Time-dependent bias when analysing COVID-19-associated pulmonary aspergillosis – Authors' reply

We thank Justin de Brabander and colleagues for their interest in our findings on COVID-19-associated pulmonary aspergillosis (CAPA) reported from the MYCOVID cohort. They raised a very interesting question on the factor time and competing risks in studying the relation between CAPA and mortality as exemplified by their own cohort.

Initially, we observed a statistically significant association between CAPA occurrence and mortality using a Cox model. Then, we decided to refine the Cox model analysis for mortality estimation with a landmark analysis, considering the mean day of proven or probable CAPA development (11 days in our cohort).¹ But, as suggested by de Brabander and colleagues, we performed a complementary analysis, considering the time-dependent bias due to CAPA occurrence on the estimation of mortality.² Austin and colleagues previously defined a competing risk as an event whose occurrence precludes the occurrence of the primary event of interest.³ Here, the competing states were “time to death” or “discharge”, both during intensive care unit (ICU) stay. No follow-up data were collected after ICU discharge as mentioned in the manuscript.² Using this model, the cause-specific hazard ratio (CS-HR) at discharge due to CAPA was 0·57 (95% CI 0·38–0·84) and the CS-HR of death due to CAPA was 2·08 (1·47–2·93), compared to 1·45 (1·03–2·03) found with the initial log-rank analysis.¹

Overall, we provide evidence that the magnitude effect of CAPA on mortality when considering the immortal bias and a cause-specific model increased the strength of the association between development of CAPA and mortality in the MYCOVID cohort.

J-PG reports personal fees from Gilead and grants and personal fees from Pfizer, outside of the submitted work. ED reports grants and non-financial support from Merck Sharp & Dohme and Gilead and non-financial support from Pfizer and Astellas, outside of the submitted work. J-FT reports personal fees from Pfizer, Merck, Astellas, and Gilead, outside of the submitted work. J-RZ reports grants and personal fees from Merck Sharp & Dohme and personal fees from Novartis and Pfizer, outside of the submitted work. M-EB reports grants from Pfizer during the conduct of the study; grants and non-financial support from Gilead and Pfizer, and non-financial support from Merck Sharp & Dohme, outside of the submitted work. JM, BL, and SR declare no competing interests.