PMID- 26929180
OWN - NLM
STAT- MEDLINE
DCOM- 20170322
LR  - 20170322
IS  - 1539-1612 (Electronic)
IS  - 1539-1604 (Linking)
VI  - 15
IP  - 4
DP  - 2016 Jul
TI  - Statistical issues in the analysis of adverse events in time-to-event data.
PG  - 297-305
LID - 10.1002/pst.1739 [doi]
AB  - The aim of this work is to shed some light on common issues in the statistical 
      analysis of adverse events (AEs) in clinical trials, when the main outcome is a 
      time-to-event endpoint. To begin, we show that AEs are always subject to 
      competing risks. That is, the occurrence of a certain AE may be precluded by 
      occurrence of the main time-to-event outcome or by occurrence of another (fatal) 
      AE. This has raised concerns on 'informative' censoring. We show that, in 
      general, neither simple proportions nor Kaplan-Meier estimates of AE occurrence 
      should be used, but common survival techniques for hazards that censor the 
      competing event are still valid, but incomplete analyses. They must be 
      complemented by an analogous analysis of the competing event for inference on the 
      cumulative AE probability. The commonly used incidence rate (or incidence 
      density) is a valid estimator of the AE hazard assuming it to be time constant. 
      An estimator of the cumulative AE probability can be derived if the incidence 
      rate of AE is combined with an estimator of the competing hazard. We discuss less 
      restrictive analyses using non-parametric and semi-parametric approaches. We 
      first consider time-to-first-AE analyses and then briefly discuss how they can be 
      extended to the analysis of recurrent AEs. We will give a practical presentation 
      with illustration of the methods by a simple example. Copyright (c) 2016 John Wiley 
      & Sons, Ltd.
CI  - Copyright (c) 2016 John Wiley & Sons, Ltd.
FAU - Allignol, Arthur
AU  - Allignol A
AD  - Institute of Statistics, Ulm University, Ulm, Germany.
FAU - Beyersmann, Jan
AU  - Beyersmann J
AD  - Institute of Statistics, Ulm University, Ulm, Germany.
FAU - Schmoor, Claudia
AU  - Schmoor C
AD  - Clinical Trials Unit, University Medical Center Freiburg, Freiburg, Germany.
LA  - eng
PT  - Journal Article
DEP - 20160301
PL  - England
TA  - Pharm Stat
JT  - Pharmaceutical statistics
JID - 101201192
SB  - IM
MH  - Clinical Trials as Topic/statistics & numerical data
MH  - Computer Simulation/*statistics & numerical data
MH  - Drug-Related Side Effects and Adverse Reactions/diagnosis/*epidemiology
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Risk Factors
MH  - Statistics as Topic/*methods
MH  - Time Factors
OTO - NOTNLM
OT  - Aalen-Johansen
OT  - competing risks
OT  - safety
OT  - survival
EDAT- 2016/03/02 06:00
MHDA- 2017/03/23 06:00
CRDT- 2016/03/02 06:00
PHST- 2015/03/30 00:00 [received]
PHST- 2015/10/09 00:00 [revised]
PHST- 2016/01/15 00:00 [accepted]
PHST- 2016/03/02 06:00 [entrez]
PHST- 2016/03/02 06:00 [pubmed]
PHST- 2017/03/23 06:00 [medline]
AID - 10.1002/pst.1739 [doi]
PST - ppublish
SO  - Pharm Stat. 2016 Jul;15(4):297-305. doi: 10.1002/pst.1739. Epub 2016 Mar 1.