A search of MEDLINE, EMBASE, the Cochrane Library, and gray literature sources identified 3026 records. After deduplication, 2154 titles and abstracts were screened and 1952 records were rejected or deemed ineligible. The full text of the remaining 202 reports were assessed, and 12 studies met the inclusion criteria and were included in the systematic review.26-37 DARE indicates Database of Abstracts of Reviews of Effects.
Forest plots demonstrate a high degree of heterogeneity for sensitivity estimates for (A) colorectal cancer and (B) advanced neoplasia. FN indicates false-negative results; FP, false-positive results; TN, true-negative results; TP, true-positive results.
eFigure 1. Search Strategies
eFigure 2. Quality assessment summary: review authors’ judgments about each risk of bias item for each included study
eFigure 3. Methodological quality of included studies graph: review authors' judgments about each item presented as percentages across all included studies
eFigure 4. Hierarchical summary receiver operating curve (HSROC) plot of sensitivity versus specificity of FIT for diagnosis of a) colorectal cancer; b) advanced neoplasia
eFigure 5. Hierarchical summary receiver operating curve (HSROC) plot of sensitivity versus specificity for performance of FIT in studies with low risk of bias or concerns for applicability (QUADAS‐2)
eFigure 6. Hierarchical summary receiver operating curve (HSROC) plot of sensitivity versus specificity for performance of FIT in studies using quantitative FIT with cut off value less than 25μg/g only in patients with familial risk of CRC
eFigure 7. Fagan’s nomogram plots
eTable 1. Synopsis of results from sensitivity analyses depending on risk of bias, patient population and reference standard used for the diagnosis of colorectal cancer and advanced neoplasia
eTable 2. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment of the quality of the body evidence regarding the diagnostic accuracy of FIT
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Katsoula A, Paschos P, Haidich A, Tsapas A, Giouleme O. Diagnostic Accuracy of Fecal Immunochemical Test in Patients at Increased Risk for Colorectal Cancer: A Meta-analysis. JAMA Intern Med. 2017;177(8):1110–1118. doi:10.1001/jamainternmed.2017.2309
What is the diagnostic accuracy of fecal immunochemical testing (FIT) for screening of colorectal cancer (CRC) or advanced neoplasia in asymptomatic high-risk populations?
In this meta-analysis, FIT has high overall diagnostic accuracy for CRC and moderate accuracy for advanced neoplasia. Heterogeneity and small sample size limit the precision of the results.
Given the safety, simplicity, low cost, and minimal discomfort of FIT, it is a viable alternative screening strategy for patients at increased risk for CRC. This is especially important for those who are averse to colonoscopy.
The potential role of the fecal immunochemical test (FIT) for screening patients at increased risk for colorectal cancer (CRC) has not yet been elucidated.
To assess the diagnostic accuracy of FIT for CRC or advanced neoplasia (AN) in asymptomatic patients at above-average risk.
MEDLINE, EMBASE, Cochrane Library, and gray literature sources through August 2016.
Diagnostic studies evaluating the accuracy of FIT for CRC or AN in patients with a personal or familial history of CRC using colonoscopy as the reference standard.
Data Extraction and Synthesis
Two authors (A.K. and P.P.) independently extracted data and evaluated study quality using the Quality Assessment of Diagnostic Accuracy Studies–2 tool, and evaluated the quality of the body of evidence by means of GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Hierarchical models were used to synthesize available evidence.
Main Outcomes and Measures
The primary outcome was the diagnostic performance of FIT for detecting CRC or AN.
We included 12 studies (6204 participants). Seven studies were deemed at high or unclear risk of bias. The average sensitivity of FIT for CRC was 93% (95% CI, 53%-99%), and the average specificity was 91% (95% CI, 89%-92%), yielding a positive likelihood ratio (LR+) of 10.30 (CI 7.7-13.9) and a negative likelihood ratio (LR−) of 0.08 (95% CI, 0.01-0.75) (GRADE: very low). The average sensitivity of FIT for AN was 48% (95% CI, 39%-57%); and the average specificity was 93% (95% CI, 91%-94%), yielding an LR+ of 6.55 (95% CI, 5.0-8.5) and an LR− of 0.57 (95% CI, 0.48-0.67) (GRADE: very low). Subgroup analyses indicated that FIT cutoff values between 15- and 25-μg/g feces provided the best combination of sensitivity and specificity for the diagnosis of CRC (93% and 94%, respectively). Quantitative and 1-sample FIT showed adequate test performance, but data on other FIT brands and multiple samples were insufficient.
