PMID- 34002935
OWN - NLM
STAT- MEDLINE
DCOM- 20220124
LR  - 20220124
IS  - 1539-1612 (Electronic)
IS  - 1539-1604 (Linking)
VI  - 20
IP  - 6
DP  - 2021 Nov
TI  - Estimating and comparing adverse event probabilities in the presence of varying 
      follow-up times and competing events.
PG  - 1125-1146
LID - 10.1002/pst.2130 [doi]
AB  - Safety analyses of adverse events (AEs) are important in assessing benefit-risk 
      of therapies but are often rather simplistic compared to efficacy analyses. AE 
      probabilities are typically estimated by incidence proportions, sometimes 
      incidence densities or Kaplan-Meier estimation are proposed. These analyses 
      either do not account for censoring, rely on a too restrictive parametric model, 
      or ignore competing events. With the non-parametric Aalen-Johansen estimator as 
      the "gold standard", that is, reference estimator, potential sources of bias are 
      investigated in an example from oncology and in simulations, for both one-sample 
      and two-sample scenarios. The Aalen-Johansen estimator serves as a reference, 
      because it is the proper non-parametric generalization of the Kaplan-Meier 
      estimator to multiple outcomes. Because of potential large variances at the end 
      of follow-up, comparisons also consider further quantiles of the observed times. 
      To date, consequences for safety comparisons have hardly been investigated, the 
      impact of using different estimators for group comparisons being unclear. For 
      example, the ratio of two both underestimating or overestimating estimators may 
      not be comparable to the ratio of the reference, and our investigation also 
      considers the ratio of AE probabilities. We find that ignoring competing events 
      is more of a problem than falsely assuming constant hazards by the use of the 
      incidence density and that the choice of the AE probability estimator is crucial 
      for group comparisons.
CI  - (c) 2021 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.
FAU - Stegherr, Regina
AU  - Stegherr R
AUID- ORCID: 0000-0002-0528-348X
AD  - Institute of Statistics, Ulm University, Ulm, Germany.
FAU - Schmoor, Claudia
AU  - Schmoor C
AD  - Clinical Trials Unit, Faculty of Medicine and Medical Center-University of 
      Freiburg, Freiburg, Germany.
FAU - Lubbert, Michael
AU  - Lubbert M
AD  - Hematology, Oncology, and Stem-Cell Transplantation, Faculty of Medicine and 
      Medical Center-University of Freiburg, Freiburg, Germany.
FAU - Friede, Tim
AU  - Friede T
AUID- ORCID: 0000-0001-5347-7441
AD  - Institut fur Medizinische Statistik, Universitatsmedizin Gottingen, Gottingen, 
      Germany.
FAU - Beyersmann, Jan
AU  - Beyersmann J
AD  - Institute of Statistics, Ulm University, Ulm, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210518
PL  - England
TA  - Pharm Stat
JT  - Pharmaceutical statistics
JID - 101201192
SB  - IM
MH  - *Follow-Up Studies
MH  - Humans
MH  - Probability
MH  - Survival Analysis
OTO - NOTNLM
OT  - Aalen-Johansen
OT  - acute myeloid leukemia
OT  - adverse events
OT  - competing events
OT  - safety
EDAT- 2021/05/19 06:00
MHDA- 2022/01/27 06:00
CRDT- 2021/05/18 08:53
PHST- 2021/03/15 00:00 [revised]
PHST- 2020/06/09 00:00 [received]
PHST- 2021/04/29 00:00 [accepted]
PHST- 2021/05/19 06:00 [pubmed]
PHST- 2022/01/27 06:00 [medline]
PHST- 2021/05/18 08:53 [entrez]
AID - 10.1002/pst.2130 [doi]
PST - ppublish
SO  - Pharm Stat. 2021 Nov;20(6):1125-1146. doi: 10.1002/pst.2130. Epub 2021 May 18.