Application of an iterative Bayesian variable selection method in a genome-wide association study of rheumatoid arthritis

Genome-wide association studies usually involve several hundred thousand of single-nucleotide polymorphisms (SNPs). Conventional approaches face challenges when there are enormous number of SNPs but a relatively small number of samples and, in some cases, are not feasible. We introduce here an iterative Bayesian variable selection method that provides a unique tool for association studies with a large number of SNPs (p) but a relatively small sample size (n). We applied this method to the simulated case-control sample provided by the Genetic Analysis Workshop 15 and compared its performance with stepwise variable selection method. We demonstrated that the results of iterative Bayesian variable selection applied to when p » n are as comparable as those of stepwise variable selection implemented to when n » p. When n > p, the iterative Bayesian variable selection performs better than stepwise variable selection does

Application of Bayesian classification with singular value decomposition method in genome-wide association studies

To analyze multiple single-nucleotide polymorphisms simultaneously when the number of markers is much larger than the number of studied individuals, as is the situation we have in genome-wide association studies (GWAS), we developed the iterative Bayesian variable selection method and successfully applied it to the simulated rheumatoid arthritis data provided by the Genetic Analysis Workshop 15 (GAW15). One drawback for applying our iterative Bayesian variable selection method is the relatively long running time required for evaluation of GWAS data. To improve computing speed, we recently developed a Bayesian classification with singular value decomposition (BCSVD) method. We have applied the BCSVD method here to the rheumatoid arthritis data distributed by GAW16 Problem 1 and demonstrated that the BCSVD method works well for analyzing GWAS data

Preventing condensation of objective lens in noncontact wide-angle viewing systems during vitrectomy

AIM: To assess the optimal conditions for preventing condensation of objective lens during vitrectomy with noncontact wide-angle viewing systems (WAVSs). METHODS: We explored the effectiveness of the coating with ophthalmic viscoelastic device (OVDs) on the corneal surface and the soaking the objective lens in warm-saline for preventing condensation of objective lens. First, to find the optimal soaking time to keep the objective lens warm, we measured the temperature of objective lens every minute after soaking in warm saline. Second, to find optimal distance between cornea and objective lens, which provide as wide a view as possible and less condensation at the same time, we measured the condensation time with different distances. With the obtained optimal soaking time and distance, we explored the effect of coating cornea with OVDs and soaking objective lens in warm saline on condensation time. RESULTS: One and 5min of soaking in warm saline was most effective for keeping the lens warm enough (45.1℃±2.1℃ for 1min and 46.4℃±1.0℃ for 5min, P=0.109). The mean condensation times for the control group at 1, 3, and 5 mm from corneal surface to objective lens were 1±0.4, 4±1.4, 190±26.1s, respectively, thus 5 mm was most optimal distance for vitrectomy with WAVSs. For the OVD coating group, the mean condensation times were 1.5±0.3, 13±1.4, and 200±23.9s at 1, 3, and 5 mm distance and borderline significant compared with control group (P=0.068, 0.051, and 0.063, respectively). With the 1-minute warm saline soaking group, the mean condensation time were extended to 188±34.4, 416±65.7, and 600±121.3s at 1, 3, and 5 mm distance and statistically significant compared with control (P=0.043, 0.041 and 0.043, respectively). CONCLUSION: OVD coating on corneal surface shows no difference on condensation time with control group. However, soaking the objective lens in warm saline revealed statistically significant extension of condensation time compared to control group. Therefore, keeping the objective lens warm with soaking in warm saline is a simple but effective to prevent condensation of objective lens during vitrectomy. The thermodynamics between objective lens and cornea during vitrectomy warrants further investigation

Application of Bayesian regression with singular value decomposition method in association studies for sequence data

Genetic association studies usually involve a large number of single-nucleotide polymorphisms (SNPs) (k) and a relative small sample size (n), which produces the situation that k is much greater than n. Because conventional statistical approaches are unable to deal with multiple SNPs simultaneously when k is much greater than n, single-SNP association studies have been used to identify genes involved in a disease’s pathophysiology, which causes a multiple testing problem. To evaluate the contribution of multiple SNPs simultaneously to disease traits when k is much greater than n, we developed the Bayesian regression with singular value decomposition (BRSVD) method. The method reduces the dimension of the design matrix from k to n by applying singular value decomposition to the design matrix. We evaluated the model using a Markov chain Monte Carlo simulation with Gibbs sampler constructed from the posterior densities driven by conjugate prior densities. Permutation was incorporated to generate empirical p-values. We applied the BRSVD method to the sequence data provided by Genetic Analysis Workshop 17 and found that the BRSVD method is a practical method that can be used to analyze sequence data in comparison to the single-SNP association test and the penalized regression method

Epigenetic Mechanism Underlying the Development of Polycystic Ovary Syndrome (PCOS)-Like Phenotypes in Prenatally Androgenized Rhesus Monkeys

