2.1.2 Representation of a
Sub-/system
Mapping out the interactions among biochemical entities as a
network provides a platform for structural and dynamical analysis
of the system. A large set of network visualization tools (e.g.,
CellDesigner [12], Cytoscape [13], VANTED [14]) are used to
construct the networks, representing biological processes from
abstract to more detailed level, depending on the requirements of
biological question and available knowledge. Based on available
knowledge and the domain expert’s opinion, the interaction
mechanisms (e.g., activation or inactivation) among molecular
entities are defined or hypothesized. Depending on network size
and kinetic details, a suitable modeling formalism is chosen to
analyze the dynamics of the systems for input stimuli and different
perturbations.2.1.3 Model Construction This step starts with the detailed description of interaction mechan-
isms providing the biochemical and biophysical information. For
example, biochemical interactions characterize the activation/inac-
tivation in terms of phosphorylation/dephosphorylation, and bio-
physical interactions describe about what enzyme or catalyst
regulates the reaction. For dynamical analyses, the interactions are
represented by a system of mathematical equations, which we refer
to as the mathematical model. Model parameter values are identi-
fied and characterized from available biological information [15]
and databases like SioABIO-RK [16] and BioModels [17].
2.1.4 Validation
and Experimentation
After the identification of model parameter values, analytical tools
(e.g., bifurcation and sensitivity analysis) are used to analyze the
model’s dynamical behavior, stability, and robustness. Then the
model is calibrated with biological data by refining its parameter
values to recapitulate the biological reality. After successful calibra-
tion of the model, new hypotheses are made using predictive simu-
lations that unravel regulatory mechanisms underlying complex
processes. Hypotheses made by model simulations need to be
validated by designing new experiments. If the model predictions
are validated by experiments, it will provide a reasonable explana-
tion of the biological phenotypes and sharpen our understanding of
the complex processes that generate them.2.2 Network
Construction
Processes in living cells are carried out by complex interactions
among biological elements such as genes, proteins, RNAs,
mRNAs, enzymes, transcription factors, and other molecules. To
understand the mechanisms behind normal and malfunctional exe-
cution of processes (linked to diseases), it is necessary to have a
blueprint of these interactions in the form of network (i.e., vertices
connected by edges). The construction of networks is a painstaking
exercise of manual validation and encoding. Various approaches are
used to map out molecular interactions underlying certain
biological processes. A number of computational techniques haveIntegrative Workflow for Predicting Disease Signatures 251