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LetItB User`s Manual - English version - OIST Groups

1. timeseries reconstruct Simulation Figure 1 SBML File Loading 2 3 Displaying Diagram From the LetltB s menu select Tool gt Show reaction diagram Then you can see a diagram export window The right figure in Figure 2 shows the resultant diagram when you load model xml m reaction diagi x File EHS Help Show reaction diagram Model ee species reactions parameters ODEs Parameter Estimation initial concentrations reaction parameters titB information Figure 2 Reaction Diagram Operation Screen Display Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved LetltB User s Manual 2 4 Running Simulation From the tree menu in the left pane click Simulation Next specify options in the ODE solver option pane on the right side of the screen Example Setting ODE solver option end time 5 Time to terminate the simulation number of time points 50 Number of simulation steps Any options other than above are set by default Finally click the run simulation button to start the simulation LetltB unknown project File Tool Help LetitB Parameters Simulation a Model model xml compartments ODE solver option species y reactions parameters end time s ODEs E Parameter Estimation number of time points a0 initial concentrations time interval s 0 1 reaction parameters data s
2. Okinawa Institute of Science and Technology 2007 All Rights Reserved 47 LetltB User s Manual 6 6 timeseries reconstruction You can run timeseries simulation with initial concentrations and reaction parameters information in the Parameter Estimation part This allows you to easily view the results of the timeseries simulation by using parameter estimation results See Chapter 7 Simulation Before running the timeseries simulation by using parameter estimation results perform update initial sample in Section 6 5 3 and update information in initial concentrations and reaction parameters LetItB Samplel Ibp File Tool Help Letit6 Parameters Model Sample1 xml compartments species end time s 10 reactions P s parameters number of time points 1000 ODEs Parameter Estimation initial concentrations relative error torelance le 08 reaction parameters data sets Monte Carlo executior results timeseries reconstruc Simulation ODE solver option time interval s 0 01 absolute torelance le 12 no dataset run simulation select results save data draw graph Figure 39 timeseries reconstruction Screen Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 48 LetltB User s Manual ODE solver option end time The time to terminate the simulation Default 10 The start time is set to 0
3. Simulation Screen Setting Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved y Simulation ODE solver option end time s number of time points time interval s relative error torelance absolute torelance results save data draw graph LetitB Samplel Ibp 1000 0 01 le 08 le 12 run simulation 53 LetltB User s Manual 7 4 Mapping Control Data After loading control data into LetltB map them to an appropriate SBML ID or name NOTE If SBML ID or name is contained as header information in line 1 of the external input file you don t need to perform this step For your information see SampleData contained in the installation folder In the control inputs pane where control data are loaded into from the combo boxes in all the columns other than time column select any SBML ID or Name you want to use as control data NOTE 1 Before mapping with the combo boxes be sure to select all columns for the factors you need to map NOTE 2 Do not select the same SBML ID or Name for different factors NOTE 3 If you define no correct mapping you cannot run Simulation with Control Data properly LetltB Samplel Ibp File Tool Help ici Simulation Sample1_controll txt Model Sample1 xml MZ compartments control inputs species reactions di a parameters 1 time no_mapping Parameter Estimation initial concentrations 315 B reaction para
4. and Exporting Files ccccccececseceeceeneeeeceeneeeeeeeneeeeeceeaeeeeseceeeeeeseneeeesenaneeeenenaees 13 4 1 Loading Project File cccccceccsecceceeneeeeeeeneeeeeecneeeeeeeeaeeeeseseeeeesecaeeeeseceeeeseceeeeeesseeeeesseneeeeeeas 13 4 2 Writing Project voca 14 4 31 Loading SBME File vue daa tota 15 44 Writing SBME Fl o e e leonado 16 45 Exporting Reaction DiagraMiita aida daa dada ld dd dd 17 46 Exporting ODES viecararacanta rr AA a aaa ds 19 8 Models NS 20 Dsl COMPAMMMENIS arrn encore lances a 20 52 eee ete ee ee ee eee ee ee ee ee ae Se ee 21 5 3 1 e 110 IPPO pu insist sanedaniednieanatr aie Ea Ea nE AEE EnEn ENE EENE EAEE EAEE 23 54 NN 24 5S B COPEC E ee ee eee es 25 6 Parameter Estimations asias a 26 6 initial concentrations sosirii datada ndo 26 6 2 O ve ves aE KE E EE KE EEEN EEEE EEEN E EEEE EENE e Eo 28 6 3 data Sets e ni po evel a duel a tal abel A EAEE A aA aaa naaa Eaa 29 6 3 1 Loading and Deleting Observation Data ccccccccceececeeeeneeeeeeeeaeeeeeenaeeeesesneeeeeseneeeeessneeeess 30 6 3 2 Loading and Deleting Control Data ooococcnnnoccccnnooccccononcccnononnccnnonancnnnonnnnnonnnnnnnnnnonnn cnn ninnnnnncnns 31 6 3 3 Mapping External Input Dalarnas AAA ieeedisede 32 64 Monte Car o oo 33 Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved LetltB User s Manual 6 4 1 Setting Monte Carlo ccccccccccceccccee
5. run simulation results time graph option y 0 0 4 0 3 0 01 0 01 0 394104 0 294104 0 0158955 0 02 0 388409 0 288409 0 021591 0 03 0 382904 0 282904 0 0270965 0 04 0 377579 0 277579 0 0324211 0 05 0 372426 0 272426 0 0375736 0 06 0 367438 0 267438 0 0425621 save data draw graph Figure 45 Simulation Screen Graph Displaying Operation Screen Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 56 LetltB User s Manual A graph window displays a timeseries graph with simulation results in Y axis and time in X axis based on the factors you select in graph option The simulation result for each factor is displayed in solid lines NOTE The colors of solid lines are automatically set LetitB timeseries graph lt 2 o c g U o o Figure 46 Timeseries Graph Screen How to Configure 1 To save an image From the menu of a graph window select File gt Save graph When a file dialog appears select where the file will be saved a name of the file and an image format you want to save and then save the data 2 To display hide graph By clicking the captions in the upper right corner of a graph window you can display hide the graph End Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 57
6. 5 3 Reflecting Estimated Values You can collectively reflect the results of parameter estimation in the following two ways by clicking an appropriate button as needed update initial sample Reflect values of the Map estimator item into those of the initial sample item The initial concentrations and reaction parameters information in the Parameter Estimation part will also be updated No information of the SBML model the Model part will be updated update model Reflect values of the Map estimator item into those of the volume item in species and the initial concentration item of parameters in the Model part No information of the Parameter Estimation part will be updated LetitB Samplel Ibp File Tool Help Letit6 Parameters Model Sample1 xml estimation results of initial concentrations 5 initial MAP standard A compartments pi PECES sample estimator deviation m reactions l species_0 0 4 0 427117 0 0413966 mol l arameters poi 2 species_1 0 3 0 298196 0 00445069 mol l Parameter Estimation 0 0114264 0 0032279 mol l initial concentrations reaction parameters 3 species 2 0 01 prior SBMLID show graph Gamma 1 3 48375 species_0 show graph Gamma 1 3 21444 species_1 show graph Gamma 1 59 1913 species_2 show graph data sets Monte Carlo executior timeseries reconstruci Simulation estimation results of reaction parameters a initial MAP standard i reaction parameter
7. after histogram smoothing Disabled by default LetItB displays the 1D graph with the above settings In addition LetltB displays numeric values for the above items in the bottom part of the histogram window LetItB histogram species 0 histogram species O m lt a cs gt E 3 o a 0 ka 0 7 x axis min 0 322832 max 0 742317 bins 20 vi smoothing replot a 99 confidence interval MAP estimators nis lower bound upper bound 0 408701 0 349173 0 646591 Figure 36 1D Histogram Window Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 43 LetltB User s Manual How to Configure 1 To save an image From the menu of the histogram window select File gt Save graph When a file dialog appears select where the file will be saved a name of the file and the image format you want to save and then save the data 2 To modify the X axis Enter values in min as the minimum value in max as the maximum value and in bins as the number of histogram bins Then click the replot button 3 To smooth the graph Enable disable the smoothing check box and then click the replot button 4 To set confidence interval Enter any number between 0 and 100 in XX confidence interval and then click the replot button NOTE You cannot edit any values in MAP estimator lower bound and upper bound To display 2D histograms How to Display W