Conclusions and Relevance
The FIT has high overall diagnostic accuracy for CRC but moderate accuracy for AN in patients at above-average personal or familial risk. Heterogeneity and wide confidence intervals limit the trustworthiness of our findings.
Quiz Ref IDColorectal cancer (CRC) is the third most common type of cancer in men and the second most common in women worldwide.1 Early detection of CRC through widely applied screening programs has proven to be effective in reduction of cancer-related mortality. Guidelines for average-risk populations support use of several screening modalities, including colonoscopy, fecal occult blood tests or computed tomography colonography. However, recommendations for increased-risk individuals are more aggressive and support only use of colonoscopy. Such a strategy is associated with higher cost, lower adherence, and higher risk for rare, but serious, complications.2-6
It has recently been suggested that fecal immunochemical testing (FIT) could be used for population-based screening owing to its high accuracy and adherence.7-9 Previous systematic reviews and meta-analyses have assessed the performance of FIT in average-risk populations.10,11 However, the potential role of FIT for screening of individuals at increased risk for CRC has not yet been fully elucidated. We conducted a systematic review and meta-analysis to explore the diagnostic accuracy of FIT for CRC or advanced neoplasia (AN) in asymptomatic individuals with a familial or personal history of CRC.
This review was based on a prespecified protocol registered with PROSPERO 2016 (CRD42016037924) and is reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.12
We included studies that reported the diagnostic accuracy of FIT for CRC or advanced neoplasia (CRC, or adenomas ≥10 mm or with ≥25% villous component and/or high-grade dysplasia) in asymptomatic adults with family history of CRC or personal history of CRC or advanced adenomas and used colonoscopy or follow-up as the reference standard. We excluded studies with symptomatic patients or patients with inflammatory bowel disease, hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, or studies for which 2 × 2 diagnostic tables could not be inferred.
We conducted a comprehensive search of several electronic databases, including MEDLINE via PubMed, EMBASE via Ovid, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database, and the Cochrane Library, without imposing any date or language restrictions. We also searched trial registries and abstracts from relevant scientific meetings, as well as scanned websites of companies manufacturing FITs. Finally, we checked reference lists of primary studies included, relevant systematic reviews and meta-analyses, and pertinent guidelines. The last search was performed in August 2016 (eFigure 1 in the Supplement).
Two authors (A.K. and P.P.) independently reviewed and screened titles and abstracts of articles retrieved and determined final eligibility through examination of full texts. Any disagreement was resolved through discussion or by consulting a third author (A.T.).
Two authors (A.K. and P.P.) independently extracted data from each included study, using Systematic Review Data Repository.13 For studies presenting results for multiple FIT thresholds, we extracted all data to maximize the yield of information. We converted units for FIT cutoff thresholds to micrograms of hemoglobin (Hb) per gram of feces.14 Two authors (A.K. and P.P.) independently evaluated the quality of included studies using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool.15 Discrepancies were resolved by consensus.
We assessed the quality of evidence by means of Grading of Recommendations Assessment, Development and Evaluation (GRADE).16-20 Two authors (A.K. and P.P.) independently assessed risk of bias, inconsistency, indirectness, imprecision, and publication bias. Overall quality was deemed very low, low, moderate, or high using GRADEpro version 3.6 (GRADEpro GDT).
For each study we recalculated the sensitivity and specificity with 95% CIs from the true-positive (TP), false-positive (FP), false-negative (FN), and true-negative (TN) results, using Review Manager 5.3 (Cochrane Community). Statistical analysis was performed with Stata software version 13.0 (Stata Corporation), using metandi and midas modules. We fitted hierarchical logistic regression models when 4 or more studies were available.21-24
In our main analysis, for studies presenting results at multiple FIT thresholds, we used data for the lowest cutoff and the minimum number of samples available. For studies using multiple-sample FIT, positivity was rated based on the highest amount of fecal Hb measured in patient samples. We synthesized data regardless of the FIT cutoff used.
