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

Objective Observational studies evaluating the effectiveness of cancer screening are often biased due to an inadequate design where I) the assessment of eligibility, II) the assignment to screening vs. no screening and III) the start of follow-up are not aligned at time zero (baseline). Such flaws can entail misleading results but are avoidable by designing the study following the principle of target trial emulation (TTE). We aimed to illustrate this by addressing the research question whether screening colonoscopy is more effective in the distal vs. the proximal colon. Methods Based on a large German health care database (20% population coverage), we assessed the effect of screening colonoscopy in preventing distal and proximal CRC over 12 years of follow-up in 55–69-year-old persons at average CRC risk. We applied four different study designs and compared the results: cohort study with / without alignment at time zero, case control study with / without alignment at time zero. Results In both analyses with alignment at time zero, screening colonoscopy showed a similar effectiveness in reducing the incidence of distal and proximal CRC (cohort analysis: 32% (95% CI: 27% - 37%) vs. 28% (95% CI: 20% - 35%); case-control analysis: 27% vs. 33%). Both analyses without alignment at time zero suggested a difference in site-specific performance: Incidence reduction regarding distal and proximal CRC, respectively, was 65% (95% CI: 61% - 68%) vs. 37% (95% CI: 31% - 43%) in the cohort analysis and 77% (95% CI: 67% - 84%) vs. 46% (95% CI: 25% - 61%) in the case-control analysis. Conclusions Our study demonstrates that violations of basic design principles can substantially bias the results of observational studies on cancer screening. In our example, it falsely suggested a much stronger preventive effect of colonoscopy in the distal vs. the proximal colon. The difference disappeared when the same data were analyzed using a TTE approach, which is known to avoid such design-induced biases. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement BIPS intramural funding ### Author Declarations 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: In Germany, the utilisation of health insurance data for scientific research is regulated by the Code of Social Law. All involved health insurance providers as well as the German Federal Office for Social Security and the Senator for Health, Women and Consumer Protection in Bremen as their responsible authorities approved the use of GePaRD data for this study. Informed consent for studies based on claims data is required by law unless obtaining consent appears unacceptable and would bias results, which was the case in this study. According to the Ethics Committee of the University of Bremen studies based on GePaRD are exempt from institutional review board review. 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][1]. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes [1]: http://ClinicalTrials.gov