A Data-Driven Reference Standard for Adverse Drug Reaction (RS-ADR) Signal Assessment: Development and Validation.

BACKGROUND: Pharmacovigilance using real-world data (RWD), such as multicenter electronic health records (EHRs), yields massively parallel adverse drug reaction (ADR) signals. However, proper validation of computationally detected ADR signals is not possible due to the lack of a reference standard for positive and negative associations. OBJECTIVE: This study aimed to develop a reference standard for ADR (RS-ADR) to streamline the systematic detection, assessment, and understanding of almost all drug-ADR associations suggested by RWD analyses. METHODS: We integrated well-known reference sets for drug-ADR pairs, including Side Effect Resource, Observational Medical Outcomes Partnership, and EU-ADR. We created a pharmacovigilance dictionary using controlled vocabularies and systematically annotated EHR data. Drug-ADR associations computed from MetaLAB and MetaNurse analyses of multicenter EHRs and extracted from the Food and Drug Administration Adverse Event Reporting System were integrated as "empirically determined" positive and negative reference sets by means of cross-validation between institutions. RESULTS: The RS-ADR consisted of 1344 drugs, 4485 ADRs, and 6,027,840 drug-ADR pairs with positive and negative consensus votes as pharmacovigilance reference sets. After the curation of the initial version of RS-ADR, novel ADR signals such as "famotidine-hepatic function abnormal" were detected and reasonably validated by RS-ADR. Although the validation of the entire reference standard is challenging, especially with this initial version, the reference standard will improve as more RWD participate in the consensus voting with advanced pharmacovigilance dictionaries and analytic algorithms. One can check if a drug-ADR pair has been reported by our web-based search interface for RS-ADRs. CONCLUSIONS: RS-ADRs enriched with the pharmacovigilance dictionary, ADR knowledge, and real-world evidence from EHRs may streamline the systematic detection, evaluation, and causality assessment of computationally detected ADR signals.

Rapid and low-cost, and disposable electrical sensor using an extended gate field-effect transistor for cardiac troponin I detection.

Field effect transistor (FET) biosensor is based on metal oxide field effect transistor that is gated by changes in the surface charges induced the reaction of biomolecules. In most cases of FET biosensor, FET biosensor is not being reused after the reaction; therefore, it is an important concept of investigate the biosensor with simplicity, cheap and reusability. However, the conventional cardiac troponin I (cTnI) sensing technique is inadequate owing to its low sensitivity and high operational time and cost. In this study, we developed a rapid and low-cost, and disposable electrical sensor using an extended gate field-effect transistor (EGFET) to detect cTnI, as a key biomarker for myocardiac infarction. We first investigated pH sensing characteristics according to the pH level, which provided a logarithmically linear sensitivity in the pH sensing buffer solution of approximately 57.9 mV/pH. Subsequently, we prepared a cTnI sample and monitored the reaction between cTnI and cTnI antibodies through the changes in the drain current and transfer curves. Our results showed that the EGFET biosensor could successfully detect the cTnI levels as well as the pH with low-cost and rapid detection.

Cost-Effectiveness of Adjuvant Immunotherapy With Cytokine-Induced Killer Cell for Hepatocellular Carcinoma Based on a Randomized Controlled Trial and Real-World Data.

