Response to commentary By Drs. Baile-Maxía And Jover on our article “Accounting for endoscopic screening in colorectal cancer risk models”

We appreciate the thoughtful commentary (1) by Drs. Baile-Maxía and Jover on our article “Accounting for endoscopic screening in colorectal cancer risk models” (2). They cogently summarize the main features and implications of our modelling approach for screening in the epidemiologic study of colorectal cancer (CRC). The main impetus for developing the method is that in the context of epidemiologic study, colonoscopic screening is not only a confounder, but it also disrupts the natural history of CRC by identifying and removing precursor lesions. Previous approaches have been typically to consider screening only as a confounder or to ignore it entirely because relevant data were not always collected. In older cohorts when population screening rates were low, these limitations may not have had a large impact on the results. However, these methodologic issues become more serious concerns as screening rates increase in study populations.

Baile-Maxía and Jover bring up several potential limitations of the study. One is the unique composition of the Nurses’ Health Study (NHS) as a relatively health-conscious cohort. We studied the issue of generalizability by systematically comparing the results from the NHS [as well as NHSII and Health Professionals Follow-Up Study (HPFS)] from results from systematic reviews by the World Cancer Fund/American Institute of Cancer Research for 17 cancer types for all risk factors with “convincing” or “probable” evidence (3). When we compared cohort-specific results for NHS, NHSII, and HPFS with corresponding sex-specific pooled meta-analysis results, the 95% confidence interval from the NHS, NHSII, or HPFS captured the pooled estimate in 44 of 45 comparisons, and in the one exception, the estimate was only 0.01 outside the confidence interval. Thus, results from these cohorts appear to be broadly generalizable. Another limitation is that we lacked information on serrated polyps, especially in earlier follow-up when pathologic criteria for these lesions were evolving. We agree that future studies should consider high-risk serrated polyps in the models.

Baile-Maxía and Jover note some other important issues regarding screening. A critical concern mentioned is the rise of CRC in individuals under the age of 50 years. As screening rates have been very low in this age group, the impact of screening on current epidemiologic results is likely negligible. As targeted screening may increase in younger age groups, modelling approaches such as ours may become more relevant in this group. We entirely agree with Baile-Maxía and Jover that future risk models need to consider differences in coverage windows for other screening programs such as faecal immunochemical tests, sigmoidoscopy, or multi-target stool DNA tests. As such, our work is the first step and hopefully will stimulate more consideration of this critical issue.

Finally, it bears emphasizing that although the goal of studies is typically to present one unconfounded risk estimate for a risk factor, by altering the natural history of CRC, the relation between screen-covered and not-screen covered cancers may have inherent differences. For example, in the screen covered, because most advanced precursors have been removed, the cancers detected over the next ten years tend to be faster growing, and necessitate going through all stages of colorectal carcinogenesis. In addition, these will be enriched with lesions more likely missed by endoscopy (e.g., proximal serrated lesions). While we would not anticipate the epidemiology of CRC to change entirely, it is likely that the relative importance of specific factors can change over time assuming screening rates increase in populations.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Cancer Epidemiology. The article did not undergo external peer review.

Funding: This study was supported by the National Cancer Institute (grant number R01 CA272489).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ace.amegroups.com/article/view/10.21037/ace-2026-0022/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Baile-Maxía S, Jover R. Beyond simple adjustment: integrating endoscopic screening into the natural history of colorectal cancer risk models. Ann Cancer Epidemiol 2026;10:14.
2. Wei EK, Wu K, Colditz GA, et al. Accounting for Endoscopic Screening in Colorectal Cancer Risk Models. Cancer Epidemiol Biomarkers Prev 2025;34:2049-57. [Crossref] [PubMed]
3. Wang P, Giovannucci EL. Are exposure-disease relationships assessed in cohorts of health professionals generalizable?: a comparative analysis based on WCRF/AICR systematic literature reviews. Cancer Causes Control 2023;34:39-45. [Crossref] [PubMed]