Methodological biases in observational hospital studies of COVID-19 treatment effectiveness: pitfalls and potential

Introduction: This study aims to discuss and assess the impact of three prevalent methodological biases: competing risks, immortal-time bias, and confounding bias in real-world observational studies evaluating treatment effectiveness. We use a demonstrative observational data example of COVID-19 patients to assess the impact of these biases and propose potential solutions. Methods: We describe competing risks, immortal-time bias, and time-fixed confounding bias by evaluating treatment effectiveness in hospitalized patients with COVID-19. For our demonstrative analysis, we use observational data from the registry of patients with COVID-19 who were admitted to the Bellvitge University Hospital in Spain from March 2020 to February 2021 and met our predefined inclusion criteria. We compare estimates of a single-dose, time-dependent treatment with the standard of care. We analyze the treatment effectiveness using common statistical approaches, either by ignoring or only partially accounting for the methodological biases. To address these challenges, we emulate a target trial through the clone-censor-weight approach. Results: Overlooking competing risk bias and employing the naïve Kaplan-Meier estimator led to increased in-hospital death probabilities in patients with COVID-19. Specifically, in the treatment effectiveness analysis, the Kaplan-Meier estimator resulted in an in-hospital mortality of 45.6% for treated patients and 59.0% for untreated patients. In contrast, employing an emulated trial framework with the weighted Aalen-Johansen estimator, we observed that in-hospital death probabilities were reduced to 27.9% in the “X”-treated arm and 40.1% in the non-“X”-treated arm. Immortal-time bias led to an underestimated hazard ratio of treatment. Conclusion: Overlooking competing risks, immortal-time bias, and confounding bias leads to shifted estimates of treatment effects. Applying the naïve Kaplan-Meier method resulted in the most biased results and overestimated pr
This study has been funded by the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) with project grant WO 1746/5-1 (MW), and Beatriu de Pinós post-doctoral programme from the Office of the Secretary of Universities and Research from the Ministry of Business and Knowledge of the Government of Catalonia programme: 2020 BP 00261 (HM); the Ministry of Science and Innovation [Ministerio de Ciencia e Innovación (MICINN)], Spain, under contract PID2020-117751RB-I00 (MAM, SR). CIBER-BBN is an initiative of the Instituto de Salud Carlos III, Spain.
Peer Reviewed
Postprint (published version)