Optical diagnosis of colorectal polyps: a randomized controlled trial comparing endoscopic image-enhancing modalities

Journal Pre-proof Optical diagnosis of colorectal polyps: a randomized controlled trial comparing endoscopic image enhancing modalities Roupen Djinbachian, Etienne Marchand, Heiko Pohl, Andres Aguilera-Fish, Mickael Bouin, , Érik Deslandres, Audrey Weber, Simon Bouchard, Benoît Panzini, Daniel von Renteln PII:

S0016-5107(20)35019-7

DOI:

https://doi.org/10.1016/j.gie.2020.11.023

Reference:

YMGE 12532

To appear in:

Gastrointestinal Endoscopy

Received Date: 17 August 2020 Accepted Date: 18 November 2020

Please cite this article as: Djinbachian R, Marchand E, Pohl H, Aguilera-Fish A, Bouin M, Deslandres É, Weber A, Bouchard S, Panzini B, von Renteln D, Optical diagnosis of colorectal polyps: a randomized controlled trial comparing endoscopic image enhancing modalities, Gastrointestinal Endoscopy (2020), doi: https://doi.org/10.1016/j.gie.2020.11.023. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020 by the American Society for Gastrointestinal Endoscopy

Optical diagnosis of colorectal polyps: a randomized controlled trial comparing endoscopic image enhancing modalities Roupen Djinbachian1, Etienne Marchand2, Heiko Pohl3, Andres Aguilera-Fish3, Mickael Bouin4, Érik Deslandres4, Audrey Weber4, Simon Bouchard4, Benoît Panzini4, Daniel von Renteln4

Division of Internal Medicine, Montreal University Hospital Center (CHUM) and Montreal University

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University of Montreal, Faculty of Medicine and Montreal University Hospital Research Center

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2

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Hospital Research Center (CRCHUM), Montreal, Canada.

Department of Veterans Affairs Medical Center, White River Junction, Vermont, and Dartmouth Geisel

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3

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(CRCHUM), Montreal, Canada.

School of Medicine, Hanover, New Hampshire, USA.

Division of Gastroenterology, Montreal University Hospital Center (CHUM) and Montreal University

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4

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Hospital Research Center (CRCHUM), Montreal, Canada.

Corresponding author

Daniel von Renteln, MD, Department of Medicine, Division of Gastroenterology, Montreal University Hospital (CHUM) and Montreal University Hospital Research Center (CRCHUM), 900 Rue Saint-Denis, Montréal, QC H2X 0A9, Montreal, Canada, Fax: +1(514)4127287, e-mail: [email protected].

Disclosures Roupen Djinbachian, Etienne Marchand, Andres Aguilera-Fish, Mickael Bouin, Érik Deslandres, Audrey Weber, Simon Bouchard and Benoît Panzini have no conflicts of interest relevant to this paper to declare. Heiko Pohl has received research funding from Boston Scientific and US Endoscopy. Daniel von Renteln is supported by a “Fonds de Recherche du Québec Santé” (FRQS) career development award and has received research funding from ERBE, Ventage, Pendopharm, and Pentax and is a consultant for Boston Scientific and Pendopharm. Daniel von Renteln has no other personal or financial conflicts of

interest relevant to this paper to declare. This study was fully funded by Pentax, and equipment used was provided by Pentax.

Author contributions to manuscript Roupen Djinbachian: Acquisition of data; analysis and interpretation of data; preliminary statistical support; drafting of the manuscript; critical revision of the manuscript for important intellectual content. Etienne Marchand: Acquisition of data; analysis and interpretation of data; critical revision of the

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manuscript for important intellectual content.

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Heiko Pohl: Statistical support; analysis and interpretation of data; critical revision of the manuscript for important intellectual content.

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manuscript for important intellectual content.

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Andres Aguilera-Fish: Statistical support; analysis and interpretation of data; critical revision of the

Mickael Bouin: Analysis and interpretation of data; critical revision of the manuscript for important

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intellectual content.

intellectual content.

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Érik Deslandres: Analysis and interpretation of data; critical revision of the manuscript for important

intellectual content.

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Audrey Weber: Analysis and interpretation of data; critical revision of the manuscript for important

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Simon Bouchard: Analysis and interpretation of data; critical revision of the manuscript for important intellectual content.

