Increasing the power of meta-analysis of genome-wide association studies to detect heterogeneous effects

Lee, C H,Eskin, E,Han, B Oxford University Press 2017 Bioinformatics Vol.33 No.14

<P><B>Abstract</B></P><P><B>Motivation</B></P><P>Meta-analysis is essential to combine the results of genome-wide association studies (GWASs). Recent large-scale meta-analyses have combined studies of different ethnicities, environments and even studies of different related phenotypes. These differences between studies can manifest as effect size heterogeneity. We previously developed a modified random effects model (RE2) that can achieve higher power to detect heterogeneous effects than the commonly used fixed effects model (FE). However, RE2 cannot perform meta-analysis of correlated statistics, which are found in recent research designs, and the identified variants often overlap with those found by FE.</P><P><B>Results</B></P><P>Here, we propose RE2C, which increases the power of RE2 in two ways. First, we generalized the likelihood model to account for correlations of statistics to achieve optimal power, using an optimization technique based on spectral decomposition for efficient parameter estimation. Second, we designed a novel statistic to focus on the heterogeneous effects that FE cannot detect, thereby, increasing the power to identify new associations. We developed an efficient and accurate <I>p</I>-value approximation procedure using analytical decomposition of the statistic. In simulations, RE2C achieved a dramatic increase in power compared with the decoupling approach (71% vs. 21%) when the statistics were correlated. Even when the statistics are uncorrelated, RE2C achieves a modest increase in power. Applications to real genetic data supported the utility of RE2C. RE2C is highly efficient and can meta-analyze one hundred GWASs in one day.</P><P><B>Availability and implementation</B></P><P>The software is freely available at http://software.buhmhan.com/RE2C.</P><P><B>Supplementary information</B></P><P>Supplementary data are available at <I>Bioinformatics</I> online.</P>

Influence of calcined medium grade clay on the properties of Portland cement pastes

Rakhimova Nailia R.,Morozov Vladimir P.,Eskin Aleksey A. 한국자원공학회 2022 Geosystem engineering Vol.25 No.6

In the recent decades, the composition of Portland cements has undergone significant changes related to an increase in the range and content of supplementary cementitious materials following development of composite and multicomposite cements. The development of these binders that meet the requirements of sustainability requires the expansion and adaptation of the mineral resource base of cement industry to the production of low-emission binders with a gradual decrease of resource and energy intensities. Efforts to find the widespread sources of pozzolans providing high reactivity and physical–chemical stability have led to intensive studies on thermally treated clays of various chemical–mineralogical composition and their industrial adoption. Due to scarcity and high cost of kaolin clays, great attention is given to medium- and low-grade clays. This article reports on a study to evaluate the effect of calcined clay with 52% of clay minerals on the properties of fresh and hardened pastes, in particular on the resistance to sodium sulfate and nitric acid attacks. The reaction products assemblage of the blended Portland cement pastes was investigated by XRD and thermal analyses. The hardened Portland cement pastes incorporated with thermally treated clay demonstrated better durability performance compared to reference ones.

Phase formation behavior of alkali-activated calcined clays: effects of the reactive phase and NaOH concentration

Rakhimova Nailia R.,Morozov Vladimir P.,Eskin Aleksey A. 한국자원공학회 2021 Geosystem engineering Vol.24 No.5

The relevance of calcined clays as sources with a great potential for non-clinker alkali-activated materials has significantly increased in recent decades. This article reports on a study to investigate how NaOH with concentrations in the 5–14 M range affects the mechanical properties, amorphouscrystalline phase transformations, and reaction product composition of alkali-activated calcined kaolinite/montmorillonite cements with reactive phases of 60% and 33%, and with the SiO2/Al2O3 ratios of 1.54 and 1.74. The hardened pastes based on both calcined clays exhibited the highest compressive strength up to 9.1 MPa following their activation with 8 M NaOH. The higher amorphous fraction in the calcined clay provided gradual zeolitisation/crystallisation at Na2O/ SiO2 and Na2O/Al2O3 molar ratios in the 0.36–0.63 and 0.56–0.98 ranges, respectively, accompanied by the deterioration of the mechanical characteristics of the samples. The zeolite content in the alkali-activated calcined clay cements with an amorphous fraction of 33% peaked for NaOH at 11 M, and the corresponding molar ratios of Na2O/SiO2 and Na2O/Al2O3 were 0.85 and 1.46, respectively. The main reaction products in the studied systems determined by XRD, TG/DSC, and FTIR spectroscopy analyses were N-A-S-H and zeolite A. The properties and reaction products obtained favor the use of proposed alkali-activated cements for controlled low-strength materials.

