{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:17:16Z","timestamp":1789654636570,"version":"4.0.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Epidemiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Recurrent clinical malaria episodes due to <jats:italic>Plasmodium falciparum<\/jats:italic> parasite infection are common in endemic regions. With each infection, acquired immunity develops, making subsequent disease episodes less likely. To capture the effect of acquired immunity to malaria, it may be necessary to model recurrent clinical disease episodes jointly with <jats:italic>P. falciparum<\/jats:italic> parasitemia data. A joint model of longitudinal parasitemia and time-to-first clinical malaria episode (single-event joint model) may be inaccurate because acquired immunity is lost when subsequent episodes are excluded. This study's informativeness assessed whether joint modeling of recurrent clinical malaria episodes and parasitemia is more accurate than a single-event joint model where the subsequent episodes are ignored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The single event joint model comprised Cox Proportional Hazards (PH) sub-model for time-to-first clinical malaria episode and Negative Binomial (NB) mixed-effects sub-model for the longitudinal parasitemia. The recurrent events joint model extends the survival sub-model to a Gamma shared frailty model to include all recurrent clinical episodes. The models were applied to cohort data from Malawi. Simulations were also conducted to assess the performance of the model under different conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The recurrent events joint model, which yielded higher hazard ratios of clinical malaria, was more precise and in most cases produced smaller standard errors than the single-event joint model; hazard ratio (HR) = 1.42, [95% confidence interval [CI]: 1.22, 2.03] vs. HR = 1.29, [95% CI:1.60, 2.45] among participants who reported not to use LLINs every night compared to those who used the nets every night; HR = 0.96, [ 95% CI: 0.94, 0.98] vs. HR = 0.81, [95% CI: 0.75, 0.88] for each 1-year increase in participants' age; and HR = 1.36, [95% CI: 1.05, 1.75] vs. HR = 1.10, [95% CI: 0.83, 4.11] for observations during the rainy season compared to the dry season.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The recurrent events joint model in this study provides a way of estimating the risk of recurrent clinical malaria in a cohort where the effect of immunity on malaria disease acquired due to <jats:italic>P. falciparum<\/jats:italic> parasitemia with aging is captured. The simulation study has shown that if correctly specified, the recurrent events joint model can give risk estimates with low bias.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fepid.2022.924783","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T04:42:07Z","timestamp":1657255327000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Analysis of Recurrent Times-to-Clinical Malaria Episodes and Plasmodium falciparum Parasitemia: A Joint Modeling Approach Applied to a Cohort Data"],"prefix":"10.3389","volume":"2","author":[{"given":"Christopher C.","family":"Stanley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mavuto","family":"Mukaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence N.","family":"Kazembe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea G.","family":"Buchwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don P.","family":"Mathanga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam K.","family":"Laufer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias F.","family":"Chirwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"key":"B1","unstructured":"Joint modeling of Longitudinal and time-to-event data: an overview80934\n            TsiatisAA\n            DavidianM\n          Stat Sin142004"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2181","DOI":"10.1002\/sim.6141","article-title":"Joint modeling of survival and longitudinal non-survival data: current methods and issues. Report of the DIA Bayesian joint modeling working group","volume":"34","author":"Lawrence Gould","year":"2015","journal-title":"Stat Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1177\/0962280212445839","article-title":"Joint latent class models for longitudinal and time-to-event data: a review","volume":"23","author":"Proust-Lima","year":"2014","journal-title":"Stat Methods Med Res"},{"key":"B4","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1186\/s12874-016-0272-6","article-title":"Joint