Incorporating Biological Pathways via a Markov Random Field Model in Genome-Wide Association Studies

Genome-wide association studies (GWAS) examine a large number of markers across the genome to identify associations between genetic variants and disease. Most published studies examine only single markers, which may be less informative than considering multiple markers and multiple genes jointly because genes may interact with each other to affect disease risk. Much knowledge has been accumulated in the literature on biological pathways and interactions. It is conceivable that appropriate incorporation of such prior knowledge may improve the likelihood of making genuine discoveries. Although a number of methods have been developed recently to prioritize genes using prior biological knowledge, such as pathways, most methods treat genes in a specific pathway as an exchangeable set without considering the topological structure of a pathway. However, how genes are related with each other in a pathway may be very informative to identify association signals. To make use of the connectivity information among genes in a pathway in GWAS analysis, we propose a Markov Random Field (MRF) model to incorporate pathway topology for association analysis. We show that the conditional distribution of our MRF model takes on a simple logistic regression form, and we propose an iterated conditional modes algorithm as well as a decision theoretic approach for statistical inference of each gene's association with disease. Simulation studies show that our proposed framework is more effective to identify genes associated with disease than a single gene–based method. We also illustrate the usefulness of our approach through its applications to a real data example

Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort

BACKGROUND AND AIMS: Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide polymorphism (SNP) array data from 29,358 individuals in the multiethnic, randomly ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease prediction and pathophysiology. METHODS: PRS were calculated from European, African American, and Ashkenazi Jewish (AJ) reference case-control studies, and a meta-GWAS run using all three association datasets. PRS were then combined using regression to assess which combination of scores best predicted IBD status in European, AJ, Hispanic, and African American cohorts in BioMe. Additionally, rare variants were assessed in genes associated with very early-onset IBD (VEO-IBD), by estimating genetic penetrance in each BioMe population. RESULTS: Combining risk scores based on association data from distinct ancestral populations improved IBD prediction for every population in BioMe and significantly improved prediction among European ancestry UK Biobank individuals. Lower predictive power for non-Europeans was observed, reflecting in part substantially lower African IBD case-control reference sizes. We replicated associations for two VEO-IBD genes, ADAM17 and LRBA, with high dominant model penetrance in BioMe. Autosomal recessive LRBA risk alleles are associated with severe, early-onset autoimmunity; we show that heterozygous carriage of an African-predominant LRBA protein-altering allele is associated with significantly decreased LRBA and CTLA-4 expression with T-cell activation. CONCLUSIONS: Greater genetic diversity in African populations improves prediction across populations, and generalizes some VEO-IBD genes. Increasing African American IBD case-collections should be prioritized to reduce health disparities and enhance pathophysiological insight.Peer reviewe

Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study.

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29)

Ambipolar Field Effect in Topological Insulator Nanoplates of (BixSb1-x)2Te3

Topological insulators represent a new state of quantum matter attractive to both fundamental physics and technological applications such as spintronics and quantum information processing. In a topological insulator, the bulk energy gap is traversed by spin-momentum locked surface states forming an odd number of surface bands that possesses unique electronic properties. However, transport measurements have often been dominated by residual bulk carriers from crystal defects or environmental doping which mask the topological surface contribution. Here we demonstrate (BixSb1-x)2Te3 as a tunable topological insulator system to manipulate bulk conductivity by varying the Bi/Sb composition ratio. (BixSb1-x)2Te3 ternary compounds are confirmed as topological insulators for the entire composition range by angle resolved photoemission spectroscopy (ARPES) measurements and ab initio calculations. Additionally, we observe a clear ambipolar gating effect similar to that observed in graphene using nanoplates of (BixSb1-x)2Te3 in field-effect-transistor (FET) devices. The manipulation of carrier type and concentration in topological insulator nanostructures demonstrated in this study paves the way for implementation of topological insulators in nanoelectronics and spintronics.Comment: 7 pages, 4 figure

College students' underlying perceptions of COVID-19 threat, healthcare discrimination, and healthcare system inequities associated with self-rated health across racial/ethnic groups in the U.S.

