Racial and ethnic minority representation in dementia risk factor research: a scoping review of cohort studies.

BACKGROUND: Despite a potentially greater burden of dementia, racial and ethnic minority populations around the world may be more likely to be excluded from research examining risk factors for incident dementia. We aimed to systematically investigate and quantify racial and ethnic minority representation in dementia risk factor research. METHODS: We performed a two-stage systematic search of databases-MEDLINE (Ovid SP), Embase (Ovid SP) and Scopus-from inception to March 2021 to identify population-based cohort studies looking at risk factors for dementia incidence. We included cohort studies which were population-based and incorporated a clinical dementia diagnosis. RESULTS: Out of the 97 identified cohort studies, fewer than half (40 studies; 41%) reported the race or ethnicity of participants and just under one-third (29 studies; 30%) reported the inclusion of racial and ethnic minority groups. We found that inadequate reporting frequently prevented assessment of selection bias and only six studies that included racial and ethnic minority participants were at low risk for measurement bias in dementia diagnosis. In cohort studies including a multiethnic cohort, only 182 out of 337 publications incorporated race or ethnicity in data analysis-predominantly (90%) through adjustment for race or ethnicity as a confounder. Only 14 publications (4.2% of all publications reviewed) provided evidence about drivers of any observed inequalities. CONCLUSIONS: Racial and ethnic minority representation in dementia risk factor research is inadequate. Comparisons of dementia risk between different racial and ethnic groups are likely hampered by significant selection and measurement bias. Moreover, the focus on 'adjusting out' the effect of race and ethnicity as a confounder prevents understanding of underlying drivers of observed inequalities. There is a pressing need to fundamentally change the way race, ethnicity and the inclusion of racial and ethnic minorities are considered in research if health inequalities are to be adequately addressed.

Current and future directions in network biology.

Summary: Network biology is an interdisciplinary field bridging computational and biological sciences that has proved pivotal in advancing the understanding of cellular functions and diseases across biological systems and scales. Although the field has been around for two decades, it remains nascent. It has witnessed rapid evolution, accompanied by emerging challenges. These stem from various factors, notably the growing complexity and volume of data together with the increased diversity of data types describing different tiers of biological organization. We discuss prevailing research directions in network biology, focusing on molecular/cellular networks but also on other biological network types such as biomedical knowledge graphs, patient similarity networks, brain networks, and social/contact networks relevant to disease spread. In more detail, we highlight areas of inference and comparison of biological networks, multimodal data integration and heterogeneous networks, higher-order network analysis, machine learning on networks, and network-based personalized medicine. Following the overview of recent breakthroughs across these five areas, we offer a perspective on future directions of network biology. Additionally, we discuss scientific communities, educational initiatives, and the importance of fostering diversity within the field. This article establishes a roadmap for an immediate and long-term vision for network biology. Availability and implementation: Not applicable.

Computational strategies for cross-species knowledge transfer and translational biomedicine.

Research organisms provide invaluable insights into human biology and diseases, serving as essential tools for functional experiments, disease modeling, and drug testing. However, evolutionary divergence between humans and research organisms hinders effective knowledge transfer across species. Here, we review state-of-the-art methods for computationally transferring knowledge across species, primarily focusing on methods that utilize transcriptome data and/or molecular networks. We introduce the term "agnology" to describe the functional equivalence of molecular components regardless of evolutionary origin, as this concept is becoming pervasive in integrative data-driven models where the role of evolutionary origin can become unclear. Our review addresses four key areas of information and knowledge transfer across species: (1) transferring disease and gene annotation knowledge, (2) identifying agnologous molecular components, (3) inferring equivalent perturbed genes or gene sets, and (4) identifying agnologous cell types. We conclude with an outlook on future directions and several key challenges that remain in cross-species knowledge transfer.

Examining the Genetic Links between Clusters of Immune-mediated Diseases and Psychiatric Disorders.

