Misleading and avoidably: design-induced biases in observational studies evaluating cancer screening-the example of site-specific effectiveness of screening colonoscopy.

Observational studies evaluating the effectiveness of cancer screening are often biased due to non-alignment at time zero, which can be avoided by target trial emulation (TTE). We aimed to illustrate this by evaluating site-specific effectiveness of screening colonoscopy regarding colorectal cancer (CRC) incidence. Based on a German health care database, we assessed the effect of screening colonoscopy vs. no screening colonoscopy in preventing CRC in the distal and the proximal colon over 12 years of follow-up in 55-69-year-old persons. We compared four different study designs: cohort and case-control study, each with/without alignment at time zero. In both analyses with time zero-alignment, screening colonoscopy showed a rather similar effectiveness in reducing the incidence of distal and proximal CRC (cohort analysis: 32% (95% CI: 27-37%) vs. 28% (20-35%); case-control analysis: 27% vs. 33%). Both analyses without alignment suggested a difference by site: Incidence reduction regarding distal and proximal CRC, respectively, was 65% (61-68%) vs. 37% (31-43%) in the cohort analysis and 77% (67-84%) vs. 46% (25-61%) in the case-control analysis. Violations of basic design principles can substantially bias the results of observational studies. In our example, it falsely suggested a much stronger preventive effect of colonoscopy in the distal vs. the proximal colon. Our study illustrates that TTE avoids such design-induced biases.