How extent of Barrett's metaplasia influences the risk of esophageal adenocarcinoma.

PURPOSE OF REVIEW: This review will focus on how the extent of Barrett's metaplasia influences the risk of esophageal adenocarcinoma (EAC). More specifically, this review will discuss the concepts of long and short-segment Barrett's metaplasia and irregular Z line as they relate to EAC risk. RECENT FINDINGS: The Prague classification can standardize reporting of Barrett's metaplasia. Recent literature has found significant associations between the length of Barrett's metaplasia and increased progression risk to EAC in multiple geographically distinct populations. Length of Barrett's metaplasia has been incorporated into the Progression of Barrett's esophagus (PIB) model that can predict individualized life-time risks of progression. The risk of malignant transformation appears to be very low in patients with irregular Z line. SUMMARY: Length of Barrett's metaplasia has emerged as an important predictor that can influence the risk of EAC and should be reported using the Prague classification. The PIB model, if further validated, could help a practicing gastroenterologist to inform patients with Barrett's metaplasia about their personal risk of progression to tailor surveillance intervals. Current guidelines do not recommend surveillance in patients with irregular Z line, but careful examination is recommended.

An analysis of the rates of discontinuation and non-publication of colorectal cancer clinical trials.

PURPOSE: Non-publication and premature discontinuation for clinical trials pose an ethical dilemma for trial participants, patients, clinicians, and researchers, as well as the general public as these studies receive significant public funding that may be further contributing to research waste. Here, we investigate the rate of trial discontinuation and non-publication among CRC trials using ClinicalTrials.gov. METHODS: We performed an advanced search on ClinicalTrials.gov pertaining to the treatment of CRC using the keyword colorectal cancer. For each clinical trial, links to the publication provided by ClinicalTrials.gov were searched and verified to be correct. If a publication was unable to be found using the methods above, we attempted to contact the lead investigator via email for the reason for non-publication. RESULTS: Of the 123 (123/428, 28.7%) discontinued trials, a reason for discontinuation was provided for 57 (57/123, 46.3%) trials. Of the 305 (305/428, 71.3%) completed trials, 244 (244/305, 80.0%) had a verifiable publication, while 61 (61/305, 20.0%) did not publish their findings or were unable to be located. CONCLUSION: We found that more than one-quarter of trials were prematurely ended, and almost one-third of completed trials did not publish their findings. Subjecting trial participants to potentially harmful treatments and interventions that fail to complete or publish study findings have the potential to undermine the patient-provider relationship, as well as public confidence in government-sponsored clinical trials.

Diagnostic accuracy of narrow-band imaging endoscopy with targeted biopsies compared with standard endoscopy with random biopsies in patients with Barrett's esophagus: A systematic review and meta-analysis.

BACKGROUND AND AIM: Endoscopic surveillance for dysplasia in Barrett's esophagus (BE) with random biopsies is the primary diagnostic tool for monitoring clinical progression into esophageal adenocarcinoma. As an alternative, narrow-band imaging (NBI) endoscopy offers targeted biopsies that can improve dysplasia detection. This study aimed to evaluate NBI-guided targeted biopsies' diagnostic accuracy for detecting dysplasia in patients undergoing endoscopic BE surveillance compared with the widely used Seattle protocol. METHODS: Cochrane DTA Register, MEDLINE/PubMed, EMBASE, OpenGrey, and bibliographies of identified papers were searched until 2018. Two independent investigators resolved discrepancies by consensus, study selection, data extraction, and quality assessment. Data on sensitivity, specificity, and predictive values were pooled and analyzed using a random-effects model. RESULTS: Of 9528 identified articles, six studies comprising 493 participants were eligible for quantitative synthesis. NBI-targeted biopsy showed high diagnostic accuracy in detection of dysplasia in BE with a sensitivity of 76% (95% confidence interval [CI]: 0.61-0.91), specificity of 99% (95% CI: 0.99-1.00), positive predictive value of 97% (95% CI: 0.96-0.99), and negative predictive value of 84% (95% CI: 0.69-0.99) for detection of all grades of dysplasia. The receiver-operating characteristic curve for NBI model performance was 0.8550 for detecting all dysplasia. CONCLUSION: Narrow-band imaging-guided biopsy demonstrated high diagnostic accuracy and might constitute a valid substitute for random biopsies during endoscopic surveillance for dysplasia in BE.

