Jessie Huang

Maryam Ige

Amar H. Sheth

Abdelilah Majdoubi

Madhvi Menon

Abhinav Godavarthi

Yu Xing

Scott Gigante

Holly R. Steach

Janhavi Narain

Kisung You

George Mourgkos

Rahul M. Dhodapkar … (voir 5 de plus)

Matthew Hirn

Bastian Rieck

Brian P. Hafler

Due to commonalities in pathophysiology, age-related macular degeneration (AMD) represents a uniquely accessible model to investigate thera… (voir plus)pies 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-1β 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.

2023-05-04

Nature Communications (publié)

Multi-view manifold learning of human brain-state trajectories.

Erica L. Busch

Andrew Benz

Tom Wallenstein

Guillaume Lajoie

Nicholas B. Turk-Browne

The complexity of the human brain gives the illusion that brain activity is intrinsically high-dimensional. Nonlinear dimensionality-reducti… (voir plus)on methods such as uniform manifold approximation and t-distributed stochastic neighbor embedding have been used for high-throughput biomedical data. However, they have not been used extensively for brain activity data such as those from functional magnetic resonance imaging (fMRI), primarily due to their inability to maintain dynamic structure. Here we introduce a nonlinear manifold learning method for time-series data—including those from fMRI—called temporal potential of heat-diffusion for affinity-based transition embedding (T-PHATE). In addition to recovering a low-dimensional intrinsic manifold geometry from time-series data, T-PHATE exploits the data’s autocorrelative structure to faithfully denoise and unveil dynamic trajectories. We empirically validate T-PHATE on three fMRI datasets, showing that it greatly improves data visualization, classification, and segmentation of the data relative to several other state-of-the-art dimensionality-reduction benchmarks. These improvements suggest many potential applications of T-PHATE to other high-dimensional datasets of temporally diffuse processes.

2022-12-31

Nature Computational Science (publié)

Time-inhomogeneous diffusion geometry and topology

Bastian Rieck

Manik Kuchroo

Matthew Hirn

Diffusion condensation is a dynamic process that yields a sequence of multiscale data representations that aim to encode meaningful abstract… (voir plus)ions. It has proven effective for manifold learning, denoising, clustering, and visualization of high-dimensional data. Diffusion condensation is constructed as a time-inhomogeneous process where each step first computes and then applies a diffusion operator to the data. We theoretically analyze the convergence and evolution of this process from geometric, spectral, and topological perspectives. From a geometric perspective, we obtain convergence bounds based on the smallest transition probability and the radius of the data, whereas from a spectral perspective, our bounds are based on the eigenspectrum of the diffusion kernel. Our spectral results are of particular interest since most of the literature on data diffusion is focused on homogeneous processes. From a topological perspective, we show diffusion condensation generalizes centroid-based hierarchical clustering. We use this perspective to obtain a bound based on the number of data points, independent of their location. To understand the evolution of the data geometry beyond convergence, we use topological data analysis. We show that the condensation process itself defines an intrinsic condensation homology. We use this intrinsic topology as well as the ambient persistent homology of the condensation process to study how the data changes over diffusion time. We demonstrate both types of topological information in well-understood toy examples. Our work gives theoretical insights into the convergence of diffusion condensation, and shows that it provides a link between topological and geometric data analysis.

2022-12-31

SIAM Journal on Mathematics of Data Science (publié)

arxiv.org

Learning Shared Neural Manifolds from Multi-Subject fMRI Data

Erica Busch

Tom Wallenstein

Michal Gerasimiuk

Andrew Benz

Guillaume Lajoie

Nicholas Turk-Browne

Functional magnetic resonance imaging (fMRI) is a notoriously noisy measurement of brain activity because of the large variations between in… (voir plus)dividuals, signals marred by environmental differences during collection, and spatiotemporal averaging required by the measurement resolution. In addition, the data is extremely high dimensional, with the space of the activity typically having much lower intrinsic dimension. In order to understand the connection between stimuli of interest and brain activity, and analyze differences and commonalities between subjects, it becomes important to learn a meaningful embedding of the data that denoises, and reveals its intrinsic structure. Specifically, we assume that while noise varies significantly between individuals, true responses to stimuli will share common, low-dimensional features between subjects which are jointly discoverable. Similar approaches have been exploited previously but they have mainly used linear methods such as PCA and shared response modeling (SRM). In contrast, we propose a neural network called MRMD-AE (manifold-regularized multiple decoder, autoencoder), that learns a common embedding from multiple subjects in an experiment while retaining the ability to decode to individual raw fMRI signals. We show that our learned common space represents an extensible manifold (where new points not seen during training can be mapped), improves the classification accuracy of stimulus features of unseen timepoints, as well as improves cross-subject translation of fMRI signals. We believe this framework can be used for many downstream applications such as guided brain-computer interface (BCI) training in the future.

