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<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" article-type="research-article">
<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">JDS</journal-id>
<journal-title-group><journal-title>Journal of Data Science</journal-title></journal-title-group>
<issn pub-type="epub">1683-8602</issn><issn pub-type="ppub">1680-743X</issn><issn-l>1680-743X</issn-l>
<publisher>
<publisher-name>School of Statistics, Renmin University of China</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="publisher-id">JDS1107</article-id>
<article-id pub-id-type="doi">10.6339/23-JDS1107</article-id>
<article-categories><subj-group subj-group-type="heading">
<subject>Statistical Data Science</subject></subj-group></article-categories>
<title-group>
<article-title>Identification of Optimal Combined Moderators for Time to Relapse</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>Wang</surname><given-names>Bang</given-names></name><xref ref-type="aff" rid="j_jds1107_aff_001">1</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-4805-203X</contrib-id>
<name><surname>Cheng</surname><given-names>Yu</given-names></name><email xlink:href="mailto:yucheng@pitt.edu">yucheng@pitt.edu</email><xref ref-type="aff" rid="j_jds1107_aff_001">1</xref><xref ref-type="aff" rid="j_jds1107_aff_002">2</xref><xref ref-type="corresp" rid="cor1">∗</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Levine</surname><given-names>Michele D.</given-names></name><xref ref-type="aff" rid="j_jds1107_aff_003">3</xref>
</contrib>
<aff id="j_jds1107_aff_001"><label>1</label>Department of Statistics, <institution>University of Pittsburgh</institution>, Pittsburgh, PA, 15213, <country>USA</country></aff>
<aff id="j_jds1107_aff_002"><label>2</label>Department of Biostatistics, <institution>University of Pittsburgh</institution>, Pittsburgh, PA, 15213, <country>USA</country></aff>
<aff id="j_jds1107_aff_003"><label>3</label>Department of Psychiatry, <institution>University of Pittsburgh</institution>, Pittsburgh, PA, 15213, <country>USA</country></aff>
</contrib-group>
<author-notes>
<corresp id="cor1"><label>∗</label>Corresponding author. Email: <ext-link ext-link-type="uri" xlink:href="mailto:yucheng@pitt.edu">yucheng@pitt.edu</ext-link>.</corresp>
</author-notes>
<pub-date pub-type="ppub"><year>2024</year></pub-date><pub-date pub-type="epub"><day>23</day><month>6</month><year>2023</year></pub-date><volume>22</volume><issue>4</issue><fpage>469</fpage><lpage>485</lpage><supplementary-material id="S1" content-type="archive" xlink:href="jds1107_s001.zip" mimetype="application" mime-subtype="x-zip-compressed">
<caption>
<title>Supplementary Material</title>
<p>Some additional simulation results and a compressed folder with the code to simulate the settings with 5 moderators (5M), implement our proposed methods, and some existing methods are provided as the online Supplementary Material.</p>
</caption>
</supplementary-material><history><date date-type="received"><day>28</day><month>8</month><year>2022</year></date><date date-type="accepted"><day>29</day><month>5</month><year>2023</year></date></history>
<permissions><copyright-statement>2024 The Author(s). Published by the School of Statistics and the Center for Applied Statistics, Renmin University of China.</copyright-statement><copyright-year>2024</copyright-year>
<license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/">
<license-p>Open access article under the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">CC BY</ext-link> license.</license-p></license></permissions>
<abstract>
<p>Identifying treatment effect modifiers (i.e., moderators) plays an essential role in improving treatment efficacy when substantial treatment heterogeneity exists. However, studies are often underpowered for detecting treatment effect modifiers, and exploratory analyses that examine one moderator per statistical model often yield spurious interactions. Therefore, in this work, we focus on creating an intuitive and readily implementable framework to facilitate the discovery of treatment effect modifiers and to make treatment recommendations for time-to-event outcomes. To minimize the impact of a misspecified main effect and avoid complex modeling, we construct the framework by matching the treated with the controls and modeling the conditional average treatment effect via regressing the difference in the observed outcomes of a matched pair on the averaged moderators. Inverse-probability-of-censoring weighting is used to handle censored observations. As matching is the foundation of the proposed methods, we explore different matching metrics and recommend the use of Mahalanobis distance when both continuous and categorical moderators are present. After matching, the proposed framework can be flexibly combined with popular variable selection and prediction methods such as linear regression, least absolute shrinkage and selection operator (Lasso), and random forest to create different combinations of potential moderators. The optimal combination is determined by the out-of-bag prediction error and the area under the receiver operating characteristic curve in making correct treatment recommendations. We compare the performance of various combined moderators through extensive simulations and the analysis of real trial data. Our approach can be easily implemented using existing R packages, resulting in a straightforward optimal combined moderator to make treatment recommendations.</p>
</abstract>
<kwd-group>
<label>Keywords</label>
<kwd>counterfactual outcomes</kwd>
<kwd>matched pair</kwd>
<kwd>personalized medicine</kwd>
<kwd>smoking cessation</kwd>
</kwd-group>
<funding-group><award-group><funding-source xlink:href="https://doi.org/10.13039/100000001">National Science Foundation Division of Mathematical Sciences</funding-source></award-group><award-group><funding-source xlink:href="https://doi.org/10.13039/100016300">University of Pittsburgh Center for Research Computing</funding-source><award-id>RRID:SCR-022735</award-id></award-group><funding-statement>This work was partially supported by the National Science Foundation Division of Mathematical Sciences (1916001 to Y.C.) and by the University of Pittsburgh Center for Research Computing, RRID:SCR-022735, through the resources provided. Specifically, this work used the H2P cluster, which is supported by NSF award number OAC-2117681. </funding-statement></funding-group>
</article-meta>
</front>
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