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Antibiotics are the most important risk factor for C. difficile, and inpatient drug use is not available in the Ontario administrative databases; therefore, our results may have been subject to indication bias.
Further, we have previously shown that the use of a 'contemporary' untreated control cohort that is, where patients are potentially eligible for a DMT in an era when the DMTs are readily available, but remain untreated is subject to indication bias and thus a historical control cohort, with data collected pre-DMT use, is likely to be more appropriate.
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Observational studies which provide most of the available evidence on the topic are potentially subject to indications-for-treatment bias, because the conditions serving as the indication for immunosuppression are themselves often associated with an intrinsically higher risk of mortality or cancer, and the patients with more severe disease are more likely to receive the treatment.
Observational studies on drugs may also be subject to confounding-by-indication in which the indication for treatment and not the treatment per se is associated with the outcome.
Inferences from all these studies are subject to confounding by indication.
We suggest that previous observational data may have been subject to confounding by indication.
Our study could be subject to confounding by indication due to group differences in diabetes severity or duration.
Although confounding can never be ruled out, several points suggest that our results are not subject to confounding by indication to a degree that would change our conclusions.
Thus, the hazard ratio of 1.47 estimated by the authors using the proper time-dependent approach is not surprising in an observational study subject to confounding by indication.
The only study that specifically investigated the risk of acute kidney injury due to these double or triple therapy combinations was probably subject to confounding by indication and severity (heart failure can itself lead to acute kidney injury).
Also, the reason for performing urine analysis in the follow-up was subject to bias by indication, as it was more frequently done in patients showing progressive renal function decline.
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