Jessie Huang

Guillaume Huguet

Janhavi Narain

Kisung You

George Mourgkos … (see 6 more)

Rahul M. Dhodapkar

Matthew J. Hirn

Bastian Rieck

Brian P. Hafler

Due to commonalities in pathophysiology, age-related macular degeneration (AMD) represents a uniquely accessible model to investigate thera… (see more)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 (published)

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… (see more)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 (published)

Learning Shared Neural Manifolds from Multi-Subject fMRI Data

Erica L. Busch

Tom Wallenstein

Michal Gerasimiuk

Andrew Benz

Guillaume Lajoie

Nicholas B. Turk-Browne

Functional magnetic resonance imaging (fMRI) is a notoriously noisy measurement of brain activity because of the large variations between in… (see more)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) (published)

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)… (see more), 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 (published)

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)… (see more), 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 (preprint)

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

Manik Kuchroo

Patrick Wong

Jean-Christophe Grenier

Dennis Shung

Alexander Tong

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 … (see 7 more)

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… (see more) 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 (preprint)

Learning Safe Policies with Expert Guidance