The pathogenesis of polycystic ovary syndrome (PCOS) is poorly understood. PCOS-like phenotypes are produced by prenatal androgenization (PA) of female rhesus monkeys. We hypothesize that perturbation of the epigenome, through altered DNA methylation, is one of the mechanisms whereby PA reprograms monkeys to develop PCOS. Infant and adult visceral adipose tissues (VAT) harvested from 15 PA and 10 control monkeys were studied. Bisulfite treated samples were subjected to genome-wide CpG methylation analysis, designed to simultaneously measure methylation levels at 27,578 CpG sites. Analysis was carried out using Bayesian Classification with Singular Value Decomposition (BCSVD), testing all probes simultaneously in a single test. Stringent criteria were then applied to filter out invalid probes due to sequence dissimilarities between human probes and monkey DNA, and then mapped to the rhesus genome. This yielded differentially methylated loci between PA and control monkeys, 163 in infant VAT, and 325 in adult VAT (BCSVD P<0.05). Among these two sets of genes, we identified several significant pathways, including the antiproliferative role of TOB in T cell signaling and transforming growth factor-β (TGF-β) signaling. Our results suggest PA may modify DNA methylation patterns in both infant and adult VAT. This pilot study suggests that excess fetal androgen exposure in female nonhuman primates may predispose to PCOS via alteration of the epigenome, providing a novel avenue to understand PCOS in humans

Cumulative burden of metabolic syndrome and its components on the risk of atrial fibrillation:a nationwide population-based study

BackgroundThe metabolic syndrome (MetS) and its components are associated with the development of atrial fibrillation (AF). However, the impact of time-burden of MetS on the risk of AF is unknown. We investigated the effect of the cumulative longitudinal burden of MetS on the development of AF.MethodsWe included 2 885 189 individuals without AF who underwent four annual health examinations during 2009-2013 from the database of the Korean national health insurance service. Metabolic burdens were evaluated in the following three ways: (1) cumulative number of MetS diagnosed at each health examination (0-4 times); (2) cumulative number of each MetS component diagnosed at each health examination (0-4 times per MetS component); and (3) cumulative number of total MetS components diagnosed at each health examination (0 to a maximum of 20). The risk of AF according to the metabolic burden was estimated using Cox proportional-hazards models.ResultsOf all individuals, 62.4%, 14.8%, 8.7%, 6.5%, and 7.6% met the MetS diagnostic criteria 0, 1, 2, 3, and 4 times, respectively. During a mean follow-up of 5.3 years, the risk of AF showed a positive association with the cumulative number of MetS diagnosed over four health examinations: adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of 1, 2, 3, and 4 times compared to 0 times were 1.18 (1.13-1.24), 1.31 (1.25-1.39), 1.46 (1.38-1.55), and 1.72 (1.63-1.82), respectively; P for trend ConclusionsGiven the positive correlations between the cumulative metabolic burdens and the risk of incident AF, maximal effort to detect and correct metabolic derangements even before MetS development might be important to prevent AF and related cardiovascular diseases

Associations between obesity parameters and the risk of incident atrial fibrillation and ischaemic stroke in the different age groups

OBJECTIVE: Obesity and aging are important predisposing factors to atrial fibrillation (AF) and ischaemic stroke (IS). However, limited data comprehensively evaluated the relationships between obesity measurements and AF and IS in different ages. METHODS: A total of 9,432,332 adults from the Korean National Health Insurance Service Database were included. The study population was categorized into the six age subgroups by an increase every decade from the twenties. We evaluated AF and IS risk according to body mass index (BMI) and waist circumference (WC) in the different age groups. RESULTS: During a mean follow-up of 8.2 ± 1.0 years, BMI-AF presented a J-shaped association across ages. The highest hazard ratio (HR) of the BMI ≥ 30 kg/m(2) group was observed in subjects aged 30–39 years [HR 1.80, 95% CI 1.63–1.98, p 60 years. Among the BMI ≥ 30 kg/m(2) groups, subjects aged 20–29 years presented the highest risk of IS [HR 3.00, 95% CI (2.34–3.84), p < 0.001]. Overall, WC-AF and WC-IS showed positive linear correlations, but the WC-IS association was weak in subjects aged ≥ 40 years. CONCLUSION: The higher risks of AF and IS according to an increment of BMI and WC were most apparent among the young ages. The association between obesity measurements and IS was not significantly above the midlife. Weight management in the young and integrated risk factor management in the elderly are warranted

Impact of components of metabolic syndrome on the risk of adverse renal outcomes in patients with atrial fibrillation: a nationwide cohort study

