ABSTRACT
Background A plethora of studies on COVID-19 investigating mortality and recovery have used the Cox Proportional Hazards (Cox PH) model without taking into account the presence of competing risks. We investigate, through extensive simulations, the bias in estimating the hazard ratio (HR) and the absolute risk reduction (ARR) of death when competing risks are ignored, and suggest an alternative method.
Methods We simulated a fictive clinical trial on COVID-19 mimicking studies investigating interventions such as Hydroxychloroquine, Remdesivir, or convalescent plasma. The outcome is time from randomization until death. Six scenarios for the effect of treatment on death and recovery were considered. The HR and the 28-day ARR of death were estimated using the Cox PH and the Fine and Gray (FG) models. Estimates were then compared with the true values, and the magnitude of misestimation was quantified.
Results The Cox PH model misestimated the true HR and the 28-day ARR of death in the majority of scenarios. The magnitude of misestimation increased when recovery was faster and/or chance of recovery was higher. In some scenarios, this model has shown harmful treatment effect when it was beneficial. Estimates obtained from FG model were all consistent and showed no misestimation or changes in direction.
Conclusion There is a substantial risk of misleading results in COVID-19 research if recovery and death due to COVID-19 are not considered as competing risk events. We strongly recommend the use of a competing risk approach to re-analyze relevant published data that have used the Cox PH model.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
Abderrahim Oulhaj and Luai A. Ahmed, are supported by a grant from Zayed Center for Health Sciences, United Arab Emirates University (31R239). Ingrid Van Keilegom gratefully acknowledges support from the European Research Council (2016-2021, Horizon 2020 / ERC grant agreement No. 694409).
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Not applicable. This is a simulation study. No data on real human patients was used. The IRB is not required.
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The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, University of Washington, and Vrije Universiteit Amsterdam.
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