Importance: Autoimmune and autoinflammatory diseases have been linked to psychiatric disorders in the phenotypic and genetic literature. However, a comprehensive model that investigates the association between a broad range of psychiatric disorders and immune-mediated disease in a multivariate framework is lacking. Objective: This study aims to establish a factor structure based on the genetic correlations of immune-mediated diseases and investigate their genetic relationships with clusters of psychiatric disorders. Design Setting and Participants: We utilized Genomic Structural Equation Modeling (Genomic SEM) to establish a factor structure of 11 immune-mediated diseases. Genetic correlations between these immune factors were examined with five established factors across 13 psychiatric disorders representing compulsive, schizophrenia/bipolar, neurodevelopmental, internalizing, and substance use disorders. We included GWAS summary statistics of individuals of European ancestry with sample sizes from 1,223 cases for Addison's disease to 170,756 cases for major depressive disorder. Main Outcomes and Measures: Genetic correlations between psychiatric and immune-mediated disease factors and traits to determine genetic overlap. We develop and validate a new heterogeneity metric, Q Factor , that quantifies the degree to which factor correlations are driven by more specific pairwise associations. We also estimate residual genetic correlations between pairs of psychiatric disorders and immune-mediated diseases. Results: A four-factor model of immune-mediated diseases fit the data well and described a continuum from autoimmune to autoinflammatory diseases. The four factors reflected autoimmune, celiac, mixed pattern, and autoinflammatory diseases. Analyses revealed seven significant factor correlations between the immune and psychiatric factors, including autoimmune and mixed pattern diseases with the internalizing and substance use factors, and autoinflammatory diseases with the compulsive, schizophrenia/bipolar, and internalizing factors. Additionally, we find evidence of divergence in associations within factors as indicated by Q Factor . This is further supported by 14 significant residual genetic correlations between individual psychiatric disorders and immune-mediated diseases. Conclusion and Relevance: Our results revealed genetic links between clusters of immune-mediated diseases and psychiatric disorders. Current analyses indicate that previously described relationships between specific psychiatric disorders and immune-mediated diseases often capture broader pathways of risk sharing indexed by our genomic factors, yet are more specific than a general association across all psychiatric disorders and immune-mediated diseases.

Prioritizing Maize Metabolic Gene Regulators through Multi-Omic Network Integration.

Elucidating gene regulatory networks is a major area of study within plant systems biology. Phenotypic traits are intricately linked to specific gene expression profiles. These expression patterns arise primarily from regulatory connections between sets of transcription factors (TFs) and their target genes. Here, we integrated 46 co-expression networks, 283 protein-DNA interaction (PDI) assays, and 16 million SNPs used to identify expression quantitative trait loci (eQTL) to construct TF-target networks. In total, we analyzed ∼4.6M interactions to generate four distinct types of TF-target networks: co-expression, PDI, trans -eQTL, and cis -eQTL combined with PDIs. To functionally annotate TFs based on their target genes, we implemented three different network integration strategies. We evaluated the effectiveness of each strategy through TF loss-of function mutant inspection and random network analyses. The multi-network integration allowed us to identify transcriptional regulators of several biological processes. Using the topological properties of the fully integrated network, we identified potential functionally redundant TF paralogs. Our findings retrieved functions previously documented for numerous TFs and revealed novel functions that are crucial for informing the design of future experiments. The approach here-described lays the foundation for the integration of multi-omic datasets in maize and other plant systems.

Joint representation of molecular networks from multiple species improves gene classification.

Network-based machine learning (ML) has the potential for predicting novel genes associated with nearly any health and disease context. However, this approach often uses network information from only the single species under consideration even though networks for most species are noisy and incomplete. While some recent methods have begun addressing this shortcoming by using networks from more than one species, they lack one or more key desirable properties: handling networks from more than two species simultaneously, incorporating many-to-many orthology information, or generating a network representation that is reusable across different types of and newly-defined prediction tasks. Here, we present GenePlexusZoo, a framework that casts molecular networks from multiple species into a single reusable feature space for network-based ML. We demonstrate that this multi-species network representation improves both gene classification within a single species and knowledge-transfer across species, even in cases where the inter-species correspondence is undetectable based on shared orthologous genes. Thus, GenePlexusZoo enables effectively leveraging the high evolutionary molecular, functional, and phenotypic conservation across species to discover novel genes associated with diverse biological contexts.

Topological data analysis reveals a core gene expression backbone that defines form and function across flowering plants.