The Fragility Index in a Cohort of HIV/AIDS Randomized Controlled Trials.

HIV/AIDS is associated with significant morbidity, mortality, and financial burden. For these reasons, robust clinical evidence is critical. We aim to investigate the fragility index, fragility quotient, and risk of bias of clinical trial endpoints in HIV medicine. The fragility index represents the minimum amount of trial endpoint "nonevents" changed to "events" in one trial arm required to nullify statistical significance. The fragility quotient contextualized the fragility index by dividing the index by the total trial sample size. We selected eligible trials from the Department of Health and Human Services guideline for the use of antiretroviral agents in HIV-1-infected adults and adolescents. We calculated the fragility index and fragility quotient for all included trials. The Cochrane "risk of bias" Tool 2.0 was used to evaluate the likelihood and sources of bias in the included trials. Thirty-nine RCTs were included for our analysis of fragility. Thirty-six were included for our analysis of the risk of bias. The median fragility index was 5. Three RCTs were at high risk of bias, all due to the selection of the endpoint or statistical test. Twenty had some concerns for risk of bias. The analyzed HIV medicine RCT endpoints were fragile, overall. This indicates that a median of 5 patients across all included studies would nullify the statistical significance of the endpoints. Furthermore, we found evidence that concerns for bias are present at a high rate.

An analysis of randomized controlled trials underpinning ST-elevation myocardial infarction management guidelines.

BACKGROUND: The fragility index (FI) is calculated by iteratively changing one outcome "event" to a "non-event" within a trial until the associated p-value exceeds 0.05. PURPOSE: To investigate the FI and fragility quotient (FQ) of trial endpoints referenced in the ACCF/AHA/SCAI guidelines in the management of ST-elevation myocardial infarctions. Secondarily, we assess the post-hoc power and risk of bias for these specific outcomes and whether differences exist between adequately and inadequately powered studies on fragility measures. BASIC PROCEDURES: All citations referenced in the guideline were screened for inclusion criteria. The FI and FQ for all included trials were then calculated. The Cochrane 'risk of bias' Tool 2.0 was used to evaluate the likelihood and sources of bias in the included trials. MAIN FINDINGS: Forty-two randomized controlled trials were included for assessment. The median FI was 10 with a FQ of 0.0055. Seven trials were at a high risk of bias, all due to bias in the randomization process. Fifteen trials were found to be underpowered. Adequately powered studies had higher FIs and FQs compared to underpowered studies. PRINCIPAL CONCLUSIONS: Our findings support the use of FI and FQ analyses with power analyses in future methodology of randomized control trials. With understanding and reporting of FI and FQ, evidence of studies can be readily available and quickly eliminate some readers' concern for possible study limitations.

Assessing quality of randomized trials supporting guidelines for laparoscopic and endoscopic surgery.

BACKGROUND: Recent studies have highlighted the risk of bias and the fragility of results in randomized controlled trials (RCTs). The aim of our study was to evaluate the clinical practice guidelines created by the Society for Gastrointestinal and Endoscopic Surgeons (SAGES) for fragility, statistical power, and risk of bias. MATERIALS AND METHODS: We screened the SAGES clinical practice guideline references for qualifying RCTs. RCTs were assessed for risk of bias using the Cochrane Collaboration Risk of Bias tool 2.0. We used the fragility index and fragility quotient to evaluate the robustness of trial results and conducted a power analysis using G*Power to determine if trials were adequately powered. RESULTS: Twenty-two (40.7%) of the 54 trials that we assessed were rated as having a high risk of bias, 17 (31.5%) were rated as having a low risk of bias, and 15 (27.8%) were rated as having some concerns. The median fragility index was 2.5 (interquartile range 1-7). The median fragility quotient was 0.021 (interquartile range 0.003-0.045). Mean sample size was 108, and the mean loss to follow-up was eight patients. Eight of 33 trials (24.2%) were found to be underpowered according to the sample size used in the primary outcome. CONCLUSIONS: Guidelines created by SAGES are supported by RCTs that are frequently fragile or underpowered or have a high risk of bias. Future RCTs should utilize the Consolidated Standards of Reporting Trials statement, implement strategies to minimize loss to follow-up, and use properly powered sample sizes.

