Limitation of site-stratified cox regression analysis in survival data: a cautionary tale of the PANAMO phase III randomized, controlled study in critically ill COVID-19 patients
Abstract Current guidelines tend to focus on a p-value threshold of a pre-specified primary endpoint tested in randomized controlled clinical trials to determine a treatment effect for a specific drug. However, a p-value does not always provide evidence on the treatment effect of a drug, especially...
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BMC
2024-12-01
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| Online Access: | https://doi.org/10.1186/s13063-024-08679-5 |
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| author | Christian E. Sandrock Peter X. K. Song |
| author_facet | Christian E. Sandrock Peter X. K. Song |
| author_sort | Christian E. Sandrock |
| collection | DOAJ |
| description | Abstract Current guidelines tend to focus on a p-value threshold of a pre-specified primary endpoint tested in randomized controlled clinical trials to determine a treatment effect for a specific drug. However, a p-value does not always provide evidence on the treatment effect of a drug, especially when stratification of the data does not account for unforeseen variables introduced into the analysis. We report and discuss a rare case in which investigational site stratification in the pre-specified analysis method of a primary endpoint results in a loss of statistical power in the evaluation of the treatment effect due to data attrition of almost 17% of outcome data in the phase III randomized, controlled PANAMO study in critically ill COVID-19 patients. Other analyses utilizing no or different stratification (e.g., stratifying by country, region, pooling low enrollment clinical sites) evaluates 100% of patient data resulting in p-values suggesting a positive treatment effect (p < 0.05). We demonstrate how this technical artifact occurs by adjustment for site stratification within the Cox regression analysis for survival outcomes and how alternative stratification corrects this discrepancy. |
| format | Article |
| id | doaj-art-aef7809dadf34cfabdb491ec1c4868b5 |
| institution | OA Journals |
| issn | 1745-6215 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Trials |
| spelling | doaj-art-aef7809dadf34cfabdb491ec1c4868b52025-08-20T02:31:50ZengBMCTrials1745-62152024-12-012511510.1186/s13063-024-08679-5Limitation of site-stratified cox regression analysis in survival data: a cautionary tale of the PANAMO phase III randomized, controlled study in critically ill COVID-19 patientsChristian E. Sandrock0Peter X. K. Song1Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, UC Davis Medical Center, University of California, DavisSchool of Public Health, University of MichiganAbstract Current guidelines tend to focus on a p-value threshold of a pre-specified primary endpoint tested in randomized controlled clinical trials to determine a treatment effect for a specific drug. However, a p-value does not always provide evidence on the treatment effect of a drug, especially when stratification of the data does not account for unforeseen variables introduced into the analysis. We report and discuss a rare case in which investigational site stratification in the pre-specified analysis method of a primary endpoint results in a loss of statistical power in the evaluation of the treatment effect due to data attrition of almost 17% of outcome data in the phase III randomized, controlled PANAMO study in critically ill COVID-19 patients. Other analyses utilizing no or different stratification (e.g., stratifying by country, region, pooling low enrollment clinical sites) evaluates 100% of patient data resulting in p-values suggesting a positive treatment effect (p < 0.05). We demonstrate how this technical artifact occurs by adjustment for site stratification within the Cox regression analysis for survival outcomes and how alternative stratification corrects this discrepancy.https://doi.org/10.1186/s13063-024-08679-5Cox proportional hazards regressionSurvival analysisVilobelimabPANAMOCOVID-19 |
| spellingShingle | Christian E. Sandrock Peter X. K. Song Limitation of site-stratified cox regression analysis in survival data: a cautionary tale of the PANAMO phase III randomized, controlled study in critically ill COVID-19 patients Trials Cox proportional hazards regression Survival analysis Vilobelimab PANAMO COVID-19 |
| title | Limitation of site-stratified cox regression analysis in survival data: a cautionary tale of the PANAMO phase III randomized, controlled study in critically ill COVID-19 patients |
| title_full | Limitation of site-stratified cox regression analysis in survival data: a cautionary tale of the PANAMO phase III randomized, controlled study in critically ill COVID-19 patients |
| title_fullStr | Limitation of site-stratified cox regression analysis in survival data: a cautionary tale of the PANAMO phase III randomized, controlled study in critically ill COVID-19 patients |
| title_full_unstemmed | Limitation of site-stratified cox regression analysis in survival data: a cautionary tale of the PANAMO phase III randomized, controlled study in critically ill COVID-19 patients |
| title_short | Limitation of site-stratified cox regression analysis in survival data: a cautionary tale of the PANAMO phase III randomized, controlled study in critically ill COVID-19 patients |
| title_sort | limitation of site stratified cox regression analysis in survival data a cautionary tale of the panamo phase iii randomized controlled study in critically ill covid 19 patients |
| topic | Cox proportional hazards regression Survival analysis Vilobelimab PANAMO COVID-19 |
| url | https://doi.org/10.1186/s13063-024-08679-5 |
| work_keys_str_mv | AT christianesandrock limitationofsitestratifiedcoxregressionanalysisinsurvivaldataacautionarytaleofthepanamophaseiiirandomizedcontrolledstudyincriticallyillcovid19patients AT peterxksong limitationofsitestratifiedcoxregressionanalysisinsurvivaldataacautionarytaleofthepanamophaseiiirandomizedcontrolledstudyincriticallyillcovid19patients |