Detecting outliers beyond tolerance limits derived from statistical process control in patient-specific quality assurance.

BACKGROUND: Tolerance limit is defined on pre-treatment patient specific quality assurance results to identify "out of the norm" dose discrepancy in plan. An out-of-tolerance plan during measurement can often cause treatment delays especially if replanning is required. In this study, we aim to develop an outlier detection model to identify out-of-tolerance plan early during treatment planning phase to mitigate the above-mentioned risks. METHODS: Patient-specific quality assurance results with portal dosimetry for stereotactic body radiotherapy measured between January 2020 and December 2021 were used in this study. Data were divided into thorax and pelvis sites and gamma passing rates were recorded using 2%/2 mm, 2%/1 mm, and 1%/1 mm gamma criteria. Statistical process control method was used to determine six different site and criterion-specific tolerance and action limits. Using only the inliers identified with our determined tolerance limits, we trained three different outlier detection models using the plan complexity metrics extracted from each treatment field-robust covariance, isolation forest, and one class support vector machine. The hyperparameters were optimized using the F1-score calculated from both the inliers and validation outliers' data. RESULTS: 308 pelvis and 200 thorax fields were used in this study. The tolerance (action) limits for 2%/2 mm, 2%/1 mm, and 1%/1 mm gamma criteria in the pelvis site are 99.1% (98.1%), 95.8% (91.1%), and 91.7% (86.1%), respectively. The tolerance (action) limits in the thorax site are 99.0% (98.7%), 97.0% (96.2%), and 91.5% (87.2%). One class support vector machine performs the best among all the algorithms. The best performing model in the thorax (pelvis) site achieves a precision of 0.56 (0.54), recall of 1.0 (1.0), and F1-score of 0.72 (0.70) when using the 2%/2 mm (2%/1 mm) criterion. CONCLUSION: The model will help the planner to identify an out-of-tolerance plan early so that they can refine the plan further during the planning stage without risking late discovery during measurement.

Repurposing DailyQA3 for an efficient and spot position sensitive daily quality assurance tool for proton therapy.

INTRODUCTION: Daily quality assurance is an integral part of a radiotherapy workflow to ensure the dose is delivered safely and accurately to the patient. It is performed before the first treatment of the day and needs to be time and cost efficient for a multiple gantries proton center. In this study, we introduced an efficient method to perform QA for output constancy, range verification, spot positioning accuracy and imaging and proton beam isocenter coincidence with DailyQA3. METHODS: A stepped acrylic block of specific dimensions is fabricated and placed on top of the DailyQA3 device. Treatment plans comprising of two different spread-out Bragg peaks and five individual spots of 1.0 MU each are designed to be delivered to the device. A mathematical framework to measure the 2D distance between the detectors and individual spot is introduced and play an important role in realizing the spot positioning and centering QA. Lastly, a 5 months trends of the QA for two gantries are presented. RESULTS: The outputs are monitored by two ion chambers in the DailyQA3 and a tolerance of ± 3 % $ \pm 3\% $ are used. The range of the SOBPs are monitored by the ratio of ion chamber signals and a tolerance of ± 1 mm $ \pm 1\ {\mathrm{mm}}$ is used. Four diodes at ± 10 cm $ \pm 10\ {\mathrm{cm}}$ from the central ion chambers are used for spot positioning QA, while the central ion chamber is used for imaging and proton beam isocenter coincidence QA. Using the framework, we determined the absolute signal threshold corresponding to the offset tolerance between the individual proton spot and the detector. A 1.5 mm $1.5\ {\mathrm{mm}}$ tolerances are used for both the positioning and centering QA. No violation of the tolerances is observed in the 5 months trends for both gantries. CONCLUSION: With the proposed approach, we can perform four QA items in the TG224 within 10 min.

Real-World Validation of a Computer-Aided Diagnosis System for Prediction of Polyp Histology in Colonoscopy: A Prospective Multicenter Study.

