Stool DNA Analysis is Cost-Effective for Colorectal Cancer Surveillance in Patients With Ulcerative Colitis

Accepted Manuscript Stool DNA Analysis is Cost Effective for Colorectal Cancer Surveillance in Patients with Ulcerative Colitis John B. Kisiel, MD, Gauree G. Konijeti, MD, MPH, Andrew J. Piscitello, MAT, Tarun Chandra, PhD, Thomas F. Goss, PharmD, David A. Ahlquist, MD, Francis A. Farraye, MD, MSc, Ashwin N. Ananthakrishnan, MBBS, MPH PII: DOI: Reference:

S1542-3565(16)30439-6 10.1016/j.cgh.2016.07.018 YJCGH 54839

To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 10 July 2016 Please cite this article as: Kisiel JB, Konijeti GG, Piscitello AJ, Chandra T, Goss TF, Ahlquist DA, Farraye FA, Ananthakrishnan AN, Stool DNA Analysis is Cost Effective for Colorectal Cancer Surveillance in Patients with Ulcerative Colitis, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.07.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.

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Title: Stool DNA Analysis is Cost Effective for Colorectal Cancer Surveillance in Patients with Ulcerative Colitis

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Short title: Stool DNA cost-effective for UC CRC

Authors: *John B. Kisiel, MD1

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*Gauree G. Konijeti, MD, MPH2,3 Andrew J. Piscitello, MAT4

Thomas F. Goss, PharmD5 David A. Ahlquist, MD1 Francis A. Farraye, MD, MSc6

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Tarun Chandra, PhD4

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Ashwin N. Ananthakrishnan, MBBS, MPH7

1. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester MN

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2. Division of Gastroenterology, Scripps Clinic, La Jolla CA 3. Scripps Translational Science Institute, La Jolla, CA

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4. EmpiraQA LLC, Long Grove IL 5. Boston Healthcare Associates, Boston MA 6. Center for Digestive Disorders, Boston Medical Center, Section of Gastroenterology, Boston University School of Medicine, Boston MA

7. Division of Gastroenterology and Hepatology, Massachusetts General Hospital and Harvard Medical School, Boston MA *Co-first authorship

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Grant Support: This was made possible by grants (to J.B.K.) from the Jack and Maxine Zarrow Family Foundation of Tulsa Oklahoma and the Paul Calabresi Program in Clinical-Translational

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Research (NCI CA90628). Additional support was provided by a National Institutes of Health KL2 grant (to G.G.K) (NCATS TR001112). Additional partial support was provided by the Carol M. Gatton endowment for Digestive Diseases Research. Additional funding was provided by

Abbreviations: CRC, Colorectal cancer CRN, Colorectal neoplasia

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HGD, High-grade dysplasia

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Exact Sciences (Madison WI).

ICER, Incremental cost-effectiveness ratio

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IPAA, Ileal pouch anal anastomosis LGD, Low-grade dysplasia

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QALY, Quality-adjusted life-year sDNA, Stool DNA

WLE, White light endoscopy WTP, Willingness to pay threshold

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Correspondence: John B. Kisiel, MD, 200 First Street SW, Rochester MN 55902, [email protected], 507-284-0959 (phone), 507-284-0538 (fax)

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Disclosures: Mayo Clinic has entered into an intellectual property agreement with Exact Sciences (Madison WI) whereby Drs. Kisiel and Ahlquist may receive royalties in accordance with Mayo Clinic policy. Drs. Konijeti, Chandra, Goss, Farraye & Ananthakrishnan and Mr.

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Piscitello have no relevant disclosures. Presented in part at Digestive Disease Week, May 2015,

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Washington DC

Author Contributions:

John B. Kisiel: study concept and design, acquisition of data, interpretation of data, drafting the manuscript, obtained funding, study supervision

Gauree G. Konijeti: study design, acquisition of data, interpretation of data, critical revision of

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the manuscript

Andrew J. Piscitello: analysis and interpretation of data, statistical analysis, critical revision of manuscript, technical support

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Tarun Chandra: analysis and interpretation of data, statistical analysis, critical revision of manuscript, technical support

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Thomas F. Goss: study design, interpretation of data, critical revision of manuscript David A. Ahlquist: study design, interpretation of data, critical revision of manuscript Francis A. Farraye: study design, interpretation of data, critical revision of manuscript Ashwin N. Ananthakrishnan: study design, analysis and interpretation of data, critical revision of manuscript

Word count, inclusive of references and legends (limit 4000): 3999

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Abstract word count inclusive of key words, as edited by Dr. Novak: 333

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References: 33

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ABSTRACT Background & Aims: Patients with chronic ulcerative colitis are at increased risk for colorectal neoplasia (CRN). Surveillance by white-light endoscopy (WLE) or chromoendoscopy may

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reduce risk of CRN, but these strategies are underused. Analysis of DNA from stool samples (sDNA) can detect CRN with high levels of sensitivity, but it is not clear if this approach is cost effective. We simulated these strategies for CRN detection to determine which approach is most

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cost effective.

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Methods: We adapted a previously published Markov model to simulate the clinical course of chronic ulcerative colitis, the incidence of cancer or dysplasia, and costs and benefits of care with 4 surveillance strategies. These strategies were: analysis of sDNA and diagnostic chromoendoscopy for patients with positive results, analysis of sDNA with diagnostic WLE for patients with positive results, chromoendoscopy with targeted collection of biopsies, or WLE

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with random collection of biopsies. Costs were based on 2014 Medicare reimbursement. The primary outcome was the incremental cost effectiveness ratio (incremental cost/incremental difference in quality-adjusted life years) compared with no surveillance and a willingness to pay

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threshold of $50,000.

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Results: All strategies fell below the willingness to pay threshold at 2 year intervals. Incremental cost effectiveness ratios were $16,362 per quality-adjusted life year for sDNA analysis with diagnostic chromoendoscopy; $18,643 per quality-adjusted life year for sDNA analysis with diagnostic WLE; $23,830 per quality-adjusted life year for chromoendoscopy alone; and $27,907 per quality-adjusted life year for WLE alone. In sensitivity analyses, sDNA analysis with diagnostic chromoendoscopy was more cost effective than chromoendoscopy alone, up to a cost of $1135 per sDNA test. sDNA analysis remained cost effective at all rates of compliance;

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when combined with diagnostic chromoendoscopy, this approach was preferred over chromoendoscopy alone, when the specificity of the sDNA test for CRN was above 65%.

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Conclusion: Based on a Markov model, surveillance for CRN is cost effective for patients with chronic ulcerative colitis. Analysis of sDNA with chromoendoscopies for patients with positive

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results was more cost effective than chromoendoscopy or WLE alone.

