user manual v 1.3
Contents
1. Recreate data from fiie Next step formation of slices Figure 4 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 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 IHE UNIVERSITY 9 C US EPA l of NORTH CAROLINA Q D Ai onto at CHAPEL HILL Toxicological Priority Index GUI User Manual 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 weights and scaling methods for your ToxPi analysis 4 Data format ad Data in the input data file should be separated using2. IHE UNIVERSITY of NORTH CAROLINA 4 CHAPEL HILL 18 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 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 3 Multiple chemical information windows can be open 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 Y 19 T m S THE UNIVERSITY H amp JUS EPA of NORTH CAROLINA Me a i at CHAPEL HILL 46 S Toxicological Priority Index GUI User Manual 6 2 Chart Window amp ToxPi chart u C X File View ToxPi scores 325 300 275 250 225 200 175 Chemical 150 125 100 if il 0 00 O25 O50 075
3. P at CHAPEL HILL Toxicological Priority Index GUI User Manual 6 1 Chemical Window Upper 95 confidence interval limit Lower 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 n y Fluoxastrobin Flyoxastrobin Overall ToxPi score 3 256 Scores calculated relative to 309 number of substances Slice 1 Value 0 727 CI 0 727 0 727 Scaling log10 x 6 Missing data 0 096 Slice 2 Value 0 667 Cl 0 471 0 794 Scaling log10 x 6 Missing data 0 096 Slice 3 Value 0 867 CI 0 414 0 869 Scaling linear x Missing data 1 7896 Slice 4 Value 0 532 CI 0 0 0 775 Scaling log10 x log10 max x Missing data 0 096 Slice 5 Value 0 246 CI 0 0 0 748 Scaling log10 x 6 Missing data 0 096 Slice 6 EEE 00 00 01 1 10 20 30 40 50 60 70 80 90 100 Value 0 217 Cl 0 0 0 53 Scaling log10 x 6 Missing data Hc E Missing data in percent Figure 9 Chemical Information Window 19 796 of the data is missing for this particular slice The color is light grey Upper and Lower 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
4. comma delimiter The file extension should be csv You can see the required data format in the example data files provided here http comptox unc edu toxpi php Those values will be Row 1 Slice Row 3 Slice name treated as missing weight Row 3 Slice Row 5 Component A B c F 1 2 Cell ele amp ronic sensing LogPow and MW LogPow and IW Y Steroid Metqbolism 3 ChemProp 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 1 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 Row 4 Component Figure 5 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 THE UNIVERSITY ef NORTH CAROLINA at CHAPEL HILL 10 Toxicological Priority Index GUI User Manual Properly formatted data files that are created outside the GUI can be anal
5. BPA extends farther from the origin than the corresponding slice for tebuthiuron indicating that BPA is more potent across ER assays than is tebuthiuron In the implementation presented here all 10 slices are weighted equally in the overall ToxPi calculation so the graphical width of all slices is equal to the angle 8 formed by dividing 2m radians into 10 sections or 271 10 rm 5 radians 36 degrees Figure 2 is a schematic that details how data are translated into ToxPi scores For this application the chemical wise slice results are normalized to the interval 0 1 by dividing each chemical result by the slice maximum where results represent relative potency in vitro assays bioavailability chemical properties or perturbation score pathways Values closer to the unit score equal to 1 translate to higher potency higher predicted bioavailability or greater pathway perturbation relative to all other chemicals Conversely values closer to the origin equal to O translate to lower potency lower bioavailability and lesser pathway perturbation across the corresponding domains Values at zero i e slices not extending at all from the origin translate to inactive no activity As conveyed by the equal radial width of all slices in Figure 1 the slices are not differentially weighted for this implementation However by using a smaller number of targeted components in the AR ER and TR slices individual component assays within these
6. 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 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 Y 21 T am THE UNIVERSITY H9 JUS EPA of NORTH CAROLINA Me a i at CHAPEL HILL 46 P 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
7. 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 the 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 7 T mm FHE UNIVERSITY H9 JUS EPA of NORTH CAROLINA Set i 1 CHAPEL HILL E Toxicological Priority Index GUI User Manual 3 Home screen Q amp ToxPi standalone GUI e 8 mcd File Settings Help Data fies Add Data File 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 iL EPA NCCT UNC SPH Figure 3 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 3 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
