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Stat Med. 2016 Mar 30;35(7):1001-16. doi: 10.1002/sim.6818. Epub 2016 Jan 14.

The missing cause approach to unmeasured confounding in pharmacoepidemiology.

Author information

1
Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada.
2
Division of Clinical Epidemiology, McGill University Health Centre, Montreal, QC, Canada.
3
Department of Family Medicine, University of Ottawa, Ottawa, ON, Canada.
4
School of Epidemiology, Public Health, and Preventive Medicine, University of Ottawa, Ottawa, ON, Canada.
5
Bruyère Research Institute, Ottawa, ON, Canada.
6
Departments of Medicine and Pharmacology, University of Montreal, Montreal, QC, Canada.
7
Pharmacoepidemiology and Pharmacoeconomics, University of Montreal Hospital Research Center, Montreal, QC, Canada.

Abstract

Unmeasured confounding is a major threat to the validity of pharmacoepidemiological studies of medication safety and effectiveness. We propose a new method for detecting and reducing the impact of unobserved confounding in large observational database studies. The method uses assumptions similar to the prescribing preference-based instrumental variable (IV) approach. Our method relies on the new 'missing cause' principle, according to which the impact of unmeasured confounding by (contra-)indication may be detected by assessing discrepancies between the following: (i) treatment actually received by individual patients and (ii) treatment that they would be expected to receive based on the observed data. Specifically, we use the treatment-by-discrepancy interaction to test for the presence of unmeasured confounding and correct the treatment effect estimate for the resulting bias. Under standard IV assumptions, we first proved that unmeasured confounding induces a spurious treatment-by-discrepancy interaction in risk difference models for binary outcomes and then simulated large pharmacoepidemiological studies with unmeasured confounding. In simulations, our estimates had four to six times smaller bias than conventional treatment effect estimates, adjusted only for measured confounders, and much smaller variance inflation than unbiased but very unstable IV estimates, resulting in uniformly lowest root mean square errors. The much lower variance of our estimates, relative to IV estimates, was also observed in an application comparing gastrointestinal safety of two classes of anti-inflammatory drugs. In conclusion, our missing cause-based method may complement other methods and enhance accuracy of analyses of large pharmacoepidemiological studies.

KEYWORDS:

bias; instrumental variables; pharmacoepidemiology; simulations; unobserved confounding

PMID:
26932124
DOI:
10.1002/sim.6818
[Indexed for MEDLINE]

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