PMID- 16903003
OWN - NLM
STAT- MEDLINE
DCOM- 20070515
LR  - 20131121
IS  - 0277-6715 (Print)
IS  - 0277-6715 (Linking)
VI  - 26
IP  - 7
DP  - 2007 Mar 30
TI  - Multivariate time-to-event analysis of multiple adverse events of drugs in 
      integrated analyses.
PG  - 1518-31
AB  - In each clinical trial the statistical evaluation of adverse events (AEs) is a 
      major part of standard safety analyses. However, the analyses of AEs usually lack 
      from adequately accounting for the occurrence of multiple, different AEs. 
      Furthermore, predictive variables other than treatment such as age, sex and 
      concomitant medication are often ignored. These issues can be addressed by the 
      Cox regression as introduced by Andersen and Gill and Wei et al. A further issue 
      arises from the fact that an ordered programme of studies is conducted during 
      clinical testing of pharmaceutical drugs. In this paper, we therefore discuss a 
      stratified multivariate Cox regression model that can be used in integrated 
      summaries of safety. We derive partial maximum likelihood estimators of the model 
      parameters which can be shown to be consistent and asymptotically normally 
      distributed. Mainly based on a sandwich estimator of their covariance matrix 
      several test statistics are proposed that can be used to test various null 
      hypotheses on the underlying parameters. Their asymptotic null distributions are 
      given. The benefit of this survival time approach for analysing AEs is 
      illustrated by evaluating symptoms of common cold from the database of a clinical 
      development project.
CI  - Copyright (c) 2006 John Wiley & Sons, Ltd.
FAU - Guttner, Achim
AU  - Guttner A
AD  - Novartis Pharma AG, Biostatistics and Statistical Reporting, CH-4002 Basel, 
      Switzerland. achim.guettner@novartis.com
FAU - Kubler, Jurgen
AU  - Kubler J
FAU - Pigeot, Iris
AU  - Pigeot I
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Stat Med
JT  - Statistics in medicine
JID - 8215016
RN  - 0 (Cholinesterase Inhibitors)
SB  - IM
MH  - Alzheimer Disease/drug therapy
MH  - Cholinesterase Inhibitors/adverse effects/therapeutic use
MH  - Clinical Trials as Topic/*methods
MH  - Common Cold/chemically induced
MH  - *Drug-Related Side Effects and Adverse Reactions
MH  - Humans
MH  - Meta-Analysis as Topic
MH  - *Multivariate Analysis
MH  - *Proportional Hazards Models
MH  - Randomized Controlled Trials as Topic/methods
EDAT- 2006/08/12 09:00
MHDA- 2007/05/16 09:00
CRDT- 2006/08/12 09:00
PHST- 2006/08/12 09:00 [pubmed]
PHST- 2007/05/16 09:00 [medline]
PHST- 2006/08/12 09:00 [entrez]
AID - 10.1002/sim.2637 [doi]
PST - ppublish
SO  - Stat Med. 2007 Mar 30;26(7):1518-31. doi: 10.1002/sim.2637.