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KEY WORDS: ICER, QALY, cost benefit analysis; inflammatory bowel diseases

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INTRODUCTION Population-level data show an increased incidence of colorectal cancer (CRC) in inflammatory bowel disease (IBD), specifically among patients with extensive, long-standing

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ulcerative colitis (UC)1 and Crohn’s disease (CD) of the colon.2 Recent data show that CRC incidence and mortality in patients with UC is reduced with surveillance colonoscopy by white light endoscopy (WLE).3 Even prior to this evidence, surveillance colonoscopy became standard of care, based on several smaller scale case-control and cohort studies, which in aggregate,

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suggested a benefit from earlier-stage CRC diagnosis.4 Over the last decade, a growing body of

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literature suggests that dye-spray-enhanced surveillance with chromoendoscopy may be superior for the detection of dysplastic precursors to CRC. While multiple specialty society guidelines endorse surveillance colonoscopy with WLE,5 the recent SCENIC consensus statement, jointly issued by the American Gastroenterology Association and the American Society for Gastrointestinal Endoscopy, now recommends chromoendoscopy over standard

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definition WLE for CRC surveillance in UC patients.6

Since its introduction over a decade ago7 uptake of chromoendoscopy has been slow, due to the requirement for additional training, perceived increased procedure time, and higher

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costs.8 A recent study showed that chromoendoscopy might be more cost-effective than WLE but both modalities appeared to be above societal willingness to pay thresholds when used at

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currently recommended intervals.9 Complicating matters, patient compliance with CRC surveillance is unacceptably low, even among commercially-insured UC patients.10 Noninvasive testing by stool DNA (sDNA) is a new potential strategy, hypothesized to reduce costs and improve surveillance adherence.11-13 Multi-target sDNA has recently been approved by the United States Food and Drug Administration for average-risk CRC screening following a pivotal study in which sensitivity and specificity of sDNA for CRC were similar to gold-standard WLE.14

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The approved multi-target sDNA test, commercialized as Cologuard™ (Exact Sciences, Madison WI), assays mutant KRAS, methylated BMP3, methylated NDRG4 and a fecal immunochemical test (FIT). FIT cannot logically be applied in CD and UC as test specificity may

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be compromised by hemorrhagic inflammatory activity. However, recent case-control data show that stool assay of aberrant DNA methylation markers, achieved >90% sensitivity at 90% specificity for CRC in patients with IBD.15, 16

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Several important questions remain that must be addressed before sDNA can be used for CRC surveillance in patients with UC and CD. What sensitivity and specificity thresholds

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should be required of an sDNA test in this setting? How frequently should the test be applied? Will sDNA be cost-effective, and if so, at what price? We approached these knowledge gaps by modeling the cost-effectiveness of sDNA in comparison to WLE, chromoendoscopy or no surveillance in a hypothetical cohort of UC patients. Further, we sought to inform test design by 1-way sensitivity analyses of test performance, interval and cost. Lastly, probabilistic sensitivity

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analyses were performed to assess the reliability of model outputs.

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METHODS

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This study was exempt from Institutional Review Board review. Model Design

We adapted a previously published Markov model with Monte Carlo simulations9 and

imputed a clinical course of UC, the incidence of colorectal neoplasia (CRN, cancer + dysplasia), and costs & benefits of care with patients committed to one of four surveillance strategies: sDNA with diagnostic chromoendoscopy for sDNA test positives, sDNA with diagnostic WLE for sDNA positives, chromoendoscopy with targeted biopsies only, or WLE with

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random biopsies. The model was originally created with TreeAge Pro 2009 (TreeAge, Williamstown, MA) and updated with TreeAge 2015. The Markov cycle length was 1 year. The simulation sampled hypothetical patients, 8 years after population-based age distribution of UC

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diagnosis, the recommended duration to begin surveillance for dysplasia.17 Termination criteria were death or a patient age greater than 90 years with 10 years of surveillance. Pancolitis and left-sided disease were treated equally according to current guidelines for surveillance.5 Health

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states included chronic UC, chronic UC with dysplasia, status post-colectomy, CRC, and death due to either baseline mortality or mortality related to colonoscopy, surgery, or CRC (Figure 1). Base case values and ranges for transition probabilities and health state utilities (Supplemental

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Table 1) were obtained from a systematic literature search as previously described.9 Several key adaptations were included to address the specific aims of this study (Table 1).

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Risk of colorectal cancer and benefit of surveillance

Patients in the simulation cohort entered the model at an age consistent with populationlevel measurements of natural history.17 The probability of developing CRC, given no prior

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dysplasia, was modeled on population-level estimates; patients entered the simulation at 8 years after diagnosis with a 1.07% incidence of CRC to match cumulative incidence estimates

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of 2% at 15 years, 3% at 20 years and 4% at 25 years.18 Surveillance colonoscopy has been recently shown to reduce colorectal cancer incidence and all-cause mortality.3 To reflect this benefit, the model was designed to confer improved survival from CRC if detected by surveillance in accordance with previously published estimates.19 Stool DNA test performance in ulcerative colitis Base-case sDNA performance estimates were derived from average-risk sDNA test

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performance,14 which are more conservative than those available from the limited literature in IBD patient populations.15, 16 Also, each surveillance strategy assumed base case compliance

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of 0.5, consistent with US surveillance adherence estimates.10

Costs and utilities

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Care and procedure expenditures were based on 2014 Medicare reimbursement for specific procedures (Table 1) or updated to 2014 United States dollars from literature estimates

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(Supplemental Table 1) 20-22 using published medical Consumer Price Index inflation factors. Because sDNA cost for use in UC has not been determined, and because Medicare has not issued a national coverage determination for sDNA testing in IBD, the base cost was set at $599, the current price billed to commercial insurance for the Cologuard multi-target sDNA test for average-risk CRC screening (Exact Sciences, Madison WI). All costs were estimated from

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the payer perspective and did not include indirect patient expenses (e.g., travel, lost work time). Transient utilities included UC flare requiring colectomy, immediate postoperative state, and adverse events from either surgery or colonoscopy; these were modeled with 1 month

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duration. In patients simulated to have those events, yearly utilities were adjusted by a weighted average of the transient utility and the underlying utility attributed to chronic UC, post-IPAA state

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or cancer (Dukes stage A/B vs C vs D). All costs and utilities were discounted at a rate of 3% per year.

Analyses

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Base-case analysis was conducted by Markov modeling with Monte Carlo microsimulation which sampled all costs, utilities and probabilities to create 500,000 hypothetical patients and disease courses. The primary outcome was the incremental cost

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effectiveness ratio (ICER, incremental cost/ incremental difference in quality adjusted life years [QALY]) for each surveillance strategy at two year intervals compared to no surveillance. A willingness to pay (WTP) threshold of $50,000 per QALY was used to estimate cost-

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effectiveness.23

One-way sensitivity analyses evaluated the impact of surveillance compliance, sDNA

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test cost, and sDNA sensitivity & specificity. A second set of sensitivity analyses studied cost thresholds for a 1-year sDNA surveillance program, compared to 2-year intervals for chromoendoscopy and WLE.

