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Abstract Due to commonalities in pathophysiology, age-related macular degeneration (AMD) represents a uniquely accessible model to investigate therapies for neurodegenerative diseases, leading us to examine whether pathways of disease progression are shared across neurodegenerative conditions. Here we use single-nucleus RNA sequencing to profile lesions from 11 postmortem human retinas with age-related macular degeneration and 6 control retinas with no history of retinal disease. We create a machine-learning pipeline based on recent advances in data geometry and topology and identify activated glial populations enriched in the early phase of disease. Examining single-cell data from Alzheimer’s disease and progressive multiple sclerosis with our pipeline, we find a similar glial activation profile enriched in the early phase of these neurodegenerative diseases. In late-stage age-related macular degeneration, we identify a microglia-to-astrocyte signaling axis mediated by interleukin-1 β which drives angiogenesis characteristic of disease pathogenesis. We validated this mechanism using in vitro and in vivo assays in mouse, identifying a possible new therapeutic target for AMD and possibly other neurodegenerative conditions. Thus, due to shared glial states, the retina provides a potential system for investigating therapeutic approaches in neurodegenerative diseases.more » « lessFree, publicly-accessible full text available December 1, 2024
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Abstract 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.
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We present a machine learning model for the analysis of randomly generated discrete signals, modeled as the points of an inhomogeneous, compound Poisson point process. Like the wavelet scattering transform introduced by Mallat, our construction is naturally invariant to translations and reflections, but it decouples the roles of scale and frequency, replacing wavelets with Gabor-type measurements. We show that, with suitable nonlinearities, our measurements distinguish Poisson point processes from common self-similar processes, and separate different types of Poisson point processes.more » « less
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Ranzato, M. ; Beygelzimer, A. ; Dauphin, Y. ; Liang, P.S. ; Vaughan, J. Wortman (Ed.)The prevalence of graph-based data has spurred the rapid development of graph neural networks (GNNs) and related machine learning algorithms. Yet, despite the many datasets naturally modeled as directed graphs, including citation, website, and traffic networks, the vast majority of this research focuses on undirected graphs. In this paper, we propose MagNet, a GNN for directed graphs based on a complex Hermitian matrix known as the magnetic Laplacian. This matrix encodes undirected geometric structure in the magnitude of its entries and directional information in their phase. A charge parameter attunes spectral information to variation among directed cycles. We apply our network to a variety of directed graph node classification and link prediction tasks showing that MagNet performs well on all tasks and that its performance exceeds all other methods on a majority of such tasks. The underlying principles of MagNet are such that it can be adapted to other GNN architectures.more » « less
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null (Ed.)We propose a nonlinear, wavelet-based signal representation that is translation invariant and robust to both additive noise and random dilations. Motivated by the multi-reference alignment problem and generalizations thereof, we analyze the statistical properties of this representation given a large number of independent corruptions of a target signal. We prove the nonlinear wavelet-based representation uniquely defines the power spectrum but allows for an unbiasing procedure that cannot be directly applied to the power spectrum. After unbiasing the representation to remove the effects of the additive noise and random dilations, we recover an approximation of the power spectrum by solving a convex optimization problem, and thus reduce to a phase retrieval problem. Extensive numerical experiments demonstrate the statistical robustness of this approximation procedure.more » « less
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Lu, Jianfeng ; Ward, Rachel (Ed.)The Euclidean scattering transform was introduced nearly a decade ago to improve the mathematical understanding of convolutional neural networks. Inspired by recent interest in geometric deep learning, which aims to generalize convolutional neural networks to manifold and graph-structured domains, we define a geometric scattering transform on manifolds. Similar to the Euclidean scattering transform, the geometric scattering transform is based on a cascade of wavelet filters and pointwise nonlinearities. It is invariant to local isometries and stable to certain types of diffeomorphisms. Empirical results demonstrate its utility on several geometric learning tasks. Our results generalize the deformation stability and local translation invariance of Euclidean scattering, and demonstrate the importance of linking the used filter structures to the underlying geometry of the data.more » « less
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Convolutional neural networks (CNNs) are revolutionizing imaging science for two- and three-dimensional images over Euclidean domains. However, many data sets are intrinsically non-Euclidean and are better modeled through other mathematical structures, such as graphs or manifolds. This state of affairs has led to the development of geometric deep learning, which refers to a body of research that aims to translate the principles of CNNs to these non-Euclidean structures. In the process, various challenges have arisen, including how to define such geometric networks, how to compute and train them efficiently, and what are their mathematical properties. In this letter we describe the geometric wavelet scattering transform, which is a type of geometric CNN for graphs and manifolds consisting of alternating multiscale geometric wavelet transforms and nonlinear activation functions. As the name suggests, the geometric wavelet scattering transform is an adaptation of the Euclidean wavelet scattering transform, first introduced by S. Mallat, to graph and manifold data. Like its Euclidean counterpart, the geometric wavelet scattering transform has several desirable properties. In the manifold setting these properties include isometric invariance up to a user specified scale and stability to small diffeomorphisms. Numerical results on manifold and graph data sets, including graph and manifold classification tasks as well as others, illustrate the practical utility of the approach.more » « less
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Big data often has emergent structure that exists at multiple levels of abstraction, which are useful for characterizing complex interactions and dynamics of the observations. Here, we consider multiple levels of abstraction via a multiresolution geometry of data points at different granularities. To construct this geometry we define a time-inhomogemeous diffusion process that effectively condenses data points together to uncover nested groupings at larger and larger granularities. This inhomogeneous process creates a deep cascade of intrinsic low pass filters on the data affinity graph that are applied in sequence to gradually eliminate local variability while adjusting the learned data geometry to increasingly coarser resolutions. We provide visualizations to exhibit our method as a “continuously-hierarchical” clustering with directions of eliminated variation highlighted at each step. The utility of our algorithm is demonstrated via neuronal data condensation, where the constructed multiresolution data geometry uncovers the organization, grouping, and connectivity between neurons.more » « less
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