user manual v 1.1 - The Carolina Center for
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1. Select slice type Select weight Select components Search field Select scaling type Slice2 Q Assay 1l INCGC VDR Agonist ICGC TRbeta Agonist ICGC PPARg Agonist ChemProp INCGC_PPARa_Agonist Exposure ICGC AR Antagonist INCGC GR Agonist INCGC AR Agonist INCGC PPARd Agonist Borm ICGC TRbeta Antagonist ARS NCGC FRalpha Antagonist GC PPARd Agonist INCGC PXR Agonist rat NNCGC RXRa Agonist NCGC p53 ICGC PXR Agonist rat aS 5 Pathway lax 1000000 0 lean 982456 7 7 ToxRefDB ledian 1000000 0 Add new slice Preview your slices Calculate ToxPi indexes and build vizualizations 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 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 e Assay gra2. Index GUI User Manual Two additional buttons Save selected data and Save plot data allow one to save the actual information ToxPi Score 95 confidence intervals and rank intervals about all or only selected chemicals 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 the Reset zoom button 6 2 3 Highlighting the Data 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 chem
3. calculated ToxPi score for each chemical Above the table you will see three buttons and two radio controls The three buttons are e Save data file This will save your data You will be asked to select or enter the file name where the current data will be saved and later the saved file can be IHE UNIVERSITY ef NORTH CAROLINA 4 CHAPEL HILL 12 Toxicological Priority Index GUI User Manual 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 Save Selected image This will save only images for selected chemicals into one file Save all image This will save all the chameical images into one file sorted according to the ToxPi score Display ToxPi 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 AII data is selected while only images will be displayed if Images only is selected If you 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 6 13 am IHE UNIVERSITY OPUS EPA of NORTH CAROLINA t at CHAPEL HILL Toxicological Priority Index GUI User Manual 6 1 Chemical Window Top 9596 confidence interval limit Bott
4. results will be based on the input file and will be an exact visual 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 ad Data in the input data file should be separated using comma delimiter File extension should be csv You can see data format in the example data files provided here http comptox unc edu toxpi ph Slice weight Those values will be treated as missing Slice type name IHE UNIVERSITY of NORTH CAROLINA i at CHAPEL HILL row order chemical source sid 1 DSSTOX 40338 2 DSSTOX 40339 3 DSSTOX 40340 4 DSSTOX 40343 5 DSSTOX 40344 6 DSSTOX 40299 7 DSSTOX 40374 8 DSSTOX 40346 o0 MO U BUNT b lp j a w PEPO User Manual casrn 50594 66 6 15972 60 8 116 06 3 834 12 8 33089 61 1 101 05 3 3337 71 1 1912 24 9 Figure 3 Input file format The default value for the slice weight should be 1 chemical name Acifluorfen Alachlor Aldicarb Ametryn Amitraz Anilazine Asulam Atrazine Toxicological Priority Index GUI E 1 Cell electronic sensing Assay ACEA ACEA IC50 1000000 64 30000001 NA 1000000 29 39999997 1000000 1000000 1000000 F 1 LogPow and MW Ch
5. The University of North Carolina at Chapel Hill Gillings School of Global Public Health ToxPi standalone GUI Version 1 1 TOXICOLOGICAL PRIORITY INDEX GUI User Manual Toxicological Priority Index GUI User Manual Table of Contents 1 lt ADOUt TOXPI GUI m 3 2 ToxPi GUI Installation and Requirements cccccessccessessececseneececseaeeecseaecesseaaeeeeseaaeeeeseaeeeesecaeeeeseaaes 4 3 HOME ieicdicR RI P 5 4 Data formateur es ener Eae ERU ERE RUN Ee ONERE ERE PEN AERE VE Ene Ven Vos a NEN UN EE UNE v ERN epus 7 5 Slices Information Window nennen entente iaaa rsen rese rr sete sites tentent tnter nennen 8 E Cc 11 1 Chemical Widow aie O 14 6 2 Chart Ihr de OM 15 6 21 Confidence intervals c erre ree tpe debe ERR aea EE RR BUR NE VENTA NUN USE E ERR AER ERR E RSS EE ERE ERR 16 6 2 2 Looming and Dragging eret caved Pp tx sere Hy Fee e PERLES XR EXE eee MERE HE ker ved SEASSA 16 6 2 3 Highlighting the Data ssc tenir neon ra eunti rea ono dena aria Ta vn ER EEA a E RRR TEMERE 16 7 Description of ToxPi Bootstrapping Algorithm ccccccssecesscesssseesseecseseecseeeescaeesessecsseeessaeesssaesssneeees 17 2 IHE UNIVERSITY of NORTH CAROLINA i at CHAPEL HILL Toxicological Priority Index GUI User Manual 1 About ToxPi GUI ToxPi G
6. UI Toxicological Priority Index graphical user interface is a flexible prioritization support software tool based on the Endocrine Profiling and Prioritization of Environmental Chemicals Using ToxCast Data article by David M Reif et 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 r
7. ava com en Starting from version 1 1 users can choose between Windows executable file or Java JAR file We recommend to use 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 1 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 application 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 4 I THE UNIVERSITY OPUS EPA of NORTH CAROLINA i at CHAPEL HILL Toxicological Priority Index GUI User Manual a Variable name and path to your java fo
8. dient of green color e Pathway gradient of blue color e ChemProp gradient of orange color e Exposure gradient of gray color 9 THE UNIVERSITY of NORTH CAROLINA 4 CHAPEL HILL Toxicological Priority Index GUI User Manual e ToxRefDB gradient of purple color e Custom type gradient of red color 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 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 log10 x log10 max x all the values x will be normalized using the following formula 1 1og x log o 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 zero
9. e 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 fthereare just a small number 1 3 of assays within each slice e If there are extreme values outliers in the data 17 F A FHE UNIVERSITY G9 US EPA meno S a i at CHAPEL HILL
10. emProp QikProp logPow QP m 1 LogPow and MW ChemProp QikProp MW QP 361 661 269 77 190 26 227 327 293 411 275 524 230 238 215 685 Steroid Metabolism Pathway PS KEGG 0 PS KEGG Androgen and estrogen metabolism 1000000 184516 032 1000000 16586 61894 1000000 1000000 36845 62222 192525 1417 Component source id Please note that first 4 four columns in the input data file are obligatory as well as first 5 five columns If your file will have different format ToxPi GUI will not accept that file Please note that the bootstrapping step will not be executed if each slice contains only one component Please note that any values that are below zero or are not numbers will be ignored and treated as a missing data 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 IHE UNIVERSITY of NORTH CAROLINA 4 CHAPEL HILL Toxicological Priority Index GUI User Manual Pal Slices information Enter slice name Select slice type Select weight Select components Select scaling type Slice1 Assay 1 CHR Rat LiverTumors linear x CHR Rat TesticularTumors 5 Rat ThyroidTumors _Rat_LiverTumors Selected data analysis dens m PEE lax 1000000 0 sae lean 666725 3 ToxRefDB ledian 1000000 0 Pathway Custom Enter slice name
11. epresentation Apache commons library for CSV files operations and Swing libraries for design purposes 3 F 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 www j
12. icals 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 16 F A FHE UNIVERSITY OPUS EPA of NORTH CAROLINA eb i at CHAPEL HILL Toxicological Priority Index GUI User Manual 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 9596 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 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 mak
13. image represents the amount of missing data denoted by the color the lighter the core the lower the amount of missing values You can open multiple Chemical information windows simultaneously You can open multiple chemical information windows simultaneously 14 THE UNIVERSITY ef NORTH CAROLINA at CHAPEL HILL Toxicological Priority Index GUI User Manual You 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 P ToxPi chart File View ToxPi scores S 2 o9 o ToxPi Score m Chemicals Saveselecteddata Saveplotdata l Save plot Enable zoom Y axis Zoom In display chemical ranked interval V Enable zoom X axis l Zoom out Figure 7 ToxPi Chart Window The ToxPi chart window will present a chart 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 You 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 THE UNIVERSITY of NORTH CAROLINA i at CHAPEL HILL 15 Toxicological Priority