Since they emerged approximately 125 million years ago, flowering plants have evolved to dominate the terrestrial landscape and survive in the most inhospitable environments on earth. At their core, these adaptations have been shaped by changes in numerous, interconnected pathways and genes that collectively give rise to emergent biological phenomena. Linking gene expression to morphological outcomes remains a grand challenge in biology, and new approaches are needed to begin to address this gap. Here, we implemented topological data analysis (TDA) to summarize the high dimensionality and noisiness of gene expression data using lens functions that delineate plant tissue and stress responses. Using this framework, we created a topological representation of the shape of gene expression across plant evolution, development, and environment for the phylogenetically diverse flowering plants. The TDA-based Mapper graphs form a well-defined gradient of tissues from leaves to seeds, or from healthy to stressed samples, depending on the lens function. This suggests that there are distinct and conserved expression patterns across angiosperms that delineate different tissue types or responses to biotic and abiotic stresses. Genes that correlate with the tissue lens function are enriched in central processes such as photosynthetic, growth and development, housekeeping, or stress responses. Together, our results highlight the power of TDA for analyzing complex biological data and reveal a core expression backbone that defines plant form and function.

Linking Composition, Structure and Thickness of CoOOH layers to Oxygen Evolution Reaction Activity by Correlative Microscopy.

The role of ß-CoOOH crystallographic orientations in catalytic activity for the oxygen evolution reaction (OER) remains elusive. We combine correlative electron backscatter diffraction/scanning electrochemical cell microscopy with X-ray photoelectron spectroscopy, transmission electron microscopy, and atom probe tomography to establish the structure-activity relationships of various faceted ß-CoOOH formed on a Co microelectrode under OER conditions. We reveal that ≈6 nm ß-CoOOH(01 1 ‾ ${\bar{1}}$ 0), grown on [ 1 ‾ 2 1 ‾ ${\bar{1}2\bar{1}}$ 0]-oriented Co, exhibits higher OER activity than ≈3 nm ß-CoOOH(10 1 ‾ ${\bar{1}}$ 3) or ≈6 nm ß-CoOOH(0006) formed on [02 2 ‾ 1 ] ${\bar{2}1]}$ - and [0001]-oriented Co, respectively. This arises from higher amounts of incorporated hydroxyl ions and more easily reducible CoIII -O sites present in ß-CoOOH(01 1 ‾ ${\bar{1}}$ 0) than those in the latter two oxyhydroxide facets. Our correlative multimodal approach shows great promise in linking local activity with atomic-scale details of structure, thickness and composition of active species, which opens opportunities to design pre-catalysts with preferred defects that promote the formation of the most active OER species.

PyGenePlexus: a Python package for gene discovery using network-based machine learning.

SUMMARY: PyGenePlexus is a Python package that enables a user to gain insight into any gene set of interest through a molecular interaction network informed supervised machine learning model. PyGenePlexus provides predictions of how associated every gene in the network is to the input gene set, offers interpretability by comparing the model trained on the input gene set to models trained on thousands of known gene sets, and returns the network connectivity of the top predicted genes. AVAILABILITY AND IMPLEMENTATION: https://pypi.org/project/geneplexus/ and https://github.com/krishnanlab/PyGenePlexus. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Accurately modeling biased random walks on weighted networks using node2vec.

MOTIVATION: Accurately representing biological networks in a low-dimensional space, also known as network embedding, is a critical step in network-based machine learning and is carried out widely using node2vec, an unsupervised method based on biased random walks. However, while many networks, including functional gene interaction networks, are dense, weighted graphs, node2vec is fundamentally limited in its ability to use edge weights during the biased random walk generation process, thus under-using all the information in the network. RESULTS: Here, we present node2vec+, a natural extension of node2vec that accounts for edge weights when calculating walk biases and reduces to node2vec in the cases of unweighted graphs or unbiased walks. Using two synthetic datasets, we empirically show that node2vec+ is more robust to additive noise than node2vec in weighted graphs. Then, using genome-scale functional gene networks to solve a wide range of gene function and disease prediction tasks, we demonstrate the superior performance of node2vec+ over node2vec in the case of weighted graphs. Notably, due to the limited amount of training data in the gene classification tasks, graph neural networks such as GCN and GraphSAGE are outperformed by both node2vec and node2vec+. AVAILABILITY AND IMPLEMENTATION: The data and code are available on GitHub at https://github.com/krishnanlab/node2vecplus_benchmarks. All additional data underlying this article are available on Zenodo at https://doi.org/10.5281/zenodo.7007164. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Systematic tissue annotations of genomics samples by modeling unstructured metadata.