models for longitudinal and time-to-event data: a review of reporting quality with a view to meta-analysis","volume":"16","author":"Sudell","year":"2016","journal-title":"BMC Med Res Methodol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1093\/biostatistics\/1.4.465","article-title":"Joint modelling of longitudinal measurements and event time data","volume":"1","author":"Henderson","year":"2000","journal-title":"Biostatistics"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1515\/ijb-2017-0047","article-title":"Joint models of longitudinal and time-to-event data with more than one event time outcome: a review","volume":"14","author":"Hickey","year":"2018","journal-title":"Int J Biostat."},{"key":"B7","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s12874-016-0212-5","article-title":"Joint modelling of time-to-event and multivariate longitudinal outcomes: recent developments and issues","volume":"16","author":"Hickey","year":"2016","journal-title":"BMC Med Res Methodol."},{"key":"B8","doi-asserted-by":"crossref","DOI":"10.1201\/b12208","volume-title":"Joint Models for Longitudinal and Time-to-Event Data: With Applications in R.","author":"Rizopoulos","year":"2012"},{"key":"B9","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1111\/j.0006-341X.2002.00742.x","article-title":"A semiparametric likelihood approach to joint modeling of longitudinal and time-to-event data","volume":"58","author":"Song","year":"2002","journal-title":"Biometrics"},{"key":"B10","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1016\/S0197-2456(02)00234-9","article-title":"Surrogate markers and joint models for longitudinal and survival data","volume":"23","author":"Taylor","year":"2002","journal-title":"Control Clin Trials"},{"key":"B11","doi-asserted-by":"publisher","first-page":"4560","DOI":"10.1002\/sim.6242","article-title":"Joint modeling of longitudinal and survival data with missing and left-censored time-varying covariates","volume":"33","author":"Chen","year":"2014","journal-title":"Stat Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1111\/j.1541-0420.2005.00448.x","article-title":"Joint models for multivariate longitudinal and multivariate survival data","volume":"62","author":"Chi","year":"2006","journal-title":"Biometrics"},{"key":"B13","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1111\/1541-0420.00028","article-title":"A Bayesian semiparametric joint hierarchical model for longitudinal and survival data","volume":"59","author":"Brown","year":"2003","journal-title":"Biometrics"},{"key":"B14","first-page":"863","article-title":"Bayesian methods for joint modeling of longitudinal and survival data with applications to cancer vaccine trials","volume":"14","author":"Ibrahim","year":"2004","journal-title":"Stat Sin"},{"key":"B15","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1191\/0962280202sm269ra","article-title":"Simultaneous analysis of quality of life and survival data","volume":"11","author":"Billingham","year":"2002","journal-title":"Stat Methods Med Res"},{"key":"B16","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1186\/1475-2875-13-293","article-title":"Modelling recurrent events: comparison of statistical models with continuous and discontinuous risk intervals on recurrent malaria episodes data","volume":"13","author":"Sagara","year":"2014","journal-title":"Malar J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1111\/j.1467-9876.2008.00641.x","article-title":"Joint analysis of correlated repeated measures and recurrent events processes in the presence of death, with application to a study on acquired immune deficiency syndrome","volume":"58","author":"Liu","year":"2009","journal-title":"J R Stat Soc Ser C Appl Stat"},{"key":"B18","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1111\/j.1365-3024.2006.00808.x","article-title":"Immune effector mechanisms in malaria","volume":"28","author":"Marsh","year":"2006","journal-title":"Parasite Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1475-2875-8-23","article-title":"Clinical trials to estimate the efficacy of preventive interventions against malaria in paediatric populations: a methodological review","volume":"8","author":"Moorthy","year":"2009","journal-title":"Malaria J."