OECD QSAR Toolbox v.4...Background • Objectives • Specific Aims • Automated workflow • The...

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OECD QSAR Toolbox v.4.0 Tutorial on how to predict skin sensitisation potential by automated workflow

Transcript of OECD QSAR Toolbox v.4...Background • Objectives • Specific Aims • Automated workflow • The...

Page 1: OECD QSAR Toolbox v.4...Background • Objectives • Specific Aims • Automated workflow • The exercise • Execution of AW for Skin sensitization Outlook The OECD QSAR Toolbox

OECD QSAR Toolbox v.4.0

Tutorial on how to predict skin sensitisationpotential by automated workflow

Page 2: OECD QSAR Toolbox v.4...Background • Objectives • Specific Aims • Automated workflow • The exercise • Execution of AW for Skin sensitization Outlook The OECD QSAR Toolbox

• Background

• Objectives

• Specific Aims

• Automated workflow

• The exercise

• Execution of AW for Skin sensitization

Outlook

The OECD QSAR Toolbox for Grouping Chemicals into Categories 2April, 2017

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• This is a step-by-step presentation designed to take theToolbox user through the filling of skin sensitization data gapsusing an automated workflow.

Background

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• Background

• Objectives

• Specific Aims

• Automated workflow

• The exercise

• Execution of AW for Skin sensitization

Outlook

The OECD QSAR Toolbox for Grouping Chemicals into Categories 4April, 2017

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• Fill data gaps for a chemical by automated workflow for skinsensitization (SS);

• Fill data gaps for a batch of chemicals by automatedworkflow for SS.

Objectives

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This presentation demonstrates how to :

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• Background

• Objectives

• Specific Aims

• Automated workflow

• The exercise

• Execution of AW for Skin sensitization

Outlook

The OECD QSAR Toolbox for Grouping Chemicals into Categories 6April, 2017

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• To introduce to the user the automated workflow for predictingof skin sensitization potential of a chemical;

• To introduce to the user the automated workflow for predictingof skin sensitization potential of a batch of chemicals;

• To familiarize the user with the new Toolbox interface;

• To familiarize the user with the new notification messages;

• To explain to the user the rationale behind each step of theexercise.

Specific Aims

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• Background

• Objectives

• Specific Aims

• Automated workflow

• The exercise

• Execution of AW for Skin sensitization

Outlook

The OECD QSAR Toolbox for Grouping Chemicals into Categories 8April, 2017

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• The automated workflow (AW) is designed to apply data gapfilling for discrete chemicals only;

• The AW follows the implemented logic and finished withprediction;

• The AWs do not allow interactions during the workflow process;

• Analogous sets of chemicals are often selected based on thehypothesis that the toxicological effects of each member of thecategory will show a common behaviour;

• AW can be executed for one chemical as well as for a batch ofchemicals.

Automated workflowOverview

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• Background

• Objectives

• Specific Aims

• Automated workflow

• The exercise

• Execution of AW for Skin sensitization

Outlook

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• In this exercise we will predict the skin sensitization potential for:

• This prediction will be accomplished by using of the developedautomated workflow for skin sensitization.

The Exercise

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o One chemical – Chlorpyrifos [CAS# 2921-88-2], which will bethe “target” chemical;

o Batch of chemicals - the first five compounds of the Skinsensitization ECETOC database, which will be the “target”chemicals.

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• Allergic contact dermatitis that results from skin sensitization isa significant health concern.

• Skin sensitization is a toxicological endpoint that is complex andconceptually difficult.

• However, there is growing agreement that most organicchemicals must react covalently with skin proteins in order tobehave as skin sensitizers.

• Therefore, mechanisms by which organic chemicals bind withproteins are relevant to grouping chemicals that may be skinsensitizing agents.

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The ExerciseSidebar On Sensitization

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• Background

• Objectives

• Specific Aims

• Automated workflow

• The exercise

• Execution of AW for Skin sensitization

Outlook

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• Only three out of six Toolbox modules are used in a sequentialworkflow:

o Input

o Data Gap Filling

o Report

Execution of AW for Skin sensitization

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The rest of the modules – Profiling, Data and Category definitionare included as a part of the algorithm of the automated workflow.

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• Background

• Objectives

• Specific Aims

• Automated workflow

• The exercise

• Execution of AW for Skin sensitization– Example 1

o Input

Outlook

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• This module provides the user with several ways of enteringthe chemical of interest (i.e. the target chemical).

