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Emulating a target trial in case-control designs: an application to statins and colorectal cancer

Dickerman, BA; García-Albéniz, X; Logan, RW; Denaxas, S; Hernán, MA; (2020) Emulating a target trial in case-control designs: an application to statins and colorectal cancer. International Journal of Epidemiology , 49 (5) pp. 1637-1646. 10.1093/ije/dyaa144. Green open access

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Abstract

BACKGROUND: Previous case-control studies have reported a strong association between statin use and lower cancer risk. It is unclear whether this association reflects a benefit of statins or is the result of design decisions that cannot be mapped to a (hypothetical) target trial (that would answer the question of interest). METHODS: We outlined the protocol of a target trial to estimate the effect of statins on colorectal cancer incidence among adults with low-density lipoprotein (LDL) cholesterol below 5 mmol/L. We then emulated the target trial using linked electronic health records of 752 469 eligible UK adults (CALIBER 1999-2016) under both a cohort design and a case-control sampling of the cohort. We used pooled logistic regression to estimate intention-to-treat and per-protocol effects of statins on colorectal cancer, with adjustment for baseline and time-varying risk factors via inverse-probability weighting. Finally, we compared our case-control effect estimates with those obtained using previous case-control procedures. RESULTS: Over the 6-year follow-up, 3596 individuals developed colorectal cancer. Estimated intention-to-treat and per-protocol hazard ratios were 1.00 (95% confidence interval [CI]: 0.87, 1.16) and 0.90 (95% CI: 0.71, 1.12), respectively. As expected, adequate case-control sampling yielded the same estimates. By contrast, previous case-control analytical approaches yielded estimates that appeared strongly protective (odds ratio 0.57, 95% CI: 0.36, 0.91, for ≥5 vs. <5 years of statin use). CONCLUSIONS: Our study demonstrates how to explicitly emulate a target trial using case-control data to reduce discrepancies between observational and randomized trial evidence. This approach may inform future case-control analyses for comparative effectiveness research.

Type: Article
Title: Emulating a target trial in case-control designs: an application to statins and colorectal cancer
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/ije/dyaa144
Publisher version: https://doi.org/10.1093/ije/dyaa144
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Case-control, causal inference, comparative effectiveness, electronic health records, target trial
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics > Clinical Epidemiology
URI: https://discovery.ucl.ac.uk/id/eprint/10112011
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