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<title>Targeted Learning with Moderated Statistics for Biomarker Discovery • biotmle</title>
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<meta property="og:description" content="Tools for differential expression biomarker discovery based on
microarray and next-generation sequencing data that leverage efficient
semiparametric estimators of the average treatment effect for variable
importance analysis. Estimation and inference of the (marginal) average
treatment effects of potential biomarkers are computed by targeted minimum
loss-based estimation, with joint, stable inference constructed across all
biomarkers using a generalization of moderated statistics for use with the
estimated efficient influence function. The procedure accommodates the use
of ensemble machine learning for the estimation of nuisance functions.">
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<div id="rbiotmle" class="section level1">
<div class="page-header"><h1 class="hasAnchor">
<a href="#rbiotmle" class="anchor"></a>R/<code>biotmle</code>
</h1></div>
<blockquote>
<p>Targeted Learning with Moderated Statistics for Biomarker Discovery</p>
</blockquote>
<p><strong>Authors:</strong> <a href="https://nimahejazi.org">Nima Hejazi</a>, <a href="https://vanderlaan-lab.org/about">Mark van der Laan</a>, and <a href="https://hubbard.berkeley.edu">Alan Hubbard</a></p>
<hr>
<div id="whats-biotmle" class="section level2">
<h2 class="hasAnchor">
<a href="#whats-biotmle" class="anchor"></a>What’s <code>biotmle</code>?</h2>
<p>The <code>biotmle</code> R package facilitates biomarker discovery through a generalization of the moderated t-statistic (Smyth 2004) that extends the procedure to locally efficient estimators of asymptotically linear target parameters (Tsiatis 2007). The set of methods implemented modify targeted maximum likelihood (TML) estimators of statistical (or causal) target parameters (e.g., average treatment effect) to apply variance moderation to the standard variance estimator based on the efficient influence function (EIF) of the target parameter (van der Laan and Rose 2011, 2018). By performing a moderated hypothesis test that pools the individual probe-specific EIF-based variance estimates, a robust variance estimator is constructed, which stabilizes the standard error estimates and improves the performance of such estimators both in smaller samples and in settings where the EIF is poorly estimated. The resultant procedure allows for the construction of conservative hypothesis tests that reduce the false discovery rate and/or the family-wise error rate (Hejazi, van der Laan, and Hubbard 2021). Improvements upon prior TML-based approaches to biomarker discovery (e.g., Bembom et al. (2009)) include both the moderated variance estimator as well as the use of conservative reference distributions for the corresponding moderated test statistics (e.g., logistic distribution), inspired by tail bounds based on concentration inequalities (Rosenblum and van der Laan 2009); the latter prove critical for obtaining robust inference when the finite-sample distribution of the estimator deviates from normality.</p>
<hr>
</div>
<div id="installation" class="section level2">
<h2 class="hasAnchor">
<a href="#installation" class="anchor"></a>Installation</h2>
<p>For standard use, install from <a href="https://bioconductor.org/packages/biotmle">Bioconductor</a> using <a href="https://CRAN.R-project.org/package=BiocManager"><code>BiocManager</code></a>:</p>
<div class="sourceCode" id="cb1"><pre class="downlit sourceCode r">
<code class="sourceCode R"><span class="kw">if</span> <span class="op">(</span><span class="op">!</span><span class="fu"><a href="https://rdrr.io/r/base/ns-load.html">requireNamespace</a></span><span class="op">(</span><span class="st">"BiocManager"</span>, quietly<span class="op">=</span><span class="cn">TRUE</span><span class="op">)</span><span class="op">)</span> <span class="op">{</span>
<span class="fu"><a href="https://rdrr.io/r/utils/install.packages.html">install.packages</a></span><span class="op">(</span><span class="st">"BiocManager"</span><span class="op">)</span>
<span class="op">}</span>
<span class="fu">BiocManager</span><span class="fu">::</span><span class="fu"><a href="https://rdrr.io/pkg/BiocManager/man/install.html">install</a></span><span class="op">(</span><span class="st">"biotmle"</span><span class="op">)</span></code></pre></div>
<p>To contribute, install the bleeding-edge <em>development version</em> from GitHub via <a href="https://CRAN.R-project.org/package=remotes"><code>remotes</code></a>:</p>
<div class="sourceCode" id="cb2"><pre class="downlit sourceCode r">
<code class="sourceCode R"><span class="fu">remotes</span><span class="fu">::</span><span class="fu"><a href="https://remotes.r-lib.org/reference/install_github.html">install_github</a></span><span class="op">(</span><span class="st">"nhejazi/biotmle"</span><span class="op">)</span></code></pre></div>
<p>Current and prior <a href="https://bioconductor.org">Bioconductor</a> releases are available under branches with numbers prefixed by “RELEASE_”. For example, to install the version of this package available via Bioconductor 3.6, use</p>
<div class="sourceCode" id="cb3"><pre class="downlit sourceCode r">
<code class="sourceCode R"><span class="fu">remotes</span><span class="fu">::</span><span class="fu"><a href="https://remotes.r-lib.org/reference/install_github.html">install_github</a></span><span class="op">(</span><span class="st">"nhejazi/biotmle"</span>, ref <span class="op">=</span> <span class="st">"RELEASE_3_6"</span><span class="op">)</span></code></pre></div>
<hr>
</div>
<div id="example" class="section level2">
<h2 class="hasAnchor">
<a href="#example" class="anchor"></a>Example</h2>
<p>For details on how to best use the <code>biotmle</code> R package, please consult the most recent <a href="https://bioconductor.org/packages/release/bioc/vignettes/biotmle/inst/doc/exposureBiomarkers.html">package vignette</a> available through the <a href="https://bioconductor.org/packages/biotmle">Bioconductor project</a>.</p>
<hr>
</div>
<div id="issues" class="section level2">
<h2 class="hasAnchor">
<a href="#issues" class="anchor"></a>Issues</h2>
<p>If you encounter any bugs or have any specific feature requests, please <a href="https://github.com/nhejazi/biotmle/issues">file an issue</a>.</p>
<hr>
</div>
<div id="contributions" class="section level2">
<h2 class="hasAnchor">
<a href="#contributions" class="anchor"></a>Contributions</h2>
<p>Contributions are very welcome. Interested contributors should consult our <a href="https://github.com/nhejazi/biotmle/blob/master/CONTRIBUTING.md">contribution guidelines</a> prior to submitting a pull request.</p>
<hr>
</div>
<div id="citation" class="section level2">
<h2 class="hasAnchor">
<a href="#citation" class="anchor"></a>Citation</h2>
<p>After using the <code>biotmle</code> R package, please cite both of the following:</p>
<pre><code> @article{hejazi2017biotmle,
author = {Hejazi, Nima S and Cai, Weixin and Hubbard, Alan E},
title = {biotmle: Targeted Learning for Biomarker Discovery},
journal = {The Journal of Open Source Software},
volume = {2},
number = {15},
month = {July},
year = {2017},
publisher = {The Open Journal},
doi = {10.21105/joss.00295},
url = {https://doi.org/10.21105/joss.00295}
}
@article{hejazi2021generalization,
author = {Hejazi, Nima S and Boileau, Philippe and {van der Laan},
Mark J and Hubbard, Alan E},
title = {A generalization of moderated statistics to data adaptive
semiparametric estimation in high-dimensional biology},
journal={under review},
volume={},
number={},
pages={},
year = {2021+},
publisher={},
doi = {},
url = {https://arxiv.org/abs/1710.05451}
}
@manual{hejazi2019biotmlebioc,
author = {Hejazi, Nima S and {van der Laan}, Mark J and Hubbard, Alan
E},
title = {{biotmle}: {Targeted Learning} with moderated statistics for
biomarker discovery},
doi = {10.18129/B9.bioc.biotmle},
url = {https://bioconductor.org/packages/biotmle},
note = {R package version 1.10.0}
}</code></pre>
