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1. Figure 5 Results Window 10 LL THE UNIVERSITY ef NORTH CAROLINA at CHAPEL HILL Toxicological Priority Index GUI User Manual 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 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 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 e 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 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 at CHAPEL HILL 11 C aA THE UNIVERSITY us EPA of NORTH CAROLINA F i a Toxicological Priority Index GUI User Manual 6 1 Chemical Window Top 95 confidence inte2. 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 Component name A B c 1 1 1 2 ell elecyonic sensing LogPow and MW LogPow and Steroid Metabolism 3 ChemProp ChemProp Pathway 4 QikProp QikProp PS KEGG 0 5 irow 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 ri 2 DSSTOX 40339 15972 60 8 Alachlor 1 3 154 269 77 184516 032 8 3 DSSTOX 40340 116 06 3 Aldicarb NA 1 032 190 26 1000000 9 4 DSSTOX 40343 834 12 8 Ametryn 1000000 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 THE UNIVERSITY of NORTH CAROLINA 4 CHAPEL HILL Toxicological Priority Index GUI User Manual 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
3. EPA NCCT UNC SPH Recreate data from file 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 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 IHE UNIVERSITY of NORTH CAROLINA i at CHAPEL HILL Toxicological Priority Index GUI User Manual 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 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
4. 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 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 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 he
5. estimates exposure data chemical structural descriptors etc aN Idi Recreate data from file Next step formation of slices 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 as needed You can remove a file from the list by selecting it and pressing the Remove File button THE UNIVERSITY ef NORTH CAROLINA 4 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
6. 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 Cl 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 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 14 T A FHE UNIVERSITY OPUS EPA of NORTH CAROLINA
7. 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 amp ToxPi standalone GUI File Help Data files c Users EXAMPLE data 6 slices csv Add Data File ToxPi standalone GUI Remove File version 1 0 Available Chemicals Available components Selected chemicals Available components for selected chemicals ACEA IC50 0 77 Mid Ametryn DSSTOX 4034 ACEA 1c50 Alachlor DSSTOX 40 J P e A Amitraz DSSTOX 40344 PS Aldicarb DSSTOX 40 P Anilazine DSSTOX 4029 Ametryn DSSTOX 4 d 1 Amitraz DSSTOX 40 P A Toxicological Priority Index Anilazine DSSTOX 4 P T ToxPi Toxicological Priority Index is a Asulam DSSTOX 40 P e BMPR2 2 Meri tiers p that incorporates chemical s bioactivity Azinphos methyl DS P profiles inferred toxicity pathways dose Azoxystrobin DSSTC 0 estimates exposure data chemical Bendocarb DSSTOX P structural descriptors etc Benfiuralin DSSTOX_ Benomyl DSSTOX 4 Bensulfuron methyl Bensulide DSSTOX 4 Bentazone DSSTOX_ Bifenazate DSSTOX flexible prioritization support software tool
8. The University of North Carolina at Chapel Hill Gillings School of Global Public Health ToxPi standalone GUI version 1 0 TOXICOLOGICAL PRIORITY INDEX GUI User Manual Toxicological Priority Index GUI User Manual Table of Contents JE Vgeikcncre e M 3 2 ToxPi GUI Installation and Requirements sess enne nensis nenis 4 3 outil e M 5 d jaa EOWA sott eroieetu eroe misterium E A A mtus rere ste ee Lene eeeus 7 5 Slices Information WindOW reete ottenere neo en rers a see n nx Rea Fee eee Erates een see nucon 8 6 Results WI COW csse C Eaa 10 6 1 Chemical Window 5 ite ett te Ene taie oe toe EYE Vna eee UE ae ete pente e etu Y EN reuse Eee Ne anaes 12 PASI 13 6 2 1 Confidence intervals oto rea Prendre etie rd te AEREE A E ae ESE TEA 14 6 2 2 Zooming and Dragglng copier tan non ra nup i nena nona ded a aria Tav RR RAEE AS 14 6 2 3 Highlighting the Data roti dit t eee prn ee Ee ER Y ERE T APERTE RE EET RR ERE ERN ERE TN RE EUER 14 7 Description of ToxPi Bootstrapping Algorithm ccccccssecssscecssecessecseseecseeeessaeesessecsseeessaesesaesseneeee 15 2 THE UNIVERSITY of NORTH CAROLINA 4 CHAPEL HILL Toxicological Priority Index GUI User Manual 1 About ToxPi GUI ToxPi GUI Toxicological P