Benoît Panzini: Analysis and interpretation of data; critical revision of the manuscript for important intellectual content. Daniel von Renteln: Study concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content.

ABSTRACT BACKGROUND AND AIMS: Optical polyp diagnosis using image enhancing endoscopy (IEE) allows for real-time histology prediction of colorectal polyps. The aim of this study was to evaluate a recently introduced IEE modality (Optivista) in a randomized controlled trial. METHODS: In a prospective cohort of subjects (age 45-80 years) undergoing elective screening, surveillance, or diagnostic colonoscopy all colorectal polyps between 1 to 5 mm underwent IEE assessment. Study subjects were randomized before their colonoscopy procedure to undergo optical polyp diagnosis either using Optivista (OV) IEE or iScan (IS) IEE. A validated IEE scale (NICE classification) was used for optical polyp diagnosis. Primary

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outcome was the agreement of surveillance intervals determined when using OV IEE compared with IS IEE in reference with pathology-based surveillance intervals. Secondary outcomes included the percentage of

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surveillance intervals that could be given on the same day as the procedure, percentage of pathology tests

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avoided, diagnostic performance, and negative predictive value (NPV) of optical diagnosis for rectosigmoid adenomas.

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RESULTS: A total of 410 patients were enrolled in the trial. The polyp detection rate was 58.6% and the

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adenoma detection rate was 38.8%. The proportion of correct surveillance interval assignment when using OV IEE or IS was 96.5% versus 96.0% (p=0.75). A total of 65.1% of patients could be given same-day surveillance

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intervals when using OV IEE versus 73.1% for IS (p=0.07). The NPV for rectosigmoid adenomas (including SSAs) was 97.5% when using OV IEE and 88.2% when using IS IEE. Using high-confidence optical diagnosis instead of

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52.8% for IS (p=0.34).

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pathology would have resulted in a 44.3% elimination of required pathology examinations for OV IEE versus

CONCLUSION: Optical diagnosis using OV IEE and IS both surpassed the 90% benchmark of surveillance interval assignment, and no significant difference with regard to correct surveillance interval assignment was found. OV IEE surpassed the ≥90% NPV for rectosigmoid adenomas whereas IS did not.

INTRODUCTION Colorectal polyps that are found during colonoscopy procedures are typically sent for histologic evaluation to determine the subsequent follow-up intervals for surveillance colonoscopies.1-3 Histopathology for these frequently found diminutive polyps, hyperplastic in the majority of cases, is costly.4 In order to reduce the costs associated with polypectomy and pathology evaluation, optical polyp diagnosis has been proposed as alternative to histopathology for diminutive (1-5 mm) polyps. Using optical polyp diagnosis, polypectomy, and then discarding the polyp or leaving benign rectosigmoid polyps unresected (so-called resect-and-discard

strategy and diagnose-and-leave strategies) has been endorsed by the American and European Societies for Gastrointestinal Endoscopy (ASGE and ESGE) if optical diagnosis can achieve >90% concordance with pathology-based surveillance intervals and a >90% negative predictive value (NPV) for rectosigmoid adenomas.5, 6 To facilitate optical diagnosis, the Pentax endoscopy platform uses IS (Pentax, Tokyo, Japan) image-enhanced endoscopy (IEE). Studies have shown that IS has been able to meet ASGE benchmarks for optical diagnosis in some studies; however, not all studies have reached the required quality benchmarks set forth by the ASGE and ESGE7, 8. Recently, a new Pentax optical enhanced imaging system (Optivista [OV]) has been introduced

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that uses a mechanical light filter instead of the previously used image postprocessing methodology (iScan [IS]). This technical update in the OV IEE platform aims to improve real-time surface and vessel description and

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IS for optical polyp diagnosis of diminutive colorectal polyps.