8. and then save the data 2 To change the axes settings Select any factors you want to display for both of the X and Y axes If you select factors for the axes the minimum value and the maximum value for them are automatically set 3 To edit the axes Enter values in min as the minimum value in max as the maximum value and in grids as grid spacing for the axes Then click the replot button NOTE The run time required to plot the 2D histogram depends your machine environment and other environment factors such as the estimated number of samples and the settings for the grid spacing specified in grids Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 46 LetltB User s Manual 6 5 5 Saving Parameter Estimation Results You can save the results of parameter estimation in the following three ways by clicking an appropriate button as needed save effective samples Display only effective results of parameter estimation by each occurrence of the number of simulation steps When you click the button a file dialog appears Specify where the file will be saved and a name of the file save all samples Display all results of parameter estimation by each occurrence of the number of simulation steps When you click the button a file dialog appears Specify where the file will be saved and a name of the file save results Save the information on the results screen in the text format When you click the
9. functions used as prior arg0 Display the first argument of prior arg1 Display the second argument of prior SBML ID Display ID information in the species tag To edit data You can edit numeric data in initial value arg0 and arg items Select any cells you want to edit and then enter values With the check boxes in the estimated item you can enable disable any factors you want for parameter estimation targets by clicking appropriate cells NOTE 1 You cannot select and edit any cells other than above NOTE 2 No values you edit in the initial value item on the initial concentrations screen will be reflected in those on the species screen NOTE 3 With the estimated item parameter estimation will be performed for only the factors selected with enabled check boxes Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 27 LetltB User s Manual 6 2 reaction parameters The reaction parameters subpart displays the information on estimating reaction parameters file Tool Help Lette Parameters reaction parameters Model Sarolel ori z s compartments reaction parameter nia value urit estimated prior argi ql SEL O Species t resection kl S UNKNOWN iv garwnalag argli 2 1 ted feaction_o reactions 2 reaction k2 DO uriknowrl y garmalar gd argll 1 le 06 reacion_0 Parameter Estimator m a concentrations ISSCloo parameta osta sets Monte Cano executior resists Dineseries re
10. information of the selected subpart in the right pane 6 1 initial concentrations The initial concentrations subpart displays the information on estimating initial concentrations LetitB Samplel lbp File Tool Help LetitB Parameters A initial concentrations of species Model Sample1 xml F compartments name initialvalue unit estimate prior argo argl SBML ID species 1A 0 4 mol l y gammatargO argl 4 1 le 06 species 0 reactions z parameters 2B 0 3 mol l iv gamma argO argl 1 le 06 species 1 ODEs 3 C 0 01 mol l iv gamma argO arg1 Parameter Estimation reaction parameters data sets Monte Carlo executior results timeseries reconstruci Simulation 4 4 le 06 species 2 Figure 22 initial concentrations Screen Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 26 LetltB User s Manual About initial concentrations screen name Display name information in the species tag If there is no name information in the tag LetltB displays ID information initial value Display initialConcentration information in the species tag If there is no initialConcentration information in the tag LetltB sets 1 as default unit Display the unit used in species Default mol l estimated Display the factors enabled for parameter estimation Default All factors are defined for parameter estimation targets prior Display applicable probability distribution
11. number of time points The number of simulation time steps Default 1000 size of time intervals The interval between simulation time steps end time number of time points size of time intervals relative error tolerance Tolerance error margin of simulation results Relative unit Default 1 x 10 absolute tolerance Tolerance range of simulation results Absolute unit Default 1 x 10 Unless expressly specified in SBML files second s is used for a unit of time To edit the data in ODE solver option You can edit numeric data in the end time number of time points relative error tolerance and absolute tolerance items Select any cells you want to edit and then enter values To run the timeseries simulation Select any data set from the select item on the middle of the timeseries reconstruction screen and then click the run simulation button to start the simulation The index dataset XX in the select item is linked to the tab index on the data sets screen described in Section 6 3 NOTE 1 If you don t select proper items from the select item you cannot run the simulation NOTE 2 If you don t load control data into LetltB on the data sets screen you can run the simulation without control data If you load control data into LetltB on the data sets screen you can run the simulation with the control data To display timeseries simulation results When the timeseries simulation completes its results wil
12. sample estimator deviation unit prior SBMLID show graph 1 reaction_0 kl 5 4 34402 0 546499 unknown gamma 1 0 0389517 reaction_0 show graph 2 reaction_0 k2 0 01 0 0136564 0 0075709 unknown gamma 1 8 78928 reaction_O show graph log posterior error function y log marginal likelihood 315 417 0 193622 323 07 open 2D stat window update initial sample update model i E save effective samples save all samples save results r p a Pi a namma as lt Figure 34 results Screen update initial sample and update model Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 41 LetltB User s Manual 6 5 4 Display 1D and 2D Histograms You can display the results of parameter estimation as 1D or 2D histograms To display a 1D histogram How to Display When you click the button in the show graph items on the results screen a 1D graph appears NOTE Before clicking the show graph button be sure to click the SBML ID cell of any factors you want to display LetitB Samplel Ibp File Tool Help LetitB Parameters estimation results of initial concentrations Model Sample1 xml initial MAP standard compartments i ii i p species sample estimator aeistion unit prior SBMLID show graph species reactions 1 species 0 0 4 0 427117 0 0413966 mol l Gamma 1 3 48375 species 0 show graph arameters PEA pm 2 species 1 0 3 0 298196 0 00445069 mol
13. save results button a file dialog appears Then specify where the file will be saved and a name of the file NOTE Only for save effective samples and save all samples LetltB supports the same file save formats as specified in Section 6 3 LetitB Samplel ibp fille Tool Help LetitB Parameters estimation results of initial concentrations Model Samplel xml A FE TT initial standar p A compartments pi species Semple estimator deviation UNH prior SBMLID show graph species reactions 1 species 0 0 4 0 427117 0 0413966 moli Gamma 1 3 48375 species_0 show graph arameters cae 2 species_l 0 3 0 298196 0 00445069 moli Gamma 1 3 21444 species_1 show graph Parameter Estimation 3 species_2 0 01 0 0114264 0 0032279 mol Gamma 1 59 1913 species_2 show graph initial concentrations reaction parameters data sets Monte Carlo executior results timeseries reconstruct Simulation estimation results of reaction parameters reaction parameter _ inital Mg penean unit prior SBMLID show graph sample estimator deviation 1 reaction_0 kl 5 4 34402 0 546499 unknown gamma 1 0 0389517 reaction_0 show graph 2 reaction_0 k2 0 01 0 0136564 0 0075709 unknown gamma 1 8 78928 reaction_O show graph log posterior error function Y log marginal likelihood 315 417 0 193622 323 07 open 2D stat window save effective samples save all samples save results Figure 38 results Screen Parameter Estimation Results Saving Copyright c
