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Maximizing their impact requires strategies that improve the reach of health screening in order to establish who could benefit. For example, HIV prevention strategies aim to expand risk screening and to improve uptake of pre\u2010exposure prophylaxis (PrEP) among those experiencing risk. Often, these strategies induce changes at the group\u2010level (e.g., health clinics or communities) and are evaluated through cluster randomized trials. This scenario creates a complex, multilevel\u2010mediation\u2010missing data problem for the following reasons: First, the strategy is delivered at the cluster\u2010level, while health screening and outcomes are at the individual\u2010level. Second, the strategy improves health outcomes directly and indirectly through improved health screening. Third, everyone has an \u201cunderlying\u201d status, which is only observed among those screened. To formally define the total effect in such settings, we use Counterfactual Strata Effects: causal estimands where the outcome is only relevant for a group whose membership is subject to missingness and\/or impacted by the exposure of interest. To identify and estimate the corresponding statistical estimand, we propose a novel extension of Two\u2010Stage targeted minimum loss\u2010based estimation (TMLE). Simulations demonstrate the practical performance of our approach as well as the limitations of existing approaches.<\/jats:p>","DOI":"10.1002\/sim.70648","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T14:39:41Z","timestamp":1782484781000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Causal Framework for Evaluating the Total Effect of Strategies Aiming to Expand Screening and to Improve Outcomes"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8193-4989","authenticated-orcid":false,"given":"Joy Z.","family":"Nakato","sequence":"first","affiliation":[{"name":"Division of Biostatistics University of California  Berkeley CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice","family":"Litunya","sequence":"additional","affiliation":[{"name":"Kenya Medical Research Institute (KEMRI)  Kisumu Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Beesiga","sequence":"additional","affiliation":[{"name":"Infectious Disease Research Collaboration (IDRC)  Kampala Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Kabami","sequence":"additional","affiliation":[{"name":"Infectious Disease Research Collaboration (IDRC)  Kampala Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0324-4006","authenticated-orcid":false,"given":"James","family":"Ayieko","sequence":"additional","affiliation":[{"name":"Kenya Medical Research Institute (KEMRI)  Kisumu Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moses R.","family":"Kamya","sequence":"additional","affiliation":[{"name":"Infectious Disease Research Collaboration (IDRC)  Kampala Uganda"},{"name":"Department of Medicine Makerere University  Kampala Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5860-8081","authenticated-orcid":false,"given":"Gabriel","family":"Chamie","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases &amp; Global Medicine University of California  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3730-410X","authenticated-orcid":false,"given":"Laura B.","family":"Balzer","sequence":"additional","affiliation":[{"name":"Division of Biostatistics University of California  Berkeley CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"e_1_2_12_2_1","unstructured":"UNAIDS \u201cThe Urgency of Now: AIDS at A Crossroads \u2014 Global AIDS Report (2024) \u201dhttps:\/\/www.unaids.org\/en\/resources\/documents\/2024\/global\u2010aids\u2010update\u20102024."},{"key":"e_1_2_12_3_1","unstructured":"UNAIDS \u201cCreating HIV Prevention Cascades: Operational Guidance on A Tool for Monitoring Programmes (2021) accessed January 23 2025 \u201dhttps:\/\/www.unaids.org\/sites\/default\/files\/media_asset\/JC3038_creating\u2010hiv\u2010prevention\u2010cascades_en.pdf."},{"key":"e_1_2_12_4_1","unstructured":"UNAIDS \u201cThe HIV Test\u2010and\u2010Treat Cascade\u00a0\u2013\u00a0AIDS \u201d (Technical report 2020) https:\/\/aids2020.unaids.org\/chapter\/chapter\u20102\u20102020\u2010commitments\/the\u2010hiv\u2010test\u2010and\u2010treat\u2010cascade\/."},{"key":"e_1_2_12_5_1","unstructured":"UNAIDS \u201cAIDS Crisis and the Power to Transform: UNAIDS Global AIDS Update (2025) Licence: CC BY\u2010NC\u2010SA 3.0 IGO \u201dhttps:\/\/www.unaids.org\/en\/resources\/documents\/2025\/2025\u2010global\u2010aids\u2010update."},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjgh\u20102020\u2010004574"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jia2.26195"},{"key":"e_1_2_12_8_1","doi-asserted-by":"crossref","unstructured":"M.Hickey A.Owaraganise S.Ogachi et al. \u201cCommunity Health Worker\u2010Facilitated Telehealth for Severe Hypertension Care in Kenya and Uganda (2025) \u201dhttps:\/\/www.croiconference.org\/abstract\/community\u2010health\u2010worker\u2010facilitated\u2010telehealth\u2010for\u2010severe\u2010hypertension\u2010care\u2010in\u2010kenya\u2010and\u2010uganda\/.","DOI":"10.1371\/journal.pmed.1004632"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jia2.26131"},{"key":"e_1_2_12_10_1","doi-asserted-by":"crossref","unstructured":"J.Kabami L. 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