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characterisation of colorectal polyps. Our study aimed to evaluate the new OV IEE system and compare it with

METHODS

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Study Design and Participants

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We conducted a single center randomized control trial comparing OV IEE with IS for diagnosis of diminutive colorectal polyps. Study protocol was approved by the Montreal University Hospital Research Center

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(CRCHUM) institutional review board in January 2018 (CER: 17.135) and registered at ClinicalTrials.gov (NCT03515343). The study was performed in accordance to the approved protocol and the declaration of

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Helsinki. Written informed consent was provided by all patients involved in the study. Eligible participants included adults between 45 to 80 years presenting at the Montreal University Hospital Center (CHUM) for a full elective colonoscopy (including screening, surveillance, or diagnostic colonoscopies). Consecutive patients were recruited from March to August 2018. Exclusion criteria were (1) known inflammatory bowel disease; (2) active colitis; (3) coagulopathy; (4) familial polyposis syndrome; (5) poor general health (defined as an American Society of Anesthesiologists class >3); and (6) emergency colonoscopies (defined as colonoscopy in the emergency or intensive care unit or patients with active upper or lower GI bleeding). We performed a secondary chart and case report form review after data collection to check for data accuracy and excluded the following cases from the polyp IEE analyses when assessing diagnostic performance: polyps that had missing pathology results; polyps that were diagnosed as cancer; and polyps >10 mm. Randomization and Procedures Participants were randomized at a 1:1 ratio using a computer-generated randomization list and assigned to undergo OV-enhanced endoscopy (Group 1) or IS-enhanced endoscopy (Group 2). We used the Research

Electronic Data Capture (RedCap, project-redcap.org) web-based platform to randomize each patient on the day of their procedure in the moments before the colonoscopy. Randomization allocation was performed by a research assistant involved in data acquisition, patient recruitment, but not involved in study data analysis. Patients and pathologists were blinded to randomization allocation groups; however, endoscopists were not. All patients were prepared for colonoscopy using usual-care bowel-cleansing preparation. Standard endoscopic equipment was used for study procedures. Colonoscopies were performed by 10 experienced gastroenterologists that have all previously used IS for more than a year but did not routinely perform optical diagnosis in their endoscopic practice. Endoscopists had no prior experience with the OV IEE system. Before the initiation of the study, participating endoscopists were given a 30-minute presentation on optical diagnosis

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using the OV IEE followed by an image-based optical diagnosis test. Further training and testing were planned

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in case of poor performance but did not prove necessary during our study as all endoscopists had accuracies

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>80% during initial testing.

Polyps detected during the procedure were measured using tip of a closed snare. Polyp location was

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documented, and morphology was assessed according to Paris classification. One to 5 mm (diminutive) polyps

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were further assessed according to NICE classification using both white-light imaging and the assigned randomized IEE.9 The OV EPK i7010 (Pentax, Tokyo, Japan) processor was used for the OV IEE arm. The OV

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Enhanced (OE) 2 setting was used for the OV IEE arm and IS 3 was used for the IS arm. Endoscopists pushed the endoscope close to detected polyps and observed the lesions for several seconds either through live video feed

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or by capturing an image and observing the polyp picture during the procedure. Specific techniques used to obtain stable images were left to the endoscopist to simulate a routine practice scenario. Diagnosis and

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confidence level (high/low) were then documented. Reference pictures for the NICE classification were kept in each endoscopy suite and were available for lookup throughout the study. All polyps were resected and sent for histopathologic evaluation and patients were assigned surveillance intervals based on pathology as per standard practices at our hospital center. Histopathology was used as the reference-standard to which each IEE was compared. Adenomatous polyps and all sessile serrated adenomas/polyps (SSA/Ps) were considered as neoplastic polyps.

Outcomes The primary outcome in this study was surveillance interval agreement with pathology-based diagnosis for OVenhanced and IS-enhanced optical diagnosis using NICE classification system. The 2012 U.S. Multi-Society Task Force (USMSTF) guideline was used as reference for surveillance interval assignment.10 First-degree family history of CRC, inadequate bowel preparation, and histopathology results of all polyps were taken into account

for surveillance interval assignment. When optical diagnosis was made with low confidence, the corresponding surveillance interval was based on pathology result instead of optical diagnosis for that particular polyp. Reported surveillance intervals were therefore based on high-confidence diagnoses when they could be made, or pathology result when they could not be made as per ASGE guidelines.5 Secondary outcomes included the effect of misdiagnoses on final surveillance interval assignment; proportion of patients who could be provided with surveillance intervals immediately post-colonoscopy; proportion of pathology testing that could be avoided. Outcomes also included negative predictive value (NPV); NPV for rectosigmoid polyps; positive predictive value (PPV); sensitivity; specificity for OV-enhanced and IS-enhanced

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diagnosis using NICE classification systems stratified by polyp histology. Proportion of pathology testing that could be avoided was defined as the percentage of polyps that were both 1 to 5 mm in size and had a high-

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confidence optical diagnosis divided by all polyps detected during the procedures.

