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Article ; Online: Pharmacogenomic and Statistical Analysis.

Bai, Haimeng / Zhang, Xueyi / Bush, William S

Methods in molecular biology (Clifton, N.J.)

2023 Volume 2629, Page(s) 305–330

Abstract: Genetic variants can alter response to drugs and other therapeutic interventions. The study of this phenomenon, called pharmacogenomics, is similar in many ways to other types of genetic studies but has distinct methodological and statistical ... ...

Abstract	Genetic variants can alter response to drugs and other therapeutic interventions. The study of this phenomenon, called pharmacogenomics, is similar in many ways to other types of genetic studies but has distinct methodological and statistical considerations. Genetic variants involved in the processing of exogenous compounds exhibit great diversity and complexity, and the phenotypes studied in pharmacogenomics are also more complex than typical genetic studies. In this chapter, we review basic concepts in pharmacogenomic study designs, data generation techniques, statistical analysis approaches, and commonly used methods and briefly discuss the ultimate translation of findings to clinical care.
MeSH term(s)	Pharmacogenetics/methods ; Pharmacogenomic Testing ; Phenotype ; Research Design
Language	English
Publishing date	2023-03-16
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2986-4_14
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Modeling transcriptional regulation using gene regulatory networks based on multi-omics data sources.

Patel, Neel / Bush, William S

BMC bioinformatics

2021 Volume 22, Issue 1, Page(s) 200

Abstract: Background: Transcriptional regulation is complex, requiring multiple cis (local) and trans acting mechanisms working in concert to drive gene expression, with disruption of these processes linked to multiple diseases. Previous computational attempts to ...

Abstract	Background: Transcriptional regulation is complex, requiring multiple cis (local) and trans acting mechanisms working in concert to drive gene expression, with disruption of these processes linked to multiple diseases. Previous computational attempts to understand the influence of regulatory mechanisms on gene expression have used prediction models containing input features derived from cis regulatory factors. However, local chromatin looping and trans-acting mechanisms are known to also influence transcriptional regulation, and their inclusion may improve model accuracy and interpretation. In this study, we create a general model of transcription factor influence on gene expression by incorporating both cis and trans gene regulatory features. Results: We describe a computational framework to model gene expression for GM12878 and K562 cell lines. This framework weights the impact of transcription factor-based regulatory data using multi-omics gene regulatory networks to account for both cis and trans acting mechanisms, and measures of the local chromatin context. These prediction models perform significantly better compared to models containing cis-regulatory features alone. Models that additionally integrate long distance chromatin interactions (or chromatin looping) between distal transcription factor binding regions and gene promoters also show improved accuracy. As a demonstration of their utility, effect estimates from these models were used to weight cis-regulatory rare variants for sequence kernel association test analyses of gene expression. Conclusions: Our models generate refined effect estimates for the influence of individual transcription factors on gene expression, allowing characterization of their roles across the genome. This work also provides a framework for integrating multiple data types into a single model of transcriptional regulation.
MeSH term(s)	Chromatin/genetics ; Gene Expression Regulation ; Gene Regulatory Networks ; Information Storage and Retrieval ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Chromatin ; Transcription Factors
Language	English
Publishing date	2021-04-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2041484-5
ISSN	1471-2105 ; 1471-2105
ISSN (online)	1471-2105
ISSN	1471-2105
DOI	10.1186/s12859-021-04126-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Brain and Blood Transcriptome-Wide Association Studies Identify Five Novel Genes Associated with Alzheimer's Disease.

Mews, Makaela A / Naj, Adam C / Griswold, Anthony J / Below, Jennifer E / Bush, William S

medRxiv : the preprint server for health sciences

2024

Abstract: Introduction: Transcriptome-wide Association Studies (TWAS) extend genome-wide association studies (GWAS) by integrating genetically-regulated gene expression models. We performed the most powerful AD-TWAS to date, using summary statistics from : ... ...

Abstract	Introduction: Transcriptome-wide Association Studies (TWAS) extend genome-wide association studies (GWAS) by integrating genetically-regulated gene expression models. We performed the most powerful AD-TWAS to date, using summary statistics from Methods: We implemented the OTTERS TWAS pipeline, leveraging Results: We identified and validated five novel gene associations in cortical brain tissue ( Discussion: Our comprehensive AD-TWAS discovered new gene associations and provided insights into the functional relevance of previously associated variants.
Language	English
Publishing date	2024-04-19
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.17.24305737
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: An X Chromosome Transcriptome Wide Association Study Implicates ARMCX6 in Alzheimer's Disease.

Zhang, Xueyi / Gomez, Lissette / Below, Jennifer E / Naj, Adam C / Martin, Eden R / Kunkle, Brian W / Bush, William S

Journal of Alzheimer's disease : JAD

2024 Volume 98, Issue 3, Page(s) 1053–1067

Abstract: Background: The X chromosome is often omitted in disease association studies despite containing thousands of genes that may provide insight into well-known sex differences in the risk of Alzheimer's disease (AD).: Objective: To model the expression ... ...

Abstract	Background: The X chromosome is often omitted in disease association studies despite containing thousands of genes that may provide insight into well-known sex differences in the risk of Alzheimer's disease (AD). Objective: To model the expression of X chromosome genes and evaluate their impact on AD risk in a sex-stratified manner. Methods: Using elastic net, we evaluated multiple modeling strategies in a set of 175 whole blood samples and 126 brain cortex samples, with whole genome sequencing and RNA-seq data. SNPs (MAF > 0.05) within the cis-regulatory window were used to train tissue-specific models of each gene. We apply the best models in both tissues to sex-stratified summary statistics from a meta-analysis of Alzheimer's Disease Genetics Consortium (ADGC) studies to identify AD-related genes on the X chromosome. Results: Across different model parameters, sample sex, and tissue types, we modeled the expression of 217 genes (95 genes in blood and 135 genes in brain cortex). The average model R2 was 0.12 (range from 0.03 to 0.34). We also compared sex-stratified and sex-combined models on the X chromosome. We further investigated genes that escaped X chromosome inactivation (XCI) to determine if their genetic regulation patterns were distinct. We found ten genes associated with AD at p < 0.05, with only ARMCX6 in female brain cortex (p = 0.008) nearing the significance threshold after adjusting for multiple testing (α = 0.002). Conclusions: We optimized the expression prediction of X chromosome genes, applied these models to sex-stratified AD GWAS summary statistics, and identified one putative AD risk gene, ARMCX6.
MeSH term(s)	Humans ; Male ; Female ; Alzheimer Disease/genetics ; Transcriptome ; Genetic Predisposition to Disease/genetics ; X Chromosome ; Brain ; Polymorphism, Single Nucleotide/genetics ; Genome-Wide Association Study
Language	English
Publishing date	2024-03-14
Publishing country	Netherlands
Document type	Meta-Analysis ; Journal Article
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-231075
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Article ; Online: Integration of Protein Structure and Population-Scale DNA Sequence Data for Disease Gene Discovery and Variant Interpretation.

Li, Bian / Jin, Bowen / Capra, John A / Bush, William S

Annual review of biomedical data science

2022 Volume 5, Page(s) 141–161

Abstract: The experimental and computational techniques for capturing information about protein structures and genetic variation within the human genome have advanced dramatically in the past 20 years, generating extensive new data resources. In this review, we ... ...

Abstract	The experimental and computational techniques for capturing information about protein structures and genetic variation within the human genome have advanced dramatically in the past 20 years, generating extensive new data resources. In this review, we discuss these advances, along with new approaches for determining the impact a genetic variant has on protein function. We focus on the potential of new methods that integrate human genetic variation into protein structures to discover relationships to disease, including the discovery of mutational hotspots in cancer-related proteins, the localization of protein-altering variants within protein regions for common complex diseases, and the assessment of variants of unknown significance for Mendelian traits. We expect that approaches that integratethese data sources will play increasingly important roles in disease gene discovery and variant interpretation.
MeSH term(s)	Base Sequence ; Genetic Association Studies ; Genetic Variation/genetics ; Genome, Human/genetics ; Humans ; Phenotype
Language	English
Publishing date	2022-05-04
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2574-3414
ISSN (online)	2574-3414
DOI	10.1146/annurev-biodatasci-122220-112147
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Article ; Online: magpie: A power evaluation method for differential RNA methylation analysis in N6-methyladenosine sequencing.

