S646 Real-World Follow-Up and Outcomes After Positive Multitarget Stool DNA Testing: A National Analysis of Diagnostic Yield, Timing, and Resource Utilization

Introduction: Multitarget stool DNA (mt-sDNA) testing is a widely used noninvasive colorectal cancer (CRC) screening tool. However, real-world data on downstream diagnostic colonoscopy timing, clinical outcomes, and healthcare utilization remain limited. This study aims to evaluate post-test follow-up patterns, diagnostic yield, and procedural utilization in a large national cohort, including a focused analysis of false-positive cases. Methods: We conducted a retrospective cohort study using the TriNetX network, a de-identified, federated health research platform comprising electronic health records from 66 healthcare organizations. Adults aged ≥45 years with a positive mt-sDNA test result between 2015 and 2025 were identified. Time-to-event analysis measured the interval from test to colonoscopy, with censoring at the time of colonoscopy or at 1,086 days. Outcomes included CRC, adenomas, diverticulosis, colectomy, diagnostic imaging and 1-year mortality. A nested analysis was performed to evaluate patients with false-positive mt-sDNA results, defined with no CRC or benign colorectal neoplasms on colonoscopy, with 10 years follow-up. Results: Among 13,364 adults with a positive mt-sDNA test, the mean age was 65 (±10) years, and 53.5% were female. The majority were White (87.8%), with 7.1% Black and 3.0% Hispanic representation. The median time to colonoscopy was 69 days (IQR: 38–142), with 25% waiting over 3 months. Among those who completed colonoscopy, 2.5% (n = 332) were diagnosed with CRC, 19.1% (n = 2,550) had adenomas, and 6.6% (n = 883) had diverticulosis. Colectomy was performed in 1.5% (n = 199), and all-cause mortality remained < 0.1%. Imaging utilization included CT abdomen/pelvis (8.5%), abdominal ultrasound (4.5%), and nuclear medicine scans (4.8%). In the subset of 5,277 patients with false-positive mt-sDNA results, the mean time to the next colonoscopy was 937 days (±642), with a median of 976 days (range: 30–3,484 days). 6.7% were later diagnosed with adenomas, 0.19% with CRC. Conclusion: In this national analysis, mt-sDNA led to clinically significant diagnostic yield in patients completing colonoscopy. However, a significant proportion of follow-ups revealed no pathology, yet incurred further testing and procedures. These findings highlight opportunities to improve risk stratification and post-test care pathways through more efficient and coordinated follow-up, particularly in false-positive cases, to maximize noninvasive screening value and optimize resource utilization and costs.