To estimate the degree of uncertainty around the model assumptions, probabilistic

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sensitivity analysis (PSA) was then performed by simulating 100 separate cohorts of 100,000 patients. Cost, utility and probability variable inputs were sampled by the simulation software according to the distribution type and margin of error around the base-case point estimates (Table 1).. Model uncertainty was also examined using cost-effectiveness acceptability curves

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which utilize a net monetary benefit calculation (NMB) that combines cost, effectiveness and WTP into a single measurement (NMB = effectiveness x WTP – cost). The strategy with the

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highest NMB is the most cost-effective given the fixed WTP parameter. The sampling variation in the PSA was used to estimate the probability that a surveillance strategy is cost-effective for a given WTP (i.e. the decision maker’s threshold ICER). Where the probabilistic sensitivity analysis disagreed with the results of the base case analysis, additional acceptability curves were generated to identify input variables which might potentially disrupt to the expected outcome.

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RESULTS

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Base Case Analysis Relative to no surveillance, the primary cost-effectiveness analysis demonstrated that ICERs for annual, biennial and every 3 year sDNA, chromoendoscopy and WLE fell below the

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WTP threshold of $50,000 (Figure 2). While all options were cost-effective, the ICERs for

sDNA-based surveillance were lower than and not dominated by endoscopic-based options.

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Consistent with prior results,9 chromoendoscopy modalities were more cost-effective that WLE. In the no surveillance strategy on 500,000 hypothetical patients, the model generated 95,987 CRC cases, resulting in 81,502 CRC-related deaths over the full duration of the simulation. Biennial WLE reduced CRC cases by 53,800 and associated fatalities by 42,274. To prevent one additional CRC case, 9 patients would have to participate in programmatic WLE

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surveillance. Biennial chromoendoscopy prevented 52,539 cases and 42,104 hypothetical deaths with 10 surveillance program participants needed to prevent one additional CRC. Though less costly, sDNA with diagnostic chromoendoscopy, and sDNA with diagnostic WLE,

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prevented 17,681 and 16,230 hypothetical CRC fatalities, respectively. To prevent one additional CRC case, 18 and 19 patients would have to participate in programmatic surveillance

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with sDNA with diagnostic chromoendoscopy or diagnostic WLE, respectively. Assuming 50% base-case compliance with colonoscopy-based surveillance, and that non-compliant patients used sDNA, 58,504 to 59,785 CRC fatalities would be prevented. For this combination approach, only 5-8 patients would need to participate in programmatic surveillance with to prevent 1 additional CRC fatality.

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Sensitivity Analyses on Individual Variables All biennial surveillance modalities became more expensive as patient compliance increased, but at all levels of compliance at sDNA remained cost-effective. Unless the specificity

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of sDNA fell below 0.65, sDNA with diagnostic chromoendoscopy was preferred over

chromoendoscopy alone. Diagnostic sensitivity of sDNA did not impact cost-effectiveness

across a wide range of performance (0.25-0.99) for any target lesion, which included low-grade

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dysplasia (LGD), high-grade dysplasia (HGD) or CRC. Test cost for sDNA was prohibitive above $1,135 at which point chromoendoscopy became more cost-effective (Table 2). Similarly,

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in comparison of sDNA with diagnostic WLE against WLE alone, sDNA remained preferred unless the specificity of sDNA fell below 0.66 or cost of sDNA exceeded $1,109. If sDNA testing were to be performed annually, the threshold cost for sDNA would decrease to $601 and $675 in order to remain cost-effective when compared to biennial interval

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chromoendoscopy or WLE, respectively.

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Probabilistic Sensitivity Analysis

Probabilistic sensitivity analyses supported the findings of the base-case analysis

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(Figure 3, Supplemental Figure 1). Compared to no surveillance, sDNA with diagnostic chromoendoscopy was below the WTP threshold of $50,000 per QALY or dominant in 71 of 100 hypothetical patient cohorts. Stool DNA with diagnostic WLE or chromoendoscopy alone were below the WTP of $50,000 per QALY or dominant in 66 of the cohorts; WLE alone was below the WTP threshold or dominant 55% of the time. Base case analyses anticipated that sDNA-based options would show maximal NMB if payers were willing to pay $18,000-$45,000 per QALY (Supplemental Table 2); however,

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acceptability curves for the full set of input variables provided contradictory results to the base case. To determine why this PSA was discordant with base case expectations, the PSA repeated with stratified sampling by each of the combined utility, cost and probability variables

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to identify those that might be disruptive when sampled across the entire Monte Carlo distribution. With this approach, the output of all utility and cost variables remained consistent with base-case expectations, while results based on probability variables appeared

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contradictory (Figure 4, A-C). Sampling by individual probability variables generated curves which were each consistent with base case, therefore interaction among probability variables

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was suspected. To further investigate this, all probability inputs were sampled in clusters of 2-4 variables at a time in combination with the CRC incidence variable; however, each of these

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DISCUSSION

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acceptability curves matched base-case expectations (Figure 4 D, Supplemental Figure 2).

In this analysis of CRC surveillance strategies, sDNA appears to be more cost-effective

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when used with either diagnostic chromoendoscopy or diagnostic WLE than chromoendoscopy alone or WLE alone. Though chromoendoscopy has recently been endorsed by the SCENIC consensus statement,6 this modality is not yet widely utilized, leaving many patients and providers to rely on WLE. Endoscopy-based surveillance could become more cost-effective if sDNA specificity falls below 0.65 in comparison to chromoendoscopy surveillance alone or below 0.66 in comparison to WLE. These specificity thresholds are well below currently published estimates of sDNA performance in either IBD patients15, 16 or in the average risk population.14 The relative cost-effectiveness of sDNA was maintained across a wide spectrum

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of patient compliance, test sensitivity, and test costs. Even annual sDNA testing was costeffective in comparison to either annual or biennial endoscopy-based options. Regardless of test strategy, surveillance for dysplasia and CRC in UC patients appears

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cost-effective. These findings shed new light on a long-standing clinical uncertainty as previous economic analyses of endoscopic surveillance for CRC in UC patients have yielded mixed results. Provanzale, and colleagues performed a cost-effectiveness analysis of WLE

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colonoscopy in UC at 1-5 year intervals in comparison to no surveillance.24 While surveillance at intervals shorter than 5 years appeared to exceed WTP, the ICERs for all intervals were

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comparable to other commonly performed screening tests, such as cervical cancer screening.24 Subsequent threshold analyses and critical reviews on surveillance cost-effectiveness have highlighted that test cost, CRC incidence, mortality reduction from surveillance and quality of life after proctocolectomy are critical factors, whereas diagnostic accuracy of colonoscopy did not greatly impact results.9, 25-27 Consistent with these model outputs, our present analysis did not

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reveal significant threshold effects when varying the sensitivity of sDNA, though thresholds for specificity and cost were observed.