Guo, Zhenxing / Duan, Daoyu / Tang, Wen / Zhu, Julia / Bush, William S / Zhang, Liangliang / Zhu, Xiaofeng / Jin, Fulai / Feng, Hao

PLoS computational biology

2024 Volume 20, Issue 2, Page(s) e1011875

Abstract: Recently, novel biotechnologies to quantify RNA modifications became an increasingly popular choice for researchers who study epitranscriptome. When studying RNA methylations such as N6-methyladenosine (m6A), researchers need to make several decisions in ...

Abstract	Recently, novel biotechnologies to quantify RNA modifications became an increasingly popular choice for researchers who study epitranscriptome. When studying RNA methylations such as N6-methyladenosine (m6A), researchers need to make several decisions in its experimental design, especially the sample size and a proper statistical power. Due to the complexity and high-throughput nature of m6A sequencing measurements, methods for power calculation and study design are still currently unavailable. In this work, we propose a statistical power assessment tool, magpie, for power calculation and experimental design for epitranscriptome studies using m6A sequencing data. Our simulation-based power assessment tool will borrow information from real pilot data, and inspect various influential factors including sample size, sequencing depth, effect size, and basal expression ranges. We integrate two modules in magpie: (i) a flexible and realistic simulator module to synthesize m6A sequencing data based on real data; and (ii) a power assessment module to examine a set of comprehensive evaluation metrics.
MeSH term(s)	RNA/genetics ; RNA/metabolism ; RNA Methylation ; Methylation ; High-Throughput Nucleotide Sequencing
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2024-02-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1011875
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Does hand position affect orienting when no action is required? An electrophysiological study.

Reed, Catherine L / Garza, John P / Bush, William S / Parikh, Natasha / Nagar, Niti / Vecera, Shaun P

Frontiers in neuroscience

2023 Volume 16, Page(s) 982005

Abstract: Previous research has shown that attention can be biased to targets appearing near the hand that require action responses, arguing that attention to the hand facilitates upcoming action. It is unclear whether attention orients to non-targets near the ... ...

Abstract	Previous research has shown that attention can be biased to targets appearing near the hand that require action responses, arguing that attention to the hand facilitates upcoming action. It is unclear whether attention orients to non-targets near the hand not requiring responses. Using electroencephalography/event-related potentials (EEG/ERP), this study investigated whether hand position affected visual orienting to non-targets under conditions that manipulated the distribution of attention. We modified an attention paradigm in which stimuli were presented briefly and rapidly on either side of fixation; participants responded to infrequent targets (15%) but not standard non-targets and either a hand or a block was placed next to one stimulus location. In Experiment 1, attention was distributed across left and right stimulus locations to determine whether P1 or N1 ERP amplitudes to non-target standards were differentially influenced by hand location. In Experiment 2, attention was narrowed to only one stimulus location to determine whether attentional focus affected orienting to non-target locations near the hand. When attention was distributed across both stimulus locations, the hand increased overall N1 amplitudes relative to the block but not selectively to stimuli appearing near the hand. However, when attention was focused on one location, amplitudes were affected by the location of attentional focus and the stimulus, but not by hand or block location. Thus, hand position appears to contribute only a non-location-specific input to standards during visual orienting, but only in cases when attention is distributed across stimulus locations.
Language	English
Publishing date	2023-01-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2022.982005
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Book: Circuit riders for mental health

Bush, William S

the Hogg Foundation in twentieth-century Texas

2016

Abstract: Circuit Riders for Mental Health explores the transformation of popular understandings of mental health, the reform of scandal-ridden hospitals and institutions, the emergence of community mental health services, and the extension of mental health ... ...