Background: The renal effect of metabolic syndrome components is unclear in patients with atrial fibrillation. This study aimed to investigate the association between metabolic syndrome components and incident end-stage renal disease among patients with atrial fibrillation. Methods: A total of 202,434 atrial fibrillation patients without prevalent end-stage renal disease were identified from the National Health Insurance Service database between 2009 and 2016. We defined the metabolic score range from 0 to 5 points such that a patient received every 1 point if the patient met each component listed in the diagnostic criteria of metabolic syndrome. The population was divided into 6 groups: MS 0–MS 5 for a metabolic score of 0–5, respectively. Multivariate Cox regression analysis was used to estimate the risks of end-stage renal disease. Results: There were 12,747, 31,059, 40,361, 48,068, 46,630, and 23,569 patients for MS 0–MS 5, respectively. Compared with MS 0, MS 5 had a higher CHA 2DS 2-VASc score (3.8 vs. 1.0) (P &lt;.001). During a median follow-up of 3.5 years, compared with MS 0, MS 1–MS 5 were associated with a gradually increasing incidence of end-stage renal disease, in relation to an increase in the metabolic score, (log-rank P &lt;.001). After multivariate adjustment, a higher metabolic score was associated with a greater risk of incident end-stage renal disease: adjusted hazard ratio [95% confidence interval] = 1.60 [0.78–3.48], 2.08 [1.01–4.31], 2.94 [1.43–6.06], 3.71 [1.80–7.66], and 4.82 [2.29–10.15], for MS 1–MS 5, respectively. Conclusions: Metabolic syndrome components additively impacts the risk of incident end-stage renal disease among patients with atrial fibrillation.</p

Impact of mental disorders on the risk of atrial fibrillation in patients with diabetes mellitus:a nationwide population-based study

BACKGROUND: It is unclear whether mental disorders are an independent risk factor for atrial fibrillation (AF) in patients with diabetes. We aimed to investigate whether patients with diabetes who have mental disorders have an increased risk for AF. METHODS: Using the Korea National Health Insurance Service database, we enrolled 2,512,690 patients diagnosed with diabetes without AF between 2009 and 2012. We assessed five mental disorders: depression, insomnia, anxiety, bipolar disorder, and schizophrenia. Newly diagnosed AF was identified during the follow-up period, and multivariate Cox regression analysis was performed. RESULTS: Among the 2,512,690 patients (mean age 57.2 ± 12.3 years; 60.1% men), 828,929 (33.0%) had mental disorders. Among the five mental disorders, anxiety (68.1%) was the most common, followed by insomnia (40.0%). During a median follow-up duration of 7.1 years, new-onset AF was diagnosed in 79,525 patients (4.66 per 1,000 person-years). Patients with diabetes who had mental disorders showed a higher risk for AF (adjusted hazard ratio [HR] 1.19; 95% confidence interval [CI] 1.17–1.21; p-value < 0.001). Depression, insomnia, and anxiety were significantly associated with higher risk for AF (adjusted HR [95% CI]: 1.15 [1.12–1.17], 1.15 [1.13–1.18], and 1.19 [1.67–1.21], respectively; all p-values < 0.001), whereas bipolar disorder and schizophrenia were not. CONCLUSIONS: Mental disorders, especially depression, insomnia, and anxiety, were associated with an increased risk for AF in patients with diabetes. Greater awareness with a prompt diagnosis of AF should be considered for patients with both DM and mental disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-022-01682-7

Net clinical benefit of antithrombotic therapy for atrial fibrillation patients with stable coronary artery disease

OBJECTIVES: To compare the net clinical benefit of oral anticoagulant (OAC) monotherapy to OAC plus single antiplatelet therapy (SAPT) in patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) at 1- and 3-year after percutaneous coronary intervention (PCI). BACKGROUND: It has not been studied whether the net clinical benefit of the antithrombotic treatment options differs depending on the elapsed time from the index PCI. METHODS: Using the Korean nationwide claims database, we included AF patients who underwent PCI from 2009 to 2019 and constructed two cohorts: 1- and 3-year after PCI. In each cohort, the baseline characteristics of two groups were balanced using propensity score weighting. Ischemic stroke, myocardial infarction, major bleeding, and composite clinical outcomes were analyzed. RESULTS: Among patients with 1-year after PCI, OAC monotherapy (n = 678), and OAC plus SAPT (n = 3,159) showed comparable results for all clinical outcomes. In patients with 3-year after PCI, OAC monotherapy (n = 1,038) and OAC plus SAPT (n = 2,128) showed comparable results for ischemic stroke and myocardial infarction, but OAC monotherapy was associated with a lower risk of composite clinical outcomes (HR 0.762, 95% CI 0.607–0.950), mainly driven by the reduction of major bleeding risk (HR 0.498, 95% CI 0.345–0.701). CONCLUSION: Oral anticoagulant monotherapy may be a comparable choice for patients with AF and stable CAD compared to OAC plus SAPT. In patients with stable CAD more than 3-year after index PCI, OAC monotherapy would be a better choice, being associated with less major bleeding and a positive net clinical benefit