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Pharmacoepidemiol Drug Saf. 2017 Dec;26(12):1520-1526. doi: 10.1002/pds.4326. Epub 2017 Oct 12.

Using probability of drug use as independent variable in a register-based pharmacoepidemiological cause-effect study-An application of the reverse waiting time distribution.

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Clinical Pharmacology and Pharmacy, University of Southern Denmark, Odense, Denmark.
Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
Hospital Pharmacy, Odense University Hospital, Odense, Denmark.
Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark.



In register-based pharmacoepidemiological studies, each day of follow-up is usually categorized either as exposed or unexposed. However, there is an underlying continuous probability of exposure, and by insisting on a dichotomy, researchers unwillingly force a nondifferential misclassification into their analyses. We have recently developed a model whereby probability of exposure can be modeled, and we tested this on an empirical case of nonsteroidal anti-inflammatory drug (NSAID)-induced upper gastrointestinal bleeding (UGIB).


We used a case-controls data set, consisting of 3568 cases of severe UGIB and 35 552 matched controls. Exposure to NSAID was based on 3 different conventional dichotomous measures. In addition, we tested 3 probabilistic exposure measures, a simple univariate backward-recurrence model, a "full" multivariable model, and a "reduced" multivariable model. Odds ratios (ORs) and 95% confidence intervals for the association between NSAID use and UGIB were calculated by conditional logistic regression, while adjusting for preselected confounders.


Compared to the conventional dichotomous exposure measures, the probabilistic exposure measures generated adjusted ORs in the upper range (4.37-4.75) while at the same time having the most narrow confidence intervals (ratio between upper and lower confidence limit, 1.46-1.50). Some ORs generated by conventional measures were higher than the probabilistic ORs, but only when the assumed period of intake was unrealistically short.


The pattern of high ORs and narrow confidence intervals in probabilistic exposure measures is compatible with less nondifferential misclassification of exposure than in a dichotomous exposure model. Probabilistic exposure measures appear to be an attractive alternative to conventional exposure measures.


NSAID; databases; exposure; misclassification; pharmacoepidemiology; upper gastrointestinal bleeding

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