Elastic-net regularization approaches for genome-wide association studies of rheumatoid arthritis

The current trend in genome-wide association studies is to identify regions where the true disease-causing genes may lie by evaluating thousands of single-nucleotide polymorphisms (SNPs) across the whole genome. However, many challenges exist in detecting disease-causing genes among the thousands of SNPs. Examples include multicollinearity and multiple testing issues, especially when a large number of correlated SNPs are simultaneously tested. Multicollinearity can often occur when predictor variables in a multiple regression model are highly correlated, and can cause imprecise estimation of association. In this study, we propose a simple stepwise procedure that identifies disease-causing SNPs simultaneously by employing elastic-net regularization, a variable selection method that allows one to address multicollinearity. At Step 1, the single-marker association analysis was conducted to screen SNPs. At Step 2, the multiple-marker association was scanned based on the elastic-net regularization. The proposed approach was applied to the rheumatoid arthritis (RA) case-control data set of Genetic Analysis Workshop 16. While the selected SNPs at the screening step are located mostly on chromosome 6, the elastic-net approach identified putative RA-related SNPs on other chromosomes in an increased proportion. For some of those putative RA-related SNPs, we identified the interactions with sex, a well known factor affecting RA susceptibility

Combined impact of elevated arterial stiffness and left ventricular filling pressure on outcomes after off-pump coronary artery bypass grafting

Abstract Background Brachial-ankle pulse wave velocity (baPWV) and early diastolic transmitral flow velocity to mitral annular tissue velocity (E/e′)—which are markers of arterial stiffness and left ventricular (LV) filling pressure, respectively—have been associated with morbidity and mortality. We investigated their combined impact on postoperative complications and long-term survival of patients undergoing off-pump coronary artery bypass grafting (OPCAB). Methods A cohort of 164 patients were divided into four groups: baPWV ≤ 19m/s and E/e′ ≤ 15 (reference), baPWV > 19m/s and E/e′ ≤ 15 (high-PWV-only), baPWV ≤ 19m/s and E/e′ > 15 (high-E/e′-only), and baPWV > 19m/s and E/e′ > 15 (high-PWV-and-E/e′). After inverse probability treatment weighting adjustment, each group was compared with the reference group to analyze the odds ratios of postoperative complications and the Kaplan–Meier survival curves, and to identify the group representing an independent prognostic predictor. Results The median age and follow-up duration were 69years and 57.2months, respectively. Both postoperative acute kidney injury (POAKI) and atrial fibrillation (POAF) were higher in the high-PWV-and-E/e′ group (adjusted odds ratio (OR) = 89.5; 95% confidence interval (CI), 8.5–942.3; p < 0.001 and OR = 12.5; CI, 2.5–63.8; p = 0.002, respectively). Compared to the reference group, only the high-PWV-and-E/e′ group showed significantly lower survival rate (91.0%; CI, 82.8–100% vs. 44.8%; CI, 21.2–94.6%) and a higher hazard for all-cause mortality after adjustment for covariates (hazard ratio = 6.1; p = 0.002). Conclusion Concurrent elevation in PWV and E/e′ may independently affect not only the rates of POAKI and POAF but also long-term survival after OPCAB

A novel method to identify high order gene-gene interactions in genome-wide association studies: Gene-based MDR

<p>Abstract</p> <p>Background</p> <p>Because common complex diseases are affected by multiple genes and environmental factors, it is essential to investigate gene-gene and/or gene-environment interactions to understand genetic architecture of complex diseases. After the great success of large scale genome-wide association (GWA) studies using the high density single nucleotide polymorphism (SNP) chips, the study of gene-gene interaction becomes a next challenge. Multifactor dimensionality reduction (MDR) analysis has been widely used for the gene-gene interaction analysis. In practice, however, it is not easy to perform high order gene-gene interaction analyses via MDR in genome-wide level because it requires exploring a huge search space and suffers from a computational burden due to high dimensionality.</p> <p>Results</p> <p>We propose dimensional reduction analysis, Gene-MDR analysis for the fast and efficient high order gene-gene interaction analysis. The proposed Gene-MDR method is composed of two-step applications of MDR: within- and between-gene MDR analyses. First, within-gene MDR analysis summarizes each gene effect via MDR analysis by combining multiple SNPs from the same gene. Second, between-gene MDR analysis then performs interaction analysis using the summarized gene effects from within-gene MDR analysis. We apply the Gene-MDR method to bipolar disorder (BD) GWA data from Wellcome Trust Case Control Consortium (WTCCC). The results demonstrate that Gene-MDR is capable of detecting high order gene-gene interactions associated with BD.</p> <p>Conclusion</p> <p>By reducing the dimension of genome-wide data from SNP level to gene level, Gene-MDR efficiently identifies high order gene-gene interactions. Therefore, Gene-MDR can provide the key to understand complex disease etiology.</p

Factors affecting the long-term outcomes of idiopathic membranous nephropathy

Abstract Background We attempted to describe the clinical features and determine the factors associated with renal survival in idiopathic membranous nephropathy (iMN) patients with nephrotic syndrome (NS) and to determine the factors associated with spontaneous complete remission (sCR) and progression to NS in iMN patients with subnephrotic proteinuria. Methods This retrospective study involved 166 iMN patients with NS and 65 patients with subnephrotic proteinuria. The primary end point was a doubling of serum creatinine or initiation of dialysis. In patients with subnephrotic proteinuria, we determined the factors associated with sCR and factors associated with progression to NS. Results Remission of NS was achieved in 125 out of 166 patients (75.3%). Of those who reached remission, 26 patients (20.8%) experienced relapse that was followed by second remission. The relapse or persistence of proteinuria was associated with the primary end points (hazard ratio [HR] = 12.40, P = 0.037, HR = 173, P < 0.001, respectively). In patients with subnephrotic proteinuria, sCR occurred in 35.4% of the patients. The patients with sCR had lower proteinuria and serum creatinine levels and higher serum albumin concentrations at baseline. The serum albumin level at diagnosis was a prognostic factor for progression to NS (Odds ratio [OR] = 0.015, P < 0.001). Conclusions The occurrence of relapse or persistence of proteinuria had negative effects on renal survival in iMN patients with NS, and low serum albumin levels at baseline were associated with non-achievement of sCR and progression to NS

Contextualized Generative Retrieval

The text retrieval task is mainly performed in two ways: the bi-encoder approach and the generative approach. The bi-encoder approach maps the document and query embeddings to common vector space and performs a nearest neighbor search. It stably shows high performance and efficiency across different domains but has an embedding space bottleneck as it interacts in L2 or inner product space. The generative retrieval model retrieves by generating a target sequence and overcomes the embedding space bottleneck by interacting in the parametric space. However, it fails to retrieve the information it has not seen during the training process as it depends solely on the information encoded in its own model parameters. To leverage the advantages of both approaches, we propose Contextualized Generative Retrieval model, which uses contextualized embeddings (output embeddings of a language model encoder) as vocab embeddings at the decoding step of generative retrieval. The model uses information encoded in both the non-parametric space of contextualized token embeddings and the parametric space of the generative retrieval model. Our approach of generative retrieval with contextualized vocab embeddings shows higher performance than generative retrieval with only vanilla vocab embeddings in the document retrieval task, an average of 6% higher performance in KILT (NQ, TQA) and 2X higher in NQ-320k, suggesting the benefits of using contextualized embedding in generative retrieval models

Age of first experience of gender incongruence among transgender and non-binary individuals

Objective Gender incongruence (GI) is a condition in which an individual’s gender identity, role, and expression differ from their assigned sex. This study aimed to evaluate when GI first arises in transgender and non-binary individuals seeking hormone therapy and their years living untreated in South Korea. Methods This retrospective study analyzed GI patients seeking gender-affirming hormone therapy (GAHT) or surgery between 2015 and 2021. The recorded data included gender identity, legal transition status, age of onset of GI, age at the initiation of therapy, and total therapy duration. Results In total, 337 patients were enrolled, including 149 (44.2%) transgender men, 153 (45.4%) transgender women, and 35 (10.4%) non-binary individuals. The mean age of onset of GI was 10.6 years (standard deviation, 5.1). Of the total patients, 29% had an onset of GI before age 6 years (preschool), 61% before age 12 (elementary-school), and 87% before age 15 (middle-school). Patients lived with GI for almost 14 years before GAHT initiation at a median age of 23.0 years. 90% of transgender men, 82.3% of transgender women, and 85% of non-binary patients disclosed their gender identities to their families. Regarding social transition, 31.5% of transgender men, 16.3% of transgender women, and none of the non-binary patients (P<0.005) changed their legal gender markers. Conclusion Many transgender and non-binary individuals experience GI early in life. These findings emphasized the need for early evaluation, timely gender-affirming care, and more accessible legal processes for gender marker changes in South Korea, aiming to enhance the safety and well-being of these individuals

Effects of reflection and immediate feedback to improve clinical reasoning of medical students in the assessment of dermatologic conditions: a randomised controlled trial

There are few studies that directly compared different interventions to improve medical students clinical reasoning for dermatologic conditions. To investigate the effectiveness of adding practice with reflection and immediate feedback on traditional dermatology electives in improving medical students ability in evaluating skin lesions. The participants were fourth-year medical students of Seoul National University College of Medicine, Korea, who were enrolled to take a 2-week dermatology elective course (n = 87). Students were assigned to one of the three educational interventions: 2-h training involving 10 written clinical cases (experimental); 1-h lecture and 1-h outpatient clinic (lecture); and 2-h outpatient clinic (no intervention). Before and at the end of rotation, diagnostic accuracy was estimated using 20 written clinical cases with photographs (10 novel cases presented in diagnostic training [training set], 10 cases with diagnoses not included in training [control set]). There was a significant interaction effect of intervention×set×time. A post hoc analysis indicated that the students in the experimental group outperformed students in the other two groups only in the training set of the final tests; after completing the 2-week rotation, for the training set, the mean score was higher in the experimental group (7.5 ± 1.3) than in the lecture (5.7 ± 1.6) and no intervention (5.6 ± 1.3) groups, producing an effect size of 1.2 standard deviation (SD) and 1.5 SD, respectively. Practicing written clinical cases with reflection and feedback is superior to a lecture-based approach and yields additional benefits to a dermatology elective, thereby enhancing medical students ability to accurately diagnose skin lesions. ClinicalTrials.gov, NCT03472001. Registered 21 March 2018.This work was supported by a clinical research grant-in-aid from the Seoul Metropolitan Government Seoul National University (SMG-SNU) Boramae Medical Center (03–2018-7). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publicatio