This will be a prospective randomized controlled trial comparing CO2 insufflation and WE in terms of right colon combined adenoma miss rate (AMR) and hyperplastic polyp miss rate (HPMR) by tandem inspection. It will be a single-site study conducted in Taiwan.

This will be a prospective RCT comparing CO2 insufflation and WE in terms of right colon combined AMR and HPMR by tandem inspection. It is originally designed as a multicenter study conducted in three community hospitals in Taiwan. Consecutive patients will be enrolled from April 2019 to October 2020. A written informed consent will be obtained from all participating patients. The study has obtained ethical approval from the Joint Institutional Review Board of Taiwan (19-002-T-1) and has been registered with ClinicalTrials.gov (NCT03845933). Due to delay in obtaining IRB approval in two of the participating hospitals (Dalin Tzu-Chi Hospital obtained IRB approval in late May 2019 and has not recruited any patient; Taipei Medical University Hospital has not obtained IRB approval in early June 2019) and rapid recruitment of Evergreen General Hospital since April 2019, which has recruited and completed more than 90 patients in the end of May 2019, we have amended the study design from multicenter study to single-center study and have obtained the approval of this amendment from the Joint Institutional Review Board of Taiwan. Consecutive patients aged 45 years or older undergoing colonoscopy for screening, surveillance, and positive FIT will be considered for enrollment from April 2019 to October 2020. Participants will be randomized in a 1:1 ratio to undergo either the CO2 insufflation colonoscopy (CO2 group) or WE colonoscopy (WE group). Colonoscopies will be performed by two board-certified colonoscopists (Chi-Liang Cheng, Yen-Lin Kuo). Standard colonoscopes (CF-Q260AL/I; Olympus Medical Systems Corp., Tokyo, Japan) will be used. All colonoscopists have performed more than 1000 conventional colonoscopies. Hands-on coaching by a WE expert (Felix W. Leung) to standardize the WE method has been completed. Each colonoscopist has completed 100 cases of WE learning curve. Felix W. Leung will be involved in the study design, data analyses, and report preparation, but not in patient enrollment. CO2 insufflation will be used for CO2 group and the withdrawal phase of the WE group. In the WE group, the air pump will be turned off before starting the procedure. During the insertion phase, air and residual water or feces in the rectum will be aspirated, and then the colon will be irrigated with warm water. When the cecum is reached, CO2 will be opened. In the CO2 group, colonoscopy is performed in the usual fashion, with minimal insufflation required to aid insertion. Cleaning in the CO2 group will be performed entirely during withdrawal. Upon arriving at the cecum, CO2 insufflation will be used in both groups and the scope will be withdrawn from the cecum to the hepatic flexure, with inspection of the mucosa at the same time. All polyps identified will be resected and sent for pathology evaluation. The most distal part of the hepatic flexure will be marked by a forceps biopsy and then the scope will be reinserted into the cecum by the first endoscopist using CO2 insufflation. A tandem inspection of the right colon will then be performed by a second endoscopist blinded to the insertion method in both study groups. All polyps found herein will be counted as the missed polyps. After the second withdrawal to the mark of distal hepatic flexure, the remainder of the colon will be examined in a standard manner by the first endoscopist. Polyp search and resection will be performed during the withdrawal phase in both groups. Insertion polypectomy will not be performed.

Inclusion Criteria:

• Consecutive patients aged 45 years or older undergoing colonoscopy for screening, surveillance, and positive FIT will be considered for enrollment.

Exclusion Criteria:

• familial adenomatous polyposis and hereditary non-polyposis CRC syndrome, personal history of CRC or inflammatory bowel disease, previous colonic resection, obstructive lesions of the colon, gastrointestinal bleeding, allergy to fentanyl, midazolam or propofol, American Society of Anesthesiology (ASA) classification of physical status grade 3 or higher, mental retardation, pregnancy, and refusal to provide a written informed consent.

2 weeks

The second endoscopist will perform tandem right colon examination and is blinded to the insertion method used by the first endoscopist.