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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
A diagnostic algorithm combining clinical and molecular data distinguishes Kawasaki disease from other febrile
Xuefeng B Ling1, Kenneth Lau, John T Kanegaye
1Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
Insights
This study developed a diagnostic algorithm combining clinical data with urine and blood biomarkers to accurately identify Kawasaki disease in children. Early diagnosis is crucial for preventing serious complications like coronary artery aneurysms.
Area of Science:
- Pediatric Rheumatology
- Clinical Diagnostics
- Biomarker Discovery
Background:
- Kawasaki disease is an acute vasculitis in children with unknown etiology.
- Clinical diagnosis is challenging due to overlapping symptoms with other childhood illnesses.
- Timely treatment is vital to prevent coronary artery aneurysms.
Purpose of the Study:
- To develop a diagnostic algorithm for distinguishing Kawasaki disease from febrile controls.
- To enable earlier initiation of treatment for Kawasaki disease.
Main Methods:
- Integrated urine peptidome profiling and whole blood cell type-specific gene expression.
- Utilized multivariate analysis of clinical parameters.
- Validated findings in independent cohorts.
Main Results:
- Identified 139 candidate urine peptide markers, confirming 13 with high accuracy (ROC AUC 0.919).
- Discovered a 32-lymphocyte-specific-gene panel from blood samples (ROC AUC 0.969).
- Integrated biomarkers and clinical data achieved high diagnostic stratification (ROC AUC 0.803).
Conclusions:
- A hybrid diagnostic algorithm combining clinical and molecular data successfully differentiates Kawasaki disease.
- This approach aids in timely diagnosis and treatment of acute Kawasaki disease.
Background:
Kawasaki disease is an acute vasculitis of infants and young children that is recognized through a constellation of clinical signs that can mimic other benign conditions of childhood. The etiology remains unknown and there is no specific laboratory-based test to identify patients with Kawasaki disease. Treatment to prevent the complication of coronary artery aneurysms is most effective if administered early in the course of the illness. We sought to develop a diagnostic algorithm to help clinicians distinguish Kawasaki disease patients from febrile controls to allow timely initiation of treatment.
Methods:
Urine peptidome profiling and whole blood cell type-specific gene expression analyses were integrated with clinical multivariate analysis to improve differentiation of Kawasaki disease subjects from febrile controls.
Results:
Comparative analyses of multidimensional protein identification using 23 pooled Kawasaki disease and 23 pooled febrile control urine peptide samples revealed 139 candidate markers, of which 13 were confirmed (area under the receiver operating characteristic curve (ROC AUC 0.919)) in an independent cohort of 30 Kawasaki disease and 30 febrile control urine peptidomes. Cell type-specific analysis of microarrays (csSAM) on 26 Kawasaki disease and 13 febrile control whole blood samples revealed a 32-lymphocyte-specific-gene panel (ROC AUC 0.969). The integration of the urine/blood based biomarker panels and a multivariate analysis of 7 clinical parameters (ROC AUC 0.803) effectively stratified 441 Kawasaki disease and 342 febrile control subjects to diagnose Kawasaki disease.
Conclusions:
A hybrid approach using a multi-step diagnostic algorithm integrating both clinical and molecular findings was successful in differentiating children with acute Kawasaki disease from febrile controls.
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