• Since all subsequent functions are based on chemicalstructure, the goal here is to make sure the molecularstructure assigned to the target chemical is the correct one.

InputOverview

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InputWays of Entering a Single Chemical

• Chemical Name

• Chemical Abstract Services (CAS) number (#)

• Drawing chemical structure with or without additional defining of the composition

• Select from User List/Inventory/Databases

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1. Click on CAS#;2. Enter the CAS# of Chlorpyrifos

(CAS 2921-88-2);3. Click on Search.

Input ScreenInput target chemical by CAS#

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InputTarget chemical identity

The Toolbox now searches the databases to find out if the CAS# you entered is linked to a molecular structure stored in the Toolbox. It is displayed as a 2-demensional depiction.Click on OK (1).

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In case the entered CAS# corresponds to more than one structure or to one structure butwith different predefined substance type, more than one chemical identity could beretrieved. In this case the user can decide which substance to be retained for thesubsequent workflow.

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• Background

• Objectives

• Specific Aims

• Automated workflow

• The exercise

• Execution of AW for Skin sensitization– Example 1

o Input

o Data Gap Filling

Outlook

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• “Data Gap Filling” (DGF) module give access to five different data gap filling tools:

o Read-across

o Trend analysis

o (Q)SAR models

o Standardized workflow

o Automated workflow

• Depending on the situation, the most relevant data gap mechanism should be chosen,taking into account the following considerations:

o Read-across is the appropriate data-gap filling method for “qualitative” endpoints like skin sensitisation

or mutagenicity for which a limited number of results are possible (e.g. positive, negative, equivocal).

Furthermore read-across is recommended for “quantitative endpoints” (e.g., 96h-LC50 for fish) if only a

low number of analogues with experimental results are identified.

o Trend analysis is the appropriate data-gap filling method for “quantitative endpoints” (e.g., 96h-LC50 for

fish) if a high number of analogues with experimental results are identified.

o “(Q)SAR models” can be used to fill a data gap if no adequate analogues are found for a target chemical.

o Standardized and Automated workflows are developed to facilitate the users work. Once started, they

follow the implemented logic and finish with prediction. The general differences between the two type of

workflows are represented on the next slide.

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Data Gap FillingOverview

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Data Gap FillingOverview

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AW SW

Databases with data for the target

endpoint are listed and user select

to use all of them or make specific

selection

Input

Profiling

Data

Category definition

Data gap filling

Report

Relevant to the workflow profilers

appropriate for DGF are listed and

ordered hierarchically based on the

population of the group and user is

able to select any of them

Additional data filtering could be

applied (e.g. different species

selection)

Same components as

defined in the AW

are used in the SW

The SW pauses at each

of the stages and user is

able to make different

selection than those

implemented in the AW

Input

Profiling

Data

Category definition

Data gap filling

STOP

STOP

Report

STOP

In this example, we will use the Automated workflow approach.

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Data Gap FillingApply Automated workflow

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1.Go to Data Gap Filling; 2. Click on Automated button;3. Select Skin sensitization; 4. Confirm with OK

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1. Select the first combined endpoint – EC3 from LLNA and SMWN from GPMTassays; 2. Confirm with OK

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Data Gap FillingApply Automated workflow

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There are three options for selection of endpoint and user should select one ofthem. The first option allows more analogues to be found because of the using oftwo types of data – EC3 and SMWN. During the workflow process all data of theseendpoints will be converted to the default scale for Skin Sensitisation - “SkinSensitisation ECETOC”. It converts all skin data into: Positive and Negative.

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Data Gap FillingApply Automated workflow

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Once the workflow is started, the Workflow controller appears. It has two main

buttons Continue/Pause (1) allowing to continue or pause and Stop (2) – which

will stop the workflow. Additionally, all actions that will be done during the

execution of the workflow are tracked down and could be seen from the Show

activity log part (3) of the Workflow controller.

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Data Gap FillingAlgorithm of Skin sensitization workflow

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Skin sensitization and Skin sensitization ECETOC databases are selected.The workflow continues with application of the relevant profilers. Thereare three possible cases to form an analogues set:

1) if the target have an active alert as a parent;2) if the target have an active alert as a result of autoxidation

or skin metabolism activation;3) if no alert is found in the target or its metabolites.