Suicide risk assessment in the emergency department: Are there any tools in the pipeline?

BACKGROUND: It is estimated that as many as 1 in 10 individuals who complete suicide had been seen in emergency departments within the prior 2months. However, very little evidence underlies the current recommendations on managing patients with suicidal ideation presenting to the emergency department. The American College of Emergency Physicians (ACEP) and Veterans Affairs/Department of Defense (VA/DoD) have developed clinical practice guidelines for the screening and treatment of patients with suicidal ideation who present to emergency departments. In this study we investigated the extent to which new and ongoing studies are being conducted to address the current limitations in suicide screening in emergency departments. METHODS: We identified low-level recommendations in clinical practice guidelines that have been set forth by the ACEP and VA/DoD. PICO questions were then created to help identify relevant studies pertaining to screening patients with suicidal ideation in the emergency department. PICO questions were used to develop search strings, which were then used to locate studies from ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform. RESULTS: Seventeen PICO questions were created for this study. We found 11 studies addressing gaps identified in the clinical practice guidelines. Of the 17 PICO questions created, 10 were being addressed by 11 studies. CONCLUSIONS: Little research is being done to improve suicide risk assessment tools in the emergency department. Further research in this area may decrease health care costs, improve patient care, and save the lives of those at risk of dying by suicide.

Lowering the threshold of statistical significance in gastroenterology trials.

A multidisciplinary international cohort of 72 expert statisticians and researchers recently proposed lowering the p value threshold from 0.05 to 0.005 to mitigate distortion of trial results and decrease bias. We hereby explored how a change to the p value threshold may alter the statistical significance of primary endpoints in gastroenterology (GE) randomized control trials (RCTs). We analyzed RCTs published in the 20 highest ranked GE and medicine journals. For each trial, we extracted the p values for the corresponding primary endpoints. We retrieved 233 RCTs, of which 159 were included in the final analysis yielding 202 primary endpoints. Of these endpoints, 60% had a p value less than 0.05 and when a threshold of less than 0.005 was applied, approximately 50% retained significance. We endorse a lower p value threshold as an actionable, provisional measure for improving statistical inference in GE RCTs until more long-term solutions become available.

Are randomized controlled trials being conducted with the right justification?

OBJECTIVE: It has been estimated that much of health research may be wasted, resulting in billions of dollars in wasteful research spending worldwide each year. Given the increased use of randomized trials and their influence on medicine, one method to combat research waste is to conduct randomized clinical trials (RCTs) only when a systematic review (SR) suggests more data are needed or when no previous SRs are identified. Here, we analyzed RCTs to determine whether SRs were cited as justification for conducting a trial. METHODS: We analyzed phase III RCTs published between 2016 and 2018 in New England Journal of Medicine, Lancet, and JAMA. We performed duplicate and independent data extraction to ensure the accuracy and validity of our data. For each trial, we extracted whether SRs were cited as justification for conducting the clinical trial. RESULTS: We examined 637 RCTs that cited 728 SRs. Overall, 38.1% (243/637) of RCTs cited an SR as either verbatim (6.9%, 44/637) or inferred (31.2%, 199/637) for trial justification. The 79 remaining RCTs cited SRs in other ways. Approximately, 49.5% (315/637) of RCTs did not cite a SR. CONCLUSIONS: Less than half of the analyzed clinical trials cited a SRs as the basis for undertaking the trial. We believe trialists should be required to present relevant SRs to an ethics or peer review committee demonstrating an unmet need prior to initiating a trial. Eliminating research waste is both a scientific and ethical responsibility.

The fragility of randomized trial outcomes underlying management of dyspepsia and Helicobacter pylori infections.

AIM: The fragility index is calculated by changing one outcome event to a nonevent within a trial until the associated P value exceeds 0.05. In this study, we assessed the robustness, risk of bias (RoB), and power of randomized controlled trials that underlie recommendations set forth by the American College of Gastroenterology (ACG) on managing dyspepsia and Helicobacter pylori infections. METHODS: All citations referenced in the guidelines were screened for inclusion criteria. The fragility indexes for eligible trials were then calculated. The likelihood and sources of bias in the included trials were evaluated by the Cochrane 'RoB' Tool 2.0. RESULTS: The median fragility index for the 52 trials was three events. Five studies (9.6%) resulted in a fragility index of 0 when statistical analysis was applied. For the 52 trials, 12 (23.1%) were at a low RoB, 15 (28.8%) had some concerns, and 25 (48.1%) were at a high RoB. High RoB was most commonly due to bias of selection in the reported result (15.5%). CONCLUSION: A median of three events was needed to nullify statistical significance in 52 trials that underpin guideline recommendations on the management of dyspepsia and H. pylori infections. In addition, concerns for RoB were found for these trials.

Are results from randomized trials in anesthesiology robust or fragile? An analysis using the fragility index.

AIM: In anesthesiology, the findings from randomized controlled trials often underpin guidelines influencing clinical decision-making and therefore directly affect patient care. The aim of this study is to evaluate the fragility index and fragility quotient of randomized controlled trials published in the eight highest ranked anesthesiology journals. In addition, we assess the extent to which risk of bias scores, loss to follow-up, Web of Science Citation Index, and journal impact factor influence fragility index and fragility quotient. METHODS: We included randomized trials published between 2014 and 2016 from the eight highest ranking anesthesiology journals based on Clarivate Analytics' Science Citation Index and Google Scholar Metrics: Anesthesiology subcategory. We included journals that published general anesthesia topics and omitted specialty anesthesia journals. The fragility index and fragility quotient for all included trials were calculated. Risk of bias for each trial was evaluated using the Cochrane 'risk of bias' Tool 2.0. RESULTS: One hundred and thirty one randomized control trials were included in this analysis. The median fragility index was 3 (interquartile range 1.0-5.5) with a fragility quotient of 0.03 (interquartile range 0.01-0.08). In 11% (14/131) of trials, the number of patients lost to follow-up was greater than the corresponding fragility index. Weak correlations were found between fragility index and total sample size (r = 0.13) and between fragility index and event frequency (r = 0.19). A near-negligible correlation was found between 5-year impact factor and fragility index (r = -0.03) and, similarly, between fragility index and Science Citation Index (r = -0.05). Ten trials were at high risk of bias with the randomization process found to be the domain at the highest risk of bias. CONCLUSION: In assessing the fragility of randomized controlled trials published in the top eight anesthesiology journals, our study suggests that statistically significant results in these journals are disconcertingly fragile. The median fragility index calculated from our 131 primary studies reveals that only three nonevents must be replaced with events to negate statistical significance. Although a current scale does not exist for fragility index ranges, many trials published by the top journals in anesthesiology are based on concerning methodology and highly fragile outcomes. With small median sample sizes and few patient events characterizing a large number of these trials, many of today's current guidelines and clinical practices may be founded on research containing statistical significance but lacking clinical significance.

The fragility index applied to liver-related trials.

The goal of this manuscript was to apply the fragility index (FI), which is a statistically sound method to evaluate robustness of test results, to liver-related randomized clinical trials. The authors searched the ClinicalTrials.gov database with the following limitations: term "liver," recruitment completed, with results, interventional study type, last updated May 01, 2016, to May 01, 2017. Forty-eight trials were included and four had FI of 0. The median FI for trials moving from significance to non-significance was 6 (IQR 18; 2 to 20), while the median for trials moving from non-significance to significance was 5 (IQR 5; 4 to 9). The median number lost to follow up was 17 (IQR 42; 3 to 45). Of the 21 trials that showed statistical significance, the number lost to follow up was greater than the FI in 13 (61.90%) trials. Investigators of liver-related studies should consider adding the FI to evaluate their work.

Analysis of completeness of reporting utilizing the Reporting Items for practice Guidelines in Healthcare Statement in gastroenterology clinical practice guidelines.