14. the species screen are selected will be the values for initial concentration the constant value Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 52 LetltB User s Manual 7 3 Loading and Deleting Control Data To load control data Click the button on the upper left corner of the Simulation screen When a file dialog appears select any control data file Selecting a file automatically moves you to a new tab window and displays the selected data in the control inputs pane in the new tab window With Files of type in a file dialog select an appropriate file format and separation type If you load multiple control data files into LetItB click the button each time Once loaded observation data is separated with tab windows to allow you to switch your data tab window LetltB supports the same file formats for loading control data as specified in Section 6 3 To delete control data Select the tab window you want to delete and then click the x button on the upper right corner of the Simulation screen You can delete observation data only when there are multiple tab windows Load Button Letit Parameters Model benchmark001 x compartments species reactions parameters ODEs Parameter Estimation initial concentrations reaction parameters data sets Monte Carlo executior results timeseries reconstruct Figure 42
15. window To delete observation data Select the dataset tab window you want to delete and click the x button on the upper right corner of the data sets screen You can delete observation data only when multiple tab windows are loaded LetItB Samplel lbp Loading Button y Delete Button LetitB Parameters Model Sample1 xml compartments observation species reactions parameters ODEs Parameter Estimation initial concentrations reaction parameters data sets Monte Carlo executior results timeseries reconstruct Simulation control inputs Figure 24 data sets Screen Observation Data Loading Deleting Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 30 LetltB User s Manual 6 3 2 Loading and Deleting Control Data To load control data As a file dialog appears by clicking the button in the center left of the dataset tab window you can select any control data in the file dialog Once selected the selected data will be automatically displayed in the control inputs pane With Files of type in the file dialog select an appropriate file format and a separation type To delete control data Select the dataset window tab you want to delete and then click the x button in the center left of the dataset tab window LetitB Samplel lbp File Tool Help LetitB Parameters dataset 00 Model Sample1 xml compartments o
16. 3559e 05 unknown gamma l 1 827e 06 unknown gamma 1 4 log posterior 1603 63 open 2D stat window error function 2 42799e 10 log marginal likelihood update initial sample update model save effective samples save all samples save results Figure 6 Estimation Results Display Screen 2 9 Storing Project File To save the current project status select File gt Save project as from the LetItB s menu When a file dialog appears specify a desirable file name and save the file Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 10 LetltB User s Manual 3 Starting and Exiting LetltB Software 3 1 Starting LetltB To start LetltB run the LetltB execution file contained in the installation directory Depending on your OS Operating System select an appropriate operation method from the below Start with GUI operation Double click LetltB contained in the installation directory Start with CUI operation Use a terminal to run LetltB contained in the installation directory After starting LetltB a LetltB Start screen shown in the figure below Figure 7 appears LetItB File Tool Help LetitB Parameters LetitB information Model compartments species reactions parameters ODEs Parameter Estimation initial concentrations reaction parameters data sets Monte Carlo executior results timeseries reconstruct Simulation Figure 7 Le
17. File Loading Screen Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved LetltB User s Manual 2 7 Performing Parameter Estimation From the tree menu on the left select Monte Carlo execution and click the run Monte Carlo sampling button on the right side of the screen Then LetItB starts parameter estimation NOTE The run time required for each parameter estimation depends on your machine environment and other environment factors LetltB unknown project File Tool Help LetitB Parameters Monte Calro setting Model model xml compartments species 1 reactions parameters method adaptive Metropc set recommend value defalut ODES number of total samples 100000 Parameter Estimation initial concentrations 3Ipha0 0 lt alphao Z k N 1e 08 reaction parameters 1st parameter of gamma prior for observation precision data sets beta0 0 lt beta0 1e 08 2st parameter of gamma prior for observation precision results timeseries reconstruc Simulation mrate 0 lt mrate lt 1 mixing rate of isotropic and adaptive Gaussian proposals 033 kappa 0 lt kappa regularization coefficient of proposal covariance matrix sd c 0 lt sd c scaling parameter of adaptive proposal eta0 0 lt eta0 lt 1 initial step size for updating proposal 2 4 0 1 lambda_a 0 lt lambda_a forgetting factor of previous history run Monte Carlo samp
18. Help LetitB Parameters estimation results of initial concentrations Model Sample1 xml initial FE aea compartments species ie A ZET Ch unit prior SBMLID show graph species sample estimator deviation reactions 1 species 0 0 4 0 427117 0 0413966 mol l Gamma 1 3 48375 species_0 show graph arameters poi 2 species 1 0 3 0 298196 0 00445069 mol l Gamma 1 3 21444 species 1 show graph Parameter Estimation 3 species 2 0 01 0 0114264 0 0032279 mol l Gamma 1 59 1913 species_2 show graph initial concentrations reaction parameters data sets Monte Carlo executior timeseries reconstruci Simulation a initial MAP standard gt reaction parameter sample estimator deviation unit prior SBMLID show graph 1 reaction_0 kl 5 4 34402 0 546499 unknown gamma 1 0 0389517 reaction_0 show graph Al 2 reaction_O k2 0 01 0 0136564 0 0075709 unknown gamma 1 8 78928 reaction_O show graph log posterior error function y log marginal likelihood 315 417 0 193622 323 07 open 2D stat window update initial sample update model i save effective samples save all samples save results 4 gt Figure 30 results Screen estimation results of initial concentrations Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 37 LetltB User s Manual estimation results of reaction parameters middle table on the results screen reaction Display name information in the reaction tag If there i
19. LetltB User s Manual Okinawa Institute of Science and Technology Neural Computation Unit Version 1 Dated April 21 2008 LetltB User s Manual Contents Ai INTRODUCTION seats E eee eden see A ene oer veae eevee ieee ie eerie 4 2 gt Getting Stame die vecnteivretreieaivertvnivicii alae AA ia rail ii e N ee e 5 2 sActivating Prograny iiss tanta ean ea tet a ake at ha a ahah ahah Racal ha alba sa ats 5 2 2 Loading SBME Sample File accio iaa quadecat quedanatenedenatenadenatenaraeededs 5 2 3 Displaying Diagraman sv roer trei itsesi a a eK EEEE EEE EE REEE EN EKEN EEK EERE Rat 6 2 4 R nning SIMULATION spear cee e r eles e e ees aber eles E aoe elles r EN r N r Ee 7 25 Saving Simulation Results Files sere e a E E E a E EEEE 8 2 6 Defining Simulation Results File Loading oooooccccnnncccnnnnocccnnnnncccccnnnnccnnnnnnncononnncnnnnnnn cnn cnnnnnno 8 2 7 Performing Parameter Estimation c ccccccscceeceeeeeeeeeeeeeeeeeecaeeeeeeeeeeeeeeeneeeeeseeeeeesseaneeessenaees 9 2 8 Displaying Parameter Estimation ReSuIts ccccccecceeeeeeeeeeeeeeeeeeeeeeaeeeeseseeeeeeseaeeeesseeeeeeeaes 10 2 9 Storing Project File ve ctcisiaestct stantial stenstai steht e o el 10 3 Starting and Exiting LetltB Software cccccccceccceeeeeeeeeeeeeeeeeeeceneeeeeeeneeeeeseeaeeeeseeeeeeeesneeeeesseeeeess 11 34 Starting LethtB cnc atinte tee der cedar cence es 11 3 2 A ciranean e E E E E E E e N i a a e oee 12 4 Loading Writing
20. Open SBML Save SBML Save SBML as Export reaction diagram Export ODEs Exit TESUMS timeseries reconstruct Simulation Figure 11 SBML File Loading Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 15 LetltB User s Manual 4 4 Writing SBML File From the LetltB s menu select File gt Save SBML or Save SBML as As a file dialog appears when you select Save SBML as specify where the file will be saved and a name of the SBML file in the file dialog Save SBML overwrite saving Automatically overwrite the existing SBML file Save SBML as saving under a new file name Create a new SBML file LetItB AGs Tool Help Open project LetitB information Save project Save project as Open SBML Save SBML Save SBML as Export reaction diagram Export ODEs Exit esur timeseries reconstruci Simulation Figure 12 SBML File Writing Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 16 LetltB User s Manual 4 5 Exporting Reaction Diagram You can export a diagram of the simulation model defined in SBML files To display Reaction Diagram After loading the SBML file See Section 4 3 select Tool gt Show reaction diagram from the LetltB s menu Then a reaction diagram export window will be displayed Figure 13 File rele y Show reaction diagram ttB information rt M