If a protein binding alert is identified in the target or is produced as aresult of autoxidation or skin metabolism (case 1 or 2) then primarygrouping is based on this alert.In the last case (case 3) the primary group is defined using structurallybased profiling schemes.

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Data Gap FillingScenario 1 – an alert is identified in the parent or produced as a result of

autoxidation or skin metabolism activation

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Data Gap FillingScenario 2 – no alert is identified in the parent neither in generated

metabolites (autoxidation products and skin metabolites)

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Data Gap FillingApply Automated workflow

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During the process, the user can see so called “Helpers” (1). This is a new functionality intended

to help the user with specific information associated with analogues used in gap filling approach.

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Data Gap FillingInformation messages and functionalities

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The helpers provide different type of information, e.g.:

• warning messages, alerting the user:

- for qualifiers availability

- for analogue(s) with composition

• notification messages:

- if the read-across prediction is obtained by more analogues thanthe default 5. This could be due to chemicals with equal descriptorvalues (logKow values)

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Functionality used to follow the progress of the active action or to cancel

an active action when an Automated workflow is run.

• To see the progress of the active action click on the clock (1)

• To cancel an active action click on Stop button (2)

Data Gap FillingInformation messages and functionalities

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Data Gap FillingApply Automated workflow

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The automated workflows follow the implemented logic in them and finish

with accepted prediction.

When the prediction is accepted successfully, it appears on the matrix (1). In this case the predicted

result (R:) corresponds to the experimental data (M:). Click on “OK” (2)

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Data Gap FillingApply Automated workflow

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The Workflow Controller does not close itself automatically. The user can expand the activity

log (1) and to examine all performed steps during the Automated workflow execution. After that

the controller have to be closed by click on the close button (2).

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Data Gap FillingApply Automated workflow

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The new organization of the Toolbox allows the Documents panel (1) to beconsistent in each of the toolbar sections. This gives the possibility to the userto go back/forward through the subcategorization steps by moving up/down tothe document tree. In this way the user can follow each step of the executedautomated workflow.

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Data Gap FillingApply Automated workflow

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Double click on the cell with the prediction (1) opens the Data points window. Here the user can see

more information for their prediction. It is seen that only EC3 data is used for the prediction (2) and

the prediction approach is read across executed by AW “Skin sensitization”.

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Data Gap FillingRecap

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The application of the automated workflow aims to facilitate the Toolbox

user`s work limiting their activities. The AW for SS requires only user

activities such as:

specification of the endpoint

Page 37: OECD QSAR Toolbox v.4...Background • Objectives • Specific Aims • Automated workflow • The exercise • Execution of AW for Skin sensitization Outlook The OECD QSAR Toolbox

• Background

• Objectives

• Specific Aims

• Automated workflow

• The exercise

• Execution of AW for Skin sensitization– Example 1

o Input

o Data Gap Filling

o Report

Outlook

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• Report module could generate report on any of predictionsperformed with the Toolbox.

• Report module contains predefined report template which userscan customized.

• Two type of report files are generated:

- Prediction report – containing information for the target

- Data matrix – containing information for the analogues used forthe prediction.

ReportOverview

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ReportGeneration report

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1. Go to the Report modul; 2. Click on the cell with the prediction;3. Click on Create

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40The OECD QSAR Toolbox for Grouping Chemicals into Categories April, 2017

The user can customize the report content (1) and appearance (2). Generationof the reports happens by click on the Create report button (3).

ReportGeneration report

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ReportWizard pages

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• Customized report - the user is able to include or exclude the sections inthe report.

• Target and prediction summary – This section includes substance ID ofthe target chemical and the prediction outcome. Fields which areautomatically populated by the system are indicated. Here the user couldadd information for the author, contact details and summary information

• Prediction details and Prediction details (II) – section predictiondetails provides details about the prediction and its reliability. Predictiondetails (II) is optional it provides specific information about the predictiondepending on the gap filling approach.

• Target profiles – this section summarize profiles used for the prediction.Additional profiles could be also included by the user.

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ReportWizard pages

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• Analogues selection details – This section illustrates how analogues wereselected. It displays selected databases, category boundaries andapplicability domain.

• Data for analogues – This section provides details information about theanalogues used for obtaining the prediction including parameters, profilersand experimental data. Additional data, available for the used analogues intoToolbox, could be also included by the user.

• Appendix: Grouping / subcategorization– This section includes thecategories used for primary categorization as well as the categories andmetadata removed during the subcategorization automatically populated bythe system.