AIM: Assessing reporting quality is important as it allows distinctions to be made between poor methodology and poor reporting practices. The Reporting Items for practice Guidelines in Healthcare (RIGHT) Statement checklist was published in 2017 to improve the thoroughness and reporting quality of clinical practice guidelines (CPGs). CPGs are evidence-based recommendations developed to assist clinician decision-making in the diagnosis and management of patients. The aim of this study is to assess the completeness of reporting in CPGs listed by the American College of Gastroenterology (ACG) and their frequency of reporting items listed in the RIGHT Statement. METHODS: Using the 22 criteria (35 items) of the RIGHT Statement checklist, two researchers independently documented the adherence to each item for all eligible guidelines listed by the ACG. This study was conducted from 01/10/18 to 05/12/18. Data were recorded onto a prespecified Google data abstraction form and extracted into MS Excel for statistical analysis. RESULTS: Out of 38 eligible guidelines, nine of the 35 RIGHT (25.7%) checklist items were met with less than 50% adherence. The mean adherence was 26.8 (SD ±â€Š9.5); median adherence was 30 (interquartile range 21.5-33.5). The publication dates ranged from 2007 to 2017 with seven of the guidelines (18.4%) published between 2007 and 2009, 11 (29%) published between 2010 and 2013, and 20 (52.6%) published between 2014 and 2017. CONCLUSION: The completeness of reporting in CPGs listed by the ACG remains inadequate in several key areas. Poor adherence to items of the RIGHT Statement checklist demonstrates that there is area for improvement in reporting quality.

From clinical practice guideline development to trial registration: A systematic investigation of research pipeline for inflammatory bowel disease.

BACKGROUND: Clinical practice guidelines help practitioners manage patients in an effective and systematic way, and they assist in making evidence-based decisions related to diagnosis and treatment. Each recommendation is ranked based on evidence. The goal of this study is to determine gaps in research for inflammatory bowel diseases (IBD) by using the low-level evidence recommendations. METHODS: We extracted low-level evidence recommendations set forth by the American College of Gastroenterology in IBD, ulcerative colitis (UC), and Crohn's disease. ClinicalTrials.gov , the World Health Organization's International Clinical Trials Registry Platform and PubMed were then used to locate studies relevant to the recommendations. RESULTS: There were 30 low-level evidence recommendations, and 23 had recent or ongoing studies addressing them. We screened 2938 trials and 4321 published articles, 221 of which addressed low-quality recommendations. There were five recommendations that received the majority of research attention (143/221, 65%). CONCLUSION: This study used clinical practice guidelines to help determine areas of needed research in IBD, UC, and Crohn's disease. By searching trial registries and articles indexed on PubMed, we identified the extent to which studies were being conducted to address research gaps. Of the gaps identified, five recommendations received most of the attention. While most of the significant gaps had some recent or ongoing research, our study found several areas where investigation is still needed. Clinical practice guidelines are an effective method to prioritize future research.

Is publication bias present in gastroenterological research? An analysis of abstracts presented at an annual congress.

BACKGROUND: Publication bias is the tendency of investigators, reviewers, and editors to submit or accept manuscripts for publication based on their direction or strength of findings. In this study, we investigated if publication bias was present in gastroenterological research by evaluating abstracts at Americas Hepato-Pancreato-Biliary Congresses from 2011 to 2013. METHODS: We searched Google, Google Scholar, and PubMed to locate the published reports of research described in these abstracts. If a publication was not found, a second investigator searched to verify nonpublication. If abstract publication status remained undetermined, authors were contacted regarding reasons for nonpublication. For articles reaching publication, the P value, study design, time to publication, citation count, and journals in which the published report appeared were recorded. RESULTS: Our study found that of 569 abstracts presented, 297 (52.2%) reported a P value. Of these, 254 (85.5%) contained P values supporting statistical significance. The abstracts reporting a statistically significant outcome were twice as likely to reach publication than abstracts with no significant findings (OR 2.10, 95% CI [1.06-4.14]). Overall, 243 (42.7%) abstracts reached publication. The mean time to publication was 14 months and a median time of nine months. CONCLUSION: In conclusion, we found evidence for publication bias in gastroenterological research. Abstracts with significant P values had a higher probability of reaching publication. More than half of abstracts presented from 2011 to 2013 failed to reach publication. Readers should take these findings into consideration when reviewing medical literature.

Financial Conflicts of Interest Among Authors of Urology Clinical Practice Guidelines.