21. Save project as As a file dialog appears when you select Save project as specify where the file will be saved and a name of the file in the file dialog displayed Save project overwrite saving Automatically overwrite the existing project file Save project as saving under a new file name Create a new project file LetitB aG Tool Help Open project LetitB information Save project Save project as Open SBML Save SBML Save SBML as Export reaction diagram Export ODES Exit jis timeseries reconstruci Simulation Figure 10 Project File Writing Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 14 LetltB User s Manual This LetltB software allows you to load write project files both in the SBML System Biology Markup Language Level 1 and Level 2 formats For the units to be used in LetltB liter 1 Mol mol and second s are used unless expressly defined in the compartment species and parameter tags in SBML files For parameter however LetltB displays unknown by default if no unit definition is found in the parameter tag 4 3 Loading SBML File From the LetItB s menu select File gt Open SBML and select a SBML file in the file dialog After selecting a file the SBML file data is automatically loaded into LetItB LetitB 5164 Tool Help Open project LetitB information Save project Save project as
22. acornsriat Simulation Figure 23 reaction parameters Screen About reaction parameters screen reaction Display name information in the reactions tag See the name item in Section 5 3 If there is no name information in the tag LetltB displays ID information parameter Display ID information in the parameter tag If there is no initialConcentration information in the tag LetltB sets the default value 1 initial value Display volume information in the parameter tag unit Display the unit used in parameter If there is no unit information in the parameter tag LetltB displays unknown by default estimated Display the factors enabled for parameter estimation Default All factors are defined for parameter estimation targets prior Display applicable probability distribution functions used as prior arg0 Display the first argument of prior arg1 Display the argument of prior SBML ID Display ID information in the reactions tag Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 28 LetltB User s Manual To edit data You can edit numeric data in the initial value arg0 and arg1 items Select any cells you want to edit and then enter values With check boxes in the estimated item you can enable disable any factors you want for parameter estimation targets by clicking appropriate cells NOTE 1 You cannot select and edit any cells other than above NOTE 2 No values you edit in the i
23. appears select where the file will be saved a name of the file and an image format you want to save and then save the data 2 To display hide the graph By clicking the captions in the upper right corner of the graph window you can display hide the graph Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 50 LetltB User s Manual 7 Simulation The Simulation part allows you to run numeric simulation display save the results data and display a results graph by using Ordinary Differential Equations ODEs of the simulation model defined in the SBML file There are two types of the methods for running the simulation Simulation which solves ODEs without using any external input control data and Simulation with Control Data which applies external data to ODEs and controls them 7 1 Simulation Setting You need to set each parameter for running numeric simulation by using ODEs LetitB Samplel ibp File Tool Help LetitB Parameters Simulation a Model benchmark001 x compartments ODE solver option species reactions parameters end time s ODEs i 3 Parameter Estimation number of time points initial concentrations time interval s reaction parameters data sets relative error torelance Monte Carlo executior results timeseries reconstruct absolute torelance run simulation results save data draw graph Figure 41 Simulation Screen Set
24. appropriate set of libraries in advance Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved LetltB User s Manual 2 Getting Started This chapter briefly describes how to use LetItB by using sample data Try to use LetltB with sample data by following the instructions in this section Also refer to Chapter 3 and later for detailed information about each function 2 1 Activating Program Run the LetltB execution file contained in the installation directory Start with GUI operation Double click LetltB contained in the installation directory Start with CUI operation Use a terminal to run LetltB contained in the installation directory Example Start with CUI operation From a terminal or like move to the installation directory and then execute the following command gt LetltB amp 2 2 Loading SBML Sample File From the LetItB s menu select File gt Open SBML In the file dialog select a SBML file Example Loading a SBML file Load the SBML sample file contained in the following folder installation directory gt sampledata gt Model01 gt model xml Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved LetltB User s Manual LetitB ales Tool Help Open project Save project LetitB information Save project as Open SBML Save SBML Save SBML as Export reaction diagram Export ODEs Exit
25. bservation species reactions parameters ODEs Parameter Estimation initial concentrations reaction parameters data sets Monte Carlo executior results timeseries reconstruct Simulation Load Button TA y Delete Button OORA inputs Figure 25 data sets Screen Control Data Loading Deleting Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 31 LetltB User s Manual 6 3 3 Mapping External Input Data After loading observation data or control data into LetltB select all the factors you need for mapping NOTE If your required factors SBML ID or name are contained as header information in line 1 of the external input file you don t need to perform this step For your reference see SampleData contained in the installation folder After loading the external file into LetltB with the observation and control inputs panes select all SBML ID or Name targets from the combo boxes in all the columns other than the time column NOTE 1 Before mapping with the combo boxes be sure to select all columns for the factors you need to map NOTE 2 Do not select the same SBML ID or Name for different factors NOTE 3 If you define no correct mapping you cannot perform parameter estimation properly LetitB Samplel bp File Tool Help LetitB Parameters Model Samplel xml compartments species reactions parameters ODES Parameter Estimation initial concentrations reactio
26. eeeeeeeeeeeeeeeeeeeceeeeececaeeeeseaeeeeeecaeeeecceaeeeeseseeeesseneeeeessneeeees 34 6 4 2 Estimating Parameters by the Monte Carlo MethoOd oooooocccnnccccnnoncccccononccoconnnccnnonanccnnonnnncnnnns 34 6 4 3 Displaying a Progress Graph during Parameter Estimation ooonnoccccnnnoccccnnoccccccnnorccnnnanancnnnno 35 O25 WESUITS hr tateotet olt taa SS 36 6 5 1 List Parameter Estimation Results ccccccccceceeccceeeeeneeeeeeeneeeeeecaeeeesceaeeeeseeeeeesesneeeeessnaeeeess 37 6 5 2 Estimating log marginal likeliNOOG ccccceceeeeeeeceeeeeeeeeeeeeneeeeeeeeeeeeesenaeeeeseeeeeeeseeeeeeeeseeeeess 40 6 5 3 Reflecting Estimated Values is startoc eoe eves vee e idilio ada aotearoa 41 6 5 4 Display 1D and 2D Histograms cccccceeeceeeeeneeeeeeceeeeeeeeeeeeeeeseaeeeesseaeeeeeeeeeeesseneeeeeseeeeeess 42 6 5 5 Saving Parameter Estimation Results oooonooccccnnnoccccnnocccccoconnccnnnnnnccnnnnnnnnnnnonnnncnnonnn cnn ninnnncnnnns 47 6 06 tiMeseries reconstruction musica 48 NN 51 LA IMA O shi seat sa ak eal ae tal hata aeaa 51 12 TRUMMING Simulation dada aaa a Ee A aa 52 7 3 Loading and Deleting Control Data oonoccccnnnnccccnnnnccccnononccccnonnncnnnnnnnccnnonnnnnnnnnnnnnnnnannnccncnnnnno 53 TA Mapping Control Data rcsceiccecoceinrcecevederecenecbeceeedeledecedcbececed sleeved E EEEN NEKE N EEEE EEEE E EOE EEE 54 7 5 Running Simulation with Control Data oooocccnnnccccnnnnocccnnnnoccccnonnccnnnnnnncnnnnnnncnnnnn
27. ent and other environment factors such as SBML models and the number of total samples LetitB Samplel Ibp File Tool Help LetitB Parameters estimation results of initial concentrations Model Sample1 xml initial MAR dad compartments species E 5 SET en unit prior SBMLID show graph species sample estimator deviation reactions 1 species 0 0 4 0 427117 0 0413966 mol l Gamma 1 3 48375 species_0 show graph arameters TEREI aah 2 species 1 0 3 0 298196 0 00445069 mol l Gamma 1 3 21444 species_1 show graph Parameter Estimation 3 species 2 0 01 0 0114264 0 0032279 mol l Gamma 1 59 1913 species_2 show graph initial concentrations reaction parameters data sets Monte Carlo executior timeseries reconstruci Simulation estimation results of reaction parameters reaction parameter LE MER DERETA unit prior SBMLID show graph sample estimator deviation 1 reaction_O kl 5 4 34402 0 546499 unknown gamma 1 0 0389517 reaction_0 show graph 2 reaction 0 k2 0 01 0 0136564 0 0075709 unknown gamma 1 8 78928 reaction_0 show graph log posterior error function y log marginal likelihood 315 417 0 193622 323 07 open 2D stat window update initial sample update model save effective samples save all samples save results Figure 33 results Screen log marginal likelihood Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 40 LetltB User s Manual 6
28. ets relative error torelance 1e 08 Monte Carlo executior absolute torelance le 12 results timeseries reconstruct run simulation results save data draw graph Figure 3 Simulation Run Screen Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved LetltB User s Manual 2 5 Saving Simulation Results File After simulation results are displayed in the results pane on the Simulation screen click the save data button and save the file with any name Example File name sim_results dat 2 6 Defining Simulation Results File Loading From the tree menu on the left select data sets On the right side of the data sets screen click the on the upper left corner of the screen and load the previously saved results file e g sim_results dat LetitB unknown project File Tool Help LetitB Parameters ET Model model xml compartments observation sim_results dat species reactions parameters ODEs Parameter Estimation initial concentrations reaction parameters Monte Carlo executior results timeseries reconstruct Simulation time A a time A 2 B e 0 0 4 0 3 0 01 0 1 0 348978 0 248978 0 061022 0 2 0 311262 0 211262 0 0987378 0 3 0 282289 0 182289 0 127711 0 4 0 259367 0 159367 0 150633 0 5 0 240808 0 140808 0 169192 0 6 0 225496 0 125496 0 184504 2 3 4 5 6 7 8 9 0 7 0 212667 0 112667 0 197333 control inputs Figure 4 Results
29. hen you click the open 2D stat window button on the results screen a 2D graph appears Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 44 LetltB User s Manual About 2D Graphs 2D histograms are displayed to show any factors you specify for both vertical and horizontal axes Each axis is automatically set by default when the 2D histogram is displayed at first time LetItB displays the 2D histogram by calculating two factors and indicates the number of histogram bins by color changes The color for bins changes from blue few bins to red many bins according to the color bar on the right side of the graph In addition numeric values for the above items are displayed at the bottom part of the histogram window LetltB histogram 2D Histogram 2D 40 0 04 30 0 03 o 1 2 v P e ps 20 Y 0 02 o E g 10 0 01 0 ST Fe AAA AA a 3 5 4 4 5 5 5 5 k1 in reaction_O x axis kl inreaction_O min 2 88144 max 5 59427 grids 200 replot y axis k2 inreaction_O min 0 000949718 max 0 0410896 grids 200 Figure 37 2D Histogram Window Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 45 LetltB User s Manual How to Configure 1 To save an image From the menu of the histogram window select File gt Save graph When a file dialog appears select where the file will be saved a name of the file and an image format you want to save
30. ior for observation precision results timeseries reconstruct Simulation 1e 08 mrate 0 lt mrate lt 1 mixing rate of isotropic and adaptive Gaussian proposals 9 73 kappa 0 lt kappa regularization coefficient of proposal covariance matrix sd_c 0 lt sd_c scaling parameter of adaptive proposal le 16 2 4 eta0 0 lt eta0 lt 1 initial step size for updating proposal 0 1 lambda_a 0 lt lambda_a forgetting factor of previous history run Monte Carlo sampling Figure 27 Monte Carlo execution Screen Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 33 LetltB User s Manual 6 4 1 Setting Monte Carlo The Monte Carlo execution subpart displays settings information for parameter estimation method Display the Monte Carlo method you use adaptive Metropolis About adaptive metropolis settings number of total samples Display the number of samples alpha0 Display the first argument of prior beta0 Display the second argument of prior mrate Display the information on the mixing rate kappa Display regularization parameters for the covariance matrix sd_c Display parameter information for scaling eta0 Display the information about default values for update interval lambda_a Display the information about forgetting factors The default values displayed on the adaptive metropolis settings screen are recommended to use as simula
31. l Gamma 1 3 21444 species 1 show graph Parameter Estimation 3 species 2 0 01 0 0114264 0 0032279 mol l Gamma 1 59 1913 species 2 show graph initial concentrations reaction parameters data sets Monte Carlo executior timeseries reconstruci Simulation estimation results of reaction parameters initial MAP standard reaction parameter AR Pi sample estimator deviation unit prior SBMLID show graph 1 reaction_O kl 5 4 34402 0 546499 unknown gamma 1 0 0389517 reaction_0 show graph 2 reaction_0 k2 0 01 0 0136564 0 0075709 unknown gamma 1 8 78928 reaction_O show graph log posterior error function y log marginal likelihood 315 417 0 193622 323 07 open 2D stat window update initial sample update model save all samples save results save effective samples Figure 35 results Screen show graph Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 42 LetltB User s Manual About 1D Graphs 1D histograms are displayed to show probability density in vertical axis and histogram bins in horizontal axis Both vertical axis and horizontal axis are automatically set by default when the 1D histogram is displayed first time About graph components Green Bar Graph Histogram Red Solid Line The MAP estimator values Blue Dotted Line The lower bound and upper bound values for confidence interval 99 by default Light Green Solid Line Resultant graph
32. l be displayed in the results pane on the bottom of the timeseries reconstruction screen To save timeseries simulation results data After the timeseries simulation completes click the save data button on the bottom of the timeseries reconstruction screen When a file dialog appears specify where the file will be saved and a name of the file NOTE LetItB supports the same file save formats as specified in Section 6 3 Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 49 LetltB User s Manual To display timeseries simulation results graphs From the graph option check box in the results pane select any factors you want to display in the graph and then click the draw graph button The timeseries graph of simulation results will be displayed For more information on how to display graphs see Section 7 5 A graph window displays a timeseries graph with simulation results in Y axis and time in X axis based on the factors you select in graph option The simulation result for each factor is displayed in solid lines and observation data from the selected dataset is displayed with x marks LetltB timeseries graph xobs B xobs C g Q 5 5 i 5 E a Q o o Figure 40 Graph Window for timeseries reconstruction How to Configure 1 To save an image From the menu of the graph window select File gt Save graph When a file dialog
33. lect and edit any cells other than those in the initial concentration and constant items Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 22 LetltB User s Manual 5 3 reactions The reactions subpart displays the information about reaction in the SBML file Ble Tao Help Lethe Parameters fentiori Model Sarplel ai H cempatments name chemical equator kinetic law pararneters SBMLID Spaces i rection A B Y Coso p el Lal BY k2 ICI ki 5k3 00 1 reaction D Parameters OODE Parsmeter Estimation intial concentrations maci n parameters data sets Monte Calo executor resulte Dirmegerieg acorta Simulstian Figure 19 reactions Screen About reactions screen name Display name information in the reaction tag If there is no name information in the tag LetltB displays ID information chemical equation Display chemical equations for reaction kinetic law Display the kinetic law for reaction parameters Display ID or name of parameter and corresponding numeric data SBML ID Display ID information in the reaction tag NOTE You cannot edit the data on the reactions screen Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 23 LetltB User s Manual 5 4 parameters The parameters subpart displays the information about parameter in the SBML file file Toot Help Letts Parameters parameters Model Sarplel ari e compstments
