user manual v 1.2 - The Carolina Center for
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1. Figure 5 below eer yy ToxPi results FI ZS File View Save data file Save selected Save selected image Save all image Display ToxPi chart All data Images only Substance name Source ToxPi value c Fipronil IDSSTOX 40466 3 747 Phosalone IDSSTOX 40555 3 688 Etoxazole IDSSTOX 40452 3 559 Indoxacarb IDSSTOX 40496 3 459 Figure 5 Results Window 11 THE UNIVERSITY of NORTH CAROLINA 4 CHAPEL HILL Toxicological Priority Index GUI User Manual Qs ToxPi results File View Save data file Save selected Save selected image Save all image Display ToxPi chart 9 im Phosalone Etoxazole Indoxacarb Tebupiri mfos 6 6 9 Hexaconazole Imazalil Bisphenol A Fluoxastrobin Cypermethrin e Methoxychlor Fenpyroxi mate Propargite ZEE X ma e Figure 6 Results Window Images only view The results window will initially display the table of all the chemicals used for the calculations The table will contain the ToxPi pie image Chemical name Source ID and calculated ToxPi score for each chemical Above the table you will see five buttons and two radio controls The buttons are e Save data file This will save your data You will be asked to select or enter the file name where the curre2. the components There are 5 scaling type allowed e log10 x 6 all the values x will be normalized using the following formula 1 log x 6 use it when 1 000 000 value indicates no effect e log x log max x all the values x will be normalized using the following formula 1 1og x log max x e hit count all the values x will be treated as binary data meaning that all non zero values will be replaced with ones and all zeros will remain zeros use it when you have only binary data in the input files e In x In max x all the values x will be normalized using the following formula 1 In x In max x IHE UNIVERSITY of NORTH CAROLINA i at CHAPEL HILL gt Toxicological Priority Index GUI d User Manual sqrt x all the values x will be normalized using the square root value of the original value linear x no normalization will be applied You will see some basic statistical analysis of the included components in the Selected data analysis field You can remove the slice by clicking Remove this slice IHE UNIVERSITY ef NORTH CAROLINA 4 CHAPEL HILL 10 Toxicological Priority Index GUI User Manual 6 Results Window One should click Calculate ToxPi indexes and build visualizations button in order to start calculation process When all the necessary calculations are completed the ToxPi GUI results window will appear
3. 1912 24 5 Azamethiphos DSSTOX 40557 35575 Azinphos methyl DSSTOX 40347 86 Azoxystrobin DSSTOX 40348 131860 Bendiocarb DSSTOX_40349 22781 2 Benfiuralin DSSTOX 40350 1861 40 Available components for selected chemicals Remove EIE TN Toxicological Priority Index Remove al ToxPi Toxicological Priority Index is a flexible prioritization support software tool that incorporates chemical s bioactivity profiles inferred toxicity pathways dose estimates exposure data chemical structural descriptors etc Benomyl DSSTOX 40351 17804 35 2 Bensulfuron methy DSSTOX 40352 t Bensulide DSSTOX 40353 741 58 2 Bentazone DSSTOX_40354 25057 89 Bifenazate DSSTOX 40359 149877 4 Bifenthrin DSSTOX 40360 82657 04 Bisphenol A DSSTOX 40362 80 05 7 Boric acid DSSTOX 40364 10043 35 Boscalid DSSTOX 40365 188425 85 t Eromacil DSSTOX 40366 314 40 5 Bromoxyni DSSTOX 40319 1689 84 IBuprofezin DSSTOX 40367 69327 76 Butachlor DSSTOX 40368 23184 66 Butafenaci DSSTOX 40357 134605 _ Pistealin meerow an2ca 22670 47 01 m Recreate data from fie Next step formation of slices Figure 2 Available chemicals and Selected chemicals Note in the case of multiple input files only common components for all selected files and chemicals will be added to the right Available components for selected Chemicals list For examp
