R33HD105618

Discovery and Clinical Validation of Host Biomarkers of Disease Severity and Multi-System Inflammatory Syndrome in Children (MIS-C) with COVID-19 - Abstract

Novel approaches for early and accurate diagnosis of COVID-19 associated syndromes and evaluation of clinical severity and outcomes of COVID-19 disease in children are urgently needed. The overarching goal of this grant proposal is to develop clinical assays that can evaluate and predict severity of pediatric COVID-19 disease, ranging from asymptomatic or mildly symptomatic to severe manifestations such as multisystem inflammatory syndrome (MIS-C).

To date, we have collected and biobanked clinical samples from more than 400 patients across 3 academic hospitals, including approximately 100 patients with MIS-C. In the first R61 phase of this project, we will continue to enroll patients with pediatric COVID-19 and MIS-C for sample collection and longitudinal chart review and testing (Aim 1). We will leverage machine learning to identify diagnostic and prognostic "omics" host biomarkers based on RNA transcriptome profiling from nasal swab and whole blood samples (Aim 2), and cell-free DNA analysis from plasma (Aim 3). Additionally, we will generate predictive models of clinical severity and outcomes by incorporating longitudinal clinical, laboratory, viral, and omics data (Aim 4).

Our rationale for including these samples is that they are routinely obtained in hospitals and clinics and permit easy and noninvasive collection without any special processing or handling requirements, which will accelerate the development of omics-based clinical assays. Our go/no-go transition milestones for transition to the R33 phase after 2 years include: (1) collection of longitudinal samples from a minimum of 120 patients for each identified presentation (mildly symptomatic outpatient, severely ill in the ICU, and MIS-C) and a comparable number of matched controls, (2) generation of panels of candidate severity biomarkers and confirmation of a subset of biomarkers by qPCR, (3) development of classifier models using machine learning with the biomarkers alone (for clinical assay development), and (4) combining these omics biomarkers with additional clinical, viral, and laboratory biomarkers into combined classifier models using machine learning. The minimum/goal performance requirements for the classifier models would be 70%/>80% sensitivity and 80%/>90% specificity.

In the second R33 phase, we propose to develop host-based clinical assays for diagnosis and severity prediction of COVID-19-associated syndromes, including MIS-C, in children from nasal swabs and blood (Aim 5), and validate these biomarker panels as a laboratory developed test (LDT) in a CLIA (Clinical Laboratory Improvement Amendments) diagnostic laboratory (Aim 6). These assays will be evaluated for accuracy, precision, reproducibility, limits of detection (LOD), matrix effect, interference, among other performance characteristics. We will work closely with the RADx-RAD Data Coordination Center (DCC) on assay development, testing, and validation for submission to the FDA for Emergency Use Authorization (EUA) and timely deployment of these assays for clinical use.

San Francisco Regents Of The University Of California

NOT APPLICABLE

93.360 - Biomedical Advanced Research and Development Authority (BARDA), Biodefense Medical Countermeasure Development

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

San Francisco, California 94143 United States

Single Zip Code

Emergency Awards: RADx-rad Predicting Viral-Associated Inflammatory Disease Severity in Children with Laboratory Diagnostics and Artificial Intelligence (PreVAIL kIds) (R61/R33 Clinical Trial Optional) (RFA-OD-20-023)

COVID-19 $3,225,866 (100%) percent of this Project Grant was funded by COVID-19 emergency acts including the American Rescue Plan Act of 2021.
Amendment Since initial award the End Date has been extended from 11/30/24 to 11/30/25 and the total obligations have increased 99% from $1,619,520 to $3,225,866.