title: Mathematical modelling and a systems science approach to describe the role of cytokines in the evolution of severe dengue.
abstract: Dengue causes considerable morbidity and mortality in Sri Lanka. Inflammatory mediators such as cytokines, contribute to its evolution from an asymptotic infection to severe forms of dengue. The majority of previous studies have analysed the association of individual cytokines with clinical disease severity. In contrast, we view evolution to Dengue Haemorrhagic Fever as the behaviour of a complex dynamic system. We therefore, analyse the combined effect of multiple cytokines that interact dynamically with each other in order to generate a mathematical model to predict occurrence of Dengue Haemorrhagic Fever. We expect this to have predictive value in detecting severe cases and improve outcomes. Platelet activating factor (PAF), Sphingosine 1- Phosphate (S1P), IL-1β, TNFα and IL-10 are used as the parameters for the model. Hierarchical clustering is used to detect factors that correlated with each other. Their interactions are mapped using Fuzzy Logic mechanisms with the combination of modified Hamacher and OWA operators. Trapezoidal membership functions are developed for each of the cytokine parameters and the degree of unfavourability to attain Dengue Haemorrhagic Fever is measured.
  
  
  
  The accuracy of this model in predicting severity level of dengue is 71.43% at 96 h from the onset of illness, 85.00% at 108 h and 76.92% at 120 h. A region of ambiguity is detected in the model for the value range 0.36 to 0.51. Sensitivity analysis indicates that this is a robust mathematical model.
  
  
  
  The results show a robust mathematical model that explains the evolution from dengue to its serious forms in individual patients with high accuracy. However, this model would have to be further improved by including additional parameters and should be validated on other data sets.
authors.affiliation: Research and Development Centre for Mathematical Modelling, University of Colombo, Colombo, Sri Lanka. pavithra_jayasundara@yahoo.com.
authors.forename: S D Pavithra
authors.initials: SD
authors.lastname: Jayasundara
authors.affiliation: Research and Development Centre for Mathematical Modelling, University of Colombo, Colombo, Sri Lanka.
authors.forename: S S N
authors.initials: SS
authors.lastname: Perera
authors.affiliation: Centre for Dengue Research, Faculty of Medicine, University of Sri Jayewardenepura, Nugegoda, Sri Lanka.
authors.forename: Gathsaurie Neelika
authors.initials: GN
authors.lastname: Malavige
authors.affiliation: Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka.
authors.forename: Saroj
authors.initials: S
authors.lastname: Jayasinghe
mesh_terms: D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods*; D016207:Cytokines / Q000378:metabolism*; D018450:Disease Progression; D017143:Fuzzy Logic; D006801:Humans; D008954:Models, Biological; D019595:Severe Dengue / Q000378:metabolism* / Q000473:pathology
chemical_list: D016207:Cytokines
keywords: Combined effect; Cytokines; Dengue; Fuzzy logic