34. ling Figure 5 Parameter Estimation Execution Screen Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved LetltB User s Manual 2 8 Displaying Parameter Estimation Results After parameter estimation completes select results from the tree menu on the left Then a list of the estimation results is displayed on the right side of the screen You can view more detailed information about the results by using the open 2D stat window button or the log marginal likelihood checkbox on the same screen NOTE For more information see Section 6 5 results File Tool Help LetitB Parameters Model model xml compartments species reactions parameters ODEs Parameter Estimation initial concentrations reaction parameters data sets Monte Carlo executior timeseries reconstruct Simulation LetItB unknown project estimation results of initial concentrations initial MAP standard species sample estimator deviation 1 species 0 0 4 0 4 2 4028e 06 2 species_1 0 3 0 3 2 26866e 06 3 species_2 0 01 unit prior SBN mol l Gamma 1 0 571058 speci mol l Gamma 1 0 905851 speci 0 00999959 1 78371e 06 mol l Gamma 1 48 7495 speci estimation results of reaction parameters reaction parameter l reaction O kl 2 reaction_O k2 initial MAP sample estimator 5 5 00003 0 01 0 00999983 standard deviation ee pr 7 2
35. lis sampling vi show error graph log scale vi show log posterior graph sum of square error T T T T T T T T T T T T T T T T T T T 1 20000 40000 60000 80000 100000 log posterior density T 3551 60000 80000 100000 T T T 40000 T T T 20000 Figure 28 Run time Progress Window displayed during Parameter Estimation Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 35 LetltB User s Manual 6 5 results The results subpart allows you to list the results after parameter estimation draw graphs reflect estimated values and save data LetltB Samplel Ibp Ele Tool Help LetitB Parameters estimation results of initial concentrations Model Sample1 xml p initial MAP standard compartments A nde A p species sample estimator Jao unit prior SBMLID show graph species reactions 1 species 0 0 4 0 427117 0 0413966 mol l Gamma 1 3 48375 species_0 show graph arameters acti 2 species_1 0 3 0 298196 0 00445069 mol l Gamma 1 3 21444 species_1 show graph Parameter Estimation 3 species 2 0 01 0 0114264 0 0032279 mol l Gamma 1 59 1913 species_2 show graph initial concentrations reaction parameters data sets Monte Carlo executior timeseries reconstruct Simulation estimation results of reaction parameters initial MAP standard reaction parameter Sample estratos RE unit prior SBMLID sh
36. meters G data sets Monte Carlo executior results timeseries reconstruci Simulation time column_00 Figure 43 Simulation Screen Control Data Mapping Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 54 LetltB User s Manual 7 5 Running Simulation with Control Data After loading control data into LetItB in Section 7 3 run Simulation with Control Data Move to the tab window where the control data you want to perform the simulation is loaded into and then click the run simulation button on the middle of the screen to start the simulation After the simulation completes its results will be displayed in the results pane on the bottom of the screen NOTE For Simulation with Control Data constant item information on the species screen will be ignored 7 6 Saving Results of Simulation with Control Data To save the results data of Simulation and Simulation with Control Data click the save data button on the bottom of the screen after their results data are displayed in the results pane When a file dialog appears specify where the file will be saved and a name of the file NOTE LetItB supports the same file save formats as specified in Section 6 3 LetltB Samplel bp File Tool Help pee peer Simulation Samplel_controll bt o Model Sample1 xml compartments control inputs species E p 3 time column_00 reactions parameters 1 time A 2 ODEs q 2l0 gt Paramete
37. n parameters Monte Carlo executior results timeseries reconstruct Simulation Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved dataset 00 observation Sample1_obs dat time column_00 column_01 1 time B no_mapping 2 0 0 307878 A 3 0 1 0 220375 9 a 10 2 0 238631 13 5 03 0 207675 0 10968 6 04 0 158616 0 150254 7 10 5 0 146949 0 1682 8 06 0 128589 0 184505 9 07 0 109533 0 190273 control inputs Figure 26 data sets Screen Input Data Mapping 4 32 LetltB User s Manual 6 4 Monte Carlo execution The Monte Carlo execution subpart allows you to change LetltB settings for parameter estimation and to perform parameter estimation by using the Monte Carlo method Then the LetltB software uses the Monte Carlo method for parameter estimation With software enhancements or new versions new methods will be added For the current version you can select only the adaptive Metropolis LetitB Samplel ibp File Tool Help Letit6 Parameters Monte Calro setting Model Sample1 xml set recommend value defalut compartments species 1 reactions parameters method adaptive Metropolis ODES number of total samples 100000 Parameter Estimation initial concentrations 2Ipha0 0 lt alpha0 1e 08 reaction parameters 1st parameter of gamma prior for observation precision data sets beta0 0 lt beta0 2st parameter of gamma pr
38. n_0 show graph 2 reaction_0 k2 0 01 0 0136564 0 0075709 unknown gamma 1 8 78928 reaction_O show graph log posterior error function y log marginal likelihood 315 417 0 193622 323 07 open 2D stat window update initial sample update model save effective samples save all samples save results Figure 31 results Screen estimation results of reaction parameters Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 38 LetltB User s Manual log posterior and error function Bottom part of the results screen The log posterior and error function fields display final log posterior and error function numeric values after parameter estimation LetitB Samplel Ibp File Tool Help LetitB Parameters estimation results of initial concentrations Model Samplel xml initial MAP dard compartments species yaa 7 san an unit prior SBMLID show graph species sample estimator deviation reactions 1 species 0 0 4 0 427117 0 0413966 mol l Gamma 1 3 48375 species_0 show graph arameters PA ZETA ola 2 species_1 0 3 0 298196 0 00445069 mol l Gamma 1 3 21444 species 1 show graph Parameter Estimation 3 species 2 0 01 0 0114264 0 0032279 mol l Gamma 1 59 1913 species 2 show graph initial concentrations reaction parameters data sets Monte Carlo executior timeseries reconstruci Simulation estimation results of reaction parameters i initial MAP sta
39. ndard i reaction parameter sample estimator deviation unit prior SBMLID show graph 1 reaction_0 kl 5 4 34402 0 546499 unknown gamma 1 0 0389517 reaction_0 show graph 2 reaction_0 k2 0 01 0 0136564 0 0075709 unknown gamma 1 8 78928 reaction_O show graph log posterior error function log marginal likelihood 315 417 0 193622 B23 07 open 2D stat window update initial sample update model x a save effective samples save all samples save results 4 gt A 4 3 gt Figure 32 results Screen log posterior and error function To edit data You can edit numeric data in the initial sample items in estimation results of initial concentrations and estimation results of reaction parameters Select any cells you want to edit and then enter values NOTE 1 You cannot select and edit any cells other than above NOTE 2 See Section 6 5 3 for how to reflect values of the MAP estimator item into those of the initial sample item collectively Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 39 LetltB User s Manual 6 5 2 Estimating log marginal likelihood You can estimate the marginal likelihood on log scale To start estimation select the log marginal likelihood check box highlighted in red below NOTE 1 By default the log marginal likelihood check box is not selected NOTE 2 The run time required for each log marginal likelihood estimation depends on your machine environm
40. nformation on how to display ODEs see Section 5 5 To save ODEs You can save ODEs as text data After loading the SBML file See Section 4 3 select File gt Export ODEs from the LetltB s menu When a file dialog appears select where the file will be exported and a name of the file and then save the data LetitB 16 Tool Help Open project A LetitB information Save project Save project as Open SBML Save SBML Save SBML as Export reaction diagram Export ODEs Exit resus timeseries reconstruci Simulation Figure 16 ODEs Export File Store Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 19 LetltB User s Manual 5 Model The Model part is divided into 5 subparts compartments species reactions parameters and ODEs With the Model part you can display a list of relevant items of the loaded SBML file and edit their numeric data By selecting one of the subparts compartments species reactions parameters or ODEs under Model in LetltB Parameters in the left pane you can list corresponding information of the selected subpart in the right pane 5 1 compartments The compartments subpart displays the information about compartment in the SBML file LetltB Samplel lbp File Tool Help LetitB Parameters compartments Model Sample1 xml name volume Un SBML ID species 1 Cytosol le 15 compartment_o reactions parameters ODEs Pa