BACKGROUND: Studies using data from randomized controlled trials (RCTs) and real-world data (RWD) have suggested that adjuvant cytokine-induced killer (CIK) cell immunotherapy after curative treatment for hepatocellular carcinoma (HCC) prolongs recurrence-free survival (RFS) and overall survival (OS). However, the cost-effectiveness of CIK cell immunotherapy as an adjuvant therapy for HCC compared to no adjuvant therapy is uncertain. METHODS: We constructed a partitioned survival model to compare the expected costs, life-year (LY), and quality-adjusted life-year (QALY) of a hypothetical population of 10,000 patients between CIK cell immunotherapy and no adjuvant therapy groups. Patients with HCC aged 55 years who underwent a potentially curative treatment were simulated with the model over a 20-year time horizon, from a healthcare system perspective. To model the effectiveness, we used OS and RFS data from RCTs and RWD. We estimated the incremental cost-effectiveness ratios (ICERs) and performed extensive sensitivity analyses. RESULTS: Based on the RCT data, the CIK cell immunotherapy incrementally incurred a cost of $61,813, 2.07 LYs, and 1.87 QALYs per patient compared to no adjuvant therapy, and the estimated ICER was $33,077/QALY. Being less than the willingness-to-pay threshold of $50,000/QALY, CIK cell immunotherapy was cost-effective. Using the RWD, the ICER was estimated as $25,107/QALY, which is lower than that obtained using RCT. The time horizon and cost of productivity loss were the most influential factors on the ICER. CONCLUSION: We showed that receiving adjuvant CIK cell immunotherapy was more cost-effective than no adjuvant therapy in patients with HCC who underwent a potentially curative treatment, attributed to prolonged survival, reduced recurrence of HCC, and better prognosis of recurrence. Receiving CIK cell immunotherapy may be more cost-effective in real-world clinical practice.

[Impact of COVID-19 on Gastroenterology Fellowship Training].

Background/Aims: The coronavirus disease 2019 (COVID-19) outbreak caused numerous social and cultural changes, but few studies focused on their effects on gastroenterology (GI) fellowship training. This study evaluated the impact of COVID-19 on GI fellowship training. Methods: A web-based questionnaire was sent out to GI fellows in Korea between 15 February and 15 March 2021. The questionnaire included questions regarding the characteristics of GI fellows, perception of COVID-19 outbreak, impact of COVID-19 outbreak, and telemedicine on the education of a GI fellowship. Results: Among 111 answers, 94 respondents were analyzed. The GI fellows were provided with sufficient information about the COVID-19 outbreak (74.7%), well educated, and provided with personal protective equipment use (74.7% and 83.9%, respectively). On the other hand, outpatient schedule and volume decreased in 25.5% and 37.8% of respondents, respectively. Moreover, endoscopy sessions and volume decreased in 51.1% and 65.6% of respondents, respectively. As a result, 78.9% of respondents were concerned that the COVID-19 outbreak adversely affected their education. Telemedicine utilization was introduced during the COVID-19 outbreak, but only 20.0% and 10.6% of respondents agreed that telemedicine has benefits from the patient's and doctor's perspectives, respectively. In addition, only 25.9% of respondents were willing to continue telemedicine if adequately reimbursed, and 68.2% of respondents were concerned that it adversely affected their education. Conclusions: The COVID-19 outbreak has adversely affected GI fellowship training in Korea for outpatient clinics, gastrointestinal endoscopy, educational conferences, and telemedicine. This study highlights that GI fellowship training needs more attention in the COVID-19 outbreak.

[The Role of Training Institutions and Academic Societies for the Training and Education of GI Fellows].

The training and education of GI fellows are crucial issues for the training institutions and academic societies. Current circumstances about GI fellows are changing rapidly according to shortage of training period of the internal medicine residency program and growing up of multimedia and web-based education system. Recently, the education board of Korean Society of Gastroenterology revised the educational objectives considering 2 years program of GI fellows. We also need to develop a concrete education program through cooperation with related organizations including the training institutions and academic societies. All of these efforts should be made with the goal of making a good gastroenterologist, not just making an endoscopist.

Quantitative Assessment of Fatty Liver using Ultrasound with Normalized Local Variance Technique.

