Gene-based association testing of dichotomous traits using generalized functional linear mixed models for family data

Gene-based association testing with rare variants requires arbitrarily aggregating or collapsing the information of the rare variants in genes into a single measure. As genotyping data can be viewed as a realization of a stochastic process that varies along the chromosome, it is more natural to summarize the genetic information using the approaches of functional data analysis. In functional data analysis, discrete genotypes are fitted by a continuous curve by using a collection of smooth basis functions. Existing generalized functional linear models (FLM) have been developed for unrelated samples to test for association between a dichotomous trait and genetic variants in a gene. In most situations, these models have higher power than well-known kernel-based methods (SKAT and SKAT-O). Here we extend this approach to accommodate family-based data using the GLOGS (genome-wide logistic mixed model/score test) approach developed by Stanhope and Abney, and develop family-based generalized functional linear mixed models (GFLMMs). This involves parallel computations to integrate out a multidimensional polygenic effect. Simulation results indicate that in most scenarios our new statistics are better than other similar statistics (famSKAT or F-SKAT), but not better than the retrospective kernel and burden statistics developed by Schaid and colleagues. We also embed FLM-smoothed genotypes in the retrospective statistics, improving the power of the kernel-based approach. We illustrate the behavior of these statistics by applying them to an age-related macular degeneration (AMD) family data set, where, as expected, we observe strong association between AMD and CFH and ARMS2, two known AMD susceptibility genes. Our proposed GFLMM provides a new tool for conducting family-based research studies in public health for complex or multifactorial diseases. The findings may improve the knowledge of existing AMD susceptibility genes and make a positive contribution to AMD treatment and prevention

Grotesque Impressions Enhance the Gaze Cueing Effect

A non-predictive gaze cue produces a reflexive shift of attention to the gazed-at location. The present study used a modified version of Posner's attentional cueing paradigm (a gaze cueing paradigm) to investigate role of grotesque facial expressions on a gaze cueing effect involving induced fear. Grotesque faces were created by vertically shifting the position of one of the two eyes (Experiment 1, N =28) or both eyes (Experiment 2, N =28).  The grotesque faces of Experiment 1 produced a larger facilitative effect of a gaze cue than did original faces, whereas the less grotesque faces of Experiment 2 did not.  Cooper & Wojan (2000) have shown that one-eye moved faces produce much more grotesque impressions than two-eye moved faces. Results suggest that a grotesque facial expression, which may induce fear, automatically attracts observers' attention and facilitates processing of the gaze, ultimately enhancing the gaze cueing effect

Grotesque Impressions Enhance the Gaze Cueing Effect

A non-predictive gaze cue produces a reflexive shift of attention to the gazed-at location. The present study used a modified version of Posner's attentional cueing paradigm (a gaze cueing paradigm) to investigate role of grotesque facial expressions on a gaze cueing effect involving induced fear. Grotesque faces were created by vertically shifting the position of one of the two eyes (Experiment 1, N =28) or both eyes (Experiment 2, N =28).  The grotesque faces of Experiment 1 produced a larger facilitative effect of a gaze cue than did original faces, whereas the less grotesque faces of Experiment 2 did not.  Cooper & Wojan (2000) have shown that one-eye moved faces produce much more grotesque impressions than two-eye moved faces. Results suggest that a grotesque facial expression, which may induce fear, automatically attracts observers' attention and facilitates processing of the gaze, ultimately enhancing the gaze cueing effect

Tuning the work function of stepped metal surfaces by adsorption of organic molecules