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ReportGeneration report

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After the click on the Create report button, Generated report files windowappears. It contains two type of files:1) Prediction report - a PDF file containing the prediction information

related to the target.2) Data matrix - a MS Excel file containing chemicals used for

prediction along with their data for selected parameters, profiles andendpoint tree positions.

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Using of an automated workflow forpredicting of skin sensitization potentialis noted in the Prediction report.

ReportGenerated report files

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45The OECD QSAR Toolbox for Grouping Chemicals into Categories April, 2017

Analogues used for the target prediction can be seen the Data matrixreport. Their selected profiling results, experimental data and/orparameters are also shown.

ReportGenerated report files

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• Background

• Objectives

• Specific Aims

• Automated workflow

• The exercise

• Execution of AW for Skin sensitization– Example 2

o Input

Outlook

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InputWays of Entering a Chemical List

• Database

• Inventory

• List: Last used files/ From examples folder

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1. Click on Database;2. Select Skin sensitization ECETOC; 3. Click on OK.

Input ScreenInput database

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Input ScreenInput database

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All chemicals of the selected databaseare loaded on the data matrix.Skin sensitization ECETOC databaseconsists of 39 compounds.

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• Background

• Objectives

• Specific Aims

• Automated workflow for

• The exercise

• Execution of AW for Skin sensitization– Example 2

o Input

o Data Gap Filling

Outlook

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Data Gap FillingApply Automated workflow

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1.Go to Data Gap Filling; 2. Click on Automated button;3. Select Skin sensitization; 4. Confirm with OK

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1. Select the first combined endpoint – EC3 from LLNA and SMWN from GPMTassays; 2. Confirm with OK

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Data Gap FillingApply Automated workflow

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Data Gap FillingApply Automated workflow

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When the preferred endpoint is selected, a new dialog relatedto the application range of the workflow appears.

The user can define the exact range of chemicals, on which theautomated workflow will be executed. The numbering ofchemicals corresponds to their number on the data matrix.

The whole range is set as default.

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Data Gap FillingApply Automated workflow

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Data Gap FillingApply Automated workflow

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1. Select to execute the automated workflow for the first five chemicals;2. Confirm with OK

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Data Gap FillingApply Automated workflow

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All chemicals in the selected range are predicted automaticallyin a row. The user can see the number of the running chemicalout of all chemicals for prediction (1).

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Data Gap FillingApply Automated workflow

April, 2017

• The workflow in a batch mode finishes when automatedworkflow is executed for each of the chemicals in thepreviously selected range.

• No messages for the individual predictions appear during theworkflow.

• In some cases following the implemented logic in theworkflow, no analogues are found or they are removed duringthe subcategorization process. Then the prediction resultlacks (see on the next slide).

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The OECD QSAR Toolbox for Grouping Chemicals into Categories 58

Data Gap FillingApply Automated workflow

April, 2017

There is no prediction

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The OECD QSAR Toolbox for Grouping Chemicals into Categories 59

Data Gap FillingApply Automated workflow

April, 2017

If automated workflow in single mode is executed for such kind ofchemicals, message proposing to try the standardized workflow appears.

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• Background

• Objectives

• Specific Aims

• Automated workflow

• The exercise

• Execution of AW for Skin sensitization– Example 2

o Input

o Data Gap Filling

o Report

Outlook

The OECD QSAR Toolbox for Grouping Chemicals into Categories 60April, 2017

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The OECD QSAR Toolbox for Grouping Chemicals into Categories 61

ReportGeneration report

April, 2017

Prediction report and Data matrix report can be generatedfor each of the predictions.

It is necessary just to be positioned on the cell with thedesired prediction and then click on the Create button.

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The OECD QSAR Toolbox for Grouping Chemicals into Categories 62

ReportGeneration report

April, 2017

1. Click on the prediction for 3rd chemical2. Click on Create

2

1

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63The OECD QSAR Toolbox for Grouping Chemicals into Categories April, 2017

ReportGenerated report files

Prediction report

Data matrix report

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• You have completed the tutorial on the automated workflow forskin sensitization data gap filling.

• You have been introduced to the automated workflow in asingle and in a batch mode.

• You have now been introduced to the consecutive steps of theAW for SS and the rationale behind each step.

• Note proficiency comes with practice.

The OECD QSAR Toolbox for Grouping Chemicals into Categories 64

Congratulation

April, 2017