We also conducted a series of prespecified subgroup analyses, based on type of FIT (qualitative or quantitative), number of samples (1, 2, or 3), or FIT cutoff used. We explored the diagnostic accuracy at 3 different FIT thresholds (<15 μg Hb/g, 15 to 25 μg Hb/g, >25 μg Hb/g feces) based on existing practice and to maximize sensitivity for an increased-risk population.
We explored robustness of our findings by means of a series of prespecified sensitivity analyses, excluding studies at high or unclear risk of bias, studies recruiting patients with prior history of CRC or advanced adenomas (potential for spectrum bias),25 or studies that used delayed colonoscopy in patients with FIT-negative results as reference standard (potential for differential reference bias).
Finally, we evaluated the clinical utility of FIT utilizing Fagan nomograms to depict posttest probability in patients at increased risk for CRC and AN.
Our search identified 3026 records (Figure 1). After deduplication, we screened 2154 titles and abstracts and rejected 1952 records as noneligible. We assessed the full text of the remaining 202 reports. Twelve studies met the inclusion criteria and were included in the systematic review.26-37
The main characteristics of included studies are displayed in Table 1. Our main analysis is based on data from 6204 participants. Sample size of studies ranged from 116 to 1041 patients. Mean age ranged from 46.0 to 63.2 years, and percentage of males ranged from 30.2 to 50.6%. Eleven studies were cross-sectional and 1 was a randomized clinical trial.34 Two studies were reported only in abstract form.26,36 Nine studies included only first-degree relatives of CRC patients.26-28,30,32-34,36,37 Three studies included individuals either with a family history of CRC or prior history of CRC or advanced adenomas.29,31,35 Of these, only 2 studies reported results for subgroups.31,35
Eight studies evaluated quantitative FIT (OC-sensor/OC-micro, Eiken Chemical),26,27,29,31,33-36 while 4 studies used qualitative FITs (Hemosure, W.H.P.M. Inc32,37; OC-light, Eiken Chemical28; and HemeSelect, Smith-Kline Diagnostics30). Eight studies used 1-sample FIT,26,28,30,32-34,36,37 2 studies used 2-sample FIT,27,35 and 2 studies used 3-sample FIT.29,31
All studies used colonoscopy as a reference standard. However, in 3 studies, the time interval between FIT and colonoscopy depended on the FIT result, such that colonoscopy was delayed more so in those with a negative FIT.26,34,37
All studies assessed the accuracy of FIT for AN,26-37 but only 7 studies (4790 patients) reported data specifically for CRC.27,29,31-35 Prevalence of AN ranged between 3.2% and 14.5% and between 0.6% and 2.1% for CRC.
The methodological quality assessment of the included studies is summarized in eFigures 2 and 3 in the Supplement. Six studies were deemed at high risk of bias,26,28,30,32,34,37 1 study at unclear risk,36 and 5 studies at low risk of bias.27,29,31,33,35
All but 1 study reported use of consecutive or random sampling.30 FIT was used prior to the reference standard in 11 studies, and only 1 study did not provide relevant data.36 All studies used prespecified FIT thresholds. The greatest risk for bias occurred owing to flow and timing. In 3 studies, individuals with positive FIT results underwent immediate colonoscopy, whereas individuals with negative FIT results underwent delayed colonoscopy, introducing potential differential verification bias.26,34,37 Moreover, 3 studies used an unacceptable interval (>3 months) between FIT and reference standard,26,34,37 while 2 studies provided no relevant details.30,36 In the rest of the studies, the interval between FIT and reference standard was less than 1 month in 5 studies27,29,31,33,35 and 2 months in 1 study.28
The greatest concern regarding applicability was due to the FIT and the reference standard used. We deemed all 4 studies employing qualitative FITs28,30,32,37 and all 3 studies using delayed colonoscopy as a reference standard26,34,37 as high risk.
