Algorithm Training and Testing for a Non-Endoscopic Barrett’s Esophagus Detection Test in Prospective Multicenter Cohorts

Background and Aims Endoscopic Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) detection is invasive and expensive. Non-endoscopic BE/EAC detection tools are guideline-endorsed alternatives. We previously described a 5-methylated DNA marker (MDM) panel assayed on encapsulated sponge cell collection device (CCD) specimens. We aimed to train a new algorithm using a 3-MDM panel and test its performance in an independent cohort. Methods Algorithm training and test samples were from two prospective multicenter cohorts. Participants: All BE cases had esophageal intestinal metaplasia (with or without dysplasia/EAC); controls had no endoscopic evidence of BE. The CCD procedure was followed by endoscopy. From CCD cell lysates, DNA was extracted, bisulfite treated, and MDMs were blindly assayed. The algorithm was set and locked using cross-validated logistic regression (training set) and its performance was assessed in an independent test set. Results Training (N=352) and test (N=125) set clinical characteristics were comparable. The final panel included 3 MDMs (NDRG4, VAV3, ZNF682). Overall sensitivity was 82% (95% CI 68-94%) at 90% (79-98%) specificity and 88% (78-94%) sensitivity at 84% (70-93%) specificity in training and test sets, respectively. Sensitivity was 90% and 68% for all long and short-segment BE respectively. Sensitivity for BE with high grade dysplasia and EAC was 100% in training and test sets. Overall sensitivity for nondysplastic BE was 82%. Areas under the receiver operating characteristic curves for BE detection were 0.92 and 0.94 in the training and test sets, respectively. Conclusions A locked 3-MDM panel algorithm for BE/EAC detection using a non-endoscopic CCD demonstrated excellent sensitivity for high risk BE cases in independent validation samples. (Clinical trials.gov : NCT02560623, NCT03060642)