Kian Kenyon-Dean

Oren Kraus, Kian Kenyon-Dean, Saber Saberian et al.

Inferring biological relationships from cellular phenotypes in high-content microscopy screens provides significant opportunity and challenge in biological research. Prior results have shown that deep vision models can capture biological signal better than hand-crafted features. This work explores how self-supervised deep learning approaches scale when training larger models on larger microscopy datasets. Our results show that both CNN- and ViT-based masked autoencoders significantly outperform weakly supervised baselines. At the high-end of our scale, a ViT-L/8 trained on over 3.5-billion unique crops sampled from 93-million microscopy images achieves relative improvements as high as 28% over our best weakly supervised baseline at inferring known biological relationships curated from public databases. Relevant code and select models released with this work can be found at: https://github.com/recursionpharma/maes_microscopy.

Kian Kenyon-Dean, Alina Selega, Ihab Bendidi et al.

RNA sequencing produces rich and diverse datasets of gene expression, offering compelling insights into cellular state and function that have many applications in drug discovery. Modeling such data is challenging due to inherent technical noise and experimental batch effects, as evidenced by many existing transcriptomic foundation models (FMs) underperforming relative to linear baselines. Such results raise the question of whether deep representation learning provides a distinct advantage over the direct use of raw transcript counts. Our work explores this by developing a new self-supervised model, TxFM, with a focus on inductive representation learning evaluations. TxFM employs a masked autoencoding approach tailored to diverse RNA-seq count data, and our ablation study empirically identifies crucial architecture configurations required for strong transfer performance. Additionally, we curate a public training corpus, DiverseRNA-1.4M, and find that TxFM trained on this curated dataset yields high-fidelity gene representations that outperform FMs trained on atlas-scale corpora over 100x larger. Overall, our results indicate that inductive self-supervised learning is a viable modeling approach for transcriptomics representation, provided a careful synthesis of model architecture and training data curation.

Oren Kraus, Kian Kenyon-Dean, Saber Saberian et al.

Featurizing microscopy images for use in biological research remains a significant challenge, especially for large-scale experiments spanning millions of images. This work explores the scaling properties of weakly supervised classifiers and self-supervised masked autoencoders (MAEs) when training with increasingly larger model backbones and microscopy datasets. Our results show that ViT-based MAEs outperform weakly supervised classifiers on a variety of tasks, achieving as much as a 11.5% relative improvement when recalling known biological relationships curated from public databases. Additionally, we develop a new channel-agnostic MAE architecture (CA-MAE) that allows for inputting images of different numbers and orders of channels at inference time. We demonstrate that CA-MAEs effectively generalize by inferring and evaluating on a microscopy image dataset (JUMP-CP) generated under different experimental conditions with a different channel structure than our pretraining data (RPI-93M). Our findings motivate continued research into scaling self-supervised learning on microscopy data in order to create powerful foundation models of cellular biology that have the potential to catalyze advancements in drug discovery and beyond.

Ihab Bendidi, Shawn Whitfield, Kian Kenyon-Dean et al.

Understanding the relationships among genes, compounds, and their interactions in living organisms remains limited due to technological constraints and the complexity of biological data. Deep learning has shown promise in exploring these relationships using various data types. However, transcriptomics, which provides detailed insights into cellular states, is still underused due to its high noise levels and limited data availability. Recent advancements in transcriptomics sequencing provide new opportunities to uncover valuable insights, especially with the rise of many new foundation models for transcriptomics, yet no benchmark has been made to robustly evaluate the effectiveness of these rising models for perturbation analysis. This article presents a novel biologically motivated evaluation framework and a hierarchy of perturbation analysis tasks for comparing the performance of pretrained foundation models to each other and to more classical techniques of learning from transcriptomics data. We compile diverse public datasets from different sequencing techniques and cell lines to assess models performance. Our approach identifies scVI and PCA to be far better suited models for understanding biological perturbations in comparison to existing foundation models, especially in their application in real-world scenarios.

Kian Kenyon-Dean, Zitong Jerry Wang, John Urbanik et al.

Large-scale cell microscopy screens are used in drug discovery and molecular biology research to study the effects of millions of chemical and genetic perturbations on cells. To use these images in downstream analysis, we need models that can map each image into a feature space that represents diverse biological phenotypes consistently, in the sense that perturbations with similar biological effects have similar representations. In this work, we present the largest foundation model for cell microscopy data to date, a new 1.9 billion-parameter ViT-G/8 MAE trained on over 8 billion microscopy image crops. Compared to a previous published ViT-L/8 MAE, our new model achieves a 60% improvement in linear separability of genetic perturbations and obtains the best overall performance on whole-genome biological relationship recall and replicate consistency benchmarks. Beyond scaling, we developed two key methods that improve performance: (1) training on a curated and diverse dataset; and, (2) using biologically motivated linear probing tasks to search across each transformer block for the best candidate representation of whole-genome screens. We find that many self-supervised vision transformers, pretrained on either natural or microscopy images, yield significantly more biologically meaningful representations of microscopy images in their intermediate blocks than in their typically used final blocks. More broadly, our approach and results provide insights toward a general strategy for successfully building foundation models for large-scale biological data.

Oren Kraus, Federico Comitani, John Urbanik et al.

High Content Screening (HCS) microscopy datasets have transformed the ability to profile cellular responses to genetic and chemical perturbations, enabling cell-based inference of drug-target interactions (DTI). However, the adoption of representation learning methods for HCS data has been hindered by the lack of accessible datasets and robust benchmarks. To address this gap, we present RxRx3-core, a curated and compressed subset of the RxRx3 dataset, and an associated DTI benchmarking task. At just 18GB, RxRx3-core significantly reduces the size barrier associated with large-scale HCS datasets while preserving critical data necessary for benchmarking representation learning models against a zero-shot DTI prediction task. RxRx3-core includes 222,601 microscopy images spanning 736 CRISPR knockouts and 1,674 compounds at 8 concentrations. RxRx3-core is available on HuggingFace and Polaris, along with pre-trained embeddings and benchmarking code, ensuring accessibility for the research community. By providing a compact dataset and robust benchmarks, we aim to accelerate innovation in representation learning methods for HCS data and support the discovery of novel biological insights.

Ihab Bendidi, Yassir El Mesbahi, Alisandra K. Denton et al.

Understanding cellular responses to stimuli is crucial for biological discovery and drug development. Transcriptomics provides interpretable, gene-level insights, while microscopy imaging offers rich predictive features but is harder to interpret. Weakly paired datasets, where samples share biological states, enable multimodal learning but are scarce, limiting their utility for training and multimodal inference. We propose a framework to enhance transcriptomics by distilling knowledge from microscopy images. Using weakly paired data, our method aligns and binds modalities, enriching gene expression representations with morphological information. To address data scarcity, we introduce (1) Semi-Clipped, an adaptation of CLIP for cross-modal distillation using pretrained foundation models, achieving state-of-the-art results, and (2) PEA (Perturbation Embedding Augmentation), a novel augmentation technique that enhances transcriptomics data while preserving inherent biological information. These strategies improve the predictive power and retain the interpretability of transcriptomics, enabling rich unimodal representations for complex biological tasks.

Konstantin Donhauser, Kristina Ulicna, Gemma Elyse Moran et al.

Sparse dictionary learning (DL) has emerged as a powerful approach to extract semantically meaningful concepts from the internals of large