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Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria: a WorldWide Antimalarial Resistance Network individual participant data meta-analysis

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dc.contributor.author WorldWide Antimalarial Resistance Network Methodology Study Group
dc.date.accessioned 2020-03-25T12:34:44Z
dc.date.available 2020-03-25T12:34:44Z
dc.date.issued 2019
dc.identifier.uri http://hdl.handle.net/123456789/1238
dc.description Research Article en_US
dc.description.abstract Background: Therapeutic efcacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections. Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan–Meier (K–M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K–M method (1 minus K–M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute diferences in the failure estimates derived using these two methods were quantifed. In comparative studies, the equality of two K–M curves was assessed using the log-rank test, and the equality of CIFs using Gray’s k-sample test (both at 5% level of signifcance). Two diferent regression modelling strategies for recrudescence were considered: cause-specifc Cox model and Fine and Gray’s sub-distributional hazard model. Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K–M approach was 0.04% (interquartile range (IQR): 0.00–0.27%, Range: 0.00–3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson’s correlation coefcient (ρ): 0.38, 95% Confdence Interval (CI) 0.30–0.46] or new infection [ρ: 0.43; 95% CI 0.35–0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K–M method was used, but remained below 10% when using the CIF approach, but the 95% confdence interval included this threshold. Conclusions: The 1 minus K–M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efcacy declined, particularly when the observed proportion of new infection en_US
dc.description.sponsorship Tropical Network Fund, Nuffield Department of Clinical Medicine, University of Oxford. The WorldWide Antimalarial Resistance Network (PD, KS, RNP, GSH, and PJG) is funded by a Bill and Melinda Gates Foundation grant and the ExxonMobil Foundation. JAS is an Australian National Health and Medical Research Council Senior Research Fellow (1104975). RNP is a Wellcome Trust Senior Fellow in Clinical Science (200909). en_US
dc.publisher BMC en_US
dc.rights Attribution-NonCommercial-ShareAlike 3.0 United States *
dc.rights.uri http://creativecommons.org/licenses/by-nc-sa/3.0/us/ *
dc.subject Plasmodium falciparum en_US
dc.subject Treatment efficacy study en_US
dc.subject Competing risk event en_US
dc.title Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria: a WorldWide Antimalarial Resistance Network individual participant data meta-analysis en_US
dc.type Article en_US


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