Diagnosis of Kawasaki disease using a minimal whole blood gene expression signature
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Importance There is no diagnostic test for Kawasaki disease (KD). Diagnosis is based on clinical features shared with other febrile conditions, frequently resulting in delayed or missed treatment and an increased risk of coronary artery aneurysms.
Objective To identify a whole blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions.
Design Case-control discovery study groups comprising training, test, and validation groups of children with KD or comparator febrile illness.
Setting Hospitals in the UK, Spain, Netherlands and USA.
Participants The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, 242 bacterial or viral infections) and 55 healthy controls. The independent validation group included 130 febrile children and 102 KD patients, including 72 in the first 7 days of illness.
Exposures Whole blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (Parallel Deterministic Model Search).
Main outcomes and measures The ability of transcript signatures - implemented as Disease Risk Scores - to discriminate KD cases from controls, was assessed by Area Under the Curve (AUC), sensitivity, and specificity at the optimal cut-point according to Youden’s index.
Results A 13-transcript signature identified in the discovery training set distinguished KD from other infectious and inflammatory conditions in the discovery test set with AUC, sensitivity, and specificity (95% confidence intervals (CI)) of 96.2% (92.5-99.9), 81.7% (60.0-94.8), and 92.1% (84.0-97.0), respectively. In the validation set, the signature distinguished KD from febrile controls with AUC, sensitivity, and specificity (95% CI) of 94.6% (91.3-98.0), 85.9% (76.8-92.6), and 89.1% (83.0-93.7) respectively. The signature was applied to clinically defined categories of Definite, Highly Probable and Possible KD resulting in AUCs of 98.1%, 96.3% and 70.0% respectively, mirroring clinical certainty.
Conclusions and relevance A 13-transcript blood gene expression signature distinguished KD from other febrile conditions. Diagnostic accuracy increased with certainty of clinical diagnosis. A test incorporating the 13-transcript Disease Risk Score may enable earlier diagnosis and treatment of KD, and reduce inappropriate treatment in those with other diagnoses.
Objective To identify a whole blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions.
Design Case-control discovery study groups comprising training, test, and validation groups of children with KD or comparator febrile illness.
Setting Hospitals in the UK, Spain, Netherlands and USA.
Participants The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, 242 bacterial or viral infections) and 55 healthy controls. The independent validation group included 130 febrile children and 102 KD patients, including 72 in the first 7 days of illness.
Exposures Whole blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (Parallel Deterministic Model Search).
Main outcomes and measures The ability of transcript signatures - implemented as Disease Risk Scores - to discriminate KD cases from controls, was assessed by Area Under the Curve (AUC), sensitivity, and specificity at the optimal cut-point according to Youden’s index.
Results A 13-transcript signature identified in the discovery training set distinguished KD from other infectious and inflammatory conditions in the discovery test set with AUC, sensitivity, and specificity (95% confidence intervals (CI)) of 96.2% (92.5-99.9), 81.7% (60.0-94.8), and 92.1% (84.0-97.0), respectively. In the validation set, the signature distinguished KD from febrile controls with AUC, sensitivity, and specificity (95% CI) of 94.6% (91.3-98.0), 85.9% (76.8-92.6), and 89.1% (83.0-93.7) respectively. The signature was applied to clinically defined categories of Definite, Highly Probable and Possible KD resulting in AUCs of 98.1%, 96.3% and 70.0% respectively, mirroring clinical certainty.
Conclusions and relevance A 13-transcript blood gene expression signature distinguished KD from other febrile conditions. Diagnostic accuracy increased with certainty of clinical diagnosis. A test incorporating the 13-transcript Disease Risk Score may enable earlier diagnosis and treatment of KD, and reduce inappropriate treatment in those with other diagnoses.
Date Issued
2018-10-01
Date Acceptance
2018-06-04
Citation
JAMA Pediatrics, 2018, 172 (10), pp.1-10
ISSN
2168-6203
Publisher
American Medical Association
Start Page
1
End Page
10
Journal / Book Title
JAMA Pediatrics
Volume
172
Issue
10
Copyright Statement
This is an open access article distributed under the terms of the CC-BY License. © 2018 Wright VJ et al. JAMA Pediatrics. (https://jamanetwork.com/journals/jamapediatrics/pages/instructions-for-authors#SecOpenAccess)
Sponsor
Wellcome Trust
Imperial College Healthcare NHS Trust- BRC Funding
European Commission
COSMIC (Children of St.Mary's Intensive Care)
Identifier
https://jamanetwork.com/journals/jamapediatrics/fullarticle/2694801
Grant Number
206508/Z/17/Z
RD501 79560
668303
R&D 21
Subjects
Science & Technology
Life Sciences & Biomedicine
Pediatrics
SYSTEMIC-LUPUS-ERYTHEMATOSUS
AMERICAN-HEART-ASSOCIATION
LONG-TERM MANAGEMENT
HEALTH-PROFESSIONALS
LEUKOCYTES
INFECTION
STATEMENT
SELECTION
PROFILES
CHILDREN
Child, Preschool
Diagnosis, Differential
Female
Gene Expression Profiling
Genetic Markers
Humans
Infant
Male
Mucocutaneous Lymph Node Syndrome
RNA
Reproducibility of Results
Retrospective Studies
Severity of Illness Index
Transcription, Genetic
Immunopathology of Respiratory, Inflammatory and Infectious Disease Study (IRIS) Consortium and the Pediatric Emergency Medicine Kawasaki Disease Research Group (PEMKDRG)
Humans
Mucocutaneous Lymph Node Syndrome
RNA
Genetic Markers
Diagnosis, Differential
Severity of Illness Index
Retrospective Studies
Reproducibility of Results
Gene Expression Profiling
Transcription, Genetic
Child, Preschool
Infant
Female
Male
Publication Status
Published
Article Number
e182293
Date Publish Online
2018-08-06