4. possible types based on the data from your input file You can create your custom type by selecting Custom and entering the type name in the field below You can select the slice color by clicking on the colored rectangle below the Select color text There are predefined color sets for five base types IHE UNIVERSITY of NORTH CAROLINA 4 CHAPEL HILL 8 Toxicological Priority Index GUI User Manual e Assay gradient of green color e Pathway gradient of blue color e ChemProp gradient of orange color e Exposure gradient of gray color e ToxRefDB gradient of purple color e Custom type gradient of red color Starting from version 1 2 all the colors defined by user will be stored into output CSV file One can reproduce exactly the same results selecting previously saved file You can set the slice weight in relation to other slices by dragging the slider in the Slice weight area to a value from 1 to 25 The weight will be displayed in percent ratio and in absolute values and controls the width of the slice i e slices with higher weights will be wider than slices with lower weights In the Select components area you will be able to select the components you want to add to a given slice You can search for some particular components using the Search field The matches will be highlighted in the components list In the Select scaling type area you will be able to select a scaling option for the data in
5. www java com en Starting from version 1 1 users can choose between Windows executable file or Java JAR file We recommend using Windows EXE file on Windows OS and JAR on any other OS For some big datasets user can face some memory errors If you see that errors you ll need to use Java JAR file but set the memory size for the application using the following string in command line java Xmx1500m jar path to jar file where path to jar file is a system path to the location here you saved ToxPi v1 2 jar file After you have successfully installed Java you can double click on the ToxPi jar file in order to launch the application The most recent version of ToxPi GUI is located on the Comptox website http comptox unc edu resources html If you have troubles running the location on Windows OS please verify that your JAVA HOME system variable is pointing to the installation directory To do so click Start and then right mouse click on the My Computer or Computer item Select Properties in the appeared list On the next window locate the Advanced System Settings button and click it Next locate the System Variables button and click it Look inside the System Variables list for JAVA HOME record If you cannot find it then click New button and enter JAVA HOME as a Variable name and path to your java folder as a value Usually the path will look like c Program Files Java jre6 bin 4 T A FHE UNIVERSITY us EPA of NORTH CAROL
6. INA V 7 i at CHAPEL HILL E Toxicological Priority Index GUI User Manual 3 Home screen Ql ToxPi standalone GUI File Settings Help Data files AddDataFie ToxPi standalone GUI version 1 2 Available chemicals Available components Selected chemicals Available components for selected chemicals Toxicological Priority Index ToxPi Toxicological Priority Index is a flexible prioritization support software tool that incorporates chemical s bioactivity profiles inferred toxicity pathways dose estimates exposure data chemical structural descriptors etc i P EPA NCCT UNC SPH Figure 1 ToxPi GUI home window Once you have opened the application you will see the ToxPi GUI main screen which allows you to select the files and chemicals to work with See Figure 1 To select your input data file click on the Add Data File button The file browsing dialog box should appear Browse to your data file select it and click Open See Section 4 for information on how the input data file should appear For a bigger file you will see the loading window with the progress bar indicating the amount of data already processed Please note that all the files will be checked for duplicated chemicals and components When there are duplicates the error window will appear indicating the name of the duplicates so you can easy locate and delete repeated data from your file or resolve the error a
