## Netsim

** Category** Cross-Omics>Pathway Analysis/Gene Regulatory
Networks/Tools

** Abstract** Netsim is a novel ‘gene network simulator’ that resembles
some of the main features of transcriptional regulatory networks related to
topology, interaction among regulators of transcription, and expression
dynamics.

The simulator generates ‘network topology’ according to the current knowledge of biological network organization, including scale-free distribution of the connectivity and clustering coefficient independent of the number of nodes in the network.

It uses fuzzy logic to represent interactions among the regulators of each gene, integrated with differential equations to generate continuous data, comparable to real data for variety and dynamic complexity.

Netsim accounts for saturation in the response to regulation and transcription activation thresholds and shows robustness to perturbations.

It therefore, provides a reliable and versatile test bed for reverse engineering algorithms applied to microarray data.

Since the simulator describes regulatory interactions and expression dynamics as two distinct, although interconnected aspects of regulation, it can also be used to test reverse engineering approaches that use both microarray and protein-protein interaction (PPI) data in the process of learning.

Netsim is implemented for the R programming language in C.

*Note: Details related to the core functions are given in the help files
provided with the software package.*

Netsim's graphical interface has four (4) Functions:

1) Netsim_generate - is the wizard for generating the network topology, the regulatory interactions, and the expression profiles;

2) Netsim_simulate is for generating expression profiles from networks of known topology;

3) Netsim_graph - draws the network as a directed graph; and

4) Netsim_profiles - plots the profiles created by Netsim_generate or Netsim_simulate.

*1) Netsim_generate Function --*

- a) Topology - Common Parameters - The function Netsim_generate provides a graphical interface to the simulatenet function which generates networks of N nodes with a constraint on the maximum number of regulators of each gene (max.reg).
- The connectivity can be MTM, random, geometric or scale-free.
- b) Topology - Specific Parameters - The parameter gamma shapes the power-law distribution, which can be applied, choosing the parameter INdegree, only to the out-degree or both to the in- and the out-degrees.
- The parameter ‘Cf.cl’ is the average clustering coefficient for each module. Each generated module has a random number of nodes ranging from one to a maximum fixed by the user. The parameter kappa is for geometric networks.
- c) Rules - Network topology defines the regulators of each node; based on them, a regulatory rule is generated by randomly combining three (3) functions for cooperative, inverse or synergic regulation.
- They are applied following a parse tree, and their probability can be modulated as dependent on the tree level, according to a function, which can be also plotted.
- d) Dynamics - The activation function (parameter act.fin) can be linear or sigmoidal. Parameters alpha, beta, and lambda of the Dynamics equations can be set for each gene.
- The simulator generates data ranging between two gene-specific constants ‘Xmin’ and ‘Xmax’, representing the minimum and maximum levels of the expression of genes; the initial conditions ‘X0’ are assigned by specifying a file or using a uniform distribution.
- The weights appearing in the equations, ‘weighted.par’, are sampled from a Gaussian distribution with mean and standard deviation.
- e) Solutions - Once the network is completely specified in terms of topology, rules, and kinetic parameters, the system is solved using the ODE solvers of the GSL library (see below...) and evaluated at given time points.
- It is also possible to specify how many experiments to generate and whether to save the results or Not.
- [GSL library - The GNU Scientific Library (GSL) is a numerical library for C and C++ programmers. It is free software under the GNU General Public License.
- The library provides a wide range of mathematical routines such as random number generators, special functions and least-squares fitting. There are over 1,000 functions in total with an extensive test suite.]
- f) Confirmation - Before the actual computation is performed, a screen with all the chosen parameters is displayed. If the user is Not sure, they can go back and modify their choices, or cancel the operation.
- g) When the computation is done the Netsim_generate wizard disappears. And you can now generate the profiles using the Netsim_simulate function; and it is also possible to draw the graph of the network using the ‘Netsim_graph’ function.

*2) Netsim_simulate Function --*

The Netsim_simulate function provides a graphical interface to the ‘simulateprofiles’ function, which generates the profiles for a gene network. It starts from the topology, which can be specified as a file containing the weights of the connections.

It is also possible to automatically consider all the files (“weights*.txt”) stored in the “Netsim” sub-directory of the working directory.

*3) Netsim_graph Function --*

The ‘Netsim_graph’ function plots the topology of the networks stored in the “Netsim” sub-directory of the working directory (in the files “weights*. txt”).

There is a spin-button which is automatically set to the maximum number of networks found and a check box that paints the nodes of the graph according to their out-degree.

*4) Netsim_profiles Function --*

The ‘Netsim_profiles’ function plots the profiles of the networks, created by Netsim_generate or Netsim_simulate functions.

Its window is dynamically created according to the experiments that have been performed: the function looks for the appropriate profiles in the Netsim sub-directory of the working directory.

On the bottom of this window there is a variable number of spin-buttons to select the profiles and check boxes that allow you to show clusters, regulators and/or differential profiles.

*System Requirements*

Contact manufacturer.

*Manufacturer*

- Information Engineering Department
- University of Padova
- Padova, Italy

** Manufacturer Web Site**
Netsim

** Price** Contact manufacturer.

** G6G Abstract Number** 20589

** G6G Manufacturer Number** 104192