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Principal Investigator: Iwijn De Vlaminck
Organization: CORNELL UNIVERSITY
Fiscal Year: 2024
Award: $203,242
Funding agency: National Institute of Allergy and Infectious Diseases
Sepsis is a deadly condition caused by a dysregulated immune response to infection which affects 700,000
patients per year in the US alone. Early and accurate diagnosis of sepsis, and infection underlying sepsis is
critical to inform treatment choices and to prevent serious organ injury and death, but diagnostic options remain
limited. This proposal addresses this unmet medical need with the development of a minimally invasive blood
test based on a multi-omics profiling of circulating cfDNA to simultaneously inform host responses, quantify organ
injury and identify infection underlying sepsis
Our recent pilot work provides significant support for the feasibility of this proposal. First, we have found that
metagenomic sequencing of circulating cell-free DNA (cfDNA) can be used to detect a broad range of viral and
bacterial pathogens in blood. To overcome the challenge of environmental contamination which limits the
specificity of metagenomic cfDNA sequencing we have developed Coffee-seq, a metagenomic sequencing
assay that is robust against environmental contamination. The core idea of Coffee-seq is to tag the DNA in the
sample prior to sample preparation with a label that can be recorded by DNA sequencing. Any contaminating
DNA that is introduced in the sample after tagging can then be bioinformatically identified and removed. Our
proof-of-principle work demonstrates that Coffee-seq leads to a reduction of noise due to contamination by up
to three orders of magnitude. Coffee-seq thereby dramatically improves the specificity of metagenomic
sequencing assays. Second, we have developed cfDNA assays to inform injury to host tissues and organs. This
test employs genome-wide profiling of methylation marks of cfDNA that are cell, tissue and organ-type specific
to trace their tissues-of-origin, and to quantify tissue-specific injury. We have demonstrated the utility of this
assay to identify host-tissue injury related to urinary tract infection, COVID-19, and Graft-Versus Host Disease,
a frequent complication of stem cell transplantation.
We have two aims: In Aim 1, we will test the utility of Coffee-seq to identify infection underlying sepsis with high
sensitivity and specificity. In Aim 2, we will investigate the utility of a cfDNA metagenomic sequencing assay to
inform sepsis related organ dysfunction. This is an exploratory study that tests the utility of cfDNA as a versatile
analyte to monitor sepsis. We will test this highly translational concept with a retrospective study of 300 bio-
banked samples (Cornell Biobank of Critical Illness), including 120 samples from septic patients with positive
blood culture, and 180 samples from patients with non-infectious critical illness. Successful implementation of
this study will lead to new avenues to identify infection underlying sepsis, to classify sepsis subtypes, to monitor
sepsis-related organ damage, and to guide treatment decisions.
Terms: <Acute Renal Failure with Renal Papillary Necrosis><Address><Affect><Assay><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Blood><Blood Reticuloendothelial System><Blood Tests><Body Tissues><COVID-19><CV-19><Cell Body><Cell Death><Cells><Cessation of life><Chemistry><Classification><Clinical><Coffee><Complication><Coronavirus Infectious Disease 2019><Critical Illness><Critically Ill><Cytosine><DNA><DNA seq><DNA sequencing><DNAseq><Data><Data Set><Deamination><Death><Deoxyribonucleic Acid><Development><Diagnostic><Dysfunction><Early Diagnosis><Environmental Pollution><Enzyme Gene><Enzymes><Functional Metagenomics><Functional disorder><Genome><Goals><GvHD><Health Care Costs><Health Costs><Healthcare Costs><Hematologic Tests><Hematological Tests><Hematology Testing><Homologous Wasting Disease><Hospital Admission><Hospitalization><Immune response><Immunological response><Incidence><Infection><Injury><Injury to Kidney><Injury to Liver><Kidney Diseases><Label><Measurement><Medical><Metagenomics><Methylation><Modeling><Monitor><Morbidity><Morbidity - disease rate><NGS Method><NGS system><Nephropathy><Noise><Non-Invasive Detection><Noninvasive Detection><Oligo><Oligonucleotides><Organ><Organ failure><Outcome><Patients><Performance><Persons><Physiopathology><Preparation><Progenitor Cell Transplantation><Renal Disease><Retrospective Studies><Runt Disease><Sampling><Sensitivity and Specificity><Sepsis><Sodium Chloride><Specificity><Stem Cell Transplantation><Stem cell transplant><Systematics><Testing><Tissues><Urinary tract infection><Urinary tract infectious disease><Work><accurate diagnosis><acute kidney injury><bacteria pathogen><bacterial pathogen><biobank><biorepository><bisulfite><blood infection><bloodstream infection><cell free DNA><cell free circulating DNA><cell type><cohort><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><developmental><early detection><end stage liver disease><end stage liver failure><environmental contamination><experiment><experimental research><experimental study><experiments><genome scale><genome-wide><genomewide><graft versus host disease><graft vs host disease><graft vs. host disease><hepatic damage><hepatic injury><host response><hydrogen sulfite><hydrosulfite><immune system response><immunoresponse><improved><injuries><injury to organs><injury to tissue><innovate><innovation><innovative><kidney disorder><kidney injury><liver damage><liver injury><metagenome sequencing><metagenomic sequencing><microorganism><minimally invasive><mortality><multiomics><multiple omics><necrocytosis><next gen sequencing><next generation sequencing><nextgen sequencing><oligos><organ injury><panomics><pathogenic bacteria><pathogenic virus><pathophysiology><preparations><prevent><preventing><progenitor transplantation><renal disorder><renal injury><salt><sepsis patients><septic patients><stem and progenitor cell transplantations><tissue injury><treatment choice><urinary infection><viral pathogen><virus pathogen>