Smita Krishnaswamy

Nicholas B Turk-Browne

2025-04-02

bioRxiv (preprint)

Deep multimodal representations and classification of first-episode psychosis via live face processing

Rahul Singh

Yanlei Zhang

Dhananjay Bhaskar

Vinod Srihari

Cenk Tek

Xian Zhang

J. Adam Noah

Joy Hirsch

Schizophrenia is a severe psychiatric disorder associated with a wide range of cognitive and neurophysiological dysfunctions and long-term s… (see more)ocial difficulties. In this paper, we test the hypothesis that integration of multiple simultaneous acquisitions of neuroimaging, behavioral, and clinical information will be better for prediction of early psychosis than unimodal recordings. We propose a novel framework to investigate the neural underpinnings of the early psychosis symptoms (that can develop into Schizophrenia with age) using multimodal acquisitions of neural and behavioral recordings including functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG), and facial features. Our data acquisition paradigm is based on live face-to-face interaction in order to study the neural correlates of social cognition in first-episode psychosis (FEP). We propose a novel deep representation learning framework, Neural-PRISM, for learning joint multimodal compressed representations combining neural as well as behavioral recordings. These learned representations are subsequently used to describe, classify, and predict the severity of early psychosis in patients, as measured by the Positive and Negative Syndrome Scale (PANSS) and Global Assessment of Functioning (GAF) scores. We found that incorporating joint multimodal representations from fNIRS and EEG along with behavioral recordings enhances classification between typical controls and FEP individuals. Additionally, our results suggest that geometric and topological features such as curvatures and path signatures of the embedded trajectories of brain activity enable detection of discriminatory neural characteristics in early psychosis.

2025-02-25

Frontiers in Psychiatry (published)

HiPoNet: A Multi-View Simplicial Complex Network for High Dimensional Point-Cloud and Single-Cell Data

Hiren Madhu

Dhananjay Bhaskar

Jake Kovalic

David R. Johnson

Rex Ying

Christopher Tape

Ian Adelstein

Michael Perlmutter

In this paper, we propose HiPoNet, an end-to-end differentiable neural network for regression, classification, and representation learning o… (see more)n high-dimensional point clouds. Our work is motivated by single-cell data which can have very high-dimensionality --exceeding the capabilities of existing methods for point clouds which are mostly tailored for 3D data. Moreover, modern single-cell and spatial experiments now yield entire cohorts of datasets (i.e., one data set for every patient), necessitating models that can process large, high-dimensional point-clouds at scale. Most current approaches build a single nearest-neighbor graph, discarding important geometric and topological information. In contrast, HiPoNet models the point-cloud as a set of higher-order simplicial complexes, with each particular complex being created using a reweighting of features. This method thus generates multiple constructs corresponding to different views of high-dimensional data, which in biology offers the possibility of disentangling distinct cellular processes. It then employs simplicial wavelet transforms to extract multiscale features, capturing both local and global topology from each view. We show that geometric and topological information is preserved in this framework both theoretically and empirically. We showcase the utility of HiPoNet on point-cloud level tasks, involving classification and regression of entire point-clouds in data cohorts. Experimentally, we find that HiPoNet outperforms other point-cloud and graph-based models on single-cell data. We also apply HiPoNet to spatial transcriptomics datasets using spatial coordinates as one of the views. Overall, HiPoNet offers a robust and scalable solution for high-dimensional data analysis.

2025-02-10

ArXiv (preprint)

Geometry-Aware Generative Autoencoders for Warped Riemannian Metric Learning and Generative Modeling on Data Manifolds

Xingzhi Sun

Danqi Liao

Kincaid MacDonald

Yanlei Zhang

Guillaume Huguet

Guy Wolf

Ian Adelstein

Tim G. J. Rudner

Rapid growth of high-dimensional datasets in fields such as single-cell RNA sequencing and spatial genomics has led to unprecedented opportu… (see more)nities for scientific discovery, but it also presents unique computational and statistical challenges. Traditional methods struggle with geometry-aware data generation, interpolation along meaningful trajectories, and transporting populations via feasible paths. To address these issues, we introduce Geometry-Aware Generative Autoencoder (GAGA), a novel framework that combines extensible manifold learning with generative modeling. GAGA constructs a neural network embedding space that respects the intrinsic geometries discovered by manifold learning and learns a novel warped Riemannian metric on the data space. This warped metric is derived from both the points on the data manifold and negative samples off the manifold, allowing it to characterize a meaningful geometry across the entire latent space. Using this metric, GAGA can uniformly sample points on the manifold, generate points along geodesics, and interpolate between populations across the learned manifold using geodesic-guided flows. GAGA shows competitive performance in simulated and real-world datasets, including a 30% improvement over the state-of-the-art methods in single-cell population-level trajectory inference.