PURPOSE: To assess the diagnostic performance of the normalized local variance (NLV) ultrasound technique in the detection of the fatty liver using histopathology as a reference standard. MATERIALS AND METHODS: We prospectively enrolled 194 consecutive patients with clinical suspicion of diffuse liver disease or history of liver transplantation. Conventional grayscale ultrasound and NLV examinations were performed and immediately followed by liver biopsies. The degrees of fatty liver, necroinflammatory activity, and fibrosis stage were evaluated by histopathological assessment. The diagnostic performance of the NLV values in detecting each grade of fatty liver was determined using receiver operating characteristics analyses, and multivariate linear regression analyses were performed to identify variables significantly associated with the NLV values. RESULTS: The number of patients in each degree of fatty liver and hepatic fibrosis was 118/37/26/13 and 81/68/24/6/14 for none/mild/moderate/severe steatosis and F0 / F1/F2 / F3/F4 fibrosis on histopathological examinations, respectively. The area under the receiver operating characteristics curve and optimal cut-off NLV value for detecting fatty liver of varying degrees were 0.911 and 1.095 for ≥ S1, 0.974 and 1.055 for ≥ S2, and 0.954 and 1.025 for ≥ S3, respectively. Multivariate analyses revealed that not fibrosis or inflammation but rather the degree of steatosis was associated with the NLV value. CONCLUSION: The NLV value demonstrated excellent diagnostic performance for detecting varying degrees of fatty liver, and the degree of steatosis on histopathological examinations was the only significant factor affecting the NLV value.

A differential risk assessment and decision model for Transarterial chemoembolization in hepatocellular carcinoma based on hepatic function.

BACKGROUND: The decision of transarterial chemoembolization (TACE) initiation and/or repetition remains challenging in patients with unresectable hepatocellular carcinoma (HCC). The aim was to develop a prognostic scoring system to guide TACE initiation/repetition. METHODS: A total of 597 consecutive patients who underwent TACE as their initial treatment for unresectable HCC were included. We derived a prediction model using independent risk factors for overall survival (OS), which was externally validated in an independent cohort (n = 739). RESULTS: Independent risk factors of OS included Albumin-bilirubin (ALBI) grade, maximal tumor size, alpha-fetoprotein, and tumor response to initial TACE, which were used to develop a scoring system ("ASAR"). C-index values for OS were 0.733 (95% confidence interval [CI] = 0.570-0.871) in the derivation, 0.700 (95% CI = 0.445-0.905) in the internal validation, and 0.680 (95% CI = 0.652-0.707) in the external validation, respectively. Patients with ASAR< 4 showed significantly longer OS than patients with ASAR≥4 in all three datasets (all P < 0.001). Among Child-Pugh class B patients, a modified model without TACE response, i.e., "ASA(R)", discriminated OS with a c-index of 0.788 (95% CI, 0.703-0.876) in the derivation, and 0.745 (95% CI, 0.646-0.862) in the internal validation, and 0.670 (95% CI, 0.605-0.725) in the external validation, respectively. Child-Pugh B patients with ASA(R) < 4 showed significantly longer OS than patients with ASA(R) ≥ 4 in all three datasets (all P < 0.001). CONCLUSIONS: ASAR provides refined prognostication for repetition of TACE in patients with unresectable HCC. For Child-Pugh class B patients, a modified model with baseline factors might guide TACE initiation.

The Impact of National Surveillance for Liver Cancer: Results from Real-World Setting in Korea.

Background/Aims: The National Liver Cancer Surveillance Program (NLCSP) was established in 2003 to reduce the socioeconomic burden imposed by liver cancer (LC). We aimed to investigate the effectiveness of the NLCSP in South Korea with respect to survival benefits and cost, after adjusting for various confounding factors. Methods: We used the National Health Insurance Service claims data linked with the NLCSP from 2004 to 2015. The Cox proportional hazard model and generalized linear model were used to determine the effects of the NLCSP on the early detection of LC, survival, and medical costs. Results: From 2006 to 2010, 66,632 patients (surveillance group: 10,527 and no surveillance group: 56,105) newly diagnosed with LC were included in the study. The odds of the early detection of LC was 1.82 (95% confidence interval [CI], 1.73 to 1.93) times higher among patients who participated in the NLCSP once within the 2-year period prior to the diagnosis of LC than among those who did not participate in the surveillance program. The mortality rate of patients who participated in the NLCSP was 22.0% lower (hazard ratio, 0.78; 95% CI, 0.76 to 0.80) than that of those who did not participate. When compared with the group who did not participate in surveillance, the group who participated in the NLCSP had higher total medical costs; however, their cost per day was lower after adjustment during the follow-up period. Conclusions: This study highlights the survival benefit in patients who participated in the NLCSP and the need for continuous improvements of the NLCSP in South Korea.

