title: Anomaly Detection in Host Signaling Pathways for the Early Prognosis of Acute Infection.
abstract: Clinical diagnosis of acute infectious diseases during the early stages of infection is critical to administering the appropriate treatment to improve the disease outcome. We present a data driven analysis of the human cellular response to respiratory viruses including influenza, respiratory syncytia virus, and human rhinovirus, and compared this with the response to the bacterial endotoxin, Lipopolysaccharides (LPS). Using an anomaly detection framework we identified pathways that clearly distinguish between asymptomatic and symptomatic patients infected with the four different respiratory viruses and that accurately diagnosed patients exposed to a bacterial infection. Connectivity pathway analysis comparing the viral and bacterial diagnostic signatures identified host cellular pathways that were unique to patients exposed to LPS endotoxin indicating this type of analysis could be used to identify host biomarkers that can differentiate clinical etiologies of acute infection. We applied the Multivariate State Estimation Technique (MSET) on two human influenza (H1N1 and H3N2) gene expression data sets to define host networks perturbed in the asymptomatic phase of infection. Our analysis identified pathways in the respiratory virus diagnostic signature as prognostic biomarkers that triggered prior to clinical presentation of acute symptoms. These early warning pathways correctly predicted that almost half of the subjects would become symptomatic in less than forty hours post-infection and that three of the 18 subjects would become symptomatic after only 8 hours. These results provide a proof-of-concept for utility of anomaly detection algorithms to classify host pathway signatures that can identify presymptomatic signatures of acute diseases and differentiate between etiologies of infection. On a global scale, acute respiratory infections cause a significant proportion of human co-morbidities and account for 4.25 million deaths annually. The development of clinical diagnostic tools to distinguish between acute viral and bacterial respiratory infections is critical to improve patient care and limit the overuse of antibiotics in the medical community. The identification of prognostic respiratory virus biomarkers provides an early warning system that is capable of predicting which subjects will become symptomatic to expand our medical diagnostic capabilities and treatment options for acute infectious diseases. The host response to acute infection may be viewed as a deterministic signaling network responsible for maintaining the health of the host organism. We identify pathway signatures that reflect the very earliest perturbations in the host response to acute infection. These pathways provide a monitor the health state of the host using anomaly detection to quantify and predict health outcomes to pathogens.
authors.affiliation: Department of Mathematics, Colorado State University, Fort Collins, CO, United States of America.|Department of Mechanical Engineering & Materials Science, Yale University, New Haven, CT, United States of America.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, WA, United States of America.
authors.forename: Stanley
authors.initials: S
authors.lastname: Langevin
authors.affiliation: Department of Mechanical Engineering & Materials Science, Yale University, New Haven, CT, United States of America.|Department of Applied Physics, Department of Physics, and Graduate Program in Computational Biology & Bioinformatics, Yale University, New Haven, CT, United States of America.
authors.forename: Corey S
authors.initials: CS
authors.lastname: O'Hern
authors.affiliation: Department of Mechanical Engineering & Materials Science, Yale University, New Haven, CT, United States of America.|Department of Physics and Benjamin Levich Institute, The City College of the City University of New York, New York, NY, United States of America.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Shattuck
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, United States of America.
authors.forename: Serenity
authors.initials: S
authors.lastname: Ogle
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, WA, United States of America.
authors.forename: Adriana
authors.initials: A
authors.lastname: Forero
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, WA, United States of America.
authors.forename: Juliet
authors.initials: J
authors.lastname: Morrison
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Slayden
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, WA, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.affiliation: Department of Mathematics, Colorado State University, Fort Collins, CO, United States of America.|Department of Computer Science, Colorado State University, Fort Collins, CO, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Kirby
mesh_terms: D000208:Acute Disease; D000465:Algorithms; D001424:Bacterial Infections / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D003141:Communicable Diseases / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology; D042241:Early Diagnosis; D004731:Endotoxins / Q000276:immunology / Q000633:toxicity; D005819:Genetic Markers; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D007251:Influenza, Human / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D018448:Models, Immunological; D015999:Multivariate Analysis; D011379:Prognosis; D012141:Respiratory Tract Infections / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D004731:Endotoxins; D005819:Genetic Markers