2025-01-21

Artificial Intelligence and Statistics (poster)

proceedings.mlr.press

ImageFlowNet: Forecasting Multiscale Image-Level Trajectories of Disease Progression with Irregularly-Sampled Longitudinal Medical Images

Chen Liu

Ke Xu

Liangbo L. Shen

Jay Stewart

Jay C. Wang

Lucian V. Del Priore

Advances in medical imaging technologies have enabled the collection of longitudinal images, which involve repeated scanning of the same pat… (see more)ients over time, to monitor disease progression. However, predictive modeling of such data remains challenging due to high dimensionality, irregular sampling, and data sparsity. To address these issues, we propose ImageFlowNet, a novel model designed to forecast disease trajectories from initial images while preserving spatial details. ImageFlowNet first learns multiscale joint representation spaces across patients and time points, then optimizes deterministic or stochastic flow fields within these spaces using a position-parameterized neural ODE/SDE framework. The model leverages a UNet architecture to create robust multiscale representations and mitigates data scarcity by combining knowledge from all patients. We provide theoretical insights that support our formulation of ODEs, and motivate our regularizations involving high-level visual features, latent space organization, and trajectory smoothness. We validate ImageFlowNet on three longitudinal medical image datasets depicting progression in geographic atrophy, multiple sclerosis, and glioblastoma, demonstrating its ability to effectively forecast disease progression and outperform existing methods. Our contributions include the development of ImageFlowNet, its theoretical underpinnings, and empirical validation on real-world datasets. The official implementation is available at https://github.com/KrishnaswamyLab/ImageFlowNet.

2024-12-31

International Conference on Acoustics, Speech, and Signal Processing (published)

Mapping the gene space at single-cell resolution with gene signal pattern analysis

Aarthi Venkat

Martina Damo

Samuel Leone

Scott E. Youlten

Nikhil S. Joshi

Eric Fagerberg

John Attanasio

Michael Perlmutter

In single-cell sequencing analysis, several computational methods have been developed to map the cellular state space, but little has been d… (see more)one to map or create embeddings of the gene space. Here, we formulate the gene embedding problem, design tasks with simulated single-cell data to evaluate representations, and establish ten relevant baselines. We then present a graph signal processing approach we call gene signal pattern analysis (GSPA) that learns rich gene representations from single-cell data using a dictionary of diffusion wavelets on the cell-cell graph. GSPA enables characterization of genes based on their patterning on the cellular manifold. It also captures how localized or diffuse the expression of a gene is, for which we present a score called the gene localization score. We motivate and demonstrate the efficacy of GSPA as a framework for a range of biological tasks, such as capturing gene coexpression modules, condition-specific enrichment, and perturbation-specific gene-gene interactions. Then, we showcase the broad utility of gene rep-resentations derived from GSPA, including for cell-cell communication (GSPA-LR), spatial transcriptomics (GSPA-multimodal), and patient response (GSPA-Pt) analysis.

2024-12-19

Nature Computational Science (published)

Beta cells are essential drivers of pancreatic ductal adenocarcinoma development

Cathy C. Garcia

Aarthi Venkat

Daniel C. McQuaid

Sherry Agabiti

Alex Tong

Rebecca L. Cardone

Rebecca Starble

Akin Sogunro

Jeremy B. Jacox

Christian F. Ruiz

Richard G. Kibbey

Mandar Deepak Muzumdar

Pancreatic endocrine-exocrine crosstalk plays a key role in normal physiology and disease. For instance, endocrine islet beta (β) cell secr… (see more)etion of insulin or cholecystokinin (CCK) promotes progression of pancreatic adenocarcinoma (PDAC), an exocrine cell-derived tumor. However, the cellular and molecular mechanisms that govern endocrine-exocrine signaling in tumorigenesis remain incompletely understood. We find that β cell ablation impedes PDAC development in mice, arguing that the endocrine pancreas is critical for exocrine tumorigenesis. Conversely, obesity induces β cell hormone dysregulation, alters CCK-dependent peri-islet exocrine cell transcriptional states, and enhances islet proximal tumor formation. Single-cell RNA-sequencing, in silico latent-space archetypal and trajectory analysis, and genetic lineage tracing in vivo reveal that obesity stimulates postnatal immature β cell expansion and adaptation towards a pro-tumorigenic CCK+ state via JNK/cJun stress-responsive signaling. These results define endocrine-exocrine signaling as a driver of PDAC development and uncover new avenues to target the endocrine pancreas to subvert exocrine tumorigenesis.

