Combinations of common drugs may, when taken together, have unexpected effects on diseases like cancer. It is not feasible to test for all combination drug effects in clinical trials, but in the real world, drugs are frequently taken in combination. Then, there may be undiscovered effects protecting users of drug combinations from cancer--or increasing their risk. By analyzing health claims data containing numerous people exposed to drug combinations, we have an opportunity to evaluate the association of drug combinations with cancer risk. Discovering these effects can not only contribute to prevention of cancer, but also suggest new clinical uses for drug combinations to prevent or treat cancer. Here we describe new methods for discovery of drug combination effects on cancer. Our approach emulates a randomized trial where one arm would have been assigned to take a drug alone, while the other arm takes the drug together with a second drug. Because discovery of associations from observational data is prone to spurious results due to confounding, we develop a number of strategies to distinguish confounding from biomedically relevant findings.

The authors have declared no competing interest.

K01 DA942367

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study used only deidentified publicly available human claims data from MarketScan IBM and has been deemed to be not human subjects research.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors