Over the past decade, the detection of gene-gene interactions has become more and more popular in the field of genome-wide association studies (GWASs). The goal of the GWAS is to identify genetic susceptibility to complex diseases by assaying and analyzing hundreds of thousands of single-nucleotide polymorphisms. However, such tests are computationally demanding and methodologically challenging. Recently, a simple but powerful method, named “BOolean Operation-based Screening and Testing” (BOOST), was proposed for genome-wide gene-gene interaction analyses. BOOST was designed with a Boolean representation of genotype data and is approximately equivalent to the log-linear model. It is extremely fast, and genome-wide gene-gene interaction analyses can be completed within a few hours. However, BOOST can not adjust for covariate effects, and its type-1 error control is not correct. Thus, we considered two-step approaches for gene-gene interaction analyses. First, we selected gene-gene interactions with BOOST and applied logistic regression with covariate adjustments to select gene-gene interactions. We applied the two-step approach to type 2 diabetes (T2D) in the Korea Association Resource (KARE) cohort and identified some promising pairs of single-nucleotide polymorphisms associated with T2D.
Cohort Studies ; Diabetes Mellitus, Type 2 ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Korea ; Linear Models ; Logistic Models ; Mass Screening ; Methods

OBJECTIVE: The mGluR1 (metabotropic glutamate receptor 1) gene, a G protein–coupled receptor, is known to mediate perceptions of umami tastes. Genetic variation in taste receptors may influence dietary intake, and in turn have an impact on nutritional status and risk of chronic disease. We investigated the association of mGluR1 rs2814863 polymorphism with lipid profiles and cardiovascular disease (CVD) risk, together with their modulation by macronutrient intake in Korean adults. METHODS: The subjects consisted of 8,380 Koreans aged 40-69 years participating in the Anseong and Ansan Cohort Study, which was a part of the Korean Genome Epidemiology Study (KoGES). Data was collected using self-administered questionnaires, anthropometric measurements, and blood chemical analysis. RESULTS: Carriers of C allele at mGluR1 rs2814863 was associated with decreased high density lipoprotein cholesterol (HDL-C) and increased triglyceride as compared to carriers of TT. Also, carriers of the C allele showed higher fat intake and lower carbohydrate intake than those with carriers of TT. After adjustment for multiple testing using false-discovery rate method, the significant difference of HDL-C, triglyceride, dietary fat, and carbohydrate across genotypes disappeared. Gene-diet interaction effects between rs2814863 and macronutrients intake were not significantly associated with HDL-C and triglyceride levels. However, carriers of C allele demonstrated significantly higher odds of CVD {odds ratio=1.13, 95% CI=1.02-1.25} compared with carriers of TT. CONCLUSIONS: Our findings support significant associations between the mGluR1 rs2814863 genotype and CVD-related variables in Korean adults. However, these associations are not modified by macronutrient intake.
Adult* ; Alleles ; Blood Chemical Analysis ; Cardiovascular Diseases* ; Cholesterol, HDL ; Chronic Disease ; Cohort Studies ; Dietary Fats ; Epidemiology ; Genes, vif ; Genetic Variation ; Genome ; Genotype ; Gyeonggi-do ; Humans ; Methods ; Nutritional Status ; Polymorphism, Single Nucleotide ; Receptors, Glutamate ; Receptors, Metabotropic Glutamate* ; Triglycerides

Background: Genome-wide association studies (GWAS) on type 2 diabetes mellitus (T2DM) have identified more than 400 distinct genetic loci associated with diabetes and nearly 120 loci for fasting plasma glucose (FPG) and fasting insulin level to date. However, genetic risk factors for the longitudinal deterioration of FPG have not been thoroughly evaluated. We aimed to identify genetic variants associated with longitudinal change of FPG over time. Methods: We used two prospective cohorts in Korean population, which included a total of 10,528 individuals without T2DM. GWAS of repeated measure of FPG using linear mixed model was performed to investigate the interaction of genetic variants and time, and meta-analysis was conducted. Genome-wide complex trait analysis was used for heritability calculation. In addition, expression quantitative trait loci (eQTL) analysis was performed using the Genotype-Tissue Expression project. Results: A small portion (4%) of the genome-wide single nucleotide polymorphism (SNP) interaction with time explained the total phenotypic variance of longitudinal change in FPG. A total of four known genetic variants of FPG were associated with repeated measure of FPG levels. One SNP (rs11187850) showed a genome-wide significant association for genetic interaction with time. The variant is an eQTL for NOC3 like DNA replication regulator (NOC3L) gene in pancreas and adipose tissue. Furthermore, NOC3L is also differentially expressed in pancreatic β-cells between subjects with or without T2DM. However, this variant was not associated with increased risk of T2DM nor elevated FPG level. Conclusion We identified rs11187850, which is an eQTL of NOC3L, to be associated with longitudinal change of FPG in Korean population.

