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

Int J Epidemiol. 2020 Oct 1;49(5):1637-1646. doi: 10.1093/ije/dyaa144.

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.

Keywords: Case-control; causal inference; comparative effectiveness; electronic health records; target trial.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Case-Control Studies
  • Colonic Neoplasms*
  • Colorectal Neoplasms* / epidemiology
  • Colorectal Neoplasms* / prevention & control
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
  • Risk Factors

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors