http://creativecommons.org/licens es/by-sa/2.0/. simulation programs: what is out there? a critical...
TRANSCRIPT
![Page 1: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/1.jpg)
http://creativecommons.org/licenses/by-sa/2.0/
![Page 2: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/2.jpg)
Simulation Programs: What is out there? A critical evaluation.
Prof:Rui [email protected]
973702406Dept Ciencies Mediques Basiques,
1st Floor, Room 1.08Website of the
Course:http://web.udl.es/usuaris/pg193845/Courses/Bioinformatics_2007/ Course: http://10.100.14.36/Student_Server/
![Page 3: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/3.jpg)
Simulation is becoming widespread
• Kinetic models are becoming a common tool for testing biological hypothesis.
• A plethora of different software packages for model building, simulation and analysis is available.
• How far are we from having reliable tools that make simulation accessible to non-expert mathematical modelers?
• What tools are more adequate for different types of problems?
![Page 4: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/4.jpg)
Addressing the questions
• Choose representative simulation packages.
• Identify features in each of them.
• Test how accurately these features work.
• Evaluate how much expertise one needs to use each program.
![Page 5: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/5.jpg)
Emphasis
• Simulators– Type of input
• Models used for testing
• Analytical capabilities of the software
• Cross-compatibility between the software
• What to use for each type of problem
![Page 6: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/6.jpg)
Rationale for excluding software
• Kinetic Modeling Packages that require expert knowledge about the mother-software excluded– Not for non-experts + expensive
• Commercial user-friendly simulation software provides no new functionality with respect to free software. Also, we could not get temporary evaluation licenses for some of them, so we excluded them all.
![Page 7: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/7.jpg)
List of software
![Page 8: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/8.jpg)
Evaluated Simulation Packages
• Kinetic Modeling Packages– Excludes software that implement functionality in a
pre-existing software platform (e.g. BST lab in MATLAB).
• Free Stand alone simulators– Excludes e.g. STELLA and MADONNA
• Free Internet Simulation Servers
• Free Network editors
![Page 9: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/9.jpg)
Evaluated software
![Page 10: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/10.jpg)
Text-based input
![Page 11: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/11.jpg)
Dialog-based input
![Page 12: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/12.jpg)
Diagrammatic input
![Page 13: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/13.jpg)
Comparison of diagrammatic interfaces
![Page 14: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/14.jpg)
Rationale for choices of models
• Models that allowed the testing of the different features.
• In some cases model with analytical solutions so that accuracy of calculations could be determined
![Page 15: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/15.jpg)
Models used in the evaluation (1)
• Escherichia coli’s phosphoenolpyruvate:glucose phosphotransferase system (mass action; 1 compartment)
• GAL4 system of Saccharomyces cerevisiae (mass action; 1 compartment)
• Tests for stochastic simulators
![Page 16: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/16.jpg)
Models used in the evaluation (2)
• Source reactions• Reactions with catalysts
• Reactions with modifiers
• Homo molecular reactions
![Page 17: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/17.jpg)
Models used in the evaluation (3)
• Simple difusion two compartment model
![Page 18: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/18.jpg)
Models used in the evaluation (4)
• Simple two reaction model with analytical solution to evaluate sensitivity and stability analysis
1 1 2k X X
X1 X22
2
VX
K X
• Tests for stability and sensitivity analysis as well as moiety conservation calculations
![Page 19: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/19.jpg)
Analytical capabilities of the software
Incorrectly implemented jacobian calculationsIncorrect for models with moiety conservation
![Page 20: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/20.jpg)
Stability/Sensitivity analysis for model 5
![Page 21: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/21.jpg)
Analytical capabilities of the software
![Page 22: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/22.jpg)
Compartmental model implementation model 4
• Write all equations/Draw diagrams
• Choose Kinetic equations/Write KEs
• Interface reaction parameters must be correct to have the appropriate units
• Permeability constant converted into apparent rate constants
• Kinetic parameters multiplied by volume of corresponding compartment
![Page 23: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/23.jpg)
Exceptions:
• V-Cell
• Dizzy – Convert everything into ammounts rather than concentrations
• Cellware – Chose a reference compartment and convert all concentrations to that compartment
![Page 24: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/24.jpg)
Crosstalk between software
• It is important to be able to share models between different software programs
• SBML is becoming the standard
![Page 25: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/25.jpg)
SBML compatibility
![Page 26: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/26.jpg)
Verified SBML compatibility
![Page 27: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/27.jpg)
Trouble in SBMLland
• reaction stoichiometries defined as floating point values;
• boundary metabolites; • source reactions• sink reactions • reactions where the stoichiometry for one of
reactants or products is larger than 1; • kinetic type definitions can prevent correct
interpretation of models by stochastic simulators. • Definition of compartments breaks down for
variable volumes
![Page 28: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/28.jpg)
There is hope in SBMLand
• A small amount of editing is in general sufficient to correct imcompatible SBML models
• A redefinition of comparments is straightforward
![Page 29: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/29.jpg)
Goals of the model (I)
• Large scale modeling– Reconstructing the full network of the genome– Red Blood Cell Metabolism
• Dialog or diagram based, with possibility for modular implementation– COPASI, GEPASI, V-CELL,
CELLDESIGNER,JDESIGNER
• Sensitivity analysis – COPASI, GEPASI, jdesigner, v-cell
![Page 30: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/30.jpg)
Goals of the model (I)
• Modeling Specific Pathways/Circuits– Non-catalytic lipid peroxidation– MAPK Pathways
• Any type of input;
• Sensitivity analysis– COPASI, GEPASI, jdesigner, PLAS, v-cell,
celldesigner
![Page 31: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/31.jpg)
Goals of the model (I)
• Generating alternative hypothesys for the topology of the model.
• Must allow for structured functional forms and for large scale parameter scans– COPASI, GEPASI, jdesigner, PLAS,
celldesigner
![Page 32: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/32.jpg)
Goals of the model (II)
• Estimating parameter values– Must have fitting algorithms
• COPASI, GEPASI,DYNAFIT
• Identifying Design Principles– None, so far; howver we have a
MATHEMATICA package that allows you to do this.
![Page 33: Http://creativecommons.org/licens es/by-sa/2.0/. Simulation Programs: What is out there? A critical evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406](https://reader035.vdocuments.net/reader035/viewer/2022070410/56649efa5503460f94c0c3ab/html5/thumbnails/33.jpg)
Final Conclusion
• Our analysis has convinced us that a non-trivial degree of expertise is still required for the use of simulation programs to create models.
• It is dangerous to expect that a non-expert will create a useful and correct model of a biological process.
• Alves et al. Nature Biotechnology 2006