BACKGROUND: External quality assessment (EQA) uses a standard deviation index (SDI), based on a peer group, to evaluate laboratory performance. However, evaluations using peer group SDIs often have limited applicability, because they are not statistically valid unless the number of institutions in the same peer group is large. The present study proposes a statistical model for simultaneously evaluating the performance of all participating institutions, as well as the performance of instruments on the market. METHODS: By assuming that proficiency test results were affected by the manufacturer, the instrument, and the institution, the effects of those factors were estimated using a linear mixed model. We used these effect estimates to calculate manufacturer, instrument, and institution SDIs. Using simulation, we evaluated the false positive rates and efficiencies of the proposed linear mixed model. RESULTS: Simulations showed that the linear mixed model empirical type I error rates preserved the nominal significance level. This model was also more statistically efficient than the peer group SDI. Rates of unacceptability were lower when using institution SDI than they were when using peer group SDI. Additional outliers that could not be evaluated using the current system were detected by the institution SDI statistic. The instrument SDI statistic detected outliers among different instrument groups. CONCLUSIONS: Institution and instrument SDIs are robust and efficient tools for EQA, and they can replace the currently used system of peer group SDI.
Laboratory Proficiency Testing ; Models, Statistical ; Peer Group

Background: Nonsteroidal anti-inflammatory drugs (NSAID) are currently among the most prescribed medications worldwide to relieve pain and reduce inflammation, especially in patients suffering osteoarthritis (OA). However, NSAIDs are known to have adverse effects on the gastrointestinal system. If a gastric ulcer occurs, planned OA treatment needs to be changed, incurring additional treatment costs and causing discomfort for both patients and clinicians. Therefore, it is necessary to create a gastric ulcer prediction model that can reflect the detailed health status of each individual and to use it when making treatment plans. Methods: Using sample cohort data from 2008 to 2013 from the National Health Insurance Service in South Korea, we developed a prediction model for NSAID-induced gastric ulcers using machine-learning algorithms and investigated new risk factors associated with medication and comorbidities. Results: The population of the study consisted of 30,808 patients with OA who were treated with NSAIDs between 2008 and 2013. After a 2-year follow-up, these patients were divided into two groups: without gastric ulcer (n=29,579) and with gastric ulcer (n=1,229). Five machine-learning algorithms were used to develop the prediction model, and a gradient boosting machine (GBM) was selected as the model with the best performance (area under the curve, 0.896; 95% confidence interval, 0.883–0.909). The GBM identified 5 medications (loxoprofen, aceclofenac, talniflumate, meloxicam, and dexibuprofen) and 2 comorbidities (acute upper respiratory tract infection [AURI] and gastroesophageal reflux disease) as important features. AURI did not have a dose-response relationship, so it could not be interpreted as a significant risk factor even though it was initially detected as an important feature and improved the prediction performance. Conclusions We obtained a prediction model for NSAID-induced gastric ulcers using the GBM method. Since personal prescription period and the severity of comorbidities were considered numerically, individual patients’ risk could be well reflected. The prediction model showed high performance and interpretability, so it is meaningful to both clinicians and NSAID users.

Background/Aims: The survival rate of gastric cancer (GC) is known to be higher in patients with a family history (FH) of GC. There is an association between a polymorphism in the transforming growth factor-β1 (Methods: Results: The proportion of stage I–II GCs was significantly higher in patients with a FH than in those without a FH of GC (83.8 vs 74.9%, p=0.005). The association between a FH of GC and stage I–II GC was not significant in subgroups divided based on the Conclusions Patient with a FH of GC had lower cancer stage (I–II) at diagnosis than those without a FH of GC, but there was no significant difference in overall survival between the patients with and without a FH of GC. A FH did not influence the tumor stage or overall survival in patients stratified by the presence of the

Recently, there has been considerable progress in developing new technologies and equipment for the medical field, including minimally invasive surgeries. Evaluating the effectiveness of these treatments requires study designs like randomized controlled trials.However, due to the nature of certain treatments, randomization is not always feasible, leading to the use of observational studies. The effect size estimated from observational studies is subject to selection bias caused by confounders. One method to reduce this bias is propensity scoring. This study aimed to introduce a propensity score matching process between two groups using a practical example with R. Additionally, Rex, an Excel add-in graphical user interface statistical program, is provided for researchers unfamiliar with R programming.Further techniques, such as matching with three or more groups, propensity score weighting and stratification, and imputation of missing values, are summarized to offer approaches for more complex studies not covered in this tutorial.

BACKGROUND/AIMS: Although diagnosis and surgical treatment for distal common bile duct cancer have enormously advanced, survival is not satisfactory and its prognostic factors are still being debated. Thus, we evaluated the outcomes and prognostic factors after major resection for distal extrahepatic cholangiocarcinoma (dCC). METHODS: One hundred and fifty-four patients who underwent major resection such as pancreaticoduodenectomy for dCC were retrospectively analyzed. We investigated clinical features, postoperative complications, survival, and prognostic factors of dCC. CONCLUSIONS: One hundred and three (66.9%) male and 51 (33.1%) female patients were enrolled and their mean age was 59.6 (31-78) years. Among them, 97 patients (63.0%) underwent Whipple's procedure, 45 (29.2%) pylorus-preserving pancreaticoduodenectomy, 7 (4.5%) total pancreatectomy, and 5 (3.3%) hepatopancreaticoduodenectomy, respectively. Mean follow-up duration was 26.6 (0.4-108.5) months. The postoperative morbidity and mortality were 42.2% and 1.3%, respectively. Five-year survival rate was 32.8% and mean survival duration was 47.2 (39.1-55.3) months. Type of biliary drainage (percutaneous transhepatic biliary drainage), lymph node status (positive), and cellular differentiation (moderate or poor) were significant indicators for death in multivariate analysis of resectable dCC. CONCLUSIONS: Moderate or poor cellular differentiation and lymph node metastasis may be independent poor prognostic factors for resectable dCC.
Adult ; Aged ; Bile Duct Neoplasms/mortality/*surgery ; *Bile Ducts, Extrahepatic ; Biliary Tract Surgical Procedures ; Cholangiocarcinoma/mortality/*surgery ; Female ; Humans ; Male ; Middle Aged ; Prognosis ; Risk Factors ; Survival Rate

Pulmonary vein thrombosis is a rare disease related to a lung malignancy or complication after lung surgery. Generally, it is caused by tumor invasion or localized stenosis of a vein anastomosis site after an operation. Here we report a case of pulmonary vein thrombosis that occurred in a patient with local thrombophlebitis due to lobar pneumonia.
Constriction, Pathologic ; Humans ; Lung ; Pneumonia* ; Pulmonary Veins* ; Rare Diseases ; Thrombophlebitis ; Thrombosis* ; Veins

BACKGROUND: This study aimed to estimate the nationwide prevalence of live births with Down syndrome (DS) and its trends and compare the observed and model-based predicted prevalence rates. Further, we compared the direct medical expenditures among DS and non-DS patients. METHODS: Using the health administrative data of Health Insurance Review and Assessment in Korea, we selected 2,301 children with DS who were born between 2007 and 2016 to estimate the prevalence of live births with DS, and 12,265 non-DS children who were born between 2010 and 2014 to compare the direct medical expenditures among patients. RESULTS: The prevalence of live births with DS was 5.03 per 10,000 births in 9 years, and 13% of children with DS were medical aid recipients during the study period. The medical expenditure of children with DS was about 10-fold higher than that of non-DS children and their out-of-pocket expenditure was about twice as high. CONCLUSION: The prevalence of live birth with DS is high in the low socioeconomic group and the healthcare costs for the children with DS are significantly higher than those for non-DS children. Therefore, health authorities should help mothers at lower socioeconomic levels to receive adequate antenatal care and consider the cost of medical care for children with DS.
Child ; Down Syndrome ; Health Care Costs ; Health Expenditures ; Humans ; Insurance, Health ; Korea ; Live Birth ; Mothers ; Parturition ; Prevalence