9. alysis 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 FHE UNIVERSITY of NORTH CAROLINA at CHAPEL HILL Toxicological Priority Index GUI User Manual 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 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 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 highlig
10. che 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 www java com e
11. hted 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 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 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 9 E m S THE UNIVERSITY HUS EPA of NORTH CAROLINA S Y i at CHAPEL HILL Toxicological Priority Index GUI User Manual 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 6 Results Window 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 Alldata Images only DSSTOX_40480 DSSTOX_40301 DSSTOX_40624 IDSSTOX 40299
12. n 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 a Variable name and path to your java folder as a value Usually the path will look like c Program Files Java jre6 bin at CHAPEL HILL 4 I Se THE UNIVERSITY OPUS EPA of NORTH CAROLINA i Toxicological Priority Index GUI User Manual 3 Home screen Add Data File ToxPi standalone GUI version 1 0 Remove File Available Chemicals Available components Selected chemicals Available components for selected chemicals Add al Toxicological Priority Index ToxPi Toxicological Priority Index is a flexible prioritization support software tool that incorporates chemical s bioactivity profiles inferred toxicity pathways dose
13. ore of the 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 IHE UNIVERSITY of NORTH CAROLINA at CHAPEL HILL 12 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 ToxPi chart File View ToxPi scores 2 E o 0 75 1 50 1 75 ToxPi Score m Chemicals Enable zoom Y axis l Zoom In V 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 13 Toxicological Priority Index GUI User Manual
14. re 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 If there are extreme values outliers in the data 15 THE UNIVERSITY of NORTH CAROLINA i at CHAPEL HILL
15. riority 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 e 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 representation Apa
16. rval limit Bottom 95 confidence interval limit Color usually represents the type of data used and is chosen for each slice Name of the chemical Source ID CASRN Flusilazole DSSTOX_40480 85509 19 9 Flusilazole DSSTOX 40480 85509 19 9 Overall ToxPi score 3 486 Scores calculated relative to 309 number of substances Slice 1 Value 0 0 Scaling linear x Cl 0 0 0 0 Slice 2 Value 0 675 Scaling linear x Clz 0 57 7 0 7 64 Slice 4 Value 0 321 Scaling linear x Cl 0 044 0 777 Slice 5 Value 0 889 Scaling linear x CI 0 7 22 1 0 Slice 6 Value 1 0 Scaling linear x 19 741 of data is missing CI 1 0 1 0 Missing data in percent EE 0 10 20 30 40 50 60 70 80 90 100 Slice 3 Value 0 601 Scaling linear x 1 78 of data is missing Cl 0 598 0 661 Figure 6 Chemical Information Window 19 74196 of the data is missing for this particular slice The color is light grey Top and bottom 9596 CI 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 1096 Legend for missing data values The chemical information window will contain a ToxPi pie image with 9596 confidence intervals CI highlighted for each slice upper limit black dashed line lower limit white dashed line The c
17. the inputs and information that will be used in the ToxPi analysis Gs Slices information Enter slice name Select slice type Select weight Select components Slice1 Assay 1 CHR Rat LiverTumors linear x l Pathway Ei ia oars CHR_Rat_LiverTumors Selected data analysis ChemProp lin 176 0 lax 1000000 0 lean 666725 3 ToxRefDB ledian 1000000 0 Exposure Custom Remove this slice Enter slice name Select slice type Select weight Select components Slice2 Assay 1 ICGC VDR Agonist 5 Pathway 7 ChemProp Exposure 7 ToxRefDB C Custom GC TRbeta Agonist INCGC PPARg Agonist ICGC PPARa Agonist INCGC AR Antagonist ICGC GR Agonist INCGC AR Agonist ICGC PXR Agonist rat NCGC RXRa Agonist ICGC PPARg Agonist GC PPARa Agonist ICGC AR Antagonist GC GR Agonist ICGC VDR Agonist ICGC TRbeta Agonist GC AR Agonist ICGC PPARd Agonist GC TRbeta Antagonist ICGC ERalpha Antagonist ICGC PXR Agonist rat Selected data analysis lin 29 39999997 lax 1000000 0 lean 982456 7 ledian 1000000 0 Remove this slice Add new slice J 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 an
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