Assessment of hepatic steatosis by using attenuation imaging: a quantitative, easy-to-perform ultrasound technique.

OBJECTIVES: To evaluate the diagnostic performance of attenuation imaging (ATI) in the detection of hepatic steatosis compared with a histopathology gold standard. METHODS: We prospectively enrolled 108 consecutive patients (35 males; median age, 54.0 years) who underwent percutaneous liver biopsy for evaluation of diffuse liver disease between January 2018 and November 2018 in a tertiary academic center. Grayscale ultrasound examination with ATI was performed just before biopsy, and an attenuation coefficient (AC) was obtained from each patient. The degree of hepatic steatosis, fibrosis stage, and necroinflammatory activity were assessed on histopathologic examination. The significant factor associated with the AC was found by a linear regression analysis, and the diagnostic performance of the AC for the classification into each hepatic steatosis stage was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: The distribution of hepatic steatosis grade on histopathology was 53/11/22/16/6 for none/mild (< 10%)/mild (≥ 10%)/moderate/severe steatosis, respectively. The area under the ROC curve, sensitivity, specificity, and optimal cutoff AC value for detection of hepatic steatosis ranged from 0.843-0.926, 74.5-100.0%, 77.4-82.8%, and 0.635-0.745, respectively. Multivariate analysis revealed that the degree of steatosis was the only significant determinant factor for the AC. CONCLUSIONS: The AC from ATI provided good diagnostic performance in detecting the varying degrees of hepatic steatosis. The degree of steatosis was the only significant factor affecting the AC, whereas fibrosis and inflammation were not. KEY POINTS: • Attenuation imaging (ATI) is based on two-dimensional grayscale ultrasound images that can incorporate into routine ultrasound examinations with less than 2 min of acquisition time. • ATI provided good diagnostic performance in detecting the varying degrees of hepatic steatosis with an area under the ROC curves ranging from 0.843 to 0.926, and there was no technical failure in this study indicating high applicability of this technique. • The degree of hepatic steatosis was the only significant factor affecting the result of ATI examination.

Assessment of the Surveillance Interval at 1 Year after Curative Treatment in Hepatocellular Carcinoma: Risk Stratification.

Background/Aims: Guidelines recommend surveillance for hepatocellular carcinoma (HCC) recurrence at 3-month intervals during the first year after curative treatment and 6-month intervals thereafter in all patients. This strategy does not reflect individual risk of recurrence. We aimed to stratify risk of recurrence to optimize surveillance intervals 1 year after treatment. Methods: We retrospectively analyzed 1,316 HCC patients treated with resection/radiofrequency ablation at Barcelona Clinic Liver Cancer stage 0/A. In patients without 1-year recurrence under 3-monthly surveillance, a new model for recurrence was developed using backward elimination methods: training (n=582)/validation cohorts (n=291). Overall survival (OS) according to risk stratified by the new model was compared according to surveillance intervals: 3-monthly versus 6-monthly (n=401) after lead time bias correction and propensity-score matching analyses. Results: Among patients without 1-year recurrence, age and international normalized ratio values were significant factors for recurrence (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.00 to 1.03; p=0.009 and HR, 5.63; 95% CI, 2.24 to 14.18; p<0.001; respectively). High-risk patients stratified by the new model showed significantly higher recurrence rates than low-risk patients in the validation cohort (HR, 1.73; 95% CI, 1.18 to 2.53; p=0.005). After propensity-score matching between the 3-monthly and 6-monthly surveillance groups, OS in high-risk patients under 3-monthly surveillance was significantly higher than that under 6-monthly surveillance (p=0.04); however, OS in low-risk patients under 3-monthly surveillance was not significantly different from that under 6-monthly surveillance (p=0.17). Conclusions: In high-risk patients, 3-monthly surveillance can prolong survival compared to 6-monthly surveillance. However, in low-risk patients, 3-monthly surveillance might not be beneficial for survival compared to 6-monthly surveillance.

Early Detection is Important to Reduce the Economic Burden of Gastric Cancer.

PURPOSE: Early detection of gastric cancer is important to improve prognosis. Early detection enables local treatment, such as endoscopic submucosal dissection (ESD). Therefore, we investigated whether early detection of gastric cancer could reduce healthcare costs by comparison according to stage and treatment modalities. MATERIALS AND METHODS: Medical care costs were investigated according to tumor stage and initial treatment modality in 1,188 patients newly diagnosed with gastric cancer at 7 medical institutions from December 2011 to June 2012. Total medical care costs during the first-year after diagnosis (total first-year costs) were examined, including the costs of initial treatment, post-initial treatment, and inpatient and outpatient visits. RESULTS: Stage I (75.3%) was the most common cancer stage. ESD was the second most common treatment following surgery. Total first-year costs increased significantly from stages I to IV. The costs of initial treatment and post-initial treatment were lowest in patients with stage I cancer. Among patients with stage I cancer, total first-year costs were significantly lower when treated by ESD; in particular, initial ESD treatment costs were much lower than others. CONCLUSIONS: The cost of healthcare has increased significantly with increasing cancer stages. ESD can greatly reduce medical care costs of gastric cancer. Thus, early detection of gastric cancer is important to reduce healthcare costs.

The Efficacy of a Newly Designed, Easy-to-Manufacture Training Simulator for Endoscopic Biopsy of the Stomach.

BACKGROUND/AIMS: We developed a new endoscopic biopsy training simulator and determined its efficacy for improving the endoscopic biopsy skills of beginners. METHODS: This biopsy simulator, which presents seven biopsy sites, was constructed using readily available materials. We enrolled 40 participants: 14 residents, 11 first-year clinical fellows, 10 second-year clinical fellows, and five staff members. We recorded the simulation completion time for all participants, and then simulator performance was assessed via a questionnaire using the 7-point Likert scale. RESULTS: The mean times for completing the five trials were 417.7±138.8, 145.2±31.5, 112.7±21.9, and 90.5±20.0 seconds for the residents, first-year clinical fellows, second-year clinical fellows, and staff members, respectively. Endoscopists with less experience reported that they found this simulator more useful for improving their biopsy technique (6.8±0.4 in the resident group and 5.7±1.0 in the first-year clinical fellow group). The realism score of the simulator for endoscopic handling was 6.4±0.5 in the staff group. CONCLUSIONS: This new, easy-to-manufacture endoscopic biopsy simulator is useful for biopsy training for beginner endoscopists and shows good efficacy and realism.

Education can improve inter-observer agreement in double balloon endoscopy assessment.

BACKGROUND/AIMS: Double balloon endoscopy (DBE) diagnoses are difficult because of the frequent occurrence of tiny lesions or longitudinally arranged erythema, which may result from true pathologies or contact trauma during DBE insertion. This study was performed to explore interobserver agreement for DBE assessment and to determine whether this can be improved by educating endoscopists. METHODOLOGY: Three experienced endoscopists independently evaluated DBE pictures of an initial training set, consisting of 124 lesions in 78 patients with suspected small bowel bleeding. Each endoscopist made DBE diagnoses independently and assessed whether each lesion was or was not a source of bleeding. Tiny lesions were assessed twice, assuming they had been detected during DBE insertion and/or DBE withdrawal. After two sessions of consensus review by the endoscopists, they evaluated a second, validation set consisting of an additional 43 lesions in 30 patients. RESULTS: Inter-observer agreement with respect to DBE assessment was moderate in the initial training set, but improved to good in the second validation set. The proportion of diagnoses changed to DBE contact lesions when they were assumed to be detected during DBE withdrawal decreased in the second validation set. CONCLUSIONS: Although inter-observer agreement for DBE assessment is not excellent, it can be improved by education of endoscopists.