INTRODUCTION: Computer-aided diagnosis (CADx) of polyp histology could support endoscopists in clinical decision-making. However, this has not been validated in a real-world setting. METHODS: We performed a prospective, multicenter study comparing CADx and endoscopist predictions of polyp histology in real-time colonoscopy. Optical diagnosis based on visual inspection of polyps was made by experienced endoscopists. After this, the automated output from the CADx support tool was recorded. All imaged polyps were resected for histological assessment. Primary outcome was difference in diagnostic performance between CADx and endoscopist prediction of polyp histology. Subgroup analysis was performed for polyp size, bowel preparation, difficulty of location of the polyps, and endoscopist experience. RESULTS: A total of 661 eligible polyps were resected in 320 patients aged ≥40 years between March 2021 and July 2022. CADx had an overall accuracy of 71.6% (95% confidence interval [CI] 68.0-75.0), compared with 75.2% (95% CI 71.7-78.4) for endoscopists ( P = 0.023). The sensitivity of CADx for neoplastic polyps was 61.8% (95% CI 56.9-66.5), compared with 70.3% (95% CI 65.7-74.7) for endoscopists ( P < 0.001). The interobserver agreement between CADx and endoscopist predictions of polyp histology was moderate (83.1% agreement, κ 0.661). When there was concordance between CADx and endoscopist predictions, the accuracy increased to 78.1%. DISCUSSION: The overall diagnostic accuracy and sensitivity for neoplastic polyps was higher in experienced endoscopists compared with CADx predictions, with moderate interobserver agreement. Concordance in predictions increased this diagnostic accuracy. Further research is required to improve the performance of CADx and to establish its role in clinical practice.

Comparing artificial intelligence to humans for endoscopic diagnosis of gastric neoplasia: An external validation study.

OBJECTIVES: Artificial intelligence (AI) uses deep learning functionalities that may enhance the detection of early gastric cancer during endoscopy. An AI-based endoscopic system for upper endoscopy was recently developed in Japan. We aim to validate this AI-based system in a Singaporean cohort. METHODS: There were 300 de-identified still images prepared from endoscopy video files obtained from subjects that underwent gastroscopy in National University Hospital (NUH). Five specialists and 6 non-specialists (trainees) from NUH were assigned to read and categorize the images into "neoplastic" or "non-neoplastic." Results were then compared with the readings performed by the endoscopic AI system. RESULTS: The mean accuracy, sensitivity, and specificity for the 11 endoscopists were 0.847, 0.525, and 0.872, respectively. These values for the AI-based system were 0.777, 0.591, and 0.791, respectively. While AI in general did not perform better than endoscopists on the whole, in the subgroup of high-grade dysplastic lesions, only 29.1% were picked up by the endoscopist rating, but 80% were classified as neoplastic by AI (P = 0.0011). The average diagnostic time was also faster in AI compared with endoscopists (677.1 s vs 42.02 s (P < 0.001). CONCLUSION: We demonstrated that an AI system developed in another health system was comparable in diagnostic accuracy in the evaluation of static images. AI systems are faster and not fatigable and may have a role in augmenting human diagnosis during endoscopy. With more advances in AI and larger studies to support its efficacy it would likely play a larger role in screening endoscopy in future.

Severity of gastric intestinal metaplasia predicts the risk of gastric cancer: a prospective multicentre cohort study (GCEP).

OBJECTIVE: To investigate the incidence of gastric cancer (GC) attributed to gastric intestinal metaplasia (IM), and validate the Operative Link on Gastric Intestinal Metaplasia (OLGIM) for targeted endoscopic surveillance in regions with low-intermediate incidence of GC. METHODS: A prospective, longitudinal and multicentre study was carried out in Singapore. The study participants comprised 2980 patients undergoing screening gastroscopy with standardised gastric mucosal sampling, from January 2004 and December 2010, with scheduled surveillance endoscopies at year 3 and 5. Participants were also matched against the National Registry of Diseases Office for missed diagnoses of early gastric neoplasia (EGN). RESULTS: There were 21 participants diagnosed with EGN. IM was a significant risk factor for EGN (adjusted-HR 5.36; 95% CI 1.51 to 19.0; p<0.01). The age-adjusted EGN incidence rates for patients with and without IM were 133.9 and 12.5 per 100 000 person-years. Participants with OLGIM stages III-IV were at greatest risk (adjusted-HR 20.7; 95% CI 5.04 to 85.6; p<0.01). More than half of the EGNs (n=4/7) attributed to baseline OLGIM III-IV developed within 2 years (range: 12.7-44.8 months). Serum trefoil factor 3 distinguishes (Area Under the Receiver Operating Characteristics 0.749) patients with OLGIM III-IV if they are negative for H. pylori. Participants with OLGIM II were also at significant risk of EGN (adjusted-HR 7.34; 95% CI 1.60 to 33.7; p=0.02). A significant smoking history further increases the risk of EGN among patients with OLGIM stages II-IV. CONCLUSIONS: We suggest a risk-stratified approach and recommend that high-risk patients (OLGIM III-IV) have endoscopic surveillance in 2 years, intermediate-risk patients (OLGIM II) in 5 years.

