Molecular classification of outcomes from dengue virus -3 infections.
OBJECTIVE
Dengue virus (DENV) infection is a significant risk to over a third of the human population that causes a wide spectrum of illness, ranging from sub-clinical disease to intermediate syndrome of vascular complications called dengue fever complicated (DFC) and severe, dengue hemorrhagic fever (DHF). Methods for discriminating outcomes will impact clinical trials and understanding disease pathophysiology.


METHODS
We integrated a proteomics discovery pipeline with a heuristics approach to develop a molecular classifier to identify an intermediate phenotype of DENV-3 infectious outcome.


RESULTS
121 differentially expressed proteins were identified in plasma from DHF vs dengue fever (DF), and informative candidates were selected using nonparametric statistics. These were combined with markers that measure complement activation, acute phase response, cellular leak, granulocyte differentiation and viral load. From this, we applied quantitative proteomics to select a 15 member panel of proteins that accurately predicted DF, DHF, and DFC using a random forest classifier. The classifier primarily relied on acute phase (A2M), complement (CFD), platelet counts and cellular leak (TPM4) to produce an 86% accuracy of prediction with an area under the receiver operating curve of >0.9 for DHF and DFC vs DF.


CONCLUSIONS
Integrating discovery and heuristic approaches to sample distinct pathophysiological processes is a powerful approach in infectious disease. Early detection of intermediate outcomes of DENV-3 will speed clinical trials evaluating vaccines or drug interventions.
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States; Sealy Center for Molecular Medicine, UTMB, United States; Institute for Translational Sciences, UTMB, United States. Electronic address: arbrasie@utmb.edu.
Allan R
AR
Brasier
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States; Sealy Center for Molecular Medicine, UTMB, United States; Institute for Translational Sciences, UTMB, United States.
Yingxin
Y
Zhao
Sealy Center for Molecular Medicine, UTMB, United States; Institute for Translational Sciences, UTMB, United States; Department of Biochemistry and Molecular Biology, UTMB, United States.
John E
JE
Wiktorowicz
Sealy Center for Molecular Medicine, UTMB, United States; Institute for Translational Sciences, UTMB, United States; Department Preventive Medicine and Community Health, UTMB, United States.
Heidi M
HM
Spratt
Department of Infectious Diseases and Microbiology and Immunology, University of Pittsburgh, United States.
Eduardo J M
EJ
Nascimento
Laboratorio de Virologia e Terapie Experimental do Centro de Pesquisas Aggeu Magalhaes-CPqAM, Fiocruz, Recife, Pernambuco, Brazil.
Marli T
MT
Cordeiro
Sealy Center for Molecular Medicine, UTMB, United States; Department of Biochemistry and Molecular Biology, UTMB, United States.
Kizhake V
KV
Soman
Department Preventive Medicine and Community Health, UTMB, United States.
Hyunsu
H
Ju
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States.
Adrian
A
Recinos
Biomolecular Resource Facility, UTMB, United States.
Susan
S
Stafford
Biomolecular Resource Facility, UTMB, United States.
Zheng
Z
Wu
Laboratorio de Virologia e Terapie Experimental do Centro de Pesquisas Aggeu Magalhaes-CPqAM, Fiocruz, Recife, Pernambuco, Brazil; Department of Infectious Diseases and Microbiology and Immunology, University of Pittsburgh, United States.
Ernesto T A
ET
Marques
Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX, United States; Center for Tropical Diseases, University of Texas Medical Branch, Galveston, TX, United States; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, United States.
Nikos
N
Vasilakis
D000210:Acute-Phase Reaction; D000328:Adult; D015415:Biomarkers / Q000032:analysis* / Q000097:blood; D003167:Complement Activation; D003715:Dengue / Q000175:diagnosis* / Q000235:genetics / Q000821:virology; D003716:Dengue Virus / Q000235:genetics*; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D008297:Male; D010641:Phenotype; D010976:Platelet Count; D040901:Proteomics; D012372:ROC Curve; D019595:Severe Dengue / Q000175:diagnosis* / Q000235:genetics / Q000821:virology; D014335:Tropomyosin / Q000032:analysis; D019562:Viral Load; D055815:Young Adult; D000511:alpha-Macroglobulins / Q000032:analysis
C578813:A2M protein, human; D015415:Biomarkers; C501213:TPM4 protein, human; D014335:Tropomyosin; D000511:alpha-Macroglobulins
Acute phase reaction; Biomarker pipeline; Dengue; Selected reaction monitoring