41. nitial value item on the reaction parameters screen will be reflected in those on the species screen NOTE 3 With the estimated item parameter estimation will be performed for only the factors selected with enabled check boxes 6 3 data sets Any observation data and control data to be used for parameter estimation can be loaded into LetltB from external files or deleted from LetltB If no observation data is loaded into LetltB you cannot perform any estimate simulation for parameter estimation LetltB supports the following five text file formats for external files e Comma Separated Values e Tab Separated Values e Space Separated Values e Semicolon Separated Values For your reference see SampleData contained in the installation folder Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 29 LetltB User s Manual 6 3 1 Loading and Deleting Observation Data To load observation data Click the button on the upper left corner of the data sets screen When a file dialog appears select any observation data Then the selected data will be automatically displayed in the observation pane With Files of type in the file dialog select an appropriate file format and a separation type If you load multiple observation data files into LetItB click the button each time Once loaded observation data is separated with tab windows to allow you to switch your observation data tab
42. nncnnnnnnnccnnnnnnno 55 7 6 Saving Results of Simulation with Control Data ooonococcnnnnccccnnnncccccnonocccnonnnnnnnonnnncnnnnnnnccnnnnnnnno 55 7 7 Displaying Simulation Results Graph cccccceeseeeeceeeeeneeeeeeeeeeeeeeeeeeeeeenaeeeeseeeeeesesieeeesennaees 56 Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved LetltB User s Manual 1 Introduction LetltB is developed as a support tool to identify parameters for biochemical reactions In the current version LetltB accepts SBML Systems Biology Markup Language files as inputs to visually perform the following operations to the SBML models SBML is the standard format for describing biochemical reaction models in systems biology Create block diagrams to illustrate biochemical reaction networks Run simulations Identify reaction parameters and estimate their confidence intervals to provide the best recreation for given experimental data concentration time series of each molecule Assess quantitative model validity from data recreation and model complexity for given experimental data You can save these results as text files or image files such as jpeg or png via easy to use GUI LetItB s internal calculation engine is programmed in C language and its Graphic User Interface is developed with the Qt toolkit Therefore you can run and recompile LetltB on any platforms including Windows Mac OS X and Linux operation systems if you install an
43. odel Tm compartments species reactions parameters ODEs Parameter Estimation initial concentrations reaction parameters Figure 13 Reaction Diagram Export Operation Screen Display reaction diagi x Diagram Export Window button Zoom in the diagram button Zoom out the diagram The right figure shows the resultant diagram when reaction loading sample data 7 Figure 14 Resultant Reaction Diagram Export Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 17 LetltB User s Manual To save the reaction diagram You can save the reaction diagram as image data After loading the SBML file See Section 4 3 select File gt Export reaction diagram from the LetItB s menu When a file dialog appears select where the file will be exported a name of the file and an image format you want to save and then save the data LetItB AGa Tool Help Open project LetitB information Save project Save project as Open SBML Save SBML Save SBML as Export reaction diagram Export ODEs Exit esur timeseries reconstruci Simulation Figure 15 Reaction Diagram Export Operation Screen File Store Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 18 LetltB User s Manual 4 6 Exporting ODEs You can export Ordinary Differential Equations ODEs of the simulation model defined in the SBML file For more i
44. ow graph 1 reaction_0 kl 5 4 34402 0 546499 unknown gamma 1 0 0389517 reaction_0 show graph 2 reaction_0 k2 0 01 0 0136564 0 0075709 unknown gamma 1 8 78928 reaction_0 show graph log posterior error function vi log marginal likelihood 315 417 0 193622 323 07 open 2D stat window update initial sample update model i _ f save effective samples Jl save all samples save results El Figure 29 results Screen Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 36 LetltB User s Manual 6 5 1 List Parameter Estimation Results The results subpart lists estimation results for each factor and any corresponding information estimation results of initial concentrations top table on the results screen species Display name information in the species tag If there is no name information in the tag LetltB displays ID information initial sample Display default values before parameter estimation MAP estimator Display results after parameter estimation standard deviation Display the standard deviation unit Display the unit the same unit as displayed on the initial concentration screen prior Display prior information used for the parameter estimation simulation SBML ID Display ID information of SBML files for each corresponding factor show graph The button to display a 1D histogram NOTE For 1D histograms see Section 6 5 4 LetitB Samplel Ibp File Tool
45. r Estimation initial concentrations 35 0 reaction parameters data sets Monte Carlo executior results timeseries reconstruct run simulation results time A B E graph option V 0 3 0 01 0 271454 0 0385464 0 245626 0 0643737 0 201118 0 108882 0 18199 0 12801 lao uN o 0 2 wn o o D 2 2 2 2 0 222259 0 0877409 2 2 2 0 164685 0 145315 X save data draw graph Figure 44 Simulation Screen Results Data Saving Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 55 LetltB User s Manual 7 7 Displaying Simulation Results Graph To display a results graph of Simulation and Simulation with Control Data select from the graph option check box in the results pane any factors you want to display in the graph and then click the draw graph button A timeseries graph of simulation results will be displayed By default not all the factors in graph option are selected If no factors in graph option is selected no graph can be displayed LetitB Samplel Ibp File Tool Help LetitB Parameters Model benchmark001 xi compartments ODE solver option species reactions parameters end time s ODEs Parameter Estimation initial concentrations time interval s reaction parameters data sets relative error torelance Monte Carlo executior results timeseries reconstruct Simulation Samplel_controll bxt number of time points absolute torelance
46. rameter Estimation initial concentrations reaction parameters data sets Monte Carlo executior results timeseries reconstruct Simulation Figure 17 compartments Screen Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 20 LetltB User s Manual About compartments screen name Display name information in the compartment tag If there is no name information in the tag LetItB displays ID information volume Display volume or size information in the compartment tag If there is no information about volume or size in the tag set as default unit Display the unit used in compartment Default liter SBML ID Display ID information in the compartment tag To edit data You can edit numeric data in the volume item Select any cells you want to edit and then enter values NOTE You cannot select and edit any cells other than those in the volume item 5 2 species The species subpart displays the information about species in the SBML file LetitB Samplel lbp File Tool Help LetitB Parameters species Model Sample1 xml E E compartments name initial f mit initial amount concentration molecules reactions 1 A 0 4 mol l 2 4088e 08 Cytosol species 0 parameters ODEs Parameter Estimation 3 c 0 01 mol l 6 022e 06 Cytosol species 2 initial concentrations reaction parameters data sets Monte Carlo executior results timeseries reconstruct Simulation compar