7. The University of North Carolina at Chapel Hill Gillings School of Global Public Health ToxPi standalone GUl Version 1 2 TOXICOLOGICAL PRIORITY INDEX GUI User Manual Toxicological Priority Index GUI User Manual Table of Contents JE Vueikcncre e aici i tion nit ath east in etait eee eis 3 2 ToxPi GUI Installation and Requirements ccccecssececssssececseneeecseaececseaaececseaaececseaaeeeeseaeeeeseqaeeeeseaaes 4 3 outil e 5 d java OMA eae a e erdt dettes fec A A muere re de eM ote ee ces 7 5b Slices Information WindOW eremo ere ne rene enr erste a nee n ex Rea sveeessa ecevereeedteengeedees 8 6 Results WIR COW csse C E EEEE E NEROS 11 6 1 Chemical windOW 5 ett ee e aie ee oe e EYE Yn Ra Eee UE RE evades epe ere etu YER reuse E eee PN re anes 14 JPASI E R 15 6 21 evuin3gehezcett e M 16 6 2 2 Zooming and Dragging iiss cocer pere ann Eon rao nup inea ona ded a pra Ta VERE pa agr aM E O 16 6 2 3 Highlighting the Data roti det tree pinea Pe EY ERE PS CARERE RU EVE ERR ERE NAE TR RE EUER 16 7 Description of ToxPi Bootstrapping Algorithm sees eene enne nnne nnn nn 17 2 THE UNIVERSITY of NORTH CAROLINA 4 CHAPEL HILL Toxicological Priority Index GUI User Manual 1 About ToxPi GUI ToxPi GUI
8. Toxicological Priority Index graphical user interface is a flexible prioritization support software tool based on the Endocrine Profiling and Prioritization of Environmental Chemicals Using X ToxCast Data article by David M Reif t al http ehsehplp03 niehs nih gov article info963Adoi962F10 1289962Fehp 1002180 This tool incorporates a chemical s bioactivity profiles inferred toxicity pathways dose estimates exposure data chemical structural descriptors etc into easy to understand output The ToxPi GUI was designed to help quickly import analyze visualize highlight and export diverse data The output can be used to e Calculate the comprehensive toxicity potential of a chemical e Provide a visual that represents relative contribution of each data domain e Enable a new weight of evidence framework for diverse prioritization e Numerically integrate multiple information domains e Incorporate existing knowledge prioritization schemes and different types of data Provide multivariate of toxicity relative to any set of chemicals e Customize components for diverse prioritization tasks e Estimate uncertainty in various indices calculated from the underlying data Provide complete transparency in deriving a toxicity score ToxPi GUI is written in Java in order to provide cross platform compatibility and can be used on any computer where Java is installed The application uses JFreeChart package for ToxPi chart repr
9. art of the chemicals based on the ToxPi scores on the X axis and ranked chemicals on the Y axis The actual calculated ToxPi score for each chemical will be represented as red dots One can use computer mouse scroll to zoom in zoom out and click drag to move the plot Also user can use Zoom in and Zoom out buttons for detailed view User can save the plot image by clicking the Save plot button The image saved will reflect the contents of the window at the time of saving One can save the data represented by the plot by using Save plot data or Save selected data both of this options will create CSV file 6 2 1 Confidence intervals The horizontal orange bars along the X axis indicate the bootstrapped 95 confidence interval for a particular chemical The vertical orange bars along the Y axis indicate the ranking interval for a specific chemical You can show or hide the confidence intervals and or the ranking intervals by checking or unchecking the Display 95 CI and Display chemical ranked interval check boxes 6 2 2 Zooming and Dragging In order to zoom in or out on the plot you are encouraged to use your mouse or track pad scroll wheel To move the plot to the area you are interested in click your left mouse button and drag You can disable zoom for either axis by unchecking the Enable zoom X axis or Enable zoom Y axis checkboxes To reset the zoom and return to the initial view click on