Understanding the binding mechanisms for aromatic molecules on transition-metal surfaces, especially with defects such as vacancies, steps and kinks, is a major challenge in designing functional interfaces for organic devices. One important parameter in the performance of organic/inorganic devices is the barrier of charge carrier injection. In the case of a metallic electrode, tuning the electronic interface potential or the work function for electronic level alignment is crucial. Here, we use density-functional theory (DFT) calculations with van der Waals (vdW) interactions treated with both screened pairwise (vdWsurf) and many-body dispersion (MBD) methods, to systematically study the interactions of benzene with a variety of stepped surfaces. Our calculations confirm the physisorptive character of Ag(2 1 1), Ag(5 3 3), Ag(3 2 2), Ag(7 5 5) and Ag(5 4 4) surfaces upon the adsorption of benzene. The MBD effects reduce the adsorption energies by about 0.15 eV per molecule compared to the results from the DFT + vdWsurf method. In addition, we find that the higher the step density, the larger the reduction of the work function upon the adsorption of benzene. We also study the effect of vdW interactions on the electronic structure using a fully selfconsistent implementation of the vdWsurf method in the Kohn–Sham DFT framework. We find that the self-consistent vdWsurf effects increase the work function due to the lowered Fermi level and the increased vacuum level. As a result, the benzene/Ag(2 1 1) system has the lowest work function (3.67 eV) among the five adsorption systems, significantly smaller than the work function of the clean Ag(1 1 1) surface (4.74 eV). Our results provide important insights into the stability and electronic properties of molecules adsorbed on stepped metal surfaces, which could help in designing more appropriate interfaces with low work functions for electron transfer

DavarOCR: A Toolbox for OCR and Multi-Modal Document Understanding

This paper presents DavarOCR, an open-source toolbox for OCR and document understanding tasks. DavarOCR currently implements 19 advanced algorithms, covering 9 different task forms. DavarOCR provides detailed usage instructions and the trained models for each algorithm. Compared with the previous opensource OCR toolbox, DavarOCR has relatively more complete support for the sub-tasks of the cutting-edge technology of document understanding. In order to promote the development and application of OCR technology in academia and industry, we pay more attention to the use of modules that different sub-domains of technology can share. DavarOCR is publicly released at https://github.com/hikopensource/Davar-Lab-OCR.Comment: Short paper, Accept by ACM MM202

Catalysis beyond frontier molecular orbitals: Selectivity in partial hydrogenation of multi-unsaturated hydrocarbons on metal catalysts

The mechanistic understanding and control over transformations of multi-unsaturated hydrocarbons on transition metal surfaces remains one of the major challenges of hydrogenation catalysis. To reveal the microscopic origins of hydrogenation chemoselectivity, we performed a comprehensive theoretical investigation on the reactivity of two a,b-unsaturated carbonyls—isophorone and acrolein—on seven (111) metal surfaces: Pd, Pt, Rh, Ir, Cu, Ag, and Au. In doing so, we uncover a general mechanism that goes beyond the celebrated frontier molecular orbital theory, rationalizing the C--C bond activation in isophorone and acrolein as a result of significant surface-induced broadening of high-energy inner molecular orbitals. By extending our calculations to hydrogen-precovered surface and higher adsorbate surface coverage, we further confirm the validity of the “inner orbital broadening mechanism” under realistic catalytic conditions. The proposed mechanism is fully supported by our experimental reaction studies for isophorone and acrolein over Pd nanoparticles terminated with (111) facets. Although the position of the frontier molecular orbitals in these molecules, which are commonly considered to be responsible for chemical interactions, suggests preferential hydrogenation of the C--O double bond, experiments show that hydrogenation occurs at the C--C bond on Pd catalysts. The extent of broadening of inner molecular orbitals might be used as a guiding principle to predict the chemoselectivity for a wide class of catalytic reactions at metal surfaces

Identification of a Rare Coding Variant in Complement 3 Associated with Age-related Macular Degeneration

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry matched controls revealed two large-effect rare variants; previously described R1210C in the CFH gene (fcase = 0.51%, fcontrol = 0.02%, OR = 23.11), and newly identified K155Q in the C3 gene (fcase = 1.06%, fcontrol = 0.39%, OR = 2.68). The variants suggest decreased inhibition of C3 by Factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H