The present results also update a recent economic analysis of chromoendoscopy and

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WLE strategies which found dominance by chromoendoscopy but at costs exceeding a WTP of $100,000.9 The substantial relative QALY gains we observed were most likely due to the

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incorporation of recent data showing that WLE lowers CRC incidence and improves mortality.3 Surveillance of UC patients with WLE has only been shown to reduce CRC incidence in one observational study; two others showed earlier stage CRC diagnosis with corresponding mortality benefit.19, 28 There has been further concern that chromoendoscopy may overestimate risk of subsequent advanced neoplasia in patients with LGD by finding more lesions with uncertain natural history.13, 29 A recent update of the St. Mark’s Hospital surveillance cohort in the United Kingdom showed that the rate of progression from LGD to CRC was similar across

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each of 4 decades suggesting that the more recent introduction of chromoendoscopy has not changed the apparent risk attributable to LGD.28 The present model also relied on encouraging but preliminary available data on sDNA performance in IBD.15, 16 Because small sample size

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and single-center experience should prompt a cautious approach, we opted to use more conservative sDNA performance inputs from a large clinical trial of average-risk, asymptomatic patients in the general population,14 and utilized 1-way and probabilistic sensitivity analyses to

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evaluate sDNA cost-effectiveness across wide hypothesized ranges of test performance.

Results from a large multi-center case-control study on sDNA performance in IBD patients are

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eagerly anticipated (ClinicalTrials.gov identifier NCT01819766).

There are several potential limitations to this study. The acceptability curve generated from the full set of variables appeared contrary to the base-case results. Stratifying by inputs of utilities, costs and probabilities appeared to isolate probability variables; however, despite sampling probability variables individually and in groups of 2-4 at a time, we were unable to

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identify any potentially disruptive inputs. Therefore, we remain confident in the base-case findings. There is also the potential to under estimate costs. Inputs for costs of endoscopic procedures, complications, surgery and cancer care were modeled from the Medicare

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perspective, and may be lower than reimbursement rates from commercial insurance carriers. Also, the model did not include any indirect costs. While there is precedent for their exclusion

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due the difficulty of accurate measurement,24, 25, 27 this may under-estimate the total burden to society.

We are encouraged that surveillance for CRC in UC patients appears cost-effective, as

the ICER estimates of all options fell below a WTP of $50,000. Based on our modeling, sDNA was most cost-effective relative to no surveillance. The user-friendly features of sDNA may improve patient compliance,30 and its addition as an option in the surveillance arsenal may enhance overall effectiveness.

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FIGURE LEGENDS Figure 1. Model health state transition diagram from chronic ulcerative colitis (UC) to dysplasia, colorectal cancer (CRC), surgery or death

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Adapted from Konijeti GG, Shrime MG, Ananthakrishnan AN, Chan AT. Cost-effectiveness analysis of chromoendoscopy for colorectal cancer surveillance in patients with ulcerative colitis.

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Gastrointest Endosc. 2014 Mar;79(3):455-65 and used with permission.

Figure 2. Incremental cost-effectiveness ratios for each surveillance strategy at (A) annual, (B)

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biennial and (C) every 3-years surveillance intervals in comparison to no surveillance, which cost $189,960 for 19.65 quality-adjusted life years (QALY). CE, chromoendoscopy; sDNA, stool DNA; WLE, white light endoscopy

Figure 3. (A) Incremental cost-effectiveness ratio (ICER) scatter plot and 95% confidence

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interval ellipse in relationship to $50,000 willingness to pay threshold (WTP) for stool DNA with diagnostic chromoendoscopy in reference to no surveillance. Quadrants (QI-IV) are defined by cost and effectiveness axes and components (C1-6) define where stool DNA is recommended or not in relationship to WTP. (B) Interpretation key shows that stool DNA with diagnostic

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chromoendoscopy was the recommended surveillance strategy in the majority (71%) of cohorts

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in which the full range of model parameters was sampled. Figure 4. Acceptability curves for the each of the major input variable categories (A) utilities, (B) costs and (C) probabilities. Probabilities were further examined in smaller clusters of variables at a time (D) which all met base-case expectations.

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EP

20.

Choi PM, Nugent FW, Schoetz DJ, Jr., et al. Colonoscopic surveillance reduces mortality from colorectal cancer in ulcerative colitis. Gastroenterology 1993;105:418-24. Gunnarsson C, Chen J, Rizzo JA, et al. Direct health care insurer and out-of-pocket expenditures of inflammatory bowel disease: evidence from a US national survey. Dig Dis Sci 2012;57:308091. Lang K, Lines LM, Lee DW, et al. Lifetime and treatment-phase costs associated with colorectal cancer: evidence from SEER-Medicare data. Clin Gastroenterol Hepatol 2009;7:198-204. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst 2011;103:117-28. Grosse SD. Assessing cost-effectiveness in healthcare: history of the $50,000 per QALY threshold. Expert Rev Pharmacoecon Outcomes Res 2008;8:165-78. Provenzale D, Wong JB, Onken JE, et al. Performing a cost-effectiveness analysis: surveillance of patients with ulcerative colitis. Am J Gastroenterol 1998;93:872-80. Delco F, Sonnenberg A. A decision analysis of surveillance for colorectal cancer in ulcerative colitis. Gut 2000;46:500-6. Inadomi JM. Cost-effectiveness of colorectal cancer surveillance in ulcerative colitis. Scand J Gastroenterol Suppl 2003:17-21. Rubenstein JH, Waljee AK, Jeter JM, et al. Cost effectiveness of ulcerative colitis surveillance in the setting of 5-aminosalicylates. Am J Gastroenterol 2009;104:2222-32. Choi CR, Rutter MD, Askari A, et al. Forty-Year Analysis of Colonoscopic Surveillance Program for Neoplasia in Ulcerative Colitis: An Updated Overview. Am J Gastroenterol 2015;110:1022-1034. Higgins PD. Editorial: Miles to Go on the SCENIC Route: Should Chromoendoscopy Become the Standard of Care in IBD Surveillance? Am J Gastroenterol 2015;110:1035-1037. Schroy PC, 3rd, Lal S, Glick JT, et al. Patient preferences for colorectal cancer screening: how does stool DNA testing fare? Am J Manag Care 2007;13:393-400. Herrinton LJ, Liu L, Levin TR, et al. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. Gastroenterology 2012;143:382-9. Holubar SD, Long KH, Loftus EV, Jr., et al. Long-term direct costs before and after proctocolectomy for ulcerative colitis: a population-based study in Olmsted County, Minnesota. Dis Colon Rectum 2009;52:1815-23. de Silva S, Ma C, Proulx MC, et al. Postoperative complications and mortality following colectomy for ulcerative colitis. Clin Gastroenterol Hepatol 2011;9:972-80.