BACKGROUND: Recent studies have highlighted the presence of disclosed and undisclosed financial conflicts of interest among authors of clinical practice guidelines. OBJECTIVE: We sought to determine to what extent urology guideline authors receive and report industry payments in accordance with the Physician Payment Sunshine Act. DESIGN, SETTING, AND PARTICIPANTS: We selected the 13 urology guidelines that were published by the American Urological Association (AUA) after disclosure was mandated by the Physician Payment Sunshine Act. Payments received by guideline authors were searched independently by two investigators using the Open Payments database. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Our primary outcome measure was the number of authors receiving payments from industry, stratified by amount thresholds. Our secondary outcome measure was the number of authors with accurate conflict of interest disclosure statements. RESULTS AND LIMITATIONS: We identified a total of 54 author disclosures. Thirty-two authors (59.3%) received at least one payment from industry. Twenty (37.0%) received >$10 000 and six (11.1%) received >$50 000. Median total payments were $578 (interquartile range $0-19 228). Twenty (37.0%) disclosure statements were inaccurate. Via Dollars for Docs, we identified $74 195.13 paid for drugs and devices directly related to guideline recommendations. We were limited in our ability to determine when authors began working on guideline panels, as this information was not provided, and by the lack of specificity in Dollars for Docs. CONCLUSIONS: Many of the AUA guideline authors received payments from industry, some in excess of $50 000. A significant portion of disclosure statements were inaccurate, indicating a need for more stringent enforcement of the AUA disclosure policy. PATIENT SUMMARY: Pharmaceutical company payments to doctors have been shown to influence how doctors treat patients. If these doctors are charged with making clinical recommendations to other doctors, in the form of clinical practice guidelines, the issue of industry payments becomes more severe. We found that many urologists on guideline panels receive money from industry and that a significant portion did not disclose all payments received.

Scientific evidence underlying the American College of Gastroenterology's clinical practice guidelines.

BACKGROUND: Clinical practice guidelines contain recommendations for physicians to determine the most appropriate care for patients. These guidelines systematically combine scientific evidence and clinical judgment, culminating in recommendations intended to optimize patient care. The recommendations in CPGs are supported by evidence which varies in quality. We aim to survey the clinical practice guidelines created by the American College of Gastroenterology, report the level of evidence supporting their recommendations, and identify areas where evidence can be improved with additional research. METHODS: We extracted 1328 recommendations from 39 clinical practice guidelines published by the American College of Gastroenterology. Several of the clinical practice guidelines used the differing classifications of evidence for their recommendations. To standardize our results, we devised a uniform system for evidence. RESULTS: A total of 39 clinical practice guidelines were surveyed in our study. Together they account for 1328 recommendations. 693 (52.2%) of the recommendations were based on low evidence, indicating poor evidence or expert opinion. Among individual guidelines, 13/39 (33.3%) had no recommendations based on high evidence. CONCLUSION: Very few recommendations made by the American College of Gastroenterology are supported by high levels of evidence. More than half of all recommendations made by the American College of Gastroenterology are based on low-quality evidence or expert opinion.

The Robustness of Trials That Guide Evidence-Based Orthopaedic Surgery.

BACKGROUND: The fragility index (FI) may prove to be a powerful metric of trial robustness. The FI is the minimum number of patient events that would need to become nonevents in order to nullify a significant result. The fragility quotient (FQ) is the FI divided by the total sample size. This study evaluates the robustness of the 20% of orthopaedic clinical trials that were cited as having strong evidence in the American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guidelines and that could be analyzed with these indices. METHODS: From the AAOS recommendations with strong evidence, we extracted the randomized controlled trials that were cited as having supporting evidence that could be analyzed with the FI. Each trial's FI was calculated using the fragility calculator (http://www.fragilityindex.com). With use of the Cochrane Risk of Bias Tool 2.0, we evaluated the likelihood of bias. We also performed a post hoc power analysis of eligible studies. RESULTS: The median FI for the 72 trials was 2 events, and the median FQ was 0.022. Of the 72 trials, only 3 (4.2%) were at a low risk of bias, and 35 (48.6%) were at a high risk of bias. Thirty-eight (53%) of the trials were underpowered. We identified a strong correlation between a trial's FI or FQ and the trial's power. CONCLUSIONS: Our study found that trials that provided strong evidence for orthopaedic surgery guidelines were largely fragile, underpowered, and at risk of bias.