8. order to provide cross platform compatibility and can be used on any computer where Java is installed The application uses the JFreeChart package for ToxPi chart representation the Apache commons library for CSV file operations and Swing libraries for design purposes 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 profile 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 6 e X THE UNIVERSITY QUS EPA of NORTH CAROLINA j i at CHAPEL HILL cor gt o Q K V pps Toxicological Priority Index GUI User Manual 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 dragg
9. slices exert a greater influence over that slice s composite score than do individual assays from one of the larger slices for other NRs or XME ADME X 4 S LN THE UNIVERSITY H9 JUS EPA of NORTH CAROLINA V P i i CHAPEL HILL t mmo im Toxicological Priority Index GUI User Manual Step 1 Sum the potency across all component assays in the ER Step 2 Normalize the Step 3 Plot the slice for each individual chemical summed potency across all normalized ToxPi 309 chemicals scores for the ER slice ER ER ER ER ER ER ER max im uM uM pM uM uM uM LELTITI RA el ORE T ER Methoxychlor j M MXC max gt ER Figure 2 Translation of results into ToxPi score profiles The concentration response curves ER for each of the six assays in the ER slice are shown for three example chemicals On each curve the red asterisk represents the AC50 potency for assay hits and flat blue lines indicate assays that are inactive for that chemical For nonassay slices the same procedure is followed with AC5O values replaced by particular chemical property values pathway scores and so forth Abbreviations 2 4 D 2 4 dichlorophenoxyacetic acid max maximum MXC methoxychlor Modified from Reif et al Environ Health Perspect 118 1714 1720 2010 In summary this tool is designed to incorporate diverse sources of information e g a chemical s bioactivity profiles inferred toxicity pathways d
10. 1 00 125 1 50 175 200 225 250 275 300 325 350 375 400 425 4 50 ToxPi Score v 7 Enable zoom Y axis Zoom In Reset zoom Save selected data l Save plot data J V display chemical ranked interval 7 Enable zoom X axis Zoom out Reset selection Save plot Figure 10 ToxPi Chart Window The ToxPi chart window shows a distributional plot 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 THE UNIVERSITY of NORTH CAROLINA i at CHAPEL HILL 20 Toxicological Priority Index GUI User Manual 6 2 1 Confidence intervals The horizontal orange bars along the X axis indicate the bootstrapped 95 confidence interval for a particular chemical see Section 7 Description of ToxPi Bootstrapping algorithm The vertical orange bars along the Y axis indicate the ranking interval for a specific chemical
11. ABCG2 pose Er Pene 8 ToxRefDB PS Gene MYC IPS Gene AR PS G ne AA Add all PS Gene BMPR2 Custom PS Gene F3 PS Gene CCL2 PS Gene GATA2 P S Gene CCL26 C Gene PS_Gene_ESRRA i seg be PS_Gene_ABCB1 ene 16 7 atid PS_Gene_CD69 Remove this slice Enter slice name Select slice type Select color Select weight Select components Search field Select scaling type Slice 3 D Assay 1 logPow_QP linear x MW 5 Add new slice Preview your slices Figure 6 Slices Information Window In the window shown in Figure 6 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 FHE UNIVERSITY of NORTH CAROLINA i at CHAPEL HILL 11 Toxicological Priority Index GUI User Manual 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 although these can be manually adjusted e Assay gradient o
12. Clicking the Calculate ToxPi indexes and build visualizations button starts the calculation process When all the necessary calculations are completed the ToxPi GUI results window will appear Figure 7 Qs ToxPi results File View Save selected Save selected image Save all image Display ToxPi chart All data Images only Image Substance name Source ToxPi value cD ipronil IDSSTOX 40466 3 747 e hosalone IDSSTOX 40555 3 688 e toxazole DSSTOX 40452 3 559 oxacarb IDSSTOX_40496 3 459 Figure 7 Results Window IHE UNIVERSITY of NORTH CAROLINA at CHAPEL HILL 15 Toxicological Priority Index GUI User Manual N ToxPi results Lo fmm File View Save data file Save selected Save selected image Save all image Display ToxPi chart Alldata images only e e e e Fipronil Phosalone Etoxazole Indoxacarb Tebupiri mfos 3 Hexaconazole Imazalil Bisphenol A gt Fluoxastrobin Cypermethrin 8 Methoxychlor Oryzalin Fenpyroxi mate ZE FS Propargite Pyridaben la r Figure 8 Results Window Images only view The results window will initially display the table of all t