AC C

19.

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Table 1. Transition probabilities and healthcare costs Base

Standard

Monte Carlo

2.5th/97.5th

case

Deviation

distribution

Percentile*

(SD)*

type*

Stool DNA

References

RI PT

Variable

0.41

SD 0.018

Beta

0.38 / 0.45

14

Sensitivity HGD

0.69

SD 0.072

Beta

0.56 / 0.85

14

Sensitivity CRC

0.92

SD 0.35

Beta

Specificity

0.87

SD 0.0036

Beta

0.5

SD 0.11

Beta

surveillance Age of UC diagnosis

14

0.86 / 0.87

14

0.28 / 0.71

10

17

-

-

17

-

-

-

17

-

-

-

17

0.238

-

-

-

17

0.054

-

-

-

17

30 years

0.354

50 years

0.279

70 years

AC C

TE D

0.075

EP

-

10 years

90 years

0.84 / 0.98

M AN U

Ulcerative colitis % Adhering to

SC

Sensitivity LGD

Annual rate of CRC incidence by UC duration At 8th year

0.0107

-

Beta

0.00045 – 0.044

18

9-15 years

0.00135

-

Beta

0.000032 - 0.0046

18

16-20 years

0.00205

-

Beta

0.000044 – 0.0089

18

≥21years

0.00207

Beta

0.000067 – 0.0075

18

Probability CRC stage at diagnosis

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Surveillance 0.86

0.13

Beta

0.50 / 1.00

19

Dukes C

0.10

0.012

Beta

0.08 / 0.13

19

Dukes D

0.04

0.0065

Beta

0.03 / 0.06

19

Dukes A/B

0.47

0.071

Beta

0.33 / 0.60

19, 31

Dukes C

0.38

0.044

Beta

0.29 / 0.49

19, 31

Dukes D

0.15

0.024

Beta

Annual care UC

$8,485

$1,061

Gamma

$6,326 / $11,048

Stool DNA test

$599

$75

Gamma

$460 / $744

CE with biopsies

$1,221

$153

Gamma

$932 / $1,589

WLE with

$1,405

$177

0.11 / 0.20

M AN U

Costs

SC

No Surveillance

RI PT

Dukes A/B

Gamma

$978 / $1714

19, 31

20

CPT G0464 CPT 88305 CPT 45380 CPT 88305 CPT

Adverse event

$7,075

colonoscopy Colectomy cost

$2,653

Gamma

$2,636 / $15,386

$35,858

Gamma

$17,004 / $153,379

$758

Gamma

$4,540 / $7,238

EP

from

TE D

45380

biopsies

$62,453

27

32, 33

AC C

+ 6 month

postoperative care

Routine care with IPAA (annual)

$6,058

20

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Cancer related expenses, initial $48,945

$6,115

Gamma

$37,994 / $64,953

21, 22

Regional

$64,746

$8,091

Gamma

$52,209 / $85,461

21, 22

Distant

$64,384

$8,046

Gamma

$49,446 / $82,898

Local

$3,796

$475

Gamma

Regional

$7,887

$986

Distant

$26,570

$3,321

expenses, continuing

expenses,

TE D

terminal

$3,126 / $4,799

21, 22

21, 22

Gamma

$6,078 / $9,916

21, 22

Gamma

$19,531 / $33,248

21, 22

M AN U

Cancer related

SC

Cancer related

RI PT

Local

$20,453

$2,556

Gamma

$16,126 / $25,261

21, 22

Regional

$36,509

$4,562

Gamma

$27,348 / $47,145

21, 22

Distant

$49,792

$6,223

Gamma

$39,566 / $62,789

21, 22

EP

Local

*Apply to probabilistic sensitivity analysis only

AC C

CE, chromoendoscopy; CRC, colorectal cancer; HGD, high-grade dysplasia; IPAA, ileal pouch anal anastomosis; LGD, low-grade dysplasia; SD, standard deviation; UC, ulcerative colitis; WLE, white light endoscopy

Please see Supplemental Table 1 for additional model inputs and distributions

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Table 2. One way sensitivity analyses assuming biennial testing intervals Variable

strategy

Chromoendoscopy Percent

Base case

N simulated

Range of

Threshold

value

individual

sensitivity

value

patients

analysis

0.50

500,000

$599

100,000

adhering to

Cost of sDNA Test Specificity of sDNA

$600 to

n/a

$1,135

$1500

0.866

100,000

0.25 - 0.99

0.65

0.923

100,000

0.25 - 0.99

n/a

0.692

100,000

0.25 - 0.99

n/a

0.409

100,000

0.25 - 0.99

n/a

0.50

500,000

25% to 100%

n/a

TE D

Sensitivity

M AN U

Screening

25% to 100%

SC

sDNA

RI PT

Comparison

sDNA to CRC

EP

Sensitivity sDNA to

AC C

HGD

Sensitivity of

sDNA to LGD

White light

Percent

endoscopy

adhering to

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sDNA Screening $599

100,000

sDNA Test Specificity of

0.866

100,000

0.923

100,000

Sensitivity sDNA to HGD

0.66

0.25 - 0.99

n/a

SC

0.25 - 0.99

0.692

100,000

0.25 - 0.99

n/a

0.409

100,000

0.25 - 0.99

n/a

TE D

Sensitivity of

M AN U

sDNA to CRC

$1,109

$1800

sDNA Sensitivity

$600 to

RI PT

Cost of

sDNA to LGD

AC C

DNA

EP

CRC, colorectal cancer; HGD, high-grade dysplasia; LGD, low-grade dysplasia; sDNA, stool

AC C

EP

TE D

M AN U

SC

RI PT

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EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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M AN U

SC

RI PT

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AC C

EP

TE D

Supplemental Figures

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Supplemental Figure 1

RI PT

A. Probabilistic Sensitivity Analysis Summary: Biennial Stool DNA Testing with Diagnostic White Light Colonoscopy Versus No Surveillance (Natural History)

Quadrant

C-1

Q-IV

Overall % (n=100)

AC C

EP

Component

TE D

M AN U

SC

C

3%

Interpretation Screening strategy is less costly and more effective than no surveillance. Screening strategy recommended because it absolutely dominates no surveillance.

Q-I

63%

Screening strategy is more costly and more effective than no surveillance. Screening strategy recommended because its ICER does not exceed WTP.