47. resection parameter value init kinetic law heme equation SomL O Species 1 resection kl unknown V_ Cytosol kl 141 IB k2 C1 A BB reaction _ o reactions a jreection jia 001 unknown V_ Cytosol kl 1AI II K2 IC A B C and COEs Parameter Estimator mtia concentrations reaction parameters data sets Monte Cardo executior resiits timeseries reconsriat Simulation Figure 20 parameters Screen About parameters screen reaction Display name information in the reaction tag See the name item in Section 5 3 If there is no name information in the tag LetltB displays ID information parameter Display ID information in the parameter tag value Display value information in the parameter tag unit Display the unit used in parameter If there is no unit information in the tag LetltB displays unknown by default kinetic law Display the kinetic law for parameter chemical equation Display the chemical equation for parameter reaction ID Display ID information in the reaction tag To edit data You can edit numeric data in the value item Select any cells you want to edit and then enter values NOTE You cannot select and edit any cells other than those in the value item Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 24 LetltB User s Manual 5 5 ODEs The ODEs subpart displays Ordinary Differential Equations ODEs of the simulation model defined in the SBML file Letl
48. s no name information in the tag LetItB displays ID information parameter Display ID information in the parameter tag initial sample Display default values before parameter estimation MAP estimator Display results after parameter estimation standard deviation Display the standard deviation unit Display the unit the same unit as displayed on the reaction parameters screen prior Display prior information used for the parameter estimation simulation SBML ID Display ID information of SBML files for each corresponding factor show graph The button to a display 1D histogram NOTE For 1D histograms see Section 6 5 4 LetitB Samplel Ibp File Tool Help LetitB Parameters estimation results of initial concentrations Model Sample1 xml a species ae Pci ef unit prior SBMLID show ga reactions l species_ 0 0 4 0 427117 0 0413966 mol l Gamma 1 3 48375 species_0 show graph read 2 species_1 0 3 0 298196 0 00445069 mol l Gamma 1 3 21444 species 1 show graph Parameter Estimation 3 species 2 0 01 0 0114264 0 0032279 mol l Gamma 1 59 1913 species_2 show graph initial concentrations reaction parameters data sets Monte Carlo executior timeseries reconstruci Simulation estimation results of reaction parameters initial MAP standard reaction parameter A es p sample estimator deviation unit prior SBMLID show graph 1 reaction_0 kl 9 4 34402 0 546499 unknown gamma 1 0 0389517 reactio
49. tB Samplel lbp File Tool Help LetitB Parameters Model Samplel xml compartments species reactions parameters ODES Parameter Estimation initial concentrations reaction parameters data sets Monte Carlo executior results timeseries reconstruct boa ODES d Al dt V_ Cytosol 5 A B 0 01 C V_ Cytosol d BJ dt V_ Cytosol 5 A B 0 01 C V_ Cytosol d C dt V_ Cytosol 5 A B 0 01 C V_ Cytosol Figure 21 ODEs Screen If you want to save the exported ODEs data see Section 4 6 NOTE 1 You cannot edit the data on the ODEs screen NOTE 2 ODEs are represented in the formats used in the SBML ODE Solver Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 25 LetltB User s Manual 6 Parameter Estimation The Parameter Estimation part is divided into 6 subparts initial concentrations reaction parameters data sets Monte Carlo execution results and timeseries reconstruction Using the simulation model defined in the loaded SBML file you can list relevant items edit numeric data perform the parameter estimation display results and save the estimation results data By selecting one of the subparts initial concentrations reaction parameters data sets Monte Carlo execution results or timeseries reconstruction under Parameter Estimation in LetltB Parameters in the left pane you can list corresponding
50. ting Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 51 LetltB User s Manual ODE solver option end time The time to terminate the simulation Default 10 The start time is set to 0 number of time points The number of time steps in simulation Default 1000 size of time intervals The interval between simulation time steps end time number of time points size of time intervals relative error tolerance Tolerance error margin of simulation results Relative unit Default 1 x 10 absolute tolerance Tolerance range of simulation results Absolute unit Default 1 x 10 Unless expressly specified in SBML files second s is used for a unit of time To edit data in ODE solver option You can edit numeric data in the end time number of time points relative error tolerance and absolute tolerance items Select any cells you want to edit and then enter values NOTE The values you set in ODE solver option will be reflected in both Simulation and Simulation with Control Data ways 7 2 Running Simulation After setting properly as shown in Section 6 1 click the run simulation button on the middle of the Simulation screen tab window to start the simulation After the simulation completes its results will be displayed in the results pane on the bottom part of the screen NOTE For Simulation without Control Data any factors where the check boxes in the constant item on
51. tion run time effective values To edit data You can edit numeric data in all the items number of total samples alpha0 beta0 mrate kappa sd_c eta0 lambda_a except for method in the Monte Carlo setting pane Select any cells you want to edit and then enter values To change the data to the recommended values click the set recommend value default button in the top of the pane NOTE 1 You cannot enter any values out of the range 6 4 2 Estimating Parameters by the Monte Carlo method To estimate parameters click the run Monte Carlo sampling button on the Monte Carlo execution screen NOTE The run time required for each parameter estimation depends on your machine environment and other environment factors such as SBML models and the number of total samples Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 34 LetltB User s Manual 6 43 Displaying a Progress Graph during Parameter Estimation During parameter estimation a progress window showing how parameter estimation is proceeding will be displayed An error graph and a log posterior graph for parameter estimation will be displayed in real time if you select their check boxes in the window show error graph show error graph log scale Display the sum of square error graph From the combo box you can change the vertical scale of a graph log posterior graph Display the log posterior density graph running adaptive Metropo
52. tltB Start Screen Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 11 LetltB User s Manual 3 2 Exiting LetltB To exit LetltB select File gt Exit from the LetltB s menu or click the x button on the upper right corner of the screen LetitB File Tool Help Letit Parameters LetitB information compartments species reactions parameters ODEs Parameter Estimation initial concentrations reaction parameters data sets Monte Carlo executior results timeseries reconstruct Simulation Figure 8 LetltB Exit Screen Sample Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 12 LetltB User s Manual 4 Loading Writing and Exporting Files 4 1 Loading Project File From the LetltB s menu select File gt Open project and in the file dialog select a project file Ibp file After you select a Ibp file the existing project data is automatically loaded into LetltB LetItB AGs Tool Help LetitB information Save project Save project as Open SBML Save SBML Save SBML as Export reaction diagram Export ODEs Exit TESUTMS timeseries reconstruct Simulation Figure 9 Project File Loading Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 13 LetltB User s Manual 4 2 Writing Project File From the LetItB s menu select File gt Save project or
53. tment constant SBMLID 2 B 0 3 mol l 1 8066e 08 Cytosol species 1 Figure 18 species Screen Copyright c Okinawa Institute of Science and Technology 2007 All Rights Reserved 21 LetltB User s Manual About species screen name Display name information in the species tag If there is no name information in the tag LetltB displays ID information initial concentration Display initialConcentration information in the species tag If there is no initialConcentration information in the tag define 1 as default unit Display the unit used in species Default mol l initial amount Display the initial amount defined as initial concentration information The initial amount is calculated by the calculation formula volume item in the compartments subpart x initial concentration item in the compartments subpart x 6 022e 23 compartment Display compartment information in the species tag constant Display constant information in the species tag If there is no information about constant in the tag false constant false is set by default SBML ID Display ID information in the species tag To edit data You can edit numeric data in the initial concentration item and the check box in the constant item If you edit the initial concentration item select any cells you want to edit and then enter values With the check box in the constant item you can enable disable the check box by clicking appropriate cells NOTE You cannot se

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