Calcined low-grade multimineral clays as supplementary cementitious materials: a feasibility study

Rakhimova Nailia R.,Rakhimov Ravil Z.,Bikmukhametov Artur R.,Morozov Vladimir P.,Eskin Aleksey A.,Gubaidullina Alfiya M. 한국자원공학회 2020 Geosystem engineering Vol.23 No.3

The relevance of calcined clays as sources with great potential for low-clinker blended Portland cements has significantly increased in recent decades. This article reports on a study to evaluate the potential of the two low-grade clays containing 9.37% of montmorillonite/chlorite and 12.26% of montmorillonite/kaolinite/chlorite accompanied with 29.73% and 32.79% of calcite, respectively, as supplementary cementitious materials. The clays after thermal treatment at 800°C demonstrated poor pozzolanic activity, slight increase in the C-(S)-H and decline in the CH contents, and decrease in the mechanical properties of the blended Portland cement pastes. The results showed that the investigated clays fall below the range of the clays suitable for pozzolan production.

Study of Mechanical Properties of an LM24 Composite Alloy Reinforced with Cu-CNT Nanofillers, Processed Using Ultrasonic Cavitation

Miranda, Alberto,Alba-Baena, Noe,McKay, Brian J.,Eskin, Dmitry G.,Ko, Se Hyun,Shin, J.S. Trans Tech Publications, Ltd. 2013 Materials science forum Vol.765 No.-

<P>This study investigates the effect of Cu-Carbon Nanotube (Cu-CNT´s) composite powders on the mechanical properties of an Al-Si9.5-Cu4-Fe1.3 wt.% (LM24) aluminium matrix composite (AMC). Carbon nanotubes (CNT’s) can exhibit exceptional mechanical properties, e.g. stiffness up to 1000 GPa and strength in the order of 100 GPa. In recent years there has been significant scientific interest in improving properties in conventional alloys, via fabricating CNT metal matrix composites in order to attempt to harness their extraordinary attributes. In this study mechanically alloyed Cu-CNTS powders were added to molten LM24. The melt was processed using ultrasonic cavitation and subsequently high pressure die casting to form as-cast tensile specimens. SEM results indicate that CNT’s can be successfully introduced into the melt using this method. Compared to the unreinforced alloy, the CNT additions resulted in an increment (~20±10 MPa) to both ultimate tensile strength and yield strength, with a corresponding decline (~1±0.5l %) in elongation. This observed increase in strengthening may be attributed to the CNT’s pinning and hindering both grain boundary and dislocation migration during applied loading. Interestingly, no significant difference in properties were found with an increase in the CNT content (from 0.05 to 0.1 wt.%) potentially indicating a saturation limit.</P>

The Effect of the Menstrual Cycle on Asthma Presentations in the Emergency Department

Skobeloff, Emil M.,Spivey, William H.,Silverman, Robert,Eskin, Bernard A.,Harchelroad, Fred,Alessi, Thomas V. MediMedia Korea 1996 JAMA-Korea Vol.11 No.12

Using genomic annotations increases statistical power to detect eGenes

Duong, Dat,Zou, Jennifer,Hormozdiari, Farhad,Sul, Jae Hoon,Ernst, Jason,Han, Buhm,Eskin, Eleazar Oxford University Press 2016 Bioinformatics Vol.32 No.12