Q-III

0%

Screening strategy is less costly and less effective than no surveillance. Screening strategy recommended because its ICER does not exceed WTP.

C-4

Q-I

28%

Screening strategy is more costly and more effective than no surveillance. Screening strategy not recommended because its ICER exceeds WTP.

C-5

Q-III

1%

Screening strategy is less costly and less effective than no surveillance. Screening strategy not recommended because its ICER exceeds WTP.

C-6

Q-II

5%

Screening strategy is more costly and less effective than no surveillance. Screening strategy not recommended because it is absolutely dominated by no surveillance.

C-2 C-3

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Supplemental Figure 1

Quadrant

C-1

Q-IV

Overall % (n=100)

EP

Component

TE D

M AN U

SC

RI PT

B. Probabilistic Sensitivity Analysis Summary: Biennial Chromoendoscopy Versus No Surveillance (Natural History)

Interpretation

Screening strategy is less costly and more effective than no surveillance. Screening strategy recommended because it absolutely dominates no surveillance.

Q-I

55%

Screening strategy is more costly and more effective than no surveillance. Screening strategy recommended because its ICER does not exceed WTP.

Q-III

0%

Screening strategy is less costly and less effective than no surveillance. Screening strategy recommended because its ICER does not exceed WTP.

C-4

Q-I

20%

Screening strategy is more costly and more effective than no surveillance. Screening strategy not recommended because its ICER exceeds WTP.

C-5

Q-III

1%

C-6

Q-II

13%

C-2 C-3

AC C

11%

Screening strategy is less costly and less effective than no surveillance. Screening strategy not recommended because its ICER exceeds WTP. Screening strategy is more costly and less effective than no surveillance. Screening strategy not recommended because it is absolutely dominated by no surveillance.

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Supplemental Figure 1

TE D

M AN U

SC

RI PT

C. Probabilistic Sensitivity Analysis Summary: Biennial White Light Colonoscopy Versus No Surveillance (Natural History)

Quadrant

Overall % (n=100)

Interpretation

C-1

Q-IV

11%

Screening strategy is less costly and more effective than no surveillance. Screening strategy recommended because it absolutely dominates no surveillance.

C-2

Q-I

C-3

Q-III

C-4

Q-I

32%

C-5

Q-III

1%

C-6

Q-II

11%

AC C

EP

Component

44% 1%

Screening strategy is more costly and more effective than no surveillance. Screening strategy recommended because its ICER does not exceed WTP. Screening strategy is less costly and less effective than no surveillance. Screening strategy recommended because its ICER does not exceed WTP. Screening strategy is more costly and more effective than no surveillance. Screening strategy not recommended because its ICER exceeds WTP. Screening strategy is less costly and less effective than no surveillance. Screening strategy not recommended because its ICER exceeds WTP. Screening strategy is more costly and less effective than no surveillance. Screening strategy not recommended because it is absolutely dominated by no surveillance.

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Supplemental Figure 2 ii. By probability of a given CRC stage in screening-based modalities

M AN U

SC

i. By probabilities of local and regional CRC mortality, and transition probabilities of local CRC to regional and regional to distant CRC.

RI PT

Sampling of CRC incidence rate with additional clusters of two or four probability-based variables

Willingness to pay, in dollars

Willingness to pay, in dollars

Willingness to pay, in dollars

TE D

AC C

EP

iii. By probabilities of chromoendoscopy accuracy for dysplasia and probability of death due to other causes

iv. By probabilities of colorectal cancer in patients with high-grade dysplasia and stool DNA accuracy for dysplasia

Willingness to pay, in dollars

No surveillance Stool DNA every 2 years, with chromoendoscopy for test + patients Chromoendoscopy every 2 years

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Supplemental Table 1: Additional transition probabilities, utilities and model variables Variable

Base case

Range

Monte Carlo

References

distribution

95% CI) Ulcerative Colitis 0.0023

flare requiring

0.0016-

Beta (0.0023;

0.0075

0.0015)

Probability of

0.0013

death due to other causes in UC Colonoscopy test characteristic 0.695

dysplasia WLE specificity for

0.9

WLE or

0.9

AC C

chromoendoscopy

EP

dysplasia

0.0001-

Beta (0.0013;

0.003

SD 0.0007)

0.00-1.00

Beta (0.695,

TE D

WLE sensitivity for

M AN U

colectomy

0.00-1.00

0.80-1.00

1,2

SC

Annual rate of UC

RI PT

(base case,

3

4-7

SD 0.100) Beta (0.90,

4, 7, 8

SD 0.15) Beta (0.9; SD

4, 6, 9

0.05)

sensitivity for CRC WLE or

0.999

0.90-1.00

chromoendoscopy

Beta (0.999;

1, 4

SD 0.025)

specificity for CRC Chromoendoscopy sensitivity for

0.833

0.36-1.00

Beta (0.833, SD 0.159)

7, 10

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dysplasia in UC Chromoendoscopy

0.913

0.44-1.00

specificity for

Beta (0.913,

8, 10

SD 0.141)

Dysplasia Probability of LGD

0.75

0.61-0.80

SD 0.048)

surveillance

M AN U

colonoscopy Probability of HGD

0.25

0.20-0.38

if dysplasia on

colonoscopy

colectomy if LGD

AC C

if LGD Probability of

0.04-0.46

EP

synchronous CRC

0.19

0-1.00

TE D

0.60

proceeding to

Probability of

Beta (0.25;

0.14

Beta (0.60;

Beta (0.19,

0.090-0.314

0.090-0.314

given LGD

SD 0.056)

synchronous CRC if HGD

13, 14

SD 0.105)

Beta (0.140;

0.53

12

SD 0.25)

developing CRC

Probability of

7, 11

SD 0.045)

surveillance

Proportion

7, 11

SC

if dysplasia on

Beta (0.75;

RI PT

dysplasia in UC

0.42-0.67

Beta (0.53, 0.06)

14

13, 15

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Probability of

0.0036

dysplasia in

0.0008-

Beta (0.0036,

0.015

SD 0.004)

16

chronic UC

From local CRC to

0.20

0.10-0.30

regional CRC

SD 0.05) 0.40

0.20-0.60

CRC to distant

0.0211

(Dukes A/B, stage 1-2)

(Dukes C, stage 3) Distant cancer

0.3467

0.024

AC C

Mortality from

EP

(Dukes D, stage 4) Adverse events

0.0158-

Beta (0.0211;

0.0263

SD 0.0026)

0.0524-

Beta (0.0699;

TE D

0.0699

M AN U

Cancer mortality

Regional cancer

17

SD 0.10)

CRC

Local cancer

Beta (0.40;

17

SC

From regional

Beta (0.20;

RI PT

Cancer progression (annual transition proportion)

0.0874

SD 0.0088)

0.2600-

Beta (0.3467;

