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NeoChip for specific and rapid identification of congenital CMV and neonatal HSV infections on minimal sample volume

NeoChip 用于以最少的样本量特异性快速识别先天性 CMV 和新生儿 HSV 感染

基本信息

批准号：
10539056
负责人：
Shelley M Lawrence
金额：
$ 56.74万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539056
关键词：
Address Advocate Antibiotics Antibodies Antimicrobial Resistance Antiviral Agents Antiviral resistance Base Sequence Biological Biological Assay Birth Blinded Blood Blood Volume Blood specimen California Child Clinical Clinical Research Congenital herpes simplex Consumption Culture Techniques Cytomegalovirus DNA Data Databases Detection Diagnosis Diagnostic Disabled Persons Disease Dyes Early Intervention Early identification Enrollment Epidemiology Etiology Evaluation Failure Fingerprint Fluorescence Funding Genome Genotype Goals Gold Health Hour Immunoglobulin G Immunoglobulin M Individual Infant Infection Investigation Laboratories Life Machine Learning Measures Microbe Modality Modernization Molecular Mothers Neonatal Neonatal Screening Newborn Infant Nucleic Acid Amplification Tests Nucleotides Outcome Pathogen detection Pathogenicity Patients Perinatal Polymerase Chain Reaction Predictive Value Pregnant Women Prevalence RNA Reaction Reporting Research Research Personnel Resistance Resolution Risk Saliva Sampling Sensitivity and Specificity Simplexvirus Spottings Symptoms Techniques Technology Testing Therapeutic Therapeutic Intervention Time TimeLine Tissues Training Translating Tube United States Universities Update Urine Variant Viral Viral Load result Virus Diseases accurate diagnosis antimicrobial artificial intelligence algorithm base biobank clinical database clinical outcome measures clinically relevant congenital cytomegalovirus cost detection limit detection method diagnosis standard diagnostic biomarker diagnostic tool digital disease prognosis interdisciplinary approach intervention program machine learning algorithm melting microbial multidisciplinary neonatal infection neonate next generation sequencing offspring pathogen pathogen genomics pathogenic virus point of care postnatal prevent prospective rapid diagnosis resistance gene screening program single molecule transmission process viral detection

项目摘要

Project Summary Congenital cytomegalovirus (cCMV) and neonatal herpes simplex virus (nHSV) impose major health threats on neonates. Although CMV and HSV are lifelong infections with periods of latency and reactivation, most maternal infections remain undiagnosed due to nonspecific or absent clinical symptoms. In the United States, a child is permanently disabled by cCMV infection every hour, even though 9 of 10 infants are asymptomatic after birth and remain undiagnosed. Invasive nHSV, on the other hand, is a rare neonatal infection that presents with a broad range of clinical symptoms, including those that may be life-threatening. Viral culture and DNA detection by polymerase chain reaction (PCR) have become the “Gold Standard” for the diagnosis of cCMV and nHSV infection, despite poor sensitivity of PCR assays in neonates and time consuming culture techniques (up to 5-7 days). Universal genotyping of pathogen genomic sequences using High Resolution Melt (U-HRM) provides a simple, low cost, rapid, and modern alternative to viral cultures and PCR techniques. By measuring the fluorescence of an intercalating dye as PCR-amplified pathogen DNA or RNA fragments are heated and disassociate, sequence defined melt curves, or “fingerprints”, are generated with single-nucleotide resolution in a closed-tube reaction. These unique microbial “fingerprints” are then automatically identified and quantified using machine learning technology, with an accuracy of 99-100% on minimal blood volume (1 mL), in a platform called NeoChip. Presently, we have established unique signature melt curves for 40 bacterial species and antimicrobial resistance genes that commonly infect neonates. Additionally, NeoChip has been expanded to distinguish individually amplified melt curve signatures for multiple pathogen identification and quantification, as required for polymicrobial infection. In this proposal, we will build out NeoChip’s comprehensive database by incorporating clinical strains of CMV and HSV with actionable antiviral resistance genes. Because NeoChip identifies variances in nucleic acid sequences, individual differentiation and quantification of CMV and HSV strains are possible. We will also translate the NeoChip for specific and rapid diagnosis of cCMV and nHSV infection in a large prospective clinical study of pregnant women and their offspring(s), as well as directly compare the platform to standard quantitative nucleic acid test (QNAT) assays, IgG/IgM antibody testing, and clinical outcome measures for statistical concordance (predictive value). Finally, we will validate and translate NeoChip for cCMV detection and clinical correlation using dried blood spot (DBS) samples for incorporation into standard universal newborn screening programs. NeoChip’s goal is to provide an accurate and valid test for the timely diagnosis of pathogen etiology (viral, bacterial, and fungal) in a single test with efficacy on broad tissue matrices and capacity to inform microbial resistance, thereby facilitating early administration of targeted antimicrobials and therapeutics. This proposal directly addresses the funding call by applying a multidisciplinary approach to address the biomedical challenges of rapidly and accurately diagnosing cCMV and nHSV to facilitate disease prognostication and early therapeutic or intervention programs.

项目总结