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<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">JDS1227</article-id>
<article-id pub-id-type="doi">10.6339/26-JDS1227</article-id>
<article-categories><subj-group subj-group-type="heading">
<subject>Statistical Data Science</subject></subj-group></article-categories>
<title-group>
<article-title>Quantifying Direct and Indirect Effects Through Joint Modeling of Terminal Events and Gap Times Between Recurrent Events</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>Niu</surname><given-names>Fang</given-names></name><xref ref-type="aff" rid="j_jds1227_aff_001">1</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-6562-870X</contrib-id>
<name><surname>Zheng</surname><given-names>Cheng</given-names></name><email xlink:href="mailto:cheng.zheng@unmc.edu">cheng.zheng@unmc.edu</email><xref ref-type="aff" rid="j_jds1227_aff_001">1</xref><xref ref-type="corresp" rid="cor1">∗</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Liu</surname><given-names>Lei</given-names></name><xref ref-type="aff" rid="j_jds1227_aff_002">2</xref>
</contrib>
<aff id="j_jds1227_aff_001"><label>1</label>Department of Biostatistics, <institution>University of Nebraska Medical Center</institution>, <country>Omaha, Nebraska, U.S.A.</country></aff>
<aff id="j_jds1227_aff_002"><label>2</label>Division of Biostatistics, <institution>Washington University in St. Louis</institution>, <country>St. Louis, Missouri, U.S.A.</country></aff>
</contrib-group>
<author-notes>
<corresp id="cor1"><label>∗</label>Corresponding author. Email: <ext-link ext-link-type="uri" xlink:href="mailto:cheng.zheng@unmc.edu">cheng.zheng@unmc.edu</ext-link>.</corresp>
</author-notes>
<pub-date pub-type="ppub"><year>2026</year></pub-date><pub-date pub-type="epub"><day>1</day><month>4</month><year>2026</year></pub-date><volume content-type="ahead-of-print">0</volume><issue>0</issue><fpage>1</fpage><lpage>17</lpage><supplementary-material id="S1" content-type="archive" xlink:href="jds1227_s001.zip" mimetype="application" mime-subtype="x-zip-compressed">
<caption>
<title>Supplementary Material</title>
<p>Supplementary Material Sections I-IV mentioned in the main text are provided as a pdf supplement file. Data supporting the findings of this paper can be requested as described in the data availability statement on page 5 of the Supplementary Material. The SAS and R codes for the simulation and data analysis of this paper are available at <uri>https://github.com/nfang-cloud/Joint_Model_Gap_Time</uri>.</p>
</caption>
</supplementary-material><history><date date-type="received"><day>24</day><month>7</month><year>2025</year></date><date date-type="accepted"><day>3</day><month>3</month><year>2026</year></date></history>
<permissions><copyright-statement>2026 The Author(s). Published by the School of Statistics and the Center for Applied Statistics, Renmin University of China.</copyright-statement><copyright-year>2026</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>Joint models can describe the relationship between recurrent and terminal events. Typically, recurrent events are modeled using the total time scale, assuming constant covariate effects on each recurrent event. However, modeling the gap time between recurrent events could allow varying covariate effects and offer greater flexibility and accuracy. For instance, in HIV-infected patients, the intervals between the first occurrence of opportunistic infections (OIs) may follow a different distribution compared to later OIs. However, limited research has focused on mediation analysis using joint modeling of gap times and survival time. In this work, we propose a novel joint modeling approach that studies the mediation effect of recurrent events on survival outcomes by modeling the recurrent events by gap time. This allows us to handle cases where the first occurrence of a recurrent event behaves differently from subsequent events. Additionally, we use a relaxed “sequential ignorability” assumption to address unmeasured confounding. Simulation studies demonstrate that our model performs well in estimating both model parameters and mediation effects. We apply our method to an AIDS study to evaluate the comparative effectiveness of two treatments and the effect of baseline CD4 counts on overall survival, mediated by recurrent opportunistic infections modeled through gap times.</p>
</abstract>
<kwd-group>
<label>Keywords</label>
<kwd>causal inference</kwd>
<kwd>frailty model</kwd>
<kwd>mediation analysis</kwd>
<kwd>survival data</kwd>
</kwd-group>
<funding-group><funding-statement>This research is partly supported by the National Institute of General Medical Sciences under grant U54 GM115458, the National Heart, Lung, and Blood Institute under grant R01 HL136942, the National Institute on Aging grant R21 AG063370, R01 AG081244, and Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS). This work was completed utilizing the Holland Computing Center of the University of Nebraska, which receives support from the UNL Office of Research and Innovation, and the Nebraska Research Initiative.</funding-statement></funding-group>
</article-meta>
</front>
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