There are currently >1.3 million human -omics samples that are publicly available. This valuable resource remains acutely underused because discovering particular samples from this ever-growing data collection remains a significant challenge. The major impediment is that sample attributes are routinely described using varied terminologies written in unstructured natural language. We propose a natural-language-processing-based machine learning approach (NLP-ML) to infer tissue and cell-type annotations for genomics samples based only on their free-text metadata. NLP-ML works by creating numerical representations of sample descriptions and using these representations as features in a supervised learning classifier that predicts tissue/cell-type terms. Our approach significantly outperforms an advanced graph-based reasoning annotation method (MetaSRA) and a baseline exact string matching method (TAGGER). Model similarities between related tissues demonstrate that NLP-ML models capture biologically-meaningful signals in text. Additionally, these models correctly classify tissue-associated biological processes and diseases based on their text descriptions alone. NLP-ML models are nearly as accurate as models based on gene-expression profiles in predicting sample tissue annotations but have the distinct capability to classify samples irrespective of the genomics experiment type based on their text metadata. Python NLP-ML prediction code and trained tissue models are available at https://github.com/krishnanlab/txt2onto .

A network-based approach for isolating the chronic inflammation gene signatures underlying complex diseases towards finding new treatment opportunities.

Complex diseases are associated with a wide range of cellular, physiological, and clinical phenotypes. To advance our understanding of disease mechanisms and our ability to treat these diseases, it is critical to delineate the molecular basis and therapeutic avenues of specific disease phenotypes, especially those that are associated with multiple diseases. Inflammatory processes constitute one such prominent phenotype, being involved in a wide range of health problems including ischemic heart disease, stroke, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, and autoimmune and neurodegenerative conditions. While hundreds of genes might play a role in the etiology of each of these diseases, isolating the genes involved in the specific phenotype (e.g., inflammation "component") could help us understand the genes and pathways underlying this phenotype across diseases and predict potential drugs to target the phenotype. Here, we present a computational approach that integrates gene interaction networks, disease-/trait-gene associations, and drug-target information to accomplish this goal. We apply this approach to isolate gene signatures of complex diseases that correspond to chronic inflammation and use SAveRUNNER to prioritize drugs to reveal new therapeutic opportunities.

GenePlexus: a web-server for gene discovery using network-based machine learning.

Biomedical researchers take advantage of high-throughput, high-coverage technologies to routinely generate sets of genes of interest across a wide range of biological conditions. Although these technologies have directly shed light on the molecular underpinnings of various biological processes and diseases, the list of genes from any individual experiment is often noisy and incomplete. Additionally, interpreting these lists of genes can be challenging in terms of how they are related to each other and to other genes in the genome. In this work, we present GenePlexus (https://www.geneplexus.net/), a web-server that allows a researcher to utilize a powerful, network-based machine learning method to gain insights into their gene set of interest and additional functionally similar genes. Once a user uploads their own set of human genes and chooses between a number of different human network representations, GenePlexus provides predictions of how associated every gene in the network is to the input set. The web-server also provides interpretability through network visualization and comparison to other machine learning models trained on thousands of known process/pathway and disease gene sets. GenePlexus is free and open to all users without the need for registration.

Robust normalization and transformation techniques for constructing gene coexpression networks from RNA-seq data.

BACKGROUND: Constructing gene coexpression networks is a powerful approach for analyzing high-throughput gene expression data towards module identification, gene function prediction, and disease-gene prioritization. While optimal workflows for constructing coexpression networks, including good choices for data pre-processing, normalization, and network transformation, have been developed for microarray-based expression data, such well-tested choices do not exist for RNA-seq data. Almost all studies that compare data processing and normalization methods for RNA-seq focus on the end goal of determining differential gene expression. RESULTS: Here, we present a comprehensive benchmarking and analysis of 36 different workflows, each with a unique set of normalization and network transformation methods, for constructing coexpression networks from RNA-seq datasets. We test these workflows on both large, homogenous datasets and small, heterogeneous datasets from various labs. We analyze the workflows in terms of aggregate performance, individual method choices, and the impact of multiple dataset experimental factors. Our results demonstrate that between-sample normalization has the biggest impact, with counts adjusted by size factors producing networks that most accurately recapitulate known tissue-naive and tissue-aware gene functional relationships. CONCLUSIONS: Based on this work, we provide concrete recommendations on robust procedures for building an accurate coexpression network from an RNA-seq dataset. In addition, researchers can examine all the results in great detail at https://krishnanlab.github.io/RNAseq_coexpression to make appropriate choices for coexpression analysis based on the experimental factors of their RNA-seq dataset.

Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion.

BACKGROUND: Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in > 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional "second-hit" variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. METHODS: We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and "second-hit" variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses. RESULTS: We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of "second-hit" variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited "second-hits" in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying "second-hits" and genes with transcriptome alterations in deletion carriers. CONCLUSIONS: Our results suggest a potential mechanism for how "second-hit" variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.

Reconciling multiple connectivity scores for drug repurposing.

The basis of several recent methods for drug repurposing is the key principle that an efficacious drug will reverse the disease molecular 'signature' with minimal side effects. This principle was defined and popularized by the influential 'connectivity map' study in 2006 regarding reversal relationships between disease- and drug-induced gene expression profiles, quantified by a disease-drug 'connectivity score.' Over the past 15 years, several studies have proposed variations in calculating connectivity scores toward improving accuracy and robustness in light of massive growth in reference drug profiles. However, these variations have been formulated inconsistently using various notations and terminologies even though they are based on a common set of conceptual and statistical ideas. Therefore, we present a systematic reconciliation of multiple disease-drug similarity metrics ($ES$, $css$, $Sum$, $Cosine$, $XSum$, $XCor$, $XSpe$, $XCos$, $EWCos$) and connectivity scores ($CS$, $RGES$, $NCS$, $WCS$, $Tau$, $CSS$, $EMUDRA$) by defining them using consistent notation and terminology. In addition to providing clarity and deeper insights, this coherent definition of connectivity scores and their relationships provides a unified scheme that newer methods can adopt, enabling the computational drug-development community to compare and investigate different approaches easily. To facilitate the continuous and transparent integration of newer methods, this article will be available as a live document (https://jravilab.github.io/connectivity_scores) coupled with a GitHub repository (https://github.com/jravilab/connectivity_scores) that any researcher can build on and push changes to.

Representation of racial and ethnic minority groups in cohort studies evaluating risk factors for dementia: protocol for a scoping review.

INTRODUCTION: Available evidence suggests that some racial/ethnic minority populations may be disproportionately burdened by dementia. Cohort studies are an important tool for defining and understanding the causes behind these racial and ethnic inequalities. However, ethnic minority populations may be more likely to be excluded from such research. Therefore, the aim of this study is to systematically investigate and quantify racial and ethnic minority representation in dementia risk factor research. METHODS AND ANALYSIS: The elements of this protocol have been designed in accordance with the relevant sections of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols which are specifically applicable to scoping review protocols. We will include population-based cohort studies looking at risk factors for dementia incidence in our review and assess the representation of racial and ethnic minority populations in these studies. We will use multiple strategies to identify relevant studies, including a systematic search of the following electronic databases: MEDLINE (Ovid SP), Embase (Ovid SP) and Scopus. Two review authors will independently perform title and abstract screening, full-text screening and data extraction. Included cohort studies will be evaluated using a comprehensive framework to assess racial/ethnic minority representation. Logistic regression will also be performed to describe associations between cohort study characteristics and outcomes related to racial and ethnic minority representation. ETHICS AND DISSEMINATION: Formal ethical approval is not required to conduct this review as no primary data are to be collected. The final results of this scoping review will be disseminated through publication in peer-reviewed journals and conference presentations.

Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis.

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while "second-hits" in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of "second-hit" genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs were less likely to interact with each other in Drosophila models or a human brain-specific interaction network, suggesting that interactions with "second-hit" genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific "second-hit" genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, patient-specific "second-hits" enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs in 32/96 pairwise combinations tested. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with "second-hit" genes determine the ultimate phenotypic manifestation.

PecanPy: a fast, efficient and parallelized Python implementation of node2vec.

SUMMARY: Learning low-dimensional representations (embeddings) of nodes in large graphs is key to applying machine learning on massive biological networks. Node2vec is the most widely used method for node embedding. However, its original Python and C++ implementations scale poorly with network density, failing for dense biological networks with hundreds of millions of edges. We have developed PecanPy, a new Python implementation of node2vec that uses cache-optimized compact graph data structures and precomputing/parallelization to result in fast, high-quality node embeddings for biological networks of all sizes and densities. AVAILABILITYAND IMPLEMENTATION: PecanPy software is freely available at https://github.com/krishnanlab/PecanPy. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.