10. esentation Apache commons library for CSV files operations and Swing libraries for design purposes 3 T A THE UNIVERSITY us EPA of NORTH CAROLINA S Y i at CHAPEL HILL Toxicological Priority Index GUI User Manual ToxPi GUI allows you to extract data from one or multiple files at a time Once you add a file you will be able to quickly see a visual representation of the data as well as the prioritization results allowing you to preview your ToxPi pies When you integrate data from multiple files you will be able to see the data or specific components in common among the files for all chemicals or for particular chemicals that you select You will also see basic statistical analysis for the selected components and will have the option to create custom data types for selected components from your input file The results window will show the table of chemical toxicity priority indexes based on the components you selected You can switch between an extended information table and a simple image table The chart visualization option allow users to focus on a particular chemical or sets of chemicals zoom into a specific area of the ToxPi chart highlight any specific chemicals and browse from one chemical to another by simply dragging the plot 2 ToxPi GUI Installation and Requirements In order to use ToxPi GUI you need to have Java installed on your machine You can download Java for free from this website http
11. is given by the 97 5 percentile of the bootstrap statistics Intuitively the width of the confidence interval for a chemical depends on the amount of variability within each slice The ToxPi score will have a narrow confidence interval if the assay values within a slice are very similar and a wide confidence interval if the assay values within a slice are very different The bootstrapping approach does not make any assumption regarding the distribution of the data values and should give appropriate confidence intervals in most contexts However we caution that confidence intervals generated using the approach described here may be unreliable in the following situations e If the measurements within each slice are on dramatically different scales e lf there are just a small number 1 3 of assays within each slice e lf there are extreme values outliers in the data at CHAPEL HILL 17 T A THE UNIVERSITY OPUS EPA of NORTH CAROLINA 5 i
12. le You have added two files F1 and F2 each containing different chemicals F1 has data for components C1 and C2 on chemical A and F2 contains data for components C1 and C3 on chemical B If you select both chemicals A and B then in the list of Available components for selected chemicals you will only see component C1 as it would be the only component for which we have data for both chemicals Recreate data from file allow you to quickly get to the results of the analysis without selecting any components The results will be based on the input file and will be an exact visual THE UNIVERSITY eof NORTH CAROLINA 4 CHAPEL HILL Toxicological Priority Index GUI User Manual representation of the input file This option is available when only one file is added to the list of files to analyze Next step formation of slices proceeds to a window where you will be able to select different combinations of slices components types colors and calculation methods for your ToxPi analysis 4 Data format Data in the input data file should be separated using comma delimiter File J extension should be csv You can see data format in the example data files provided here http comptox unc edu toxpi ph Those values will be treated as missing Slice type Component name A B 5 E 1 1 2 ell eleKonic sensing LogPow and MW LogPow and Steroid Metabolism 3 ChemP
13. nt data will be saved and later the saved file can be used to recreate your current results using the Recreate data from file button on the home screen e Save selected This will save only selected chemicals into a file 12 T m S THE UNIVERSITY HUS EPA of NORTH CAROLINA AT i 74 ppg at CHAPEL HILL E Toxicological Priority Index GUI User Manual e Save selected image This will save images in one file for selected chemicals e Save image of all This will save images of all chemicals in a single PNG file sorted by ToxPi score Display chart This will display the ToxPi chart in a new window Radio controls allow you to switch between different views of your results data Extended information will be displayed when All data See Figure 5 is selected while only images will be displayed if Images only See Figure 6 is selected Click on a ToxPi image on either table extended or images only a new window will appear containing detailed information about the selected chemical See Figure 7 S at CHAPEL HILL 13 f e THE UNIVERSITY us EPA of NORTH CAROLINA EN 1 gt Toxicological Priority Index GUI User Manual 6 1 Chemical Window r Fluoxestrobin 19 74196 of the data is missing Top 9596 confidence interval limit for this particular slice The color is light grey Bottom 9596 confidence Top and bottom 9596 CI limits match the actual in