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For rectosigmoid adenoma NPV, we computed a binomial variable by combining adenomas and SSAs versus hyperplastic polyps. ASGE guidelines do not mention SSAs in their benchmark for implementing “diagnose and

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leave” strategies.5 Current guidelines assign similar risks for these polyp histologies and should be treated as

Sample Size Calculation

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considered an undesired outcome.11

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equivalent to adenomas within “diagnose and leave” as misdiagnosing an leaving in place a SSA would be

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For sample size calculations we assumed that OV-enhanced diagnosis would achieve a 85% concordance with pathology and that IS would achieve 70% concordance with pathology.12 Assuming a 60% polyp detection rate,

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we needed to enrol at least 200 patients per randomization arm to detect an effect size of 15% (power of 80%, and alpha of 0.05). We calculated a need for a total of 400 randomized patients enrolled into the study. Statistical Analysis A cohort of all eligible ≤5 mm polyps were used for optical diagnosis accuracy analysis (Figure 1). Descriptive analysis with presentation of crude numbers, proportions or means with SD were used to present patient, procedure, and polyp outcomes. Agreement between the optical diagnosis for each imaging modality and pathology-based recommendations were presented as proportions with a 95% confidence interval (CI). Outcomes were presented as proportions or proportional estimates with a 95% CI. We used the Chi square test for categorical variables and t-test for continuous variables. A 2-tailed p<0.05 was considered statistically significant. We computed sensitivity, specificity, NPV, and PPV of OV IEE and IS-based diagnosis for each polyp type, along with 95% 2-sided confidence intervals. We performed a sensitivity analysis, removing the bestperforming and worst-performing endoscopist to measure the effects of outliers on optical diagnosis performance.

RESULTS Patient and Polyp Characteristics A total of 425 patients were assessed for eligibility and 399 patients were randomized and included in our patient-based analysis (198 for OV IEE and 201 for IS). In these patients, a total of 318 eligible polyps ≤5 mm were found and included in our polyp-based analysis (170 for OV IEE and 148 for IS) (Figure 1). Polyps were identified in 61.6% of patients for the OV IEE arm and 55.7% of patients for the IS arm (p=0.23). Adenoma detection rate was 39.4% for the OV IEE arm versus 38.3% for the IS arm (p=0.82). There was no statistically significant difference for both allocation groups with regards to age, sex, and all other patient and procedure

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for all diminutive polyp−related characteristics (Table 2).

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characteristics tested for (Table 1). There was no statistically significant difference for both allocation groups

Surveillance Interval Assignment

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When using the NICE classification for optical diagnosis, 96.5% of patients were assigned correct surveillance

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intervals for the OV IEE arm versus 96% for the IS arm (p=0.76). A total of 1.5% of intervals were shorter than recommended for OV IEE, and 2% were longer. For IS, 1% of surveillance intervals were shorter than

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recommended and 3% were longer. Sensitivity analysis yielded similar results when removing the best- and worst-performing endoscopist (Table 1S).

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In patients for whom at least one diminutive polyp underwent optical diagnosis, 93.6% of patients were assigned correct surveillance intervals for the OV IEE arm versus 90.6% for the IS arm (p=0.48). A total of 3.2%

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of intervals were shorter than recommended for OV IEE and 3.2% were longer. For IS, 2.3% of surveillance intervals were shorter than recommended and 7.6% were longer. A total of 65.1% of patients could be assigned a surveillance interval on the same day as the colonoscopy when using OV IEE versus 73.1% for IS (p=0.07) (Table 3).

Polyp-based performance Detailed information for diagnosis based on polyp type can be found in Table 4. Histopathology could be avoided in 44.3% of polyps in the OV IEE arm versus 52.8% for IS. OV IEE had lower proportion of diagnoses made with high confidence when compared to IS3 (71.7% vs 80.1%, p=0.08).