2024-12-02

bioRxiv (preprint)

Exploring the Manifold of Neural Networks Using Diffusion Geometry

Elliott Abel

Peyton Crevasse

Yvan Grinspan

Selma Mazioud

Folu Ogundipe

Kristof Reimann

Ellie Schueler

Andrew J. Steindl

Ellen Zhang

Dhananjay Bhaskar

Yanlei Zhang

Tim G. J. Rudner

Ian Adelstein

Drawing motivation from the manifold hypothesis, which posits that most high-dimensional data lies on or near low-dimensional manifolds, we … (see more)apply manifold learning to the space of neural networks. We learn manifolds where datapoints are neural networks by introducing a distance between the hidden layer representations of the neural networks. These distances are then fed to the non-linear dimensionality reduction algorithm PHATE to create a manifold of neural networks. We characterize this manifold using features of the representation, including class separation, hierarchical cluster structure, spectral entropy, and topological structure. Our analysis reveals that high-performing networks cluster together in the manifold, displaying consistent embedding patterns across all these features. Finally, we demonstrate the utility of this approach for guiding hyperparameter optimization and neural architecture search by sampling from the manifold.

2024-11-18

ArXiv (preprint)

ImmunoStruct: Integration of protein sequence, structure, and biochemical properties for immunogenicity prediction and interpretation

Kevin Bijan Givechian

João Felipe Rocha

Edward Yang

Chen Liu

Kerrie Greene

Rex Ying

Etienne Caron

Akiko Iwasaki

2024-11-02

bioRxiv (preprint)

ProtSCAPE: Mapping the landscape of protein conformations in molecular dynamics

Dhananjay Bhaskar

David R. Johnson

João Felipe Rocha

Egbert Castro

Jackson Grady

Alex T. Grigas

Michael Perlmutter

Corey S. O'Hern

Understanding the dynamic nature of protein structures is essential for comprehending their biological functions. While significant progress… (see more) has been made in predicting static folded structures, modeling protein motions on microsecond to millisecond scales remains challenging. To address these challenges, we introduce a novel deep learning architecture, Protein Transformer with Scattering, Attention, and Positional Embedding (ProtSCAPE), which leverages the geometric scattering transform alongside transformer-based attention mechanisms to capture protein dynamics from molecular dynamics (MD) simulations. ProtSCAPE utilizes the multi-scale nature of the geometric scattering transform to extract features from protein structures conceptualized as graphs and integrates these features with dual attention structures that focus on residues and amino acid signals, generating latent representations of protein trajectories. Furthermore, ProtSCAPE incorporates a regression head to enforce temporally coherent latent representations.

2024-10-26

ArXiv (preprint)

Convergence of Manifold Filter-Combine Networks

David R. Johnson

Joyce Chew

Edward De Brouwer

Deanna Needell

Michael Perlmutter

In order to better understand manifold neural networks (MNNs), we introduce Manifold Filter-Combine Networks (MFCNs). The filter-combine fra… (see more)mework parallels the popular aggregate-combine paradigm for graph neural networks (GNNs) and naturally suggests many interesting families of MNNs which can be interpreted as the manifold analog of various popular GNNs. We then propose a method for implementing MFCNs on high-dimensional point clouds that relies on approximating the manifold by a sparse graph. We prove that our method is consistent in the sense that it converges to a continuum limit as the number of data points tends to infinity.

2024-10-17

ArXiv (preprint)

Neurospectrum: A Geometric and Topological Deep Learning Framework for Uncovering Spatiotemporal Signatures in Neural Activity

Dhananjay Bhaskar

Yanlei Zhang

Jessica Moore

Feng Gao

Bastian Rieck

Firas Khasawneh

Elizabeth Munch

Guy Wolf

Valentina Greco

J. Adam Noah

Helen Pushkarskaya

Christopher Pittenger

Neural signals are high-dimensional, noisy, and dynamic, making it challenging to extract interpretable features linked to behavior or disea… (see more)se. We introduce Neurospectrum , a framework that encodes neural activity as latent trajectories shaped by spatial and temporal structure. At each timepoint, signals are represented on a graph capturing spatial relationships, with a learnable attention mechanism highlighting important regions. These are embedded using graph wavelets and passed through a manifold-regularized autoencoder that preserves temporal geometry. The resulting latent trajectory is summarized using a principled set of descriptors - including curvature, path signatures, persistent homology, and recurrent networks -that capture multiscale geometric, topological, and dynamical features. These features drive downstream prediction in a modular, interpretable, and end-to-end trainable framework. We evaluate Neurospectrum on simulated and experimental datasets. It tracks phase synchronization in Kuramoto simulations, reconstructs visual stimuli from calcium imaging, and identifies biomarkers of obsessive-compulsive disorder in fMRI. Across tasks, Neurospectrum uncovers meaningful neural dynamics and outperforms traditional analysis methods.

2024-10-12

bioRxiv (preprint)