14. rop ChemProp Pathway 4 QikProp QikProp Ps_KEGG 0 5 row_order chemical source sid casrn chemical name logPow QP MW QP PS KEGG Androgen and estrogen metabolism 6 1 DSSTOX 40338 50594 66 6 Acifluorfen 3 73 361 661 1000000 7 2 DSSTOX 40339 15972 60 8 Alachlor 3 154 269 77 184516 032 8 3 DSSTOX 40340 116 06 3 Aldicarb 1 032 190 26 1000000 9 4 DSSTOX 40343 834 12 8 Ametryn 3 401 227 327 16586 61894 10 5 DSSTOX 40344 33089 61 1 Amitraz 29 39999997 5 497 293 411 1000000 11 6 DSSTOX 40299 101 05 3 Anilazine 1000000 3 101 275 524 1000000 12 7 DSSTOX 40374 3337 71 1 Asulam 1000000 0 071 230 238 36845 62222 13 8 DSSTOX 40346 1912 24 9 Atrazine 1000000 2 609 215 685 192525 1417 Component Figure 3 Input file format source id Please note that any values that are below zero or are not numbers will be ignored and treated as a missing data IHE UNIVERSITY of NORTH CAROLINA 4 CHAPEL HILL Toxicological Priority Index GUI User Manual 5 Slices Information Window After you click Next step formation of slices you will see the window where you can control the inputs and information that will be used in the ToxPi analysis Ws Slices information File View Enter slice name Select slice type Select color Select weight Select components Search field Select scaling type Slice 1 Q Assay 1 NCGC_VDR_Agonist 4og10 x 6 NCGC_TRbeta_Agonist z Pathwa
15. s needed You can remove a file from the list by selecting it and pressing the Remove File button 5 f TN IHE UNIVERSITY HUS EPA of NORTH CAROLINA d i gt at CHAPEL HILL Toxicological Priority Index GUI User Manual At this point you should see the list of the chemicals and list of the components from the file you loaded in the left side of the window under Available chemicals and Available components respectively You can add one chemical or multiple chemicals to your analysis by selecting a chemical from the left Available Chemicals list and pressing the Add button If you d like to add and analyze all available chemicals click the Add all button To remove chemicals from your analysis list select chemicals from the Selected chemicals list and click the Remove button or the Remove all button to clear the list See Figure 2 Kis ToxPi standalone GUI File Settings Help Data files C Users van Desktop EXAMPLE data 6 slices csv Add Data File ToxPi standalone GUI oe version 1 2 Remove File Available chemicals Available components Selected chemicals Acifluorfen DSSTOX_40338 50594 6 ACEA_IC5O Add Alachlor DSSTOX 40339 15972 60 8 Aldicarb DSSTOX_40340 116 06 3 Ametryn DSSTOX 40343 834 12 8 Amitraz DSSTOX 40344 33089 61 1 Anilazine DSSTOX 40299 101 05 3 Asulam DSSTOX 40374 3337 71 1 Atrazine DSSTOX 40346
16. terval limit ToxPi score meaning that all Color usually represents the components used in this slice have exactly the the type of same values data used andis chosen for No missing data each slice or the amount of Flyoxastrobin missing data is Overall ToxPi score 3 256 less than 1096 Scores calculated relative to 309 number of substances Slice 1 Name of the I Value 0 727 Cl 0 727 0 727 Scaling log10 x 6 Missing data 0 0 chemical Slice 2 Value 0 667 Cl 0 471 0 794 Scaling log10 x 6 Missing data 0 0 Source ID Slice 3 CASRN Value 0 867 Cl 0 414 0 869 Scaling linear x Missing data 1 7896 Slice 4 Value 0 532 Cl 0 0 0 775 Scaling log10 x log10 max x Missing data 0 096 Slice 5 Value 0 246 CI 0 0 0 7 48 Scaling log10 x 6 Missing data 0 096 Slice 6 Value 0 217 Cl 0 0 0 53 Scaling log10 x 6 Missing data Do E Legend for Missing data in percent missing data EE 00 00 01 1 10 20 30 40 50 60 70 80 90 100 values IHE UNIVERSITY of NORTH CAROLINA at CHAPEL HILL 14 Toxicological Priority Index GUI User Manual The chemical information window will contain a ToxPi pie image with 95 confidence intervals Cl highlighted for each slice upper limit black dashed line lower limit white dashed line The core of the image represents the amount of missing data denoted by