0.4334

SD 0.0434)

0.018-0.16

Beta (0.024;

emergent

18

18

18

19

SD 0.036)

colectomy

Mortality from

0.006

elective colectomy Mortality from colectomy for CRC

0.00350.066

0.042

0.039-0.057

Beta (0.006;

1, 19

SD 0.016) Beta (0.042; SD 0.005)

20

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Morbidity from

0.421

0.316-0.526

emergent

Beta (0.421;

19

SD 0.053)

colectomy 0.260-0.433

elective colectomy Morbidity from

SD 0.043) 0.384

0.278-0.405

colectomy for CRC Mortality from

0.00007

0.005

0.00006-

Beta

0.0003

(0.00007; SD

0.001-0.009

TE D

colonoscopy 0.0001

surveillance

EP

colonoscopy

Beta (0.005;

AC C

0.94

0.00003-

Beta (0.0001;

0.003

SD 0.0007)

0.85-1.0

Triangular

or without

(0.94, 0.85,

dysplasia

1.0)

Post-IPAA

21

21

SD 0.002)

surveillance

Chronic UC, with

21

0.00006)

event from

Utilities

19

M AN U

colonoscopy

Perforation from

Beta (0.384; SD 0.032)

surveillance

Morbid adverse

Beta (0.346;

RI PT

0.346

SC

Morbidity from

0.9

0.84-0.94

Triangular

21

22, 23

21

(0.90, 0.84, 0.94) Local cancer

0.74

0.69-0.78

Triangular

24

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(Dukes A/B, stage

(0.74, 0.69,

1-2)

0.78) 0.59

0.54-0.69

(Dukes C, stage 3)

Triangular (0.59, 0.54, 0.69)

0.25

0.20-0.31

(Dukes D, stage 4)

Triangular (0.25, 0.20,

24

SC

Distant cancer

24

RI PT

Regional cancer

0.31) 0.42 (1 mo)

resulting in

0.61 (1 mo)

Triangular

23

TE D

0.84)

0.031 (1 mo)

EP

adverse events

0.55 (1 mo)

0.001-0.125

0.30-0.70

Triangular

1

(0.031, 0.001, 0.125) Triangular

23

(0.55, 0.30,

AC C

adverse events

0.32-0.84

(0.61, 0.32,

colectomy)

Postoperative

21, 23

0.70)

other type of

Colonoscopy

Triangular

(0.42, 0.10,

colectomy Surgery (IPAA or

0.10-0.70

M AN U

Severe UC flare

0.70)

Other variables Discount rate

3%

Cycle length

1y

Willingness to pay

$50,000/QALY

threshold

25, 26 0-10 y 27

ACCEPTED MANUSCRIPT

CI, Confidence interval; UC, ulcerative colitis; SD, standard deviation; WLE, white-light endoscopy; CRC, colorectal cancer; LGD, low-grade dysplasia; HGD, high-grade dysplasia; IPAA, ileal pouch anal anastomosis; QALY, quality-adjusted life year

4. 5.

6. 7.

8.

9.

10.

M AN U

TE D

3.

EP

2.

Rubenstein JH, Waljee AK, Jeter JM, Velayos FS, Ladabaum U, Higgins PD. Cost effectiveness of ulcerative colitis surveillance in the setting of 5-aminosalicylates. The American journal of gastroenterology 2009;104:2222-32. Kohn A, Fano V, Monterubbianesi R, Davoli M, Marrollo M, Stasi E, Perucci C, Prantera C. Surgical and nonsurgical hospitalization rates and charges for patients with ulcerative colitis in Italy: a 10-year cohort study. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2012;44:369-74. Herrinton LJ, Liu L, Levin TR, Allison JE, Lewis JD, Velayos F. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. Gastroenterology 2012;143:382-9. Gorfine SR, Bauer JJ, Harris MT, Kreel I. Dysplasia complicating chronic ulcerative colitis: is immediate colectomy warranted? Dis Colon Rectum 2000;43:1575-81. Rubin CE, Haggitt RC, Burmer GC, Brentnall TA, Stevens AC, Levine DS, Dean PJ, Kimmey M, Perera DR, Rabinovitch PS. DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. Gastroenterology 1992;103:1611-20. Rubin DT, Rothe JA, Hetzel JT, Cohen RD, Hanauer SB. Are dysplasia and colorectal cancer endoscopically visible in patients with ulcerative colitis? Gastrointest Endosc 2007;65:998-1004. Matsumoto T, Iwao Y, Igarashi M, Watanabe K, Otsuka K, Watanabe T, Iizuka B, Hida N, Sada M, Chiba T, Kudo SE, Oshitani N, Nagawa H, Ajioka Y, Hibi T. Endoscopic and chromoendoscopic atlas featuring dysplastic lesions in surveillance colonoscopy for patients with long-standing ulcerative colitis. Inflammatory Bowel Diseases 2008;14:259-64. Subramanian V, Mannath J, Ragunath K, Hawkey CJ. Meta-analysis: the diagnostic yield of chromoendoscopy for detecting dysplasia in patients with colonic inflammatory bowel disease. Alimentary Pharmacology & Therapeutics 2011;33:304-12. Pickhardt PJ, Choi JR, Hwang I, Butler JA, Puckett ML, Hildebrandt HA, Wong RK, Nugent PA, Mysliwiec PA, Schindler WR. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N Engl J Med 2003;349:2191-200. Wu L, Li P, Wu J, Cao Y, Gao F. The diagnostic accuracy of chromoendoscopy for dysplasia in ulcerative colitis: meta-analysis of six randomized controlled trials. Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland 2012;14:416-20.

AC C

1.

SC

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Adapted from Konijeti GG, Shrime MG, Ananthakrishnan AN, Chan AT. Cost-effectiveness analysis of chromoendoscopy for colorectal cancer surveillance in patients with ulcerative colitis. Gastrointest Endosc. 2014 Mar;79(3):455-65 and used with permission.

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16.

17. 18.

19.

20.

21.

22. 23.

24. 25.

RI PT

SC

15.

M AN U

14.

TE D

13.

EP

12.