},{"key":"B20","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1128\/CMR.00025-08","article-title":"Acquired immunity to malaria","volume":"22","author":"Doolan","year":"2009","journal-title":"Clin Microbiol Rev"},{"key":"B21","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1111\/j.1365-3083.2007.02047.x","article-title":"Naturally acquired immunity and reduced susceptibility to falciparum malaria in two subpopulations of endemic Eastern India","volume":"67","author":"Biswas","year":"2008","journal-title":"Scand J Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1198\/016214502753479220","article-title":"Latent class models for joint analysis of longitudinal biomarker and event process data: application to longitudinal prostate-specific antigen readings and prostate cancer","volume":"97","author":"Lin","year":"2002","journal-title":"J Am Stat Assoc"},{"key":"B23","doi-asserted-by":"publisher","first-page":"5285","DOI":"10.1002\/sim.2915","article-title":"Parametric latent class joint model for a longitudinal biomarker and recurrent events","volume":"26","author":"Han","year":"2007","journal-title":"Stat Med"},{"key":"B24","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1093\/biomet\/asm087","article-title":"Shared parameter models under random effects misspecification","volume":"95","author":"Rizopoulos","year":"2008","journal-title":"Biometrika"},{"key":"B25","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1093\/biomet\/65.1.141","article-title":"A model for association in bivariate life tables and its application in epidemiological studies of familial tendency in chronic disease incidence","volume":"65","author":"Clayton","year":"1978","journal-title":"Biometrika"},{"key":"B26","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1177\/096228029400300304","article-title":"Some approaches to the analysis of recurrent event data","volume":"3","author":"Clayton","year":"1994","journal-title":"Stat Methods Med Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"4306","DOI":"10.1002\/sim.7001","article-title":"A conditional estimating equation approach for recurrent event data with additional longitudinal information","volume":"35","author":"Shen","year":"2016","journal-title":"Stat Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1093\/aje\/kwy213","article-title":"Association between age and Plasmodium falciparum infection dynamics","volume":"188","author":"Buchwald","year":"2019","journal-title":"Am J Epidemiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1093\/cid\/ciy427","article-title":"Clinical implications of asymptomatic Plasmodium falciparum infections in Malawi","volume":"68","author":"Buchwald","year":"2019","journal-title":"Clin Infect Dis"},{"key":"B30","doi-asserted-by":"publisher","first-page":"412","DOI":"10.4269\/ajtmh.19-0093","article-title":"Impact of multiplicity of Plasmodium falciparum infection on clinical disease in Malawi","volume":"101","author":"Earland","year":"2019","journal-title":"Am J Trop Med Hyg."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7243\/2053-7662-7-1","article-title":"Joint modelling of time-to-clinical malaria and parasite count in a cohort in an endemic area","volume":"7","author":"Stanley","year":"2019","journal-title":"J Med Stat Informatics."},{"key":"B32","unstructured":"Epidemiological profile of malaria in Malawi in 2015 [Internet]2017"},{"key":"B33","doi-asserted-by":"publisher","first-page":"840","DOI":"10.4269\/ajtmh.13-0028","article-title":"Mapping malaria transmission intensity in Malawi, 2000-2010","volume":"89","author":"Bennett","year":"2013","journal-title":"Am J Trop Med Hyg"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e134061","DOI":"10.1371\/journal.pone.0134061","article-title":"School-age children are a reservoir of malaria infection in Malawi","volume":"10","author":"Walldorf","year":"2015","journal-title":"PLoS ONE"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e2012026","DOI":"10.4084\/mjhid.2012.026","article-title":"Clinical aspects of uncomplicated and severe malaria","volume":"4","author":"Bartoloni","year":"2012","journal-title":"Mediterr J Hematol Infect Dis"},{"key":"B36","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s12859-016-1441-7","article-title":"Negative binomial mixed models for analyzing microbiome count data","volume":"18","author":"Zhang","year":"2017","journal-title":"BMC Bioinformatics"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1002\/sim.4780141305","article-title":"A comparison of frailty models for multivariate survival data","volume":"14","author":"Pickles","year":"1995","journal-title":"Stat Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1111\/j.1541-0420.2006.00570.x","article-title":"Joint modeling of survival and longitudinal data: likelihood approach revisited","volume":"62","author":"Hsieh","year":"2006","journal-title":"Biometrics"},{"key":"B39","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1198\/016214501753209031","article-title":"Analyzing recurrent event data with informative censoring","volume":"96","author":"Wang","year":"2001","journal-title":"J Am Stat Assoc."