A transit portal dosimetry method for respiratory gating quality assurance with a dynamic 3D printed tumor phantom.

BACKGROUNDS: Respiratory gating is one of the motion management techniques that is used to deliver radiation dose to a tumor at a specific position under free breathing. However, due to the dynamic feedback process of this approach, regular equipment quality assurance (QA) and patient-specific QA checks need to be performed. This work proposes a new QA methodology using electronic portal imaging detector (EPID) to determine the target localization accuracy of phase gating. METHODS: QA tools comprising 3D printed spherical tumor phantoms, programmable stages, and an EPID detector are characterized and assembled. Algorithms for predicting portal dose (PD) through moving phantoms are developed and verified using gamma analysis for two spherical tumor phantoms (2 cm and 4 cm), two different 6 MV volumetric modulated arc therapy plans, and two different gating windows (30%-70% and 40%-60%). Comparison between the two gating windows is then performed using the Wilcoxon signed-rank test. An optimizer routine, which is used to determine the optimal window, based on maximal gamma passing rate (GPR), was applied to an actual breathing curve and breathing plan. This was done to ascertain if our method yielded a similar result with the actual gating window. RESULTS: High GPRs of more than 97% and 91% were observed when comparing the predicted PD with the measured PD in moving phantom at 2 mm/2% and 1 mm/1% levels, respectively. Analysis of gamma heatmaps shows an excellent agreement with the tumor phantom. The GPR of 40%-60% PD was significantly lower than that of the 30%-70% PD at the 1 mm/1% level (p = 0.0064). At the 2 mm/2% level, no significant differences were observed. The optimizer routine could accurately predict the center of the gating window to within a 10% range. CONCLUSION: We have successfully performed and verified a new method for QA with the use of a moving phantom with EPID for phase gating with real-time position management.

Development and validation of a serum microRNA biomarker panel for detecting gastric cancer in a high-risk population.

OBJECTIVE: An unmet need exists for a non-invasive biomarker assay to aid gastric cancer diagnosis. We aimed to develop a serum microRNA (miRNA) panel for identifying patients with all stages of gastric cancer from a high-risk population. DESIGN: We conducted a three-phase, multicentre study comprising 5248 subjects from Singapore and Korea. Biomarker discovery and verification phases were done through comprehensive serum miRNA profiling and multivariant analysis of 578 miRNA candidates in retrospective cohorts of 682 subjects. A clinical assay was developed and validated in a prospective cohort of 4566 symptomatic subjects who underwent endoscopy. Assay performance was confirmed with histological diagnosis and compared with Helicobacter pylori (HP) serology, serum pepsinogens (PGs), 'ABC' method, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). Cost-effectiveness was analysed using a Markov decision model. RESULTS: We developed a clinical assay for detection of gastric cancer based on a 12-miRNA biomarker panel. The 12-miRNA panel had area under the curve (AUC)=0.93 (95% CI 0.90 to 0.95) and AUC=0.92 (95% CI 0.88 to 0.96) in the discovery and verification cohorts, respectively. In the prospective study, overall sensitivity was 87.0% (95% CI 79.4% to 92.5%) at specificity of 68.4% (95% CI 67.0% to 69.8%). AUC was 0.848 (95% CI 0.81 to 0.88), higher than HP serology (0.635), PG 1/2 ratio (0.641), PG index (0.576), ABC method (0.647), CEA (0.576) and CA19-9 (0.595). The number needed to screen is 489 annually. It is cost-effective for mass screening relative to current practice (incremental cost-effectiveness ratio=US$44 531/quality-of-life year). CONCLUSION: We developed and validated a serum 12-miRNA biomarker assay, which may be a cost-effective risk assessment for gastric cancer. TRIAL REGISTRATION NUMBER: This study is registered with ClinicalTrials.gov (Registration number: NCT04329299).

Defining the endoscopic ultrasound features of chronic pancreatitis in Asians: a multicenter validation study.

BACKGROUND: Although endoscopic ultrasound (EUS) features and criteria have been described in chronic pancreatitis, challenges remain with interoperator variability and ease of adoption. The aim of this study was to define and validate the EUS features of chronic pancreatitis in a multicenter prospective study in Asia. METHOD: The study was divided into two parts: the first part was conducted to derive the EUS features of chronic pancreatitis with adequate interoperator agreement; the second was to prospectively evaluate these features in a multicenter cross-sectional study and determine the optimal combination of features for the diagnosis of chronic pancreatitis. Prospectively enrolled cases had standard internationally validated radiologic or histologic features of chronic pancreatitis, and controls were patients without chronic pancreatitis who underwent EUS examination. RESULTS: The top six EUS features that had good interobserver agreement (mean kappa 0.73, range 0.60 - 0.90) were selected to be further evaluated in part II of the study. These included: hyperechoic foci with shadowing, lobularity with honeycombing, cysts, dilated main pancreatic duct, dilated side branches, and calculi in the main pancreatic duct. A total of 284 subjects (132 cases, 152 controls) were enrolled from 12 centers in Asia. All six features had high accuracy ranging from 63.3 % to 89.1 %. Two or more of these six EUS features accurately defined chronic pancreatitis (sensitivity 94.7 %, specificity 98.0 %), with an area under the receiver operating curve of 0.986. CONCLUSION: This multicenter Asian study characterized and defined the EUS features of chronic pancreatitis. This provides a useful tool in clinical practice and further research in pancreatic cancer surveillance.

Endoscopy training in COVID-19: Challenges and hope for a better age.

The COVID-19 pandemic is a unique challenge that has disrupted endoscopy training. Initial infection control measures aimed at protecting patients and staff meant nonessential endoscopic activity was suspended in many countries. The decrease in elective caseload from the pandemic also reduced training numbers during this period. While hands-on training took a backseat, more efforts were directed to didactic training of cognitive competencies. We review the literature describing the impact of COVID-19 on endoscopy training and summarize key measures aimed at mitigating this effect. These include leveraging on web-based didactic material and video-conferences, increased use of simulation and models to hone technical competencies, and a shift in focus from numbers-based accreditation to competency-based accreditation. While COVID-19 was hoped to be short-lived, it is clear the impact is long-lasting. Hence, it is crucial for training programs to take stock of how endoscopy training is evolving and use this opportunity to implement new paradigms into their endoscopic training curricula. COVID-19 might just be the catalyst that transforms endoscopy training into a new digital era.

Review of the role of gastrointestinal multiplex polymerase chain reaction in the management of diarrheal illness.

Acute and chronic diarrheal illness secondary to gastrointestinal infection is a significant cause of morbidity and mortality around the world. A cornerstone of management includes prompt diagnosis and appropriate treatment of culprit pathogens. Timely diagnosis can improve patient care, assist in infection control, and prevent disease outbreaks. Historical methods of diagnosis include traditional culture methods and stool analysis. These are limited by long turnaround time and inability to simultaneously assess multiple pathogens. The advent of multiplexed nucleic acid amplification tests first began with the Food and Drug Administration-approved respiratory virus multiplex polymerase chain reaction (PCR) panel in 2009, followed by gastrointestinal infections in 2013, and neurological infections in 2014. We conducted a review of current literature pertaining to the clinical utility of a gastrointestinal multiplex PCR in management of acute and chronic diarrhea in patients. To date, seven platforms approved by the US Food and Drug Administration are used in detection of various bacterial, viral, and parasitic causative organisms for diagnosis of gastrointestinal infections. The sensitivity and specificity of each assay vary depending on the tested organism. Interpretation of a positive result has to be tailored to the clinical context. Further studies are required to establish the utility of gastrointestinal multiplex PCR from a cost-based perspective, whether specific enteropathogens such as Clostridioides difficile are better assessed with toxin gene detection and whether new parameters such as cycle threshold values can improve clinical application of test results.

Opportunistic upper endoscopy during colonoscopy as a screening strategy for countries with intermediate gastric cancer risk.

BACKGROUND AND AIM: Screening upper endoscopy can detect esophagogastric (OG) cancers early with improved outcomes. Recent cost-utility studies suggest that opportunistic upper endoscopy at the same setting of colonoscopy might be a useful strategy for screening of OG cancers, and it may be more acceptable to the patients due to cost-saving and convenience. We aim to study the diagnostic performance of this screening strategy in a country with intermediate gastric cancer risk. METHODS: A retrospective cohort study using a prospective endoscopy database from 2015 to 2017 was performed. Patients included were individuals age > 40 who underwent opportunistic upper endoscopy at the same setting of colonoscopy without any OG symptoms. Neoplastic OG lesions are defined as cancer and high-grade dysplasia. Pre-neoplastic lesions include Barrett's esophagus (BE), intestinal metaplasia (IM), and atrophic gastritis (AG). RESULTS: The study population involved 1414 patients. Neoplastic OG lesions were detected in five patients (0.35%). Pre-neoplastic lesions were identified in 174 (12.3%) patients. IM was found in 146 (10.3%) patients with 21 (1.4%) having extensive IM. The number needed to scope to detect a neoplastic OG lesion is 282.8 with an estimated cost of USD$141 400 per lesion detected. On multivariate regression, age ≥ 60 (RR: 1.84, 95% CI: 1.29-2.63) and first-degree relatives with gastric cancer (RR: 1.64, 95% CI: 1.06-2.55) were independent risk factors for neoplastic or pre-neoplastic OG lesion. CONCLUSION: For countries with intermediate gastric cancer risk, opportunistic upper endoscopy may be an alternative screening strategy in a selected patient population. Prospective trials are warranted to validate its performance.

Probiotics in health and disease: fooling Mother Nature?

Probiotics are ubiquitous, consumption by the general public is common, and the dogma remains that they are beneficial for general and gut health. However, evolving evidence suggests a potentially "harmful" impact of many commercially available probiotics. There is also significant variability in formulations that leads to a lack of a universally acceptable definition of probiotics. In this perspective, we review the flaws with definition, relevant observational and randomized studies that showed both positive and negative impacts on health and disease, unbiased interpretation of key trials, emerging evidence from microbiome and immuno-oncological studies, and impact on systemic immunity. We propose that caution be exercised prior to endorsements of their illness-directed consumption and rampant general usage. As a deeper understanding of the human microbiome accrues and our ability to manipulate this complex ecosystem improves, the probiotic of tomorrow might be the precision tool that deals with diseases on a broad front. Gut microbiome, akin to fingerprints, is indigenous to an individual and 'one size fits all' prescription strategy should be discouraged until a more universally acceptable 'favorable taxa' or a 'personalized probiotic,' to complement an individual's native microbiota, gets fashioned.

Cost-effectiveness of strategy-based approach to treatment of genotype 1 chronic hepatitis C.

BACKGROUND AND AIM: The high cost of chronic hepatitis C (HCV) direct-acting antivirals (DAAs) poses significant financial challenges for health payers, especially in Asia. A personalized treatment strategy based on individualized probability of virological response using oral DAAs as second-line therapy would seem practical but has not been studied. METHODS: We performed a Markov model to project health outcomes and costs for patients with genotype 1 HCV through 10 treatment strategies over a lifetime period. The implication of retreatment was also incorporated to reflect real-life situation. RESULTS: Using boceprevir and peginterferon/ribavirin (BOC/PR, the least costly treatment) as a base case, the all-oral therapies such as ombitasvir/paritaprevir/ritonavir-dasabuvir are cost-effective with an incremental cost-effective ratio of $US50 828. However, the all-oral DAAs would no longer be cost-effective compared with conventional therapies if retreatment were taken into account. A road map strategy using rapid virological response to guide use of BOC/PR and sofosbuvir/PR had the most favorable incremental cost-effective ratio ($US27 782) relative to BOC/PR. Nevertheless, the trade-off with the cost-effectiveness of the road map strategy is an increased number of liver-related deaths compared with all-oral DAAs (52 vs 10-20 per 10 000 patients) by incorporating retreatment. CONCLUSIONS: The 12-week all-oral DAAs were cost-effective options using conventional drug-to-drug comparison. However, they cease to be cost-effective when treatment strategies incorporating DAA retreatment for interferon failures are incorporated. HCV management can be optimized by adopting individualized treatment algorithm providing a practical solution to health payers to make oral DAAs accessible to those who need them most.