17. the Reset zoom button 6 2 3 Highlighting the Data 16 T A FHE UNIVERSITY OPUS EPA of NORTH CAROLINA eb i at CHAPEL HILL Toxicological Priority Index GUI User Manual In order to highlight specific data simply click on the red dot representing the chemical you are interested in The highlighted chemical should become blue and will be highlighted in the results table as well You can also select chemicals in your results table and then see the selected chemicals highlighted blue on the chart plot To unselect chemicals click on your selections and the dot should change color from blue to red Alternatively one can use Reset selection button to clear all selections 7 Description of ToxPi Bootstrapping algorithm Confidence intervals for the ToxPi score of each chemical are generated by bootstrapping the values within each slice The assay values within each slice are sampled with replacement and these resampled values are used to calculate a bootstrap ToxPi statistic This bootstrap ToxPi statistic is calculated exactly as the original statistic but on the resampled data This process is repeated 1000 times and these 1000 or more bootstrap statistics are used to assess the stability of the estimated ToxPi score for the chemical In particular a 95 confidence interval for the ToxPi score is generated in the standard way the lower bound is given by the 2 5 percentile in the bootstrap statistics and the upper bound
18. the color the lighter the core the lower the amount of missing values You can open multiple Chemical information windows simultaneously One can see the Pie Chart without missing data core and or without 95 confidence intervals by unchecking boxes on the Data display settings window This window will appear upon selecting Settings gt Data display settings menu on the main window See Figure 1 One can open multiple chemical information windows simultaneously User can save your image by clicking Save image and specifying the file name The image will be saved in PNG format with a transparent background and publication ready quality You can close the window by clicking the Close button 6 2 Chart Window Moi chart no File View ToxPi scores ws 9 E175 7 5 150 125 100 75 50 25 0 IL 0 00 0 25 0 50 0 75 1 00 125 1 50 175 2 000 225 250 275 3 00 3 25 3 50 3 75 4 00 4 25 450 ToxPi Score v di V Enable zoom Y axis Zoomin Resetzoom Saveselecteddata Savepiotdata V display chemical ranked interval V Enable zoom X axis Zoom out l Reset selection l Save plot Figure 8 ToxPi Chart Window 15 c OS THE UNIVERSITY US EPA of NORTH CAROLINA i at CHAPEL HILL Toxicological Priority Index GUI User Manual The ToxPi chart window will present a ch
19. y y INCGC_PPARG_ Agonist ACEA_IC50 Selected data analysis e INCGC_PPARa_Agonist 0 176 Exposure NCGC_AR_Antagonist ipie NCGC GR Agonit pe ToxRefDB assign a dian 1000000 0 INCGC_PPARd_Agonist Addai D Custom INCGC TRbeta Antagonist D INCGC ERalpha Antagonist INCGC PXR Agonist rat 0 INCGC RXRa Agonist 16 7 Yo INCGC_p53 v Remove this slice Enter slice name Select slice type Select color Select weight Select components Search field Select scaling type Slice 2 D Assay 1 PPS Gene NR4A2 Pathway IPS Gene SOX1 PS_Gene_CEBPB E icid PS_Gene_CXCL9 Exposure PS_Gene_PPARG PS_Gene_E2F1 fem PS Gene MYC JPS Gene SAA1 Custom PS Gene F3 PS_Gene_GATA2 IPS Gene ESRRA oy PS Gene_ABCB1 16 7 Yo 4 Remove this slice Enter slice name Select slice type Select color Select weight Select components Search field Select scaling type Slice 3 Assay 1 llogPow_QP linear x z IMW_QP Add new slice l Preview your slices Figure 4 Slices Information Window In the window shown in Figure 3 you can add a new slice by clicking Add new slice preview the slices by clicking Preview your slices and start the analysis calculation by clicking Calculate ToxPi scores and build visualizations Initially you will see one slice in the window You can set some unique name for the slice by rewriting the text in the Enter slice name field In the Select slice type area you will see the
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