In our main analysis, FIT sensitivity and specificity for diagnosing CRC ranged from 0.25 to 1.00 (median, 0.81) and from 0.87 to 0.95 (median, 0.91), respectively. Respective values for diagnosing AN ranged from 0.29 to 0.83 (median, 0.50) and from 0.85 to 0.98 (median, 0.92). Forest plots demonstrated a high degree of heterogeneity for sensitivity estimates (Figure 2). Pooled estimates of sensitivity and specificity for CRC were 93% (95% CI, 53%-99%) and 91% (95% CI, 89%-92%), yielding a positive likelihood ratio (LR+) of 10.30 (95% CI, 7.7-13.9) and a negative likelihood ratio (LR−) of 0.08 (95% CI, 0.01-0.75). Positive and negative predictive values were 7.7% and 99.9%, respectively. The pooled sensitivity and specificity for AN were 48% (95% CI, 39%-57%) and 93% (95% CI, 91%-94%), yielding an LR+ of 6.5 (95% CI, 5.0-8.5) and an LR− of 0.57 (95% CI, 0.48-0.67). Positive and negative predictive values were 43.8% and 94.0%, respectively. The diagnostic odds ratio (DOR) for diagnosis of CRC and AN was 129 (95% CI, 11-1579) and 11 (95% CI, 8-17), respectively. The area under the ROC (AUC) for diagnosis of CRC and AN was 0.93 (95% CI, 0.90-0.95) and 0.86 (95% CI, 0.83-0.89), respectively (eFigure 4 in the Supplement).
Results for all subgroup analyses are summarized in Table 2.
We assessed the stability of our findings in a series of sensitivity analyses (eTable 1 in the Supplement).
We pooled results from 5 studies that were deemed at low risk of bias. Pooled test characteristic estimates for diagnosing CRC were sensitivity, 97% (95% CI, 62%-100%); specificity, 91% (95% CI, 89%-93%); LR+, 11.20 (95% CI, 8.30-15.10); and LR−, 0.03 (95% CI, 0.00-0.60). Respective values for AN were sensitivity, 44% (95% CI, 34%-53%); specificity, 94% (95% CI, 92%-96%); LR+, 7.70 (95% CI, 5.10-11.70), and LR−, 0.60 (95% CI, 0.51-0.71) (eFigure 5 in the Supplement).
We also conducted a sensitivity analysis including data only from patients with family history of CRC. Pooled test characteristics estimates for diagnosing CRC were sensitivity, 86% (95% CI, 31%-99%); specificity, 91% (95% CI, 89%-93%); LR+, 10.00 (95% CI, 5.80-17.5); and LR−, 0.16 (95% CI, 0.02-1.48). Respective values for AN were sensitivity, 46% (95% CI, 37%-56%); specificity, 93% (95% CI, 90%-95%); LR+, 6.60 (95% CI, 4.90-8.70); and LR−, 0.58 (95% CI, 0.48-0.69).
Moreover, we conducted a sensitivity analysis excluding studies that used delayed colonoscopy as the reference standard. The pooled test characteristics for CRC were sensitivity, 97% (95% CI, 31%-100%); specificity, 91% (95% CI, 89%-93%); LR+, 10.80 (95% CI, 8.00-14.60); and LR−, 0.04 (95% CI, 0.00-2.02). Respective values for AN were sensitivity, 47% (95% CI, 37%-58%); specificity, 93% (95% CI, 91%-95%); LR+, 6.90 (95% CI, 4.90-9.70); and LR−, 0.56 (95% CI, 0.46-0.69).
We explored the robustness of our results in a post hoc sensitivity analysis including only studies in patients with family history of CRC that used quantitative FIT with a cut-off value of less than 25 μg Hb/g feces. Pooled estimates for CRC were sensitivity, 91% (95% CI, 51%-99%); specificity, 92% (95% CI, 88%-94%); LR+, 10.80 (95% CI, 6.60-17.80); and LR−, 0.1 (95% CI, 0.01-0.80). Respective estimates for AN were sensitivity, 47% (95% CI, 39%-55%); specificity, 94% (95% CI, 91%-96%); LR+, 8.10 (95% CI, 5.90-11.20); and LR−, 0.56 (95% CI, 0.49-0.65) (eFigure 6 in the Supplement).
