title: Serum proteome and cytokine analysis in a longitudinal cohort of adults with primary dengue infection reveals predictive markers of DHF.
abstract: BACKGROUND
  Infections caused by dengue virus are a major cause of morbidity and mortality in tropical and subtropical regions of the world. Factors that control transition from mild forms of disease such as dengue fever (DF) to more life-threatening forms such as dengue hemorrhagic fever (DHF) are poorly understood. Consequently, there are no reliable methods currently available for early triage of DHF patients resulting in significant over-hospitalization.
  
  
  RESULTS
  We have systematically examined the proteome, cytokines and inflammatory markers in sera from 62 adult dengue patients (44 DF; 18 DHF) with primary DENV infection, at three different times of infection representing the early febrile, defervescence and convalescent stages. Using fluorescent bioplex assays, we measured 27 cytokines in these serum samples. Additionally, we used multiple mass spectrometry methods for iTRAQ-based comparative analysis of serum proteome as well as measurements of protein adducts- 3-nitrotyrosine and 3-chlorotyrosine as surrogate measures of free radical activity. Using multiple methods such as OPLS, MRMR and MSVM-RFE for multivariate feature selection and classification, we report molecular markers that allow prediction of primary DHF with sensitivity and specificity of >80%.
  
  
  CONCLUSIONS
  This report constitutes a comprehensive analysis of molecular signatures of dengue disease progression and will help unravel mechanisms of dengue disease progression. Our analysis resulted in the identification of markers that may be useful for early prediction of DHF during the febrile phase. The combination of highly sensitive analytical methods and novel statistical approaches described here forms a robust platform for biomarker discovery.
authors.affiliation: Interdisciplinary Research Group in Infectious diseases, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.
authors.forename: Yadunanda
authors.initials: Y
authors.lastname: Kumar
authors.forename: Cui
authors.initials: C
authors.lastname: Liang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Bo
authors.forename: Jagath C
authors.initials: JC
authors.lastname: Rajapakse
authors.forename: Eng Eong
authors.initials: EE
authors.lastname: Ooi
authors.forename: Steven R
authors.initials: SR
authors.lastname: Tannenbaum
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood*; D003716:Dengue Virus / Q000472:pathogenicity*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D020543:Proteome / Q000032:analysis*; D044967:Serum / Q000737:chemistry*; D019595:Severe Dengue / Q000175:diagnosis* / Q000473:pathology*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D020543:Proteome