<hr>
</div>
<div id="related" class="section level2">
<h2 class="hasAnchor">
<a href="#related" class="anchor"></a>Related</h2>
<ul>
<li>
<a href="https://github.com/nhejazi/biotmleData">R/<code>biotmleData</code></a> - R package with example experimental data for use with this analysis package.</li>
</ul>
<hr>
</div>
<div id="funding" class="section level2">
<h2 class="hasAnchor">
<a href="#funding" class="anchor"></a>Funding</h2>
<p>The development of this software was supported in part through grants from the National Institutes of Health: <a href="https://projectreporter.nih.gov/project_info_details.cfm?aid=9260357&map=y">P42 ES004705-29</a> and <a href="https://projectreporter.nih.gov/project_info_description.cfm?aid=9210551&icde=37849782&ddparam=&ddvalue=&ddsub=&cr=1&csb=default&cs=ASC&pball=">R01 ES021369-05</a>.</p>
<hr>
</div>
<div id="license" class="section level2">
<h2 class="hasAnchor">
<a href="#license" class="anchor"></a>License</h2>
<p>© 2016-2021 <a href="https://nimahejazi.org">Nima S. Hejazi</a></p>
<p>The contents of this repository are distributed under the MIT license. See file <code>LICENSE</code> for details.</p>
<hr>
</div>
<div id="references" class="section level2">
<h2 class="hasAnchor">
<a href="#references" class="anchor"></a>References</h2>
<div id="refs" class="references">
<div id="ref-bembom2009biomarker">
<p>Bembom, Oliver, Maya L Petersen, Soo-Yon Rhee, W Jeffrey Fessel, Sandra E Sinisi, Robert W Shafer, and Mark J van der Laan. 2009. “Biomarker Discovery Using Targeted Maximum-Likelihood Estimation: Application to the Treatment of Antiretroviral-Resistant Hiv Infection.” <em>Statistics in Medicine</em> 28 (1): 152–72.</p>
</div>
<div id="ref-hejazi2021generalization">
<p>Hejazi, Nima S, Mark J van der Laan, and Alan E Hubbard. 2021. “A Generalization of Moderated Statistics to Data Adaptive Semiparametric Estimation in High-Dimensional Biology.” <em>Under Review</em>. <a href="https://arxiv.org/abs/1710.05451" class="uri">https://arxiv.org/abs/1710.05451</a>.</p>
</div>
<div id="ref-rosenblum2009confidence">
<p>Rosenblum, Michael A, and Mark J van der Laan. 2009. “Confidence Intervals for the Population Mean Tailored to Small Sample Sizes, with Applications to Survey Sampling.” <em>The International Journal of Biostatistics</em> 5 (1).</p>
</div>
<div id="ref-smyth2004linear">
<p>Smyth, Gordon K. 2004. “Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments.” <em>Statistical Applications in Genetics and Molecular Biology</em> 3 (1): 1–25. <a href="https://doi.org/10.2202/1544-6115.1027" class="uri">https://doi.org/10.2202/1544-6115.1027</a>.</p>
</div>
<div id="ref-tsiatis2007semiparametric">
<p>Tsiatis, Anastasios. 2007. <em>Semiparametric Theory and Missing Data</em>. Springer Science & Business Media.</p>
</div>
<div id="ref-vdl2011targeted">
<p>van der Laan, Mark J., and Sherri Rose. 2011. <em>Targeted Learning: Causal Inference for Observational and Experimental Data</em>. Springer Science & Business Media.</p>
</div>
<div id="ref-vdl2018targeted">
<p>van der Laan, Mark J, and Sherri Rose. 2018. <em>Targeted Learning in Data Science: Causal Inference for Complex Longitudinal Studies</em>. Springer Science & Business Media.</p>
</div>
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<li>Nima Hejazi <br><small class="roles"> Author, maintainer, copyright holder </small> <a href="https://orcid.org/0000-0002-7127-2789" target="orcid.widget" aria-label="ORCID"><span class="fab fa-orcid orcid" aria-hidden="true"></span></a> </li>
<li>Alan Hubbard <br><small class="roles"> Author, thesis advisor </small> <a href="https://orcid.org/0000-0002-3769-0127" target="orcid.widget" aria-label="ORCID"><span class="fab fa-orcid orcid" aria-hidden="true"></span></a> </li>
<li>Mark van der Laan <br><small class="roles"> Author, thesis advisor </small> <a href="https://orcid.org/0000-0003-1432-5511" target="orcid.widget" aria-label="ORCID"><span class="fab fa-orcid orcid" aria-hidden="true"></span></a> </li>
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