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Principal Investigator: Sharlee Climer
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2020
Award: $650,002
Funding agency: National Institute on Aging
The COVID-19 global pandemic has led to more than 470,000 deaths. This disease is especially perilous
for the elderly - 80% of deaths in the US have been individuals over the age of 65, and the social isolation created
by lockdowns have increased risks of serious physical and mental health issues.
COVID-19 is a heterogeneous disease exhibiting a broad spectrum of symptoms, ranging from mild (e.g.
loss of smell, dry cough) to critical (e.g. cytokine storm, renal failure, cardiovascular damage, respiratory failure,
lethal blood clotting, neurological disorders). This clinical heterogeneity demands a precision medicine approach
that elucidates distinct pathways underlying the disease, develops treatments for each pathway, and defines
biomarker patterns to diagnose patients for classification within the subsets. A key benefit of precision medicine
is that drugs may be repurposed or may already exist to treat specific subsets of infected individuals. For
example, one critical outcome for COVID-19 infection is the onset of a cytokine storm, in which the body's
immune system gets caught in a positive feedback loop, leading to shock and rapid failure of multiple organs.
There are existing drugs for treating cytokine storm syndrome, but practitioners have no clear guidelines if such
treatments are beneficial or destructive. If the individual is not in a hyperinflammatory state, the administration
of these drugs could cripple their immune response, leading to increased viral load. Plasma biomarker patterns
of proteins and metabolites hold potential to identify impending cytokine storms and other lethal outcomes.
To advance precision medicine for COVID-19 treatment, this work will generate large-scale omics data
and evaluate levels of proteins and metabolites for plasma drawn from 350 COVID-19 positive cases and 750
normal controls. These data will be immediately released to the research community. Our research team will
take a concerted multipronged approach for analyzing these data using diverse complementary techniques. Our
labs' research focuses on the discovery of combinations of genes and proteins expressing synchronously and
the associations of these combinations with traits of interest, as well as endophenotype discovery. In addition to
thorough single analyte analyses, this research will employ three computational strategies to reveal combinations
of factors defining patterns: 1) network modeling, 2) explainable-AI systems biology, and 3) linear programming.
These intensive analyses will require significant computational resources and we will utilize Summit at Oak Ridge
National Laboratory, one of the most powerful supercomputers in the world, for these tasks.
The comprehensive protein and metabolite profiles, based on a large cohort of COVID-19 cases and
normal controls, along with our rigorous interrogation of these data for complex biomarker patterns indicative of
patient outcomes, hold unprecedented potential to drive solid advances in precision medicine and to reduce
mortality rates due to COVID-19. In addition, this research will provide an agile model for use when tackling other
heterogeneous diseases plaguing humankind, as well as novel viruses that may arise in the future.
Terms: <2019 novel coronavirus><2019-nCoV><65+ years old><AI system><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Age><Aged 65 and Over><Algorithms><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Artificial Intelligence><Biological><Biological Markers><Blood><Blood Clotting><Blood Plasma><Blood Reticuloendothelial System><Blood coagulation><COVID><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cessation of life><Characteristics><Circulatory Collapse><Classification><Clinical><Clinical Sciences><CoV disease><Communities><Complex><Computer Reasoning><Consumption><Coughing><Data><Data Analyses><Data Analysis><Data Set><Dataset><Death><Death Rate><Development><Diagnosis><Disabled Persons><Disabled Population><Disease><Disease Outcome><Disease Progression><Disorder><Drug Targeting><Drugs><Ebola><Effectiveness><Elderly><Exhibits><Extremities><Feedback><Foundations><Future><Gene Combinations><Gene Proteins><Genetic><Guidelines><HIV><Handicapped><Heart Vascular><High Performance Computing><Hospital Admission><Hospitalization><Human Immunodeficiency Viruses><Immune response><Immune system><Immunological response><Individual><Infection><Institute of Medicine><Institute of Medicine (U.S.)><Kidney Failure><Kidney Insufficiency><LAV-HTLV-III><Laboratories><Limb structure><Limbs><Linear Programming><Lymphadenopathy-Associated Virus><MERS><MERS coronavirus disease><MERS-CoV disease><MOF syndrome><Machine Intelligence><Medication><Mental Health><Mental Hygiene><Metadata><Methods><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Modeling><Molecular><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Mutate><NAS/IOM><Natural Selections><Nervous System Diseases><Neurologic Disorders><Neurological Disorders><Non-Trunk><Olfaction><Outcome><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pattern><People with Disabilities><Performance><Persons with Disabilities><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Plasma><Plasma Serum><Pneumonia><Precision therapeutics><Protein Gene Products><Proteins><Proteomics><Psychological Health><Receptor Protein><Records><Renal Failure><Renal Insufficiency><Research><Research Resources><Resources><Respiratory Failure><Reticuloendothelial System, Serum, Plasma><Risk><SARS><SARS coronavirus disease><SARS-CoV disease><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Sample Size><Sampling><Severe Acute 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