P4568 - False Positives and Follow-Up in Cologuard: Who’s at Risk?

Cologuard is an increasingly used, non-invasive stool DNA test that combines molecular and hemoglobin markers to detect colorectal cancer (CRC) and advanced precancerous lesions (APLs) in average-risk individuals. Although replacing conventional screening modalities like colonoscopy with stool-based tests may reduce clinical benefit, implementation in populations unable or unlikely to undergo colonoscopy could enhance screening adherence and early detection. This study evaluates false positive Cologuard results to identify patient-level factors that may increase false positive risk to inform clinical decision making.


Methods:

This is a retrospective chart review of patients who underwent Cologuard testing at a single academic medical center from 2/212022 to 2/212025. A random sample of 123 charts was manually reviewed to compare characteristics of true positives (n=15) versus false positives (n=6), based on follow-up colonoscopy findings. Patients with prior CRC or hereditary cancer syndromes were excluded. Data collected included age, gastrointestinal symptoms, colonoscopy history, medication use, and colonoscopy findings.


Results:

25% of the patients with a positive Cologuard did not follow-up with colonoscopy at time of this review. Among patients with positive Cologuard results, those who did not complete colonoscopy had similar age (74.6 vs. 74.9 years) but more frequently reported constipation (85.7% vs. 68.2%), diarrhea (42.9% vs. 9.1%), and were more likely to be on anticoagulants, antiplatelets, or NSAIDs (85.71% vs. 72.73%) suggesting symptoms or other comorbidities may contribute to deferred follow-up.

False positives were more frequently observed in older individuals (mean age 80.33 vs. 73.67 years) and correlated with higher rates of hemorrhoids (83.3% vs. 53.3%), constipation (83.3% vs. 60.0%), prior colonoscopy (83.3% vs. 53.3%), and antiplatelet therapy (66.7% vs. 46.7%), suggesting potential confounding from benign pathology that may reduce test specificity.


Discussion: Patient factors such as advanced age, benign GI conditions such as diverticulosis or hemorrhoids, and antiplatelet, anticoagulation, or NSAID use may impact both Cologuard specificity and follow-up adherence. While limited by small sample size, these descriptive findings highlight the need for refined risk stratification. Future directions include expanding the sample size to enable statistical analysis and improve generalizability of results, ultimately guiding more personalized screening strategies.

Disclosures:
Madison Force indicated no relevant financial relationships.
Danielle Zolontinsky indicated no relevant financial relationships.
Mansi Sheth indicated no relevant financial relationships.
Breanne McDermott indicated no relevant financial relationships.
Cindy Xin Fang indicated no relevant financial relationships.
Yan Yan Xie indicated no relevant financial relationships.
Charles Kistler indicated no relevant financial relationships.

Madison Force, MD¹, Danielle Zolontinsky, RD², Mansi Sheth, DO³, Breanne McDermott, BS⁴, Cindy Xin Fang, BS⁴, Yan Yan Xie, BS², Charles Kistler, MD⁵. P4568 - False Positives and Follow-Up in Cologuard: Who’s at Risk?, ACG 2025 Annual Scientific Meeting Abstracts. Phoenix, AZ: American College of Gastroenterology.