelmatigheid. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 668303. RN was awarded a National Institute of Health Research Academic Clinical Lectureship (CL-2018-21-007), enabling this work. The studies from Alder Hey were funded by National Institute of Health Research Liverpool Biomedical Research Centre in Microbial Diseases, the Alder Hey Charity (PICU) and National Institute for Health Research Research for Innovation, Speculation and Creativity Programme grant RC-PG-0309-10053 (EC). The study from St. Mary’s hospital was supported by the Imperial College Comprehensive Biomedical Research Centre (DMPED P26077 to JH); the Wellcome Trust Centre for Respiratory Infection at Imperial College; and the Southampton NIHR Wellcome Trust Clinical Research Facility and NIHR Wessex Local Clinical Research Network. The studies from the Erasmus ED and Maasstad ED cohorts were funded by ZonMW, a Dutch organization for health research and development, and Erasmus MC Doelmatigheid. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© Copyright © 2021 Nijman, Oostenbrink, Moll, Casals-Pascual, von Both, Cunnington, De, Eleftheriou, Emonts, Fink, van der Flier, de Groot, Kaforou, Kohlmaier, Kuijpers, Lim, Maconochie, Paulus, Martinon-Torres, Pokorn, Romaine, Calle, Schlapbach, Smit, Tsolia, Usuf, Wright, Yeung, Zavadska, Zenz, Levin, Herberg, Carrol and the PERFORM consortium (Personalized Risk assessment in febrile children to optimize Real-life Management across the European Union).
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/7/28
Y1 - 2021/7/28
N2 - Background: The limited diagnostic accuracy of biomarkers in children at risk of a serious bacterial infection (SBI) might be due to the imperfect reference standard of SBI. We aimed to evaluate the diagnostic performance of a new classification algorithm for biomarker discovery in children at risk of SBI. Methods: We used data from five previously published, prospective observational biomarker discovery studies, which included patients aged 0– <16 years: the Alder Hey emergency department (n = 1,120), Alder Hey pediatric intensive care unit (n = 355), Erasmus emergency department (n = 1,993), Maasstad emergency department (n = 714) and St. Mary's hospital (n = 200) cohorts. Biomarkers including procalcitonin (PCT) (4 cohorts), neutrophil gelatinase-associated lipocalin-2 (NGAL) (3 cohorts) and resistin (2 cohorts) were compared for their ability to classify patients according to current standards (dichotomous classification of SBI vs. non-SBI), vs. a proposed PERFORM classification algorithm that assign patients to one of eleven categories. These categories were based on clinical phenotype, test outcomes and C-reactive protein level and accounted for the uncertainty of final diagnosis in many febrile children. The success of the biomarkers was measured by the Area under the receiver operating Curves (AUCs) when they were used individually or in combination. Results: Using the new PERFORM classification system, patients with clinically confident bacterial diagnosis (“definite bacterial” category) had significantly higher levels of PCT, NGAL and resistin compared with those with a clinically confident viral diagnosis (“definite viral” category). Patients with diagnostic uncertainty had biomarker concentrations that varied across the spectrum. AUCs were higher for classification of “definite bacterial” vs. “definite viral” following the PERFORM algorithm than using the “SBI” vs. “non-SBI” classification; summary AUC for PCT was 0.77 (95% CI 0.72–0.82) vs. 0.70 (95% CI 0.65–0.75); for NGAL this was 0.80 (95% CI 0.69–0.91) vs. 0.70 (95% CI 0.58–0.81); for resistin this was 0.68 (95% CI 0.61–0.75) vs. 0.64 (0.58–0.69) The three biomarkers combined had summary AUC of 0.83 (0.77–0.89) for “definite bacterial” vs. “definite viral” infections and 0.71 (0.67–0.74) for “SBI” vs. “non-SBI.” Conclusion: Biomarkers of bacterial infection were strongly associated with the diagnostic categories using the PERFORM classification system in five independent cohorts. Our proposed algorithm provides a novel framework for phenotyping children with suspected or confirmed infection for future biomarker studies.
AB - Background: The limited diagnostic accuracy of biomarkers in children at risk of a serious bacterial infection (SBI) might be due to the imperfect reference standard of SBI. We aimed to evaluate the diagnostic performance of a new classification algorithm for biomarker discovery in children at risk of SBI. Methods: We used data from five previously published, prospective observational biomarker discovery studies, which included patients aged 0– <16 years: the Alder Hey emergency department (n = 1,120), Alder Hey pediatric intensive care unit (n = 355), Erasmus emergency department (n = 1,993), Maasstad emergency department (n = 714) and St. Mary's hospital (n = 200) cohorts. Biomarkers including procalcitonin (PCT) (4 cohorts), neutrophil gelatinase-associated lipocalin-2 (NGAL) (3 cohorts) and resistin (2 cohorts) were compared for their ability to classify patients according to current standards (dichotomous classification of SBI vs. non-SBI), vs. a proposed PERFORM classification algorithm that assign patients to one of eleven categories. These categories were based on clinical phenotype, test outcomes and C-reactive protein level and accounted for the uncertainty of final diagnosis in many febrile children. The success of the biomarkers was measured by the Area under the receiver operating Curves (AUCs) when they were used individually or in combination. Results: Using the new PERFORM classification system, patients with clinically confident bacterial diagnosis (“definite bacterial” category) had significantly higher levels of PCT, NGAL and resistin compared with those with a clinically confident viral diagnosis (“definite viral” category). Patients with diagnostic uncertainty had biomarker concentrations that varied across the spectrum. AUCs were higher for classification of “definite bacterial” vs. “definite viral” following the PERFORM algorithm than using the “SBI” vs. “non-SBI” classification; summary AUC for PCT was 0.77 (95% CI 0.72–0.82) vs. 0.70 (95% CI 0.65–0.75); for NGAL this was 0.80 (95% CI 0.69–0.91) vs. 0.70 (95% CI 0.58–0.81); for resistin this was 0.68 (95% CI 0.61–0.75) vs. 0.64 (0.58–0.69) The three biomarkers combined had summary AUC of 0.83 (0.77–0.89) for “definite bacterial” vs. “definite viral” infections and 0.71 (0.67–0.74) for “SBI” vs. “non-SBI.” Conclusion: Biomarkers of bacterial infection were strongly associated with the diagnostic categories using the PERFORM classification system in five independent cohorts. Our proposed algorithm provides a novel framework for phenotyping children with suspected or confirmed infection for future biomarker studies.
KW - biomarkers
KW - children
KW - clinical phenotypes
KW - sepsis
KW - serious bacterial infection
UR - https://www.scopus.com/pages/publications/85112440417
U2 - 10.3389/fped.2021.688272
DO - 10.3389/fped.2021.688272
M3 - Article
C2 - 34395340
SN - 2296-2360
VL - 9
JO - Frontiers in pediatrics
JF - Frontiers in pediatrics
M1 - 688272
ER -