Rutter MD, Saunders BP, Wilkinson KH, Rumbles S, Schofield G, Kamm MA, Williams CB, Price AB, Talbot IC, Forbes A. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006;130:1030-8. Siegel CA, Schwartz LM, Woloshin S, Cole EB, Rubin DT, Vay T, Baars J, Sands BE. When should ulcerative colitis patients undergo colectomy for dysplasia? Mismatch between patient preferences and physician recommendations. Inflammatory Bowel Diseases 2010;16:1658-62. Hassan C, Pickhardt PJ, Zullo A, Di Giulio E, Laghi A, Kim DH, Iafrate F. Cost-effectiveness of early colonoscopy surveillance after cancer resection. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2009;41:881-5. Ullman T, Croog V, Harpaz N, Sachar D, Itzkowitz S. Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 2003;125:1311-9. Hata K, Watanabe T, Kazama S, Suzuki K, Shinozaki M, Yokoyama T, Matsuda K, Muto T, Nagawa H. Earlier surveillance colonoscopy programme improves survival in patients with ulcerative colitis associated colorectal cancer: results of a 23-year surveillance programme in the Japanese population. Br J Cancer 2003;89:1232-6. Jess T, Loftus EV, Jr., Velayos FS, Harmsen WS, Zinsmeister AR, Smyrk TC, Tremaine WJ, Melton LJ, 3rd, Munkholm P, Sandborn WJ. Incidence and prognosis of colorectal dysplasia in inflammatory bowel disease: a population-based study from Olmsted County, Minnesota. Inflamm Bowel Dis 2006;12:669-76. Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet 1994;343:71-4. Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KAe. SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, April 2012, 2012. de Silva S, Ma C, Proulx MC, Crespin M, Kaplan BS, Hubbard J, Prusinkiewicz M, Fong A, Panaccione R, Ghosh S, Beck PL, Maclean A, Buie D, Kaplan GG. Postoperative complications and mortality following colectomy for ulcerative colitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2011;9:97280. Schneider EB, Hyder O, Brooke BS, Efron J, Cameron JL, Edil BH, Schulick RD, Choti MA, Wolfgang CL, Pawlik TM. Patient readmission and mortality after colorectal surgery for colon cancer: impact of length of stay relative to other clinical factors. J Am Coll Surg 2012;214:390-8; discussion 398-9. Fisher DA, Maple JT, Ben-Menachem T, Cash BD, Decker GA, Early DS, Evans JA, Fanelli RD, Fukami N, Hwang JH, Jain R, Jue TL, Khan KM, Malpas PM, Sharaf RN, Shergill AK, Dominitz JA. Complications of colonoscopy. Gastrointest Endosc 2011;74:745-52. Nguyen GC, Frick KD, Dassopoulos T. Medical decision analysis for the management of unifocal, flat, low-grade dysplasia in ulcerative colitis. Gastrointest Endosc 2009;69:1299-310. Tsai HH, Punekar YS, Morris J, Fortun P. A model of the long-term cost effectiveness of scheduled maintenance treatment with infliximab for moderate-to-severe ulcerative colitis. Alimentary Pharmacology & Therapeutics 2008;28:1230-9. Ness RM, Holmes AM, Klein R, Dittus R. Utility valuations for outcome states of colorectal cancer. The American journal of gastroenterology 1999;94:1650-7. Siegel JE, Weinstein MC, Russell LB, Gold MR. Recommendations for reporting cost-effectiveness analyses. Panel on Cost-Effectiveness in Health and Medicine. Jama 1996;276:1339-41.

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Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the Panel on Cost-effectiveness in Health and Medicine. Jama 1996;276:1253-8. Grosse SD. Assessing cost-effectiveness in healthcare: history of the $50,000 per QALY threshold. Expert review of pharmacoeconomics & outcomes research 2008;8:165-78.

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19.65 19.92 20.05

0 4953.626 11151.933

COST

EFF

INCRCOST

INCREFF

189960.2578 19.65055763 0 0 194913.8841 19.91627132 4953.626267 0.265714 201112.1913 20.05016251 6198.30722 0.133891

NMB at WTP 10000 0 -189960.26 -91707.5 6545.319 -194913.88 -95332.5 4248.829 18643 -201112.19 -100861 -610.566 46294 NMB at WTP 0

ICER

NMB at WTP 5000

NMB at WTP 15000 104798.1 103830.2 99640.25

NMB at 18642.73

NMB at 25000

NMB at 30000

NMB at 35000

NMB at 40000

RI PT

No Surveillance (Natural History) sDNA testing with WLE Confirmatory q2 year White light endoscopy q2 year

189960.26 194913.88 201112.19

INCREFF ICER_vs_Bas vs eline Baseline 0 0 0.266 18643 0.400 27907

NMB at 45000

NMB at 46294

Net monetary benefit (NMB) analysis (and acceptability curve) directly relates to ICER (G8 through G10) Acceptability curves provide the additional information of quantifying how *often* a strategy has a higher NMB at a given WTP ICERs *imply* optimal WTP thresholds No Surv: Optimal at WTP $0 - <$18,643 sDNA: Optimal at WTP > $18,643 - < $46294 WLE: Optimal at WTP >$46,294

NMB at 50000

176379.8 301303.7 399556.5 497809.3 596062 694314.8 719742.7 792567.6 176379.8 302992.9 402574.3 502155.6 601737 701318.3 727090 800899.7 172677.6 300141.9 400392.7 500643.5 600894.3 701145.1 727090 801395.9

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INCRCOST vs Baseline

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"Incremental" Analysis

EFF

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No Surveillance (Natural History) sDNA testing with WLE Confirmatory q2 year White light endoscopy q2 year

COST

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STRATEGYNAME

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"Relative to Baseline" Analysis

NMB at 100000 1775096 1796713 1803904

highest NMB = optimal strategy at WTP (note the concordance with

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tegy at WTP (note the concordance with ICER thresholds)

ACCEPTED MANUSCRIPT

19.65 19.95 20.08

0 4852.173 10300.532

COST

EFF

INCRCOST vs Baseline

189960.26 194812.43 200260.79

19.65 19.95 20.08

INCREFF NMB at ICER_vs_Bas NMB at NMB at vs WTP eline WTP 0 WTP 5000 Baseline 10000 0 0 0 -189960 -91707 6545 -194812 -95077 4852.1727 0.2965 16362 4659 -200261 -99847 5448.3589 0.1357 40151 567

NMB at NMB at WTP 15000 16362 104798 104394 100981

NMB at 25000

NMB at 30000

NMB at 35000

NMB at 40000

NMB at 40151

NMB at 45000

NMB at 50000

NMB at 100000

131562 301304 131562 303865 128334 301809

399556 403601 402223

497809 503336 502637

596062 603072 603051

599029 606084 606084

694315 702807 703465

792568 802543 803879

1775096 1799898 1808020

RI PT

No Surveillance (Natural History) sDNA testing with Chromo Confirmatory q2 year Chromoendoscopy q2 year

189960.26 194812.43 200260.79

INCREFF ICER_vs_Bas vs eline Baseline 0 0 0.297 16362 0.432 23830

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INCRCOST vs Baseline

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"Incremental" Analysis

EFF

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No Surveillance (Natural History) sDNA testing with Chromo Confirmatory q2 year Chromoendoscopy q2 year

COST

EP

STRATEGYNAME

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"Relative to Baseline" Analysis

highest NMB = optimal strategy at WTP

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ptimal strategy at WTP