2022-08-21

2022 IEEE 32nd International Workshop on Machine Learning for Signal Processing (MLSP) (publié)

openreview.net

Population Genomics Approaches for Genetic Characterization of SARS-CoV-2 Lineages

Fatima Mostefai

Isabel Gamache

Arnaud N'Guessan

Justin Pelletier

Carmen Lia Murall

Ahmad Pesaranghader

Vanda Gaonac’h-Lovejoy

David J. Hamelin

Raphaël Poujol

Jean-Christophe Grenier

Martin Smith

Etienne Caron

Morgan Craig

B. Jesse Shapiro

Julie G. Hussin

The genome of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19)… (voir plus), has been sequenced at an unprecedented scale leading to a tremendous amount of viral genome sequencing data. To assist in tracing infection pathways and design preventive strategies, a deep understanding of the viral genetic diversity landscape is needed. We present here a set of genomic surveillance tools from population genetics which can be used to better understand the evolution of this virus in humans. To illustrate the utility of this toolbox, we detail an in depth analysis of the genetic diversity of SARS-CoV-2 in first year of the COVID-19 pandemic. We analyzed 329,854 high-quality consensus sequences published in the GISAID database during the pre-vaccination phase. We demonstrate that, compared to standard phylogenetic approaches, haplotype networks can be computed efficiently on much larger datasets. This approach enables real-time lineage identification, a clear description of the relationship between variants of concern, and efficient detection of recurrent mutations. Furthermore, time series change of Tajima's D by haplotype provides a powerful metric of lineage expansion. Finally, principal component analysis (PCA) highlights key steps in variant emergence and facilitates the visualization of genomic variation in the context of SARS-CoV-2 diversity. The computational framework presented here is simple to implement and insightful for real-time genomic surveillance of SARS-CoV-2 and could be applied to any pathogen that threatens the health of populations of humans and other organisms.

2022-02-20

Frontiers in Medicine (publié)

Data-driven approaches for genetic characterization of SARS-CoV-2 lineages

Fatima Mostefai

Isabel Gamache

Arnaud N’Guessan

Justin Pelletier

Ahmad Pesaranghader

David Hamelin

Carmen Lia Murall

Raphaël Poujol

Jean-Christophe Grenier

Martin Smith

Etienne Caron

Morgan Craig

Jesse Shapiro

Julie G. Hussin

The genome of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19)… (voir plus), has been sequenced at an unprecedented scale, leading to a tremendous amount of viral genome sequencing data. To understand the evolution of this virus in humans, and to assist in tracing infection pathways and designing preventive strategies, we present a set of computational tools that span phylogenomics, population genetics and machine learning approaches. To illustrate the utility of this toolbox, we detail an in depth analysis of the genetic diversity of SARS-CoV-2 in first year of the COVID-19 pandemic, using 329,854 high-quality consensus sequences published in the GISAID database during the pre-vaccination phase. We demonstrate that, compared to standard phylogenetic approaches, haplotype networks can be computed efficiently on much larger datasets, enabling real-time analyses. Furthermore, time series change of Tajima’s D provides a powerful metric of population expansion. Unsupervised learning techniques further highlight key steps in variant detection and facilitate the study of the role of this genomic variation in the context of SARS-CoV-2 infection, with Multiscale PHATE methodology identifying fine-scale structure in the SARS-CoV-2 genetic data that underlies the emergence of key lineages. The computational framework presented here is useful for real-time genomic surveillance of SARS-CoV-2 and could be applied to any pathogen that threatens the health of worldwide populations of humans and other organisms.

2021-09-28

BioRxiv (prépublication)

Exploring the Geometry and Topology of Neural Network Loss Landscapes

Bastian Rieck

Recent work has established clear links between the generalization performance of trained neural networks and the geometry of their loss lan… (voir plus)dscape near the local minima to which they converge. This suggests that qualitative and quantitative examination of the loss landscape geometry could yield insights about neural network generalization performance during training. To this end, researchers have proposed visualizing the loss landscape through the use of simple dimensionality reduction techniques. However, such visualization methods have been limited by their linear nature and only capture features in one or two dimensions, thus restricting sampling of the loss landscape to lines or planes. Here, we expand and improve upon these in three ways. First, we present a novel "jump and retrain" procedure for sampling relevant portions of the loss landscape. We show that the resulting sampled data holds more meaningful information about the network's ability to generalize. Next, we show that non-linear dimensionality reduction of the jump and retrain trajectories via PHATE, a trajectory and manifold-preserving method, allows us to visualize differences between networks that are generalizing well vs poorly. Finally, we combine PHATE trajectories with a computational homology characterization to quantify trajectory differences.