13. The University of North Carolina at Chapel Hill Gillings School of Global Public Health ToxPi standalone GUl Version 1 3 TOXICOLOGICAL PRIORITY INDEX GUI User Manual Toxicological Priority Index GUI User Manual Table of Contents 1 About TOXPIGUlisccatienciGhai aici ition nit antes asl ie at amet eee ean 3 2 ToxPi GUI Installation and Requirements ccccceesscecssssececeeneececeeaeeeceeaaececseaaececseaaeeeeseaeeeeseaeeeeeeaaes 7 3 Deut e ts 8 4 gata TONAL ee a E E ET ftu l esses seu b t utres E Doe EUR 10 5 Slices Information WindOW eeeti nete net eene neenon vena nent baa enn dg Re aen ee uen verre ena 11 6 Results WINGOW csse ae I 15 6 1 Chemical WindOW 5 ett te et aieo oe EYE Yn Re eee UE ER ete pene E EAE EEES 18 JPASI M 20 6 2 1 Confidence intervals oett nat Prep ett nene t iere d tee une ee Ru Exe er SERE EIA eee vage Ee 21 6 2 2 Zooming AN RPIETICIICONEEE n 21 6 2 3 Highlighting the Data riore tr tee knee Ee ER AER TR CARERE RU KEEPER ERE XA ERE TN GRE RECO 21 7 Description of ToxPi Bootstrapping Algorithm esses nennen enne nnne nnne 22 D 2 E aA FHE UNIVERSITY us EPA of NORTH CAROLINA M a i at CHAPEL HILL Toxicological Priority Index GUI User Manual 1 About ToxPi GUI ToxPi GUI Toxicological Prio
14. as been zeroed prior to loading in the GUI In x max x Component values will be scaled using the formula 1 In x In max x This scaling is the natural log alternative to the log base 10 scaling and is intended for data where values represent a level at which activity was defined e g a concentration level observed as a hit for assay data The max x portion of the equation is for data with any top end not active definition This scaling is appropriate for input data that represent components where smaller numerical values should have larger ToxPi slices e g assay potency estimates or measured distance from some source hazard The natural log should be used when the input data represent exponential decay or some quantity where scaling by orders of magnitude is not desired 13 m 7S FHE UNIVERSITY H9 JUS EPA of NORTH CAROLINA Ve i 1 CHAPEL HILL Toxicological Priority Index GUI User Manual e sqrt x Component values will be scaled by taking the square root of the original value The square root transformation is most often used for count data e linear x No scaling will be applied This is the default scaling and is the appropriate choice for input data that should be represented by larger ToxPi radii for larger numbers All input data scaling occurs prior to ToxPi normalization Because ToxPi normalization converts all component numeric values in a given slice into relative ToxPi index value
15. e just a small number of assays within each slice e If there are extreme values outliers in the data Q XIX 22 m 7S FHE UNIVERSITY HS JUS EPA of NORTH CAROLINA i e i 1 CHAPEL HILL
16. f 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 and scaling types defined by user will be stored into the output CSV file One can reproduce exactly the same results by selecting previously saved files 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 as a percent relative to the overall ToxPi and as absolute values The weight 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 6 scaling types allowed e log10 x 6 Component values are scaled using the formula 1 log x 6 This scaling is intended for ToxCast style data where values represent the micromolar concentration at which half maximal assay activity was achieved i e the hit concentration The convention is to assign negative i e no hit resul
17. he 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 16 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 Save selected This will save only selected chemicals into a file FHE UNIVERSITY of NORTH CAROLINA at CHAPEL HILL 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 7 is selected while only images will be displayed if Images only See Figure 8 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 9 Y 17 F mm THE UNIVERSITY Q US EPA of NORTH CAROLINA Ras i V pps 46
18. ing the plot All information can be saved in the form of shareable input files and or graphical output The following sections detail implementation usage and capabilities of the ToxPi GUI 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 en For version 1 1 and later users can choose between a Windows executable file or a Java JAR file We recommend using the Windows EXE file on Windows OS and the JAR on any other OS For some big datasets users can face memory errors If you see those errors use the Java JAR file but set the memory size for the application using the following string in command the line java Xmx1500m jar path to jar file where path to jar file is a system path to the location where you saved the 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 website http comptox unc edu resources html If you have trouble 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 list On the next window locate the Advanced System Settings button