Finally, we could not calculate the pooled estimates in a sensitivity analysis including only studies at low risk of bias in patients with family history of CRC that used immediate colonoscopy due to limited data. In 3 relevant studies, sensitivity for CRC varied from 67% to 100% and specificity from 83% to 95%. Respective values for AN varied from 37% to 56% for sensitivity and 92 to 98% for specificity.
Finally, we explored the clinical utility of FIT for patients at increased risk of CRC by means of Fagan nomogram. Assuming a pretest probability of 0.8% for CRC and 10.2% for AN (median prevalence in 7 and 12 studies included in the present meta-analysis, respectively), a positive result increases the probability of CRC to 8.0% and probability of AN to 42.0%. On the other hand, the posttest probability for CRC or AN following a negative result of FIT is 0% or 6.0% respectively (eFigure 7 in the Supplement).
We assessed the quality of the evidence in our main analysis but also separately for patients with family history or personal history of CRC. Based on GRADE summaries (eTable 2 in the Supplement) we deemed the quality of the evidence to be low or very low.
In this systematic review and meta-analysis, we found reasonable diagnostic accuracy of FIT for CRC (AUC, 0.93) and AN (AUC, 0.86) in individuals with either a personal or family history of CRC. The pooled sensitivity was approximately 93% for CRC but much lower for AN (48%). Quiz Ref IDUse of cutoff values between 15 to 25 μg Hb/g feces had the best combination of sensitivity and specificity for the diagnosis of CRC (93% and 94%, respectively), as well as the highest LR+ (15.1) and lowest LR− (0.07). The sensitivity was overall lower in individuals with a family history of CRC compared with a personal history. However, it was restored in a post hoc analysis excluding studies with qualitative FIT or utilizing a threshold of less than 25 μg Hb/g feces. Quiz Ref IDThe type of FIT used and cutoff threshold were the most important contributors to the heterogeneity of results. Subgroup analyses for quantitative FIT and 1-sample FIT showed consistent findings supporting their accuracy; however, we could not draw any conclusions about the diagnostic accuracy of qualitative FIT or use of multiple samples due to insufficient evidence. A sensitivity analysis excluding studies at high or unclear risk of bias verified robustness of our conclusions. However, the validity of our conclusions is undermined by low or very low quality of the body of evidence.
To our knowledge, this is the first systematic review and meta-analysis evaluating the diagnostic accuracy of FIT in individuals at increased risk for CRC. Results were at least as good as from previous systematic reviews focusing οn average-risk individuals.10,11,38 To ensure internal validity of our conclusions, we implemented current guidelines for the conduct and reporting of systematic reviews12,39 and used a prespecified protocol. We undertook a comprehensive search of multiple electronic databases and gray literature sources without imposing any restrictions based on language or publication type. Data extraction and quality assessment were conducted in duplicate. We assessed quality using a meticulous, recently developed tool (QUADAS-2). We synthesized existing data using hierarchical models to account for the correlation between sensitivity and specificity. Finally, we graded the quality of the body of evidence using appropriate methodology (GRADE).
Quiz Ref IDColonoscopy is currently the only recommended screening modality for participants at increased risk of CRC owing to personal or family history.3 However, no study has documented the effectiveness of this policy on CRC incidence or mortality. Colonoscopy is an invasive, expensive procedure with an established risk of complications.40,41 Population-based studies and randomized trials suggest that adherence to use of colonoscopy for screening in average and increased-risk populations is usually suboptimal.42 This undermines the efficacy of screening programs43 and underlines the need for alternative screening modalities that may limit the need for colonoscopy only to those participants with positive results. Several recently published guidelines support the use of FIT for screening of average-risk participants.44,45 The Canadian Task Force on Preventive Health Care excludes colonoscopy as a primary screening test and recommends screening only with FIT, guaiac–based fecal occult blood tests, or flexible sigmoidoscopy.46 Our results are in line with these suggestions and support use of FIT for screening of increased-risk individuals.