14. lder as a value Usually the path will look like c Program Files Java jre6 bin 3 Home screen Add Data File ToxPi standalone GUI Remove File Available Chemicals Available components Selected chemicals Available components for selected chemicals Remove eos 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 EN lui Recreate data from file Next step formation of slices EPA NCCT UNC SPH Remove all 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 IHE UNIVERSITY ef NORTH CAROLINA 4 CHAPEL HILL Toxicological Priority Index GUI User Manual chemicals and comp
15. lide DSSTOX 4 Bentazone DSSTOX_ ACEA_ICSO air Ma Ti Recreate data from file Selected chemicals Available components for selected chemicals Ametryn DSSTOX 4034 Anilazine DSSTOX 4029 ACEA ICSO Amitraz DSSTOX 40344 Ps c Next step formation of slices ToxPi standalone GUI 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 EPA NCCT UNC SPH IHE UNIVERSITY ef NORTH CAROLINA 4 CHAPEL HILL Toxicological Priority Index GUI User Manual 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 example 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 allows you to quickly get to the results of the analysis without selecting any components The
16. om 9596 confidence interval limit Color usually represents the type of data used andis chosen for each slice Name of the chemical Source ID CASRN Flusilazole Overall ToxPi score 3 486 Scores calculated relative to 309 number of substances Slice 1 BJ Value 0 0 CI 0 0 0 0 Scaling linear x Missing data 0 0 Slice 2 Value 0 675 Cl 0 584 0 76 Scaling linear x Missing data 0 096 Slice 3 Value 0 601 Cl 0 598 0 661 Scaling linear x Missing data 1 7896 Slice 4 Value 0 321 CI 0 044 0 77 7 Scaling linear x Missing data 0 096 Slice 5 Value 0 889 CI 0 7 22 1 0 Scaling linear x Missing data 0 096 Slice 6 Value 1 0 CI 1 0 1 0 Scaling linear x Missing data 19 741 Missing data in percent O 0 10 20 30 40 50 60 70 80 90 100 L Figure 6 Chemical Information Window 19 741 of the data is missing for this particular slice The color is light grey Top and bottom 95 Cl limits match the actual ToxPi score meaning that all the components used in this slice have exactly the same values No missing data or the amount of missing data is less than 10 Legend for missing data values 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
17. onents 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 as needed You can remove a file from the list by selecting it and pressing the Remove File button 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 Ws ToxPi standalone GUI File Help Data files C Users EXAMPLE_data_6 slices csv Add Data File Remove File Available Chemicals Available components Acifluorfen DSSTOX_ Alachlor DSSTOX 40 PS Aldicarb DSSTOX_40 P Ametryn DSSTOX_ amp Amitraz DSSTOX 40 Anilazine DSSTOX 4 Asulam DSSTOX 40 Atrazine DSSTOX_4 Azamethiphos DSST Azinphos methyl DS Azoxystrobin DSSTC Bendiocarb DSSTOX Benfluralin DSSTOX_ Benomyl DSSTOX 4 Bensulfuron methyl I Bensu
18. s use it when you have only binary data in the input files e In x all the values x will be normalized using the following formula 1 In x e sqrt x all the values x will be normalized using the square root value of the original value e 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 10 T m S THE UNIVERSITY HUS EPA of NORTH CAROLINA S Y i at CHAPEL HILL Toxicological Priority Index GUI User Manual 6 Results Window THE UNIVERSITY of NORTH CAROLINA at CHAPEL HILL 11 gt Toxicological Priority Index GUI d User Manual Click Calculate ToxPi indexes and build visualizations to see the output of your selections above When all the necessary calculations are completed the ToxPi GUI results window will appear Figure 5 below yw ToxPi results Save data fle Saveselected Saveselectedimage Saveallimage Display ToxPichart Alldata Images only Substance name Source ToxPi value Mesosulfuron methyl IDSSTOX 40511 Iodosulfuron methyl sodium Figure 5 Results Window 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
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