19. onents Selected chemicals Available components for selected chemicals Acifiuorfen DSSTOX_40338 50594 6 Alachlor DSSTOX_40339 15972 60 8 lAldicarb 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 1912 24 9 Azamethiphos DSSTOX 40557 35575 Azinphos methyl DSSTOX 40347 86 Azoxystrobin DSSTOX 40348 13186 Bendiocarb DSSTOX 40349 22781 2 Benfluralin DSSTOX_40350 186 1 40 Benomyl DSSTOX_40351 17804 35 2 Bensulfuron methyl DSSTOX 40352 Bensulide DSSTOX 40353 741 58 2 Bentazone DSSTOX 40354 25057 89 IBifenazate 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 Bromacil DSSTOX 40366 314 40 9 Bromoxynil DSSTOX_40319 1689 84 Buprofezin DSSTOX _40367 69327 76 IButachlor DSSTOX_40368 23184 66 Butafenaci DSSTOX 40357 134605 _ ntes MECTAV anaca 22670_47 01 4 add Remove F Add all Toxicological Priority Index ToxPi Toxicological Priority Index is a flexible prioritization support software tool C Remwea that incorporates chemical s bioactivity profiles inferred toxicity pathways dose estimates exposure data chemical structural descriptors etc EPA NCCT UNC SPH
20. ose 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 5 am S THE UNIVERSITY USUS EPA ef NORTH CAROLINA a a i at CHAPEL HILL Q Toxicological Priority Index GUI User Manual 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 e Provide complete transparency in deriving a toxicity score e Prioritize chemicals for additional targeted testing experiments or tiered assessment strategies e Promote principles of sustainable development by providing decision support for selecting amongst manufacturing alternatives e Integrating novel data streams such as environmental exposure metrics or socioeconomic status into decisions e Facilitate arguments on chemical similarity i e read across of ToxPi profiles ToxPi GUI is written in Java in
21. perties or pathways 3 Fawr FHE UNIVERSITY HS JUS EPA of NORTH CAROLINA 1 Cas ono Aci MC S 4 CHAPEL HILL Toxicological Priority Index GUI User Manual including AR ER TR and seven other slices see Reif et al Environ Health Perspect 118 1714 1720 2010 for a full description Ninety assays two properties and 27 pathways make up the 119 components of this endocrine ToxPi e g the ERa transcription factor assay is one of six components in the ER slice The number of components in each slice is shown in parentheses ToxPi profiles for bisphenol A and tebuthiuron are shown as examples of high and low ranked chemicals Modified from Reif et al Environ Health Perspect 118 1714 1720 2010 Specifically ToxPi is a dimensionless index score that is calculated for each chemical as a weighted combination of all data sources that represents a formalized rational integration of information from different domains Visually ToxPi is represented as component slices of a unit circle with each slice representing one piece or related pieces of information Figure 1 For each slice distance from the origin center is proportional to the normalized value e g assay potency or predicted bioavailability of the component data points composing that slice and the width in radians indicates the relative weight of that slice in the overall ToxPi calculation For example in Figure 1 the slice representing ER assays for bisphenol A
22. rity 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 Reif et al http ehsehplp03 niehs nih gov article info 3Ado0i 2F10 1289 2Fehp 1002180 While we refer the users to the above mentioned open access publication for more details below and in Section 7 of this Manual we briefly describe the mathematical transformations of the data performed by the software The framework for this profiling and prioritization system is detailed in Figure 1 profile Each chemical signature gives a Toxicological Priority Index ToxPi score that is fingerprint useful for ranking chemicals I P ToxPi w assay Y w chemProp w pathway l I l ToxPi f In vitro assays Chemical properties Pathways Bisphenol A Tebuthiuron XME ADME Other NR AR 5 LogP OMIM Phenotypes 7 Predicted Ingenui Caco 2 g ty Pathways 8 KEGG Pathways 12 Figure 1 ToxPi definitions and notation Weighted combinations of data were integrated for each chemical from multiple domains with relative scores represented in ToxPi profiles composed of slices based on one or more components Domains are basic data types represented by slices of a given color family green in vitro assay slices orange chemical properties blue pathways Slices represent data from related assays pro