Hyperplastic polyps For high-confidence diagnoses using the NICE classification, the sensitivity, specificity, NPV, and PPV for OVassisted diagnosis were 78.7% (95% CI, 66.4 – 88.1); 87.9% (95% CI, 76.7 – 95.0); 78.5% (95% CI, 66.5 – 87.7);

and 88.9% (95% CI, 77.4 – 95.8). Sensitivity, specificity, NPV, PPV for IS assisted diagnosis were 80.4% (95% CI, 66.9 – 90.2); 74.2% (95% CI, 62.0 – 84.2); 83.0% (95% CI, 71.0 – 91.6); and 70.7% (95% CI, 57.3 – 81.9).

Adenomas For high confidence diagnoses using the NICE classification, the sensitivity, specificity, NPV, and PPV for OV assisted diagnosis were 89.5% (95% CI, 78.5 – 96.0); 83.9% (95% CI, 72.3 – 92.0); 89.7% (95% CI, 78.8 – 96.1); and 83.6% (95% CI, 71.9 – 91.8). Sensitivity, specificity, NPV, PPV for IS assisted diagnosis were 75.4% (95% CI, 63.1 – 85.2); 86.5% (95% CI, 74.2 – 94.4); 73.8% (95% CI, 60.9 – 84.2); and 87.5% (95% CI, 75.9 – 94.8). Rectosigmoid adenoma NPV was higher for OV assisted diagnosis when compared with IS (97.5% [95% CI, 86.8

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– 99.9] vs 88.2% [95% CI, 72.5 – 96.7]). Sensitivity analysis yielded similar results when removing the best and

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worst-performing endoscopist (Table 1S).

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DISCUSSION

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In this randomised controlled trial, we compared the performance of a novel endoscopic imaging modality (OV IEE) for the first time with an established predecessor in routine clinical use. OV IEE and IS-enhanced

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endoscopy both surpassed the 90% benchmark with regard to pathology-based and guideline conforming

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surveillance intervals when used for optical diagnosis of diminutive polyps. However only OV IEE reached the ASGE benchmark (rectosigmoid adenoma NPV) required for the “diagnose and leave” strategy, likely due to the

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better characterisation of adenomatous and serrated features allowing for decreased false-negative rates. Both OV IEE and IS qualify to be used as a replacement for histologic evaluation of resected 1 to 5 mm polyps

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(“resect and discard” strategy). OV IEE can be used for leaving diminutive polyps in place in the rectosigmoid (“diagnose and leave” strategy).5 OV IEE should therefore be preferentially used for optical diagnosis of diminutive polyps.

Our study showed a marked improvement over a previous study that found only 70% concordance with pathology-based surveillance intervals when using IS.12 In our study, endoscopists were provided with a training module at the initiation of the study, which could explain the increased performance compared with previous studies.12 Multiple studies have shown that endoscopists can improve optical diagnostic performance through training.13, 14 In our study, IS had a trend towards higher percentage of diagnoses made with high confidence when compared with OV IEE. This could be explained by the novelty of OV technology and the need for endoscopists to get accustomed before gaining confidence with their diagnoses. There were no improvements in diagnostic accuracy between the first and second half of optical diagnoses during the course of our study (6 months) for both OV IEE and IS. Endoscopists enrolled in our study did not receive feedback on their diagnoses and therefore could not improve upon the accuracy of their diagnoses. This highlights the need

for dedicated Pentax training modules for optical diagnosis to increase performance when using both IS and OV IEE. The choice of classification systems for optical diagnosis is another important factor for diagnostic accuracy. In our study, we chose to use the NICE classification as it has previously achieved ASGE quality benchmarks using varied imaging modalities in multiple independent studies.13 This could partially explain the improvement in concordance with pathology-based surveillance interval when compared with a previous study where pit patterns were used as diagnostic criteria.12 The SIMPLE classification has been designed for use with IS but was not originally validated for OV IEE. If used, this could have potentially biased results in favor of IS-assisted

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diagnoses. Further studies validating the SIMPLE classification for OV IEE should be performed.

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There exist multiple other optical classification systems, with some, such as WASP including specific criteria for the diagnosis of SSAs.15 Clinical comparison in the literature between these classification systems is lacking, and

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studies need to be performed to determine the optimal classification system for optical diagnosis.