2021-01-30

arXiv (prépublication)

arxiv.org

Topological analysis of single-cell data reveals shared glial landscape of macular degeneration and neurodegenerative diseases

Manik Kuchroo

Marcello DiStasio

Eda Calapkulu

Maryam Ige

Amar H. Sheth

Madhvi Menon

Yu Xing

Scott Gigante

Rahul M. Dhodapkar

Bastian Rieck

Brian P. Hafler

1 A novel topological machine learning approach applied to single-nucleus RNA sequencing from human retinas… (voir plus) with age-related macular degeneration identifies interacting disease phase-specific glial activation states shared with Alzheimer’s disease and multiple sclerosis. 2 Neurodegeneration occurs in a wide range of diseases, including age-related macular degeneration (AMD), Alzheimer’s disease (AD), and multiple sclerosis (MS), each with distinct inciting events. To determine whether glial transcriptional states are shared across phases of degeneration, we sequenced 50,498 nuclei from the retinas of seven AMD patients and six healthy controls, generating the first single-cell transcriptomic atlas of AMD. We identified groupings of cells implicated in disease pathogenesis by applying a novel topologically-inspired machine learning approach called ‘diffusion condensation.’ By calculating diffusion homology features and performing persistence analysis, diffusion condensation identified activated glial states enriched in the early phases of AMD, AD, and MS as well as an AMD-specific proangiogenic astrocyte state promoting pathogenic neovascularization in advanced AMD. Finally, by mapping the expression of disease-associated genes to glial states, we identified key signaling interactions creating hypotheses for therapeutic intervention. Our topological analysis identified an integrated disease-phase specific glial landscape that is shared across neurodegenerative conditions affecting the central nervous system.

2021-01-19

bioRxiv (prépublication)

Topological Analysis of Single-Cell Hierarchy Reveals Inflammatory Glial Landscape of Macular Degeneration

Manik Kuchroo

Marcello DiStasio

Eric Song

Eda Calapkulu

Maryam Ige

Amar H. Sheth

Madhvi Menon

Abhinav Godavarthi

Yu Xing

Scott Gigante

Holly Steach

Janhavi Narain

George Mourgkos

Rahul M. Dhodapkar

Matthew J. Hirn

Bastian Rieck … (voir 3 de plus)

Brian P. Hafler

2020-12-31

SSRN Electronic Journal (publié)

Topological Analysis of Single-Cell Hierarchy Reveals Inflammatory Glial Landscape of Macular Degeneration

Manik Kuchroo

Marcello DiStasio

Eric Song

Eda Calapkulu

Maryam Ige

Amar H. Sheth

Madhvi Menon

Abhinav Godavarthi

Yu Xing

Scott Gigante

Holly Steach

Janhavi Narain

George Mourgkos

Rahul M. Dhodapkar

Matthew J. Hirn

Bastian Rieck … (voir 3 de plus)

Brian P. Hafler

2020-12-31

SSRN Electronic Journal (inconnu)

Multiscale PHATE Exploration of SARS-CoV-2 Data Reveals Multimodal Signatures of Disease

Manik Kuchroo

Patrick Wong

Jean-Christophe Grenier

Dennis Shung

Carolina Lucas

Jon Klein

Daniel B. Burkhardt

Scott Gigante

Abhinav Godavarthi

Benjamin Israelow

Tianyang Mao

Ji Eun Oh

Julio Silva

Takehiro Takahashi

Camila D. Odio

Arnau Casanovas-Massana

John Fournier

Shelli Farhadian … (voir 7 de plus)

Charles S. Dela Cruz

Albert I. Ko

F. Perry Wilson

Julie Hussin

Akiko Iwasaki

Abstract

The biomedical community is producing increasingly high dimensional datasets, integrated from hundreds of… (voir plus) patient samples, which current computational techniques struggle to explore. To uncover biological meaning from these complex datasets, we present an approach called Multiscale PHATE, which learns abstracted biological features from data that can be directly predictive of disease. Built on a coarse graining process called diffusion condensation, Multiscale PHATE learns a data topology that can be analyzed at coarse levels for high level summarizations of data, as well as at fine levels for detailed representations on subsets. We apply Multiscale PHATE to study the immune response to COVID-19 in 54 million cells from 168 hospitalized patients. Through our analysis of patient samples, we identify CD16-hi,CD66b-lo neutrophil and IFNγ+,GranzymeB+ Th17 cell responses enriched in patients who die. Furthermore, we show that population groupings Multiscale PHATE discovers can be directly fed into a classifier to predict disease outcome. We also use Multiscale PHATE-derived features to construct two different manifolds of patients, one from abstracted flow cytometry features and another directly on patient clinical features, both associating immune subsets and clinical markers with outcome.

2020-11-16

bioRxiv (prépublication)

TrajectoryNet: A Dynamic Optimal Transport Network for Modeling Cellular Dynamics

David van Dijk

It is increasingly common to encounter data from dynamic processes captured by static cross-sectional measurements over time, particularly i… (voir plus)n biomedical settings. Recent attempts to model individual trajectories from this data use optimal transport to create pairwise matchings between time points. However, these methods cannot model continuous dynamics and non-linear paths that entities can take in these systems. To address this issue, we establish a link between continuous normalizing flows and dynamic optimal transport, that allows us to model the expected paths of points over time. Continuous normalizing flows are generally under constrained, as they are allowed to take an arbitrary path from the source to the target distribution. We present TrajectoryNet, which controls the continuous paths taken between distributions to produce dynamic optimal transport. We show how this is particularly applicable for studying cellular dynamics in data from single-cell RNA sequencing (scRNA-seq) technologies, and that TrajectoryNet improves upon recently proposed static optimal transport-based models that can be used for interpolating cellular distributions.

2020-07-13

International Conference on Machine Learning (Accept)