<P><B>Motivation:</B> Expression quantitative trait loci (eQTLs) are genetic variants that affect gene expression. In eQTL studies, one important task is to find eGenes or genes whose expressions are associated with at least one eQTL. The standard statistical method to determine whether a gene is an eGene requires association testing at all nearby variants and the permutation test to correct for multiple testing. The standard method however does not consider genomic annotation of the variants. In practice, variants near gene transcription start sites (TSSs) or certain histone modifications are likely to regulate gene expression. In this article, we introduce a novel eGene detection method that considers this empirical evidence and thereby increases the statistical power.</P><P><B>Results:</B> We applied our method to the liver Genotype-Tissue Expression (GTEx) data using distance from TSSs, DNase hypersensitivity sites, and six histone modifications as the genomic annotations for the variants. Each of these annotations helped us detected more candidate eGenes. Distance from TSS appears to be the most important annotation; specifically, using this annotation, our method discovered 50% more candidate eGenes than the standard permutation method.</P><P><B>Contact:</B>buhm.han@amc.seoul.kr or eeskin@cs.ucla.edu</P>

Applying meta-analysis to genotype-tissue expression data from multiple tissues to identify eQTLs and increase the number of eGenes

Duong, Dat,Gai, Lisa,Snir, Sagi,Kang, Eun Yong,Han, Buhm,Sul, Jae Hoon,Eskin, Eleazar Oxford University Press 2017 Bioinformatics Vol.33 No.14

<P><B>Abstract</B></P><P><B>Motivation</B></P><P>There is recent interest in using gene expression data to contextualize findings from traditional genome-wide association studies (GWAS). Conditioned on a tissue, expression quantitative trait loci (eQTLs) are genetic variants associated with gene expression, and eGenes are genes whose expression levels are associated with genetic variants. eQTLs and eGenes provide great supporting evidence for GWAS hits and important insights into the regulatory pathways involved in many diseases. When a significant variant or a candidate gene identified by GWAS is also an eQTL or eGene, there is strong evidence to further study this variant or gene. Multi-tissue gene expression datasets like the Gene Tissue Expression (GTEx) data are used to find eQTLs and eGenes. Unfortunately, these datasets often have small sample sizes in some tissues. For this reason, there have been many meta-analysis methods designed to combine gene expression data across many tissues to increase power for finding eQTLs and eGenes. However, these existing techniques are not scalable to datasets containing many tissues, like the GTEx data. Furthermore, these methods ignore a biological insight that the same variant may be associated with the same gene across similar tissues.</P><P><B>Results</B></P><P>We introduce a meta-analysis model that addresses these problems in existing methods. We focus on the problem of finding eGenes in gene expression data from many tissues, and show that our model is better than other types of meta-analyses.</P><P><B>Availability and Implementation</B></P><P>Source code is at https://github.com/datduong/RECOV.</P><P><B>Supplementary information</B></P><P>Supplementary data are available at <I>Bioinformatics</I> online.</P>

Chromosome conformation elucidates regulatory relationships in developing human brain

Won, Hyejung,de la Torre-Ubieta, Luis,Stein, Jason L.,Parikshak, Neelroop N.,Huang, Jerry,Opland, Carli K.,Gandal, Michael J.,Sutton, Gavin J.,Hormozdiari, Farhad,Lu, Daning,Lee, Changhoon,Eskin, Elea Nature Publishing Group 2016 Nature Vol. No.

Three-dimensional physical interactions within chromosomes dynamically regulate gene expression in a tissue-specific manner. However, the 3D organization of chromosomes during human brain development and its role in regulating gene networks dysregulated in neurodevelopmental disorders, such as autism or schizophrenia, are unknown. Here we generate high-resolution 3D maps of chromatin contacts during human corticogenesis, permitting large-scale annotation of previously uncharacterized regulatory relationships relevant to the evolution of human cognition and disease. Our analyses identify hundreds of genes that physically interact with enhancers gained on the human lineage, many of which are under purifying selection and associated with human cognitive function. We integrate chromatin contacts with non-coding variants identified in schizophrenia genome-wide association studies (GWAS), highlighting multiple candidate schizophrenia risk genes and pathways, including transcription factors involved in neurogenesis, and cholinergic signalling molecules, several of which are supported by independent expression quantitative trait loci and gene expression analyses. Genome editing in human neural progenitors suggests that one of these distal schizophrenia GWAS loci regulates FOXG1 expression, supporting its potential role as a schizophrenia risk gene. This work provides a framework for understanding the effect of non-coding regulatory elements on human brain development and the evolution of cognition, and highlights novel mechanisms underlying neuropsychiatric disorders.