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As shown in a previous study we found that an incorrect optical diagnoses sometimes does not negatively affect the final surveillance interval assignment.16 We found that 35% to 40% of patients had at least one

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misdiagnosed polyp that did not result in an altered final surveillance interval. When the 2012 USMSTF guidelines were used, 2 small adenomas confer a 5 to 10 year surveillance interval, whereas misdiagnosing

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both polyps as hyperplastic confers a 10-year interval which is within the previous recommendation.2 Most

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misdiagnoses in our study involved similar scenarios where only 1 or 2 polyps were misdiagnosed. With the updated 2020 guidelines, this will likely still hold true as 10-year surveillance intervals still applied to many

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situations encountered in our study.17 Endoscopists therefore have more leeway when making optical diagnoses based on the 2020 guidelines and despite that incorrect individual polyp diagnosis occurs the ASGE benchmark for surveillance interval assignment is easily surpassed.

The use of optical diagnosis instead of pathology evaluation has taken increasing importance in recent years for small and diminutive polyps, as their potential of harboring advanced pathology or cancer is low and the polyp detection rate has increased significantly during the last decade.18 Studies have shown that removing the need for histologic evaluation of resected polyps can provide significant cost savings and allow for the allocation of these resources towards other healthcare needs.4 Optical diagnosis also allows for same day assignment of surveillance intervals, decreasing the potential for loss of follow, incorrectly assigning surveillance intervals, and removing the requirement for pathology follow-up. Strategies such as “diagnose and leave” have the potential to decrease endoscopy time through elimination of polyp resection and retrieval. Performing optical diagnosis might add to procedure time; however, our endoscopists performed a diagnosis within seconds of visualizing each polyp and is therefore unlikely to extend endoscopy time significantly. To allow for widespread

use of optical diagnosis, endoscopists need to be confident in their diagnostic abilities and in the tools provided to them to assist in performing these diagnoses. Providing better tools that increase endoscopist comfort with optical diagnosis is important, as uptake of optical diagnosis is currently exceedingly low.19

A recent study found that endoscopists cited the fear of missing lesions, leading to legal repercussions as the main barrier for implementation of optical diagnosis.19 For adenomatous polyps, OV IEE had higher sensitivity and similar specificity when compared with IS; however, OV IEE had much higher NPV (89.7% vs 73.8%). This could have beneficial implications in routine clinical practice as OV IEE could provide endoscopists with more certainty compared with IS when ruling out adenomas, thus potentially increasing implementation of optical

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diagnosis.

The strength of our study is in the inclusion of multiple endoscopists for the diagnosis of polyps, which better

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reflects performance of these IEE in general practice and improves the external validity of our results.

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Performance using optical diagnosis was also much higher using IS than previous studies.12 Limitations include the single-center nature of the study and the presence of missing data for some polyps and patients, although

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these represent a very small proportion of our results. Another limitation is the lack of dedicated Pentax training modules for practicing optical diagnosis, as all our endoscopists have trained using NBI-enhanced

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training modules. Because endoscopists were closely observed during the study, this could have affected their

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performance throughout the procedures and reduced its generalizability to general endoscopic practice.

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The use of NICE classifications instead of classification systems specifically designed and validated for IS such as SIMPLE20 could have potentially lowered diagnostic performance. However, correct surveillance interval assignment was still high (>90%) for both arms. Another limitation of the NICE classification was the lack of criteria for the diagnosis of SSA/Ps. Endoscopists were instead instructed to revise their diagnoses if polyp aspect suggested the presence of SSA/Ps. The low proportion of pathology diagnosed SSA/Ps prohibited performing analyses for both IEE modalities for those polyp histologies. Because guidelines had loose recommendations for surveillance intervals for some polyp histologies (eg, 5 – 10 years), we chose to use the longest of the proposed intervals for both IEEs and pathology-based intervals. This study evaluated 2 imaging modalities from the same manufacturer (Pentax), and more studies need to be performed to evaluate whether optical diagnosis is feasible for all image enhancing modalities.

In conclusion, OV IEE performed superior to IS in our randomised controlled trial. Both IEE achieved ASGE quality metrics for optical diagnosis for surveillance interval assignment and can be used safely in routine clinical practice. OV IEE achieved ASGE quality metrics for rectosigmoid adenoma NPV allowing its use for

“diagnose and leave” strategies. OV IEE had higher sensitivity and NPV for adenoma diagnosis in the complete colon and rectosigmoid, allowing for higher confidence when ruling out adenomas. OV IEE should be the preferably used modality, but combining it with IS should be considered as a complementary IEE modality for optical diagnosis of colorectal polyps to achieve optimal pathology prediction, NPV, and surveillance interval assignment.

