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This retrospective study aims to evaluate the prognostic value of a broad range of variables by conducting a comprehensive survival analysis on longitudinal data from RAP\u2010ALS, a clinical trial investigating the effects of rapamycin in ALS patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200963).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Covariates were classified as risk or protective factors according to their hazard ratios. Regularized Cox regression was utilized to select the best\u2010performing multivariate models in cross\u2010validation. Longitudinal measures were incorporated by modeling covariates as time\u2010dependent. Survival times of treated C9orf72 mutation carriers (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20096) were further investigated through log\u2010rank tests and restricted mean survival time analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Univariate analyses confirmed several previously established prognostic factors. Multivariate regularized Cox models incorporated neurofilaments, creatinine, clinical scores, and markers of immune activation. Moreover, the inclusion of time\u2010varying covariates allowed us to investigate late\u2010stage risk factors, such as the neutrophil\u2010to\u2010lymphocyte ratio. Additionally, the analysis indicated a protective effect in treated C9orf72 mutation carriers (log\u2010rank test,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.026), which was confirmed after comparing this treatment subgroup with an independent C9orf72+ cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200940; RMST test,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.04).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The survival analysis confirmed the role of previously identified prognostic factors, while suggesting that high\u2010performing multivariate models should integrate multiple ALS pathological hallmarks. Moreover, the observed longer survival among C9orf72 mutation carriers contrasts with prior reports. Due to the small sample size and potential confounding factors, the observed benefits in treated C9orf72 patients should be considered exploratory, supporting evaluation in a larger, genetically stratified trial.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ene.70756","type":"journal-article","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T07:33:06Z","timestamp":1789803186000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multivariate Survival Analysis of a Comprehensive Clinical Trial of Rapamycin in Amyotrophic Lateral Sclerosis Explores Prognostic Factors and Survival Patterns in C9orf72 Carriers"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6451-3911","authenticated-orcid":false,"given":"Alex","family":"De Nardi","sequence":"first","affiliation":[{"name":"Fondazione The Microsoft Research \u2010 University of Trento Centre for Computational 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