},{"key":"B40","volume-title":"R Core Team. R: A Language and Environment for Statistical Computing","author":"R","year":"2017"},{"key":"B41","volume-title":"Stata Statistical Software: Release 15","year":"2017"},{"key":"B42","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1111\/j.1541-0420.2006.00719.x","article-title":"A joint frailty model for survival and gap times between recurrent events","volume":"63","author":"Huang","year":"2007","journal-title":"Biometrics"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e32625","DOI":"10.7554\/eLife.32625","article-title":"Variation in natural exposure to anopheles mosquitoes and its effects on malaria transmission","volume":"7","author":"Guelb\u00e9ogo","year":"2018","journal-title":"Elife"},{"key":"B44","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.ijpara.2010.09.008","article-title":"Human immune responses that reduce the transmission of Plasmodium falciparum in African populations","volume":"41","author":"Bousema","year":"2011","journal-title":"Int J Parasitol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1038\/192733a0","article-title":"Gamma-globulin and acquired immunity to human malaria","volume":"192","author":"Cohen","year":"1961","journal-title":"Nature"},{"key":"B46","doi-asserted-by":"publisher","first-page":"6538","DOI":"10.1128\/IAI.72.11.6538-6545.2004","article-title":"Modeling the development of acquired clinical immunity to Plasmodium falciparum malaria","volume":"72","author":"Gatton","year":"2004","journal-title":"Infect Immun"},{"key":"B47","doi-asserted-by":"publisher","first-page":"e242","DOI":"10.1371\/journal.pmed.0040242","article-title":"Age interactions in the development of naturally acquired immunity to Plasmodium falciparum and its clinical presentation","volume":"4","author":"Aponte","year":"2007","journal-title":"PLoS Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1186\/s12874-019-0873-y","article-title":"Joint model robustness compared with the time-varying covariate Cox model to evaluate the association between a longitudinal marker and a time-to-event endpoint","volume":"19","author":"Arisido","year":"2019","journal-title":"BMC Med Res Methodol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"7409284","DOI":"10.1155\/2018\/7409284","article-title":"A proposed approach for joint modeling of the longitudinal and time-to-event data in heterogeneous populations: an application to HIV\/AIDS's disease","volume":"2018","author":"Roustaei","year":"2018","journal-title":"Biomed Res Int"},{"key":"B50","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1002\/bimj.201200159","article-title":"A joint model for longitudinal continuous and time-to-event outcomes with direct marginal interpretation","volume":"55","author":"Efendi","year":"2013","journal-title":"Biometr J."},{"key":"B51","doi-asserted-by":"publisher","first-page":"2074","DOI":"10.1002\/sim.8086","article-title":"Using simulation studies to evaluate statistical methods","volume":"38","author":"Morris","year":"2019","journal-title":"Stat Med"},{"key":"B52","doi-asserted-by":"publisher","first-page":"3933","DOI":"10.1002\/sim.6972","article-title":"Joint modelling of longitudinal and multi-state processes: application to clinical progressions in prostate cancer","volume":"35","author":"Ferrer","year":"2016","journal-title":"Stat Med"},{"key":"B53","doi-asserted-by":"publisher","first-page":"2771","DOI":"10.1002\/sim.7682","article-title":"Joint modeling of recurrent events and a terminal event adjusted for zero inflation and a matched design","volume":"37","author":"Xu","year":"2018","journal-title":"Stat Med."}],"container-title":["Frontiers in Epidemiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fepid.2022.924783\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T04:42:20Z","timestamp":1657255340000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fepid.2022.924783\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,8]]},"references-count":53,"alternative-id":["10.3389\/fepid.2022.924783"],"URL":"https:\/\/doi.org\/10.3389\/fepid.2022.924783","relation":{},"ISSN":["2674-1199"],"issn-type":[{"value":"2674-1199","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,8]]},"article-number":"924783"}}