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Table 1 Patient/procedure characteristics P value 0.51 0.87 0.95

81 (40.9) 59 (29.8) 41 (20.7) 17 (8.6) 187 (94.4) 221 122 (61.6) 107 78 (39.4)

72 (35.8) 52 (25.9) 59 (29.3) 18 (8.9) 190 (94.5) 192 112 (55.7) 116 77 (38.3)

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IS IEE 62.7 111 (55.2) 175 (87.0)

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Age (Mean) Sex, female (%) Bowel preparation quality adequate* (%) Colonoscopy indication (%) Screening Surveillance Diagnostic Other Cecal Intubation (%) No. of polyps Polyp detection rate, n (%)** No. of adenomas Adenoma detection rate, n (%)**

OV IEE 62.1 111 (56.0) 172 (86.9)

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*Defined as Boston score ≥6, **Defined as percentage of patients where at least one polyp/adenoma was found.

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Table 2 Diminutive Polyp Characteristics

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Size (Mean) Paris classification (%) Is Ip ≥IIa Segment Proximal to rectosigmoid Rectosigmoid Polyp type Hyperplastic Adenoma SSA/P HGD

OV IEE (n=170) 3.3

IS IEE (n=148) 3.1

P value

165 (97.0) 0 (0) 5 (3.0)

143 (96.6) 0 (0) 5 (3.4)

0.82

94 (56.3) 76 (44.7)

94 (63.5) 54 (36.5)

0.137

87 (51.2) 80 (47.1) 3 (1.7) 0 (0)

60 (40.5) 86 (58.1) 2 (1.4) 0 (0)

0.144

0.07

SSA/P: Sessile serrated adenoma/polyp; HGD: high-grade dysplasia

94

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Patients with at least one ≤5 mm polyp diagnosed optically

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Effect of misdiagnosis (mis-Dx) on final surveillance intervals (%) Correct diagnosis for all polyps At least 1 mis-Dx but did not affect final surveillance interval At least 1 mis-Dx that affected final surveillance interval

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Surveillance interval can be provided immediately postcolonoscopy

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Pathology tests for polyps avoided, n (%)

193 (96.0) 2 (1.0) 6 (3.0)

P value

0.75

85

88 (93.6) 3 (3.2) 3 (3.2)

77 (90.6) 2 (2.3) 6 (7.6)

53 (56.4) 37 (39.4) 4 (4.2)

47 (55.3) 31 (36.5) 7 (8.2)

0.53

129 (65.1)

147 (73.1)

0.07

117/242 (44.3)

113/214 (52.8)

0.34

-p

Concordance with pathology for surveillance intervals (%) Same Shorter Longer

IS IEE 201

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Table 3 Optical diagnosis results OV IEE versus IS IEE using NICE classification OV IEE All patients 198 Concordance with pathology for surveillance intervals (%) Same 191 (96.5) Shorter 3 (1.5) Longer 4 (2.0)

0.48

Table 4 Diagnostic performance based on polyp type using NICE for diminutive polyps, OV IEE versus IS IEE* OV IEE

IS IEE

119 (71.7)

117 (80.1)

48/61 78.7 (66.4 – 88.1) 51/58 87.9 (76.7 – 95.0) 51/65 78.5 (66.5 – 87.7) 48/54 88.9 (77.4 – 95.8)

41/51 80.4 (66.9 – 90.2) 49/66 74.2 (62.0 – 84.2) 49/59 83.0 (71.0 – 91.6) 41/58 70.7 (57.3 – 81.9)

Diagnosis made with high confidence n, (%) Hyperplastic polyps n, %, (95%CI) Sensitivity

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Specificity

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NPV

-p

PPV Adenoma n, %, (95%CI)

51/57 89.5 (78.5 – 96.0) 52/62 83.9 (72.3 – 92.0) 52/58 89.7 (78.8 – 96.1) 51/61 83.6 (71.9 – 91.8) 39/40 97.5 (86.8 – 99.9)

