Browsing by Author "Limburg, Paul J."

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    Algorithm Development and Early Performance Evaluation of a Next-Generation Multitarget Stool DNA Screening Test for Colorectal Cancer
    (Elsevier, 2024-05-17) Imperiale, Thomas F.; Gagrat, Zubin D.; Krockenberger, Martin; Porter, Kyle; Ziegler, Emily; Leduc, Christine M.; Matter, Michael B.; Olson, Marilyn C.; Limburg, Paul J.; Medicine, School of Medicine
    Background and aims: The multitarget stool DNA (mt-sDNA) assay is a noninvasive average-risk colorectal cancer (CRC) screening test. A new biomarker panel was developed for a next-generation test to improve specificity while maintaining/increasing sensitivity. We aimed first to establish an algorithm and cutoff for the next-generation mt-sDNA test and then to validate it using archived samples from the pivotal DeeP-C study (NCT01397747) of the first-generation test. Methods: Algorithm development and cross-validation included 3011 samples from 2 specimen collection studies (NCT03821948 and NCT03789162). The algorithm and cutoff were locked before validation. Validation test set samples included 57 CRC, 583 advanced precancerous lesions (APLs), and 7022 samples negative for CRC or APLs from the DeeP-C study, which prospectively enrolled average-risk, asymptomatic adults aged 50-84 years before screening colonoscopy. Next-generation biomarkers included methylated DNA markers ceramide synthase 4 gene, leucine-rich repeat-containing protein 4 gene, serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform gene, and zinc finger DHHC-type containing 1 gene (reference marker), and fecal hemoglobin. Primary validation end points were CRC sensitivity and specificity for the absence of advanced neoplasia. Secondary end points included APL sensitivity and specificity for non-neoplastic findings or negative colonoscopy. Results: Cross-validation and best-fit results from algorithm development closely matched, confirming algorithm reliability and reproducibility. For the test set, next-generation mt-sDNA test sensitivity was 93.0% (95% confidence interval [CI], 83.0%-98.1%) for CRC and 48.4% (95% CI, 44.2%-52.5%) for APLs. Specificity was 88.5% (95% CI, 87.7%-89.2%) for the absence of advanced neoplasia and 90.4% (95% CI, 89.5%-91.2%) for the combination of non-neoplastic findings or negative colonoscopy. Conclusion: Based on archived samples, the next-generation mt-sDNA test demonstrated promising CRC screening performance characteristics that will be further assessed in a prospective clinical validation study (BLUE-C; NCT04144738).
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    Specificity of the Multi-Target Stool DNA Test for Colorectal Cancer Screening in Average-Risk 45–49 Year-Olds: A Cross-Sectional Study
    (AACR, 2021-04) Imperiale, Thomas F.; Kisiel, John B.; Itzkowitz, Steven H.; Scheu, Bradley; Duimstra, Emma Kate; Statz, Sandra; Berger, Barry M.; Limburg, Paul J.; Medicine, School of Medicine
    High-specificity colorectal cancer screening is desirable to triage patients <50 years for colonoscopy; however, most endorsed colorectal cancer screening tests have not been rigorously evaluated in younger populations. This prospective cross-sectional study determined the specificity of the multitarget stool DNA (mt-sDNA) test in an average-risk screening population of 45 to 49 year-olds. Specificity was the primary outcome and was measured in participants without colorectal cancer or advanced precancerous lesions [APL– advanced adenomas (AA), and sessile serrated lesions ≥10 mm], and in the subgroup of participants with negative colonoscopic findings. APL sensitivity was a secondary outcome. The evaluable cohort included those who completed the study without protocol deviations and had a usable mt-sDNA test. Of 983 enrolled participants, 816 formed the evaluable cohort, with a mean age of 47.8 (SD, 1.5) years; 47.7% were women. No participants had colorectal cancer, 49 had APL, 253 had nonadvanced adenomas (NAA), and 514 had negative colonoscopic findings. mt-sDNA test specificity was 95.2% (95% CI, 93.4–96.6) in participants with NAA or negative findings [96.3% (confidence interval (CI), 94.3%–97.8%)] in those with negative findings, and did not differ by sex (P = 0.75) or race (P = 0.36) in participants with NAA or negative findings. Sensitivity for APL was 32.7% (CI, 19.9–47.5%), with most APL (83.7%) measuring 10–19 mm and none having high-grade dysplasia. The area under the ROC curve for discriminating between APL and lesser findings was 0.72 (CI, 0.64–0.81). mt-sDNA's high specificity would help minimize risk from unnecessary diagnostic procedures in this age group. This study shows that mt-sDNA has high specificity among average-risk 45 to 49-year olds, supporting its use as a noninvasive option for colorectal cancer screening.
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    Three-Year Interval for the Multi-Target Stool DNA Test for Colorectal Cancer Screening: A Longitudinal Study
    (American Association for Cancer Research, 2023) Imperiale, Thomas F.; Lavin, Philip T.; Marti, Tara N.; Jakubowski, Debbie; Itzkowitz, Steven H.; May, Folasade P.; Limburg, Paul J.; Sweetser, Seth; Daghestani, Anas; Berger, Barry M.; Medicine, School of Medicine
    Data supporting the clinical utility of multi-target stool DNA (mt-sDNA) at the guideline-recommended 3-year interval have not been reported.Between April 2015 and July 2016, candidates for colorectal cancer screening whose providers prescribed the mt-sDNA test were enrolled. Participants with a positive baseline test were recommended for colonoscopy and completed the study. Those with a negative baseline test were followed annually for 3 years. In year 3, the mt-sDNA test was repeated and colonoscopy was recommended independent of results. Data were analyzed using the Predictive Summary Index (PSI), a measure of the gain in certainty for dichotomous diagnostic tests (where a positive value indicates a net gain), and by comparing observed versus expected colorectal cancers and advanced precancerous lesions.Of 2,404 enrolled subjects, 2,044 (85%) had a valid baseline mt-sDNA result [284 (13.9%) positive and 1,760 (86.1%) negative]. Following participant attrition, the year 3 intention to screen cohort included 591 of 1,760 (33.6%) subjects with valid mt-sDNA and colonoscopy results, with no colorectal cancers and 63 advanced precancerous lesions [22 (34.9%) detected by mt-sDNA] and respective PSI values of 0% (P = 1) and 9.3% (P = 0.01). The observed 3-year colorectal cancer yield was lower than expected (one-sided P = 0.09), while that for advanced precancerous lesions was higher than expected (two-sided P = 0.009).Repeat mt-sDNA screening at a 3-year interval resulted in a statistically significant gain in detection of advanced precancerous lesions. Due to absence of year 3 colorectal cancers, the PSI estimate for colorectal cancer was underpowered and could not be reliably quantified. Larger studies are required to assess the colorectal cancer study findings. Prevention relevance: Understanding the 3-year yield of mt-sDNA for colorectal cancer and advanced precancerous polyps is required to ensure the clinical appropriateness of the 3-year interval and to optimize mt-sDNA's screening effectiveness.