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<h1>In silico methods for toxicity prediction</h1>
<h2>2012-10-04 <em>in silico</em> toxicology gmbh</h2>
</div>
</div>
<div class="presentation">
<div class="slide" id="slide0">
<h1 class="title">In silico methods for toxicity prediction</h1>
<table class="docinfo" frame="void" rules="none">
<col class="docinfo-name" />
<col class="docinfo-content" />
<tbody valign="top">
<tr><th class="docinfo-name">Author:</th>
<td>Christoph Helma</td></tr>
<tr class="field"><th class="docinfo-name">Affiliation:</th><td class="field-body">in silico toxicology gmbh</td>
</tr>
<tr><th class="docinfo-name">Date:</th>
<td>2012-10-04</td></tr>
</tbody>
</table>
</div>
<div class="slide" id="outline">
<h1>Outline</h1>
<ul class="incremental simple">
<li>In silico toxicology methods</li>
<li>Lazar framework</li>
<li>Products and services</li>
</ul>
</div>
<div class="slide" id="in-silico-methods">
<h1>In silico methods</h1>
<ul class="incremental simple">
<li>Systems biology/molecular modeling</li>
<li>Expert systems</li>
<li>Data driven techniques</li>
</ul>
</div>
<div class="slide" id="systems-biology-molecular-modeling">
<h1>Systems biology/molecular modeling</h1>
<p>Model individual events (e.g. receptor interactions, (de)toxification) of the <em>adverse outcome pathway</em></p>
<ul class="incremental small green simple">
<li>Mechanistic interpretation</li>
</ul>
<ul class="incremental small red simple">
<li>Calculations/simulations may be very time consuming</li>
<li>May require a lot of experimental data for parameterization</li>
<li>Impossible to model mechanisms of complex toxicological endpoints</li>
</ul>
<p>Examples: VirtualToxLab/Biograf</p>
</div>
<div class="slide" id="expert-systems">
<h1>Expert systems</h1>
<p>Formalize expert knowledge about chemicals and toxicity mechanisms and create a software program</p>
<ul class="incremental small green simple">
<li>Mechanistic interpretation</li>
</ul>
<ul class="incremental small red simple">
<li>Model creation very time consuming</li>
<li>Many toxicity mechanisms are poorly understood or even unknown</li>
<li>Error prone and hard to validate (strong tendency towards overfitting)</li>
</ul>
<p>Examples: Derek/Lhasa</p>
</div>
<div class="slide" id="data-driven">
<h1>Data driven</h1>
<p>Use all existing data for a particular endpoint and apply machine learning/QSAR algorithms in order to create a prediction model</p>
<ul class="incremental small green simple">
<li>Comparably fast</li>
<li>Applicable for every endpoint with sufficient experimental data</li>
<li>Sound validation possible</li>
</ul>
<ul class="incremental small red simple">
<li>Applicability domain/model quality depends on experimental data</li>
<li>Mechanistic relevance has to be extracted from models/descriptors/predictions</li>
</ul>
<p>Examples: Classical QSARs, Topkat, Multicase, lazar</p>
</div>
<div class="slide" id="lazy-structure-activity-relationships-lazar">
<h1>Lazy-Structure-Activity Relationships (lazar)</h1>
<p>Automated read across predictions</p>
<ul class="incremental small simple">
<li>Find <em>similar</em> compounds (=neighbors) with measured activities</li>
<li>Create a local (Q)SAR model with neighbors as training compounds</li>
<li>Make a prediction with this model</li>
</ul>
<p class="incremental">Lazar estimates the confidence (<em>applicability domain</em>) for each prediction</p>
</div>
<div class="slide" id="chemical-similarity">
<h1>Chemical Similarity</h1>
<p>Can be based on</p>
<ul class="incremental simple">
<li>Chemical structures</li>
<li>Chemical properties</li>
<li>Biological properties</li>
<li>...</li>
</ul>
<p class="incremental">Lazar uses <em>activity specific similarities</em></p>
</div>
<div class="slide" id="activity-specific-similarities">
<h1>Activity specific similarities</h1>
<p>Consider only <em>relevant</em> (i.e. statistically significant) substructures, properties, ... for similarity calculations</p>
<p>Algorithms for finding relevant substructures (by A. Maunz):</p>
<ul class="simple">
<li>Backbone refinement classes (BBRC)</li>
<li>Latent structure mining (LAST)</li>
</ul>
</div>
<div class="slide" id="http-lazar-in-silico-ch">
<h1><a class="reference external" href="http://lazar.in-silico.ch">http://lazar.in-silico.ch</a></h1>
<img alt="lazar-input.png" class="align-center" src="lazar-input.png" style="height: 13em;" />
</div>
<div class="slide" id="id1">
<h1><a class="reference external" href="http://lazar.in-silico.ch">http://lazar.in-silico.ch</a></h1>
<img alt="lazar-output1.png" class="align-center" src="lazar-output1.png" style="height: 13em;" />
</div>
<div class="slide" id="id2">