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Sensitivity

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Specificity

PPV

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Rectosigmoid NPV‡

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NPV

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* For high confidence diagnoses. ‡ SSAs were considered equivalent to adenomas. NPV: Negative Predictive Value; PPV: Positive Predictive Value

Figure 1 Study inclusion and randomization flow chart

49/65 75.4 (63.1 – 85.2) 45/52 86.5 (74.2 – 94.4) 45/61 73.8 (60.9 – 84.2) 49/56 87.5 (75.9 – 94.8) 30/34 88.2 (72.5 – 96.7)

P value 0.08

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Journal CME Conflict of Interest: Disclosure and Attestation Lead Author: Article: Date:

Daniel von Renteln Optical diagnosis of colorectal polyps: A randomized controlled trial comparing Optivista versus iScan image enhanced endoscopy 2020-08-17

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The purpose of this form is to identify all potential conflicts of interests that arise from financial relationships between any author for this article and any commercial or proprietary entity that produces healthcare-related products and/or services relevant to the content of the article. This includes any financial relationship within the last twelve months, as well as known financial relationships of authors’ spouse or partner. The lead author is responsible for submitting the disclosures of all listed authors, and must sign this form at the bottom. Additional forms may be submitted if the number of authors exceeds the space provided. Email Address*:

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No financial relationships with a commercial entity producing health-care related products and/or services relevant to this article. Company Type of Relationship** Content Area (if applicable)

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Author:

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No financial relationships with a commercial entity producing health-care related products and/or services relevant to this article. Company Type of Relationship** Content Area (if applicable)

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No financial relationships with a commercial entity producing health-care related products and/or services relevant to this article. Company Type of Relationship** Content Area (if applicable)

As corresponding author of this article, I attest that I have received disclosure information from all participating authors as listed above and acknowledge that I am responsible for verifying the accuracy of and reporting completely the information provided to me. Financial relationships relevant to this article can be researched at https://www.cms.gov/openpayments/. I understand that typing my name below serves as an electronic signature for the purposes of this form.

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Abbreviations ASGE American Society for Gastrointestinal Endoscopy CRC Colorectal Cancer ESGE European Society for Gastrointestinal Endoscopy IEE Image Enhanced Endoscopy NPV Negative Predictive Value OE Optivista Enhanced PPV Positive Predictive Value

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SSA/P Sessile Serrated Adenoma/Polyp

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na

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USMSTF US Multi-Society Task Force

Journal CME Conflict of Interest: Disclosure and Attestation Lead Author: Article: Date:

Daniel von Renteln Optical diagnosis of colorectal polyps: A randomized controlled trial comparing Optivista versus iScan image enhanced endoscopy 2020-08-17

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The purpose of this form is to identify all potential conflicts of interests that arise from financial relationships between any author for this article and any commercial or proprietary entity that produces healthcare-related products and/or services relevant to the content of the article. This includes any financial relationship within the last twelve months, as well as known financial relationships of authors’ spouse or partner. The lead author is responsible for submitting the disclosures of all listed authors, and must sign this form at the bottom. Additional forms may be submitted if the number of authors exceeds the space provided. Email Address*: [email protected]

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Lead Author: Daniel von Renteln

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Research funding Research funding Research funding, consultant Research funding Consultant

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Pentax ERBE Pendopharm Ventage Boston Scientific Author: Etienne Marchand

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Boston Scientific US Endoscopy

Author: Andres Aguilera-Fish

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Author: Roupen Djinbachian

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No financial relationships with a commercial entity producing health-care related products and/or services relevant to this article. Company Type of Relationship** Content Area (if applicable)

As corresponding author of this article, I attest that I have received disclosure information from all participating authors as listed above and acknowledge that I am responsible for verifying the accuracy of and reporting completely the information provided to me. Financial relationships relevant to this article can be researched at https://www.cms.gov/openpayments/. I understand that typing my name below serves as an electronic signature for the purposes of this form.

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* We will use email addresses only for questions related to this article 2 ** Type of relationship may include: full-time or part-time employee, independent contractor, consultant, research or other grant recipient, paid speaker or teacher, membership on advisory committee or review panels, ownership interest (product royalty/licensing fees, owning stocks, shares, etc.), relationship of a spouse or partner, or any other financial relationship.