High specificity and sensitivity of FIT allow prompt referral of patients with positive results for further diagnostic investigation with colonoscopy, and exclusion of CRC with high certainty in individuals with negative results respectively. FIT LR+ is more than 10 and LR− is less than 0.1, hence having a significant effect on pretest probabilities and providing strong evidence for the presence or absence of CRC, respectively.47 In a population with a prevalence of CRC equal to 0.8%, a negative result decreases the posttest probability to less than 0.1%, whereas a positive result increases the posttest probability to 8.0%, which crosses a conventional threshold of risk to perform colonoscopy. Thus, our results suggest that in increased-risk individuals FIT has high diagnostic accuracy for CRC. On the other hand, our results also show that FIT could diagnose only half of the cases with AN. Nevertheless, all included studies evaluated 1-time application of the test, and results could not be transferred to repeat screening programs. In a pragmatic trial34 assessing the effectiveness of a diagnostic strategy using annual FIT for 3 years for detection of AN vs colonoscopy in asymptomatic patients with a family history of CRC, annual FIT was as good as colonoscopy for AN; however, it missed almost 40% of advanced adenomas. These data support the annual use of FIT in individuals at increased risk for CRC as an alternative screening strategy for patients who refuse to use colonoscopy. Repeat use of FIT and higher compliance to screening schedules48 could potentially counterbalance the superior accuracy of colonoscopy in the diagnosis of AN.
Our results suggest that given FIT safety, simplicity, low cost, and low discomfort, it could be used as an acceptable alternative for screening of individuals at increased risk for CRC.
The latest US Preventive Services Task Force recommendations for colorectal screening support that “the best screening test is the one that gets done,” and that the ultimate goal of screening strategies is maximization of screening uptake to reduce CRC mortality.45
Although our results verify the diagnostic accuracy of FIT for CRC in individuals at increased risk, this body of evidence is limited by a relatively small sample size. It is thus imperative for future studies to include larger and better-defined patient populations. It is also important to establish optimal thresholds, test cutoff values, and number and frequency of FIT samples.10 Our results also should prompt randomized trials to assess the implementation of FIT either alone or in combination with other screening procedures into screening strategies for increased-risk individuals. Finally, the effects on quality of life, morbidity, mortality and overall cost-effectiveness need to be clarified in future studies.49-51
Several limitations have to be acknowledged about the evidence and the review itself. Quiz Ref IDDespite the use of an exhaustive and meticulous search strategy, we could only find 12 eligible studies. Most of these were at high or unclear risk of bias due to suboptimal study design.26,28,30,32,34,36,37 Only 3 studies had a mixed population with personal or familial history of CRC,29,31,35 and 2 studies presented results separately based on the patient history.31,35 A post hoc analysis of studies in individuals with family history of CRC using quantitative FIT resulted in similar summary estimates with the main analysis. However, most studies had a small sample size or low prevalence of CRC or AN, limiting the precision of effect estimates. Finally, 3 studies were prone to differential verification bias as they invited participants with negative FIT results to undergo a delayed colonoscopy as the reference standard.26,34,37 Most analyses had high heterogeneity and wide confidence intervals of pooled estimates, hence raising concerns about the reliability of our findings. However, the robustness of our results was verified in a series of subgroup analyses.
FIT has high overall diagnostic accuracy for CRC in increased-risk individuals. The accuracy for advanced neoplasia however is moderate, and so further study of annual FIT to assess increased performance is warranted. Heterogeneity and small sample sizes undermine the quality and validity of these findings. Further research with rigorous diagnostic accuracy studies and randomized clinical trials is warranted to assess the full effectiveness of FIT implementation as a means to promote more individualized and more flexible alternative screening options in patients at higher risk of CRC based on their own values and preferences.
Corresponding Author: Anastasia Katsoula, MD, MSc, Hippokration General Hospital of Thessaloniki 54642, Thessaloniki, Greece (email@example.com).
Accepted for Publication: March 8, 2017.
Published Online: June 19, 2017. doi:10.1001/jamainternmed.2017.2309
Author Contributions: Dr Tsapas had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Katsoula, Paschos, Tsapas, Giouleme.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Katsoula, Paschos, Tsapas.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Katsoula, Paschos, Haidich, Tsapas.
Administrative, technical, or material support: Katsoula, Paschos, Tsapas, Giouleme.
Study supervision: Katsoula, Haidich, Tsapas, Giouleme.
Conflict of Interest Disclosures: None reported.
Previous Presentation: This study was presented as an abstract at the 24th United European Gastroenterology Week; October 18, 2016; Vienna, Austria.