<h1><a class="reference external" href="http://lazar.in-silico.ch">http://lazar.in-silico.ch</a></h1>
<img alt="lazar-output2.png" class="align-center" src="lazar-output2.png" style="height: 13em;" />
</div>
<div class="slide" id="id3">
<h1><a class="reference external" href="http://lazar.in-silico.ch">http://lazar.in-silico.ch</a></h1>
<img alt="lazar-output3.png" class="align-center" src="lazar-output3.png" style="height: 13em;" />
</div>
<div class="slide" id="lazar-limitations">
<h1>Lazar limitations</h1>
<ul class="incremental simple">
<li>Model quality depends on data quality</li>
<li>Applicability domain depends on learning instances</li>
</ul>
</div>
<div class="slide" id="in-silico-toxicology-gmbh">
<h1>in silico toxicology gmbh</h1>
<p>Open source software and algorithm development</p>
<ul class="incremental simple">
<li>Predictive toxicology and QSAR models</li>
<li>Toxicological data mining</li>
<li>Life science webservices and data warehouses</li>
</ul>
</div>
<div class="slide" id="why-open-source">
<h1>Why open source?</h1>
<ul class="incremental simple">
<li>Clear and unambiguous documentation of implemented algorithms essential for scientific software (also required by many regulatory guidelines)</li>
<li>Collaboration with partners, projects and external contributors</li>
<li>Establishment of international standards</li>
<li>Security of investment</li>
</ul>
</div>
<div class="slide" id="eu-research-projects-fp6-7">
<h1>EU Research projects (FP6/7)</h1>
<table class="small docutils field-list" frame="void" rules="none">
<col class="field-name" />
<col class="field-body" />
<tbody valign="top">
<tr class="field"><th class="field-name">Sens-it-iv:</th><td class="field-body">Novel testing strategies for in vitro assessment of allergens</td>
</tr>
<tr class="field"><th class="field-name">Scarlet:</th><td class="field-body">Network on in silico methods for carcinogenicity and mutagenicity</td>
</tr>
<tr class="field"><th class="field-name">OpenTox:</th><td class="field-body">Open source framework for predictive toxicology</td>
</tr>
<tr class="field"><th class="field-name">ToxBank:</th><td class="field-body">Integrated data analysis and servicing of alternative testing methods in toxicology</td>
</tr>
<tr class="field"><th class="field-name">ModNanoTox:</th><td class="field-body">Modelling toxicity behaviour of engineered nanoparticles</td>
</tr>
</tbody>
</table>
</div>
<div class="slide" id="free-products-and-services">
<h1>Free products and services</h1>
<table class="docutils field-list" frame="void" rules="none">
<col class="field-name" />
<col class="field-body" />
<tbody valign="top">
<tr class="field"><th class="field-name" colspan="2">Lazar application:</th></tr>
<tr class="field"><td> </td><td class="field-body"><a class="reference external" href="http://lazar.in-silico.ch">http://lazar.in-silico.ch</a></td>
</tr>
<tr class="field"><th class="field-name" colspan="2">OpenTox Webservices:</th></tr>
<tr class="field"><td> </td><td class="field-body"><a class="reference external" href="http://webservices.in-silico.ch">http://webservices.in-silico.ch</a></td>
</tr>
<tr class="field"><th class="field-name">Source code:</th><td class="field-body"><a class="reference external" href="https://github.com/opentox">https://github.com/opentox</a></td>
</tr>
</tbody>
</table>
<p>Issue tracker, documentation, ...</p>
</div>
<div class="slide" id="commercial-products-and-services">
<h1>Commercial products and services</h1>
<ul class="incremental simple">
<li>Lazar "software as a service" (SaaS): secure access for confidential predictions, batch predictions, ...</li>
<li>Virtual appliances with lazar software for in-house/desktop installation</li>
<li>Installation services</li>
<li>Phone and email support</li>
</ul>
</div>
<div class="slide" id="id4">
<h1>Commercial products and services</h1>
<ul class="incremental simple">
<li>Virtual toxicity screening of compounds and libraries</li>
<li>Development of prediction models for new endpoints</li>
<li>Scientific programming, contract research and consulting</li>
</ul>
</div>
<div class="slide" id="contact">
<h1>Contact</h1>
<table class="docutils field-list" frame="void" rules="none">
<col class="field-name" />
<col class="field-body" />
<tbody valign="top">
<tr class="field"><th class="field-name">Web:</th><td class="field-body"><a class="reference external" href="http://www.in-silico.ch">http://www.in-silico.ch</a></td>
</tr>
<tr class="field"><th class="field-name">Email:</th><td class="field-body"><a class="reference external" href="mailto:helma@in-silico.ch">helma@in-silico.ch</a></td>
</tr>
</tbody>
</table>
</div>
</div>
</body>
</html>
|