23. s visualized as profiles the GUI software is agnostic as to the interpretation of the radial length of those slices Restated If the user maintains inear x scaling i e no scaling for all input data larger numbers will translate into longer slices For a particular input component if the goal is to flag the largest numbers in a set by drawing ToxPi slices with long radii then inear x scaling is appropriate Conversely if the goal is to flag the smallest numbers e g input data are lowest effective concentrations ICsos ACsos then one of the negative log or negative In scaling would be appropriate Users can always implement whatever scaling is appropriate for their data prior to importing files into the GUI with the only exception being that negative values will be interpreted as missing In the case that lt 0 values have meaning other than missing users should take care to properly scale all component columns containing negative data prior to importing the data into the GUI For example the minimum most negative value in a given column should be added to all values in that column You will see some basic summary statisticals of the included components in the Selected data analysis field You can remove entire slices by clicking Remove this slice 14 T mm FHE UNIVERSITY H9 JUS EPA of NORTH CAROLINA Ve i i CHAPEL HILL Toxicological Priority Index GUI User Manual 6 Results Window
24. 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 eof NORTH CAROLINA 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 4 Ws ToxPi standalone GUI File Settings Help Data files C Users Ivan Desktop EXAMPLE_data_6 slices csv Add Data File ToxPi standalone GUI version 1 RemweFie Available chemicals Available comp
25. ts the value 10 Therefore this PI 12 oy A FHE UNIVERSITY QUS EPA of NORTH CAROLINA e i i CHAPEL HILL Toxicological Priority Index GUI User Manual scaling inverts a micromolar activity concentration into a log scaled measure of potency where larger numbers indicate higher potency i e lower concentration at which a hit was observed log10 x log10 max x Component values will be scaled using the formula 1 log x log max x This scaling is intended for data where values represent a level at which activity was defined e g a concentration level observed as a hit for assay data The max x portion of the equation is for data with any top end not active definition Otherwise the interpretation is similar to the 6 scaling above where higher scaled values indicate higher hazard concern etc This scaling is appropriate for input data that represent components where smaller numerical values should have larger ToxPi slices e g assay potency estimates or measured distance from some source hazard e hit count Component values will be treated as binary data meaning that all non zero values will be replaced with ones and all zeros will remain zeros This scaling is appropriate for input data represented occurrence counts or where the absolute numerical value is less important than whether or not an event was observed For thresholds this scaling type could be applied to input data that h
26. 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 here may be unreliable in the following situations e If the measurements within each slice are on dramatically different scales While different scales can be combined within ToxPi individual slices are best used to represent similar related data e If there ar
27. yzed using the one step Recreate data from file button Files saved from within the GUI can also be edited outside the GUI and reloaded as new input files When creating original data files outside of the GUI note that all columns having the same slice name Row 2 will be aggregated into a single slice by the ToxPi algorithm 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 amp Slices information File View Enter slice name Select slice type Select color Select weight Select components Search field Select scaling type Slice 1 Assay 1 INCGC_VDR_Agonist 4og10 x 6 NCGC TRbeta Agonist n R Pathway CGC PP ARG pisse t ACEA_IC50 Selected data analysis ChemProp NCGC PPARa Agonist in 0 176 Exposure NCGC_AR_Antagonist E lax ipd NCGC GR Agonist ideo EST NCGC AR Agonist 30009009 INCGC PPARd Agonist Custom NCGC_TRbeta_Antagonist UE NCGC_ERalpha_Antagonist NCGC_PXR_Agonist_rat 0 NCGC RXRa Agonist 16 7 Yo NCGC_ps3 X L Remove this slice Enter slice name Select slice type Select color Select weight Select components Search field Slice 2 7 Assay 1 PS Gene NR4A2 z IPS Gene SOX1 J Lr 1 renun cpap eee PS_Gene_ABCB1 7 ChemProp PS Gene CXCL9 PPS Gene ABCB11 E EE PS Gene PPARG IPS Gene
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