Institution	Hogg Foundation for Mental Health
Author's details	William S. Bush
Abstract	Circuit Riders for Mental Health explores the transformation of popular understandings of mental health, the reform of scandal-ridden hospitals and institutions, the emergence of community mental health services, and the extension of mental health services to minority populations around the state of Texas. Author Williams S. Bush focuses especially on the years between 1940 and 1980 to demonstrate the dramatic, though sometimes halting and conflicted, progress made in Texas to provide mental health services to its people over the second half of the twentieth century. At the story's center is the Hogg Foundation for Mental Health, a private-public philanthropic organization housed at the University of Texas. For the first three decades of its existence, the Hogg Foundation was the state's leading source of public information, policy reform, and professional education in mental health. Its staff and allies throughout the state described themselves as "circuit riders" as they traveled around Texas to introduce urban and rural audiences to the concept of mental health, provide consultation for all manner of social services, and sometimes intervene in thorny issues surrounding race, ethnicity, gender, class, region, and social and cultural change. (From summary in ECIP data view).
MeSH term(s)	Community Mental Health Services/history ; Mentally Ill Persons/history ; Mental Disorders/history ; Health Policy/history ; History, 20th Century
Keywords	Texas
Language	English
Size	xii, 201 pages :, illustrations, portraits ;, 24 cm
Edition	First edition.
Document type	Book
ISBN	9781623494445 ; 1623494443
Database	Catalogue of the US National Library of Medicine (NLM)

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Article ; Online: Packaging Biocomputing Software to Maximize Distribution and Reuse.

Bush, William S / Wheeler, Nicholas / Darabos, Christian / Beaulieu-Jones, Brett

Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing

2021 Volume 27, Page(s) 412–416

Abstract: The majority of publications in computational biology and biocomputing develop or apply software approaches to relevant biological problems to some degree. While journals and conferences often prompt authors to make their source code available, these are ...

Abstract	The majority of publications in computational biology and biocomputing develop or apply software approaches to relevant biological problems to some degree. While journals and conferences often prompt authors to make their source code available, these are often only basic requirements. Investigators often wish their software and tools were widely usable to the scientific community, but there are limited resources available to maximize the distribution and provide easy use of developed software. Even when authors adhere to standards of source code availability, the growing problem of system configuration issues, language and library version conflicts, and other implementation issues often impede the broad distribution, availability of software tools, and reproducibility of research. There are a variety of solutions to these implementation issues, but the learning curve for applying these solutions can be steep. This tutorial demonstrates tools and approaches for packaging and distribution of published code, and provides methodological practices for the broad and open sharing of new biocomputing software.
MeSH term(s)	Computational Biology ; Gene Library ; Humans ; Reproducibility of Results ; Software
Language	English
Publishing date	2021-12-10
Publishing country	United States
Document type	Journal Article
ISSN	2335-6936
ISSN (online)	2335-6936
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: An X Chromosome Transcriptome Wide Association Study Implicates ARMCX6 in Alzheimer's Disease.

Zhang, Xueyi / Gomez, Lissette / Below, Jennifer / Naj, Adam / Martin, Eden / Kunkle, Brian / Bush, William S

bioRxiv : the preprint server for biology

2023

Abstract: Background: The X chromosome is often omitted in disease association studies despite containing thousands of genes which may provide insight into well-known sex differences in the risk of Alzheimer's Disease.: Objective: To model the expression of X ... ...

Abstract	Background: The X chromosome is often omitted in disease association studies despite containing thousands of genes which may provide insight into well-known sex differences in the risk of Alzheimer's Disease. Objective: To model the expression of X chromosome genes and evaluate their impact on Alzheimer's Disease risk in a sex-stratified manner. Methods: Using elastic net, we evaluated multiple modeling strategies in a set of 175 whole blood samples and 126 brain cortex samples, with whole genome sequencing and RNA-seq data. SNPs (MAF>0.05) within the Results: Across different model parameters, sample sex, and tissue types, we modeled the expression of 217 genes (95 genes in blood and 135 genes in brain cortex). The average model R Conclusions: We optimized the expression prediction of X chromosome genes, applied these models to sex-stratified AD GWAS summary statistics, and identified one putative AD risk gene,
Language	English
Publishing date	2023-10-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.06.543877
Database	MEDical Literature Analysis and Retrieval System OnLINE

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