{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T08:15:58Z","timestamp":1776759358654,"version":"3.51.2"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["324730_149792"],"award-info":[{"award-number":["324730_149792"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["324730_149792"],"award-info":[{"award-number":["324730_149792"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med Res Methodol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>The ICH E9 (R1) addendum on Estimands and Sensitivity analysis in Clinical trials proposes a framework for the design and analysis of clinical trials aimed at improving clarity around the definition of the targeted treatment effect (the <jats:italic>estimand<\/jats:italic>) of a study.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We adopt the estimand framework in the context of a study using \u201ctrial emulation\u201d to estimate the risk of pneumocystis pneumonia, an opportunistic disease contracted by people living with HIV and AIDS having a weakened immune system, when considering two antibiotic treatment regimes for stopping antibiotic prophylaxis treatment against this disease. A \u201cwhile on treatment\u201d strategy has been implemented for post-randomisation (intercurrent) events. We then perform a sensitivity analysis using <jats:italic>reference based multiple imputation<\/jats:italic> to model a scenario in which patients lost to follow-up stop taking prophylaxis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The primary analysis indicated a protective effect for the new regime which used viral suppression as prophylaxis stopping criteria (hazard ratio (HR) 0.78, 95% confidence interval [0.69, 0.89], <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). For the sensitivity analysis, when we apply the \u201cjump to off prophylaxis\u201d approach, the hazard ratio is almost the same compared to that from the primary analysis (HR 0.80 [0.69, 0.95], <jats:italic>p<\/jats:italic>\u2009=\u20090.009). The sensitivity analysis confirmed that the new regime exhibits a clear improvement over the existing guidelines for PcP prophylaxis when those lost to follow-up \u201cjump to off prophylaxis\u201d.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our application using reference based multiple imputation demonstrates the method\u2019s flexibility and simplicity for sensitivity analyses in the context of the estimand framework for (emulated) trials.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12874-024-02364-6","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T06:02:07Z","timestamp":1729231327000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Application of the estimand framework for an emulated trial using reference based multiple imputation to investigate informative censoring"],"prefix":"10.1186","volume":"24","author":[{"given":"A.","family":"Atkinson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Zwahlen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"De Wit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Furrer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. R.","family":"Carpenter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,10,18]]},"reference":[{"key":"2364_CR1","unstructured":"CHMP. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles in clinical trials. 17 Feb 2020. https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/ich-e9-r1-addendum-estimands-sensitivity-analysis-clinical-trials-guideline-statistical-principles_en.pdf. Accessed 31 July 2023."},{"key":"2364_CR2","doi-asserted-by":"publisher","first-page":"e052953","DOI":"10.1136\/bmjopen-2021-052953","volume":"12","author":"TP Clark","year":"2022","unstructured":"Clark TP, Kahan BC, Philipps A, White I, Carpenter JR. Estimands: bringing clarity and focus to research questions in clinical trials. 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Accessed 31 July 2024."}],"container-title":["BMC Medical Research Methodology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12874-024-02364-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12874-024-02364-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12874-024-02364-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T06:03:15Z","timestamp":1729231395000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedresmethodol.biomedcentral.com\/articles\/10.1186\/s12874-024-02364-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,18]]},"references-count":21,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["2364"],"URL":"https:\/\/doi.org\/10.1186\/s12874-024-02364-6","relation":{},"ISSN":["1471-2288"],"issn-type":[{"value":"1471-2288","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,18]]},"assertion":[{"value":"9 October 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 October 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 October 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval was applied for and granted for the research from the respective ethics committees in the host country of the cohort contributing the data to COHERE. Informed consent was obtained from all individual participants included from each of the COHERE participating cohorts for the original study. We confirm the original study was performed in accordance with relevant guidelines and regulations according to the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable for the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"AA is a consultant at the University Children\u2019s Hospital in Basel. SdW received grants from Gilead Sciences, Janssen, Merck, Sharp & Dohme (MSD), and ViiV Healthcare, all paid to his institution. JRC is supported by the UK Medical Research Council grant MC_UU_12023\/21 and has received a grant to his department from Astra Zeneca and consulting honoraria from Pfizer and GSK, outside of the submitted work. HF reports grants to the institution from ViiV Healthcare, Gilead Sciences, MSD, AbbVie, and Sandoz, outside the submitted work. All other authors report no potential conflicts.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"245"}}