BackgroundCOVID-19-related health perceptions may differentially impact college students' stress, and in turn, their mental and physical health. This study examined racial/ethnic differences in college students' underlying perceptions of COVID-19 threat, healthcare discrimination, and U.S. healthcare system inequities and their associations with self-rated mental and physical health.MethodsFour-hundred-thirty-two university students completed an online survey (December 2020–December 2021). Latent class analyses identified classes of perceived COVID-19 threat (i.e., severity, susceptibility), healthcare discrimination, and U.S. healthcare system inequities. Regression analyses examined whether class membership varied by race/ethnicity and was associated with self-rated mental and physical health.ResultsClass 1 members (27.3% of the sample) were more likely to identify as Hispanic or Latino, Non-Hispanic Asian, Non-Hispanic Black or African American, and Non-Hispanic Multiracial vs. Non-Hispanic White (vs. Class 4). Class 1 had high perceived COVID-19 threat, medium perceived healthcare discrimination, and high perceived U.S. healthcare system inequities, as well as higher odds of poorer mental and physical health (vs. Class 4).ConclusionsCollege students' underlying perceptions of COVID-19 threat, healthcare discrimination, and U.S. healthcare system inequities were associated with poorer health. Given that students with these perceptions were more likely to belong to minoritized racial/ethnic groups, concerns over COVID-19 risk and healthcare may partially explain racial/ethnic disparities in college students' health. This study contributes to a limited body of evidence on college students' perceptions of the U.S. healthcare system and suggests important ways that structural inequalities and racial/ethnic disparities in COVID-19 risk, healthcare discrimination, and concerns over U.S. healthcare system inequity may affect college students' health

The Relationship between Subjective and Objective Parameters in CT Phantom Image Evaluation

Objective: To evaluate whether there is a relationship between subjective parameters determined by a reviewer (spatial resolution, low contrast resolution, and artifacts) and objective parameters (the CT number of water, noise, and image uniformity) in CT phantom image evaluations. Materials and Methods: We reviewed the CT results of phantom image evaluations conducted by Korean Institute for Accreditation of Medical Image (KIAMI) from May 2007 to June 2007. We compared the objective parameters against the pass or fail groups for the subjective parameters. We also evaluated whether there is a relationship between the artifact types and the other subjective parameters. Results: The mean noise value was significantly higher in the fail groups for the subjective parameters compared to the pass groups (p = 0.006). Specifically, noise and low contrast resolution were found to have a statistically significant positive correlation (r = 0. 183, p < 0.001). In the fail group for low contrast resolution, the failure due to artifacts was significantly higher than the pass group (p < 0.001). In contrast, no statistically significant differences were found for the mean CT number of water, noise, or image uniformity based on the types of artifacts. Conclusion: Subjective CT image parameters evaluated by a reviewer correlate with objectively measured parameters, especially noise. Therefore, a stricter noise standard might be able to improve the subjective parameters results, such as low contrast resolution.Park HJ, 2008, KOREAN J RADIOL, V9, P354, DOI 10.3348/kjr.2008.9.4.354IM TH, 2007, 1 KIAMI, P1*KIAMI DEP ED, 2006, WORKSH EX QUAL ASS P, P141*FLUK CORP, 2005, NUCL ASS 76 410 4130*KIAMI DEP ED, 2005, WORKSH EX QUAL ASS P, P13McCollough CH, 2004, MED PHYS, V31, P2423, DOI 10.1118/1.1769632MCCOLLOUGH CM, 2000, CATEGORICAL COURSE D, P189WIL R, 1998, CT IMAGE QUALITYEUCLID S, 1994, COMPUT TOMOGR, P174BETHESDA MD, 1988, 99 NCRPJUDY PF, 1977, 1 AAPM*ACR, CT ACCR PROGR REQ

Integrated Magnetic MEMS Relays:Status of the Technology

The development and application of magnetic technologies employing microfabricated magnetic structures for the production of switching components has generated enormous interest in the scientific and industrial communities over the last decade. Magnetic actuation offers many benefits when compared to other schemes for microelectromechanical systems (MEMS), including the generation of forces that have higher magnitude and longer range. Magnetic actuation can be achieved using different excitation sources, which create challenges related to the integration with other technologies, such as CMOS (Complementary Metal Oxide Semiconductor), and the requirement to reduce power consumption. Novel designs and technologies are therefore sought to enable the use of magnetic switching architectures in integrated MEMS devices, without incurring excessive energy consumption. This article reviews the status of magnetic MEMS technology and presents devices recently developed by various research groups, with key focuses on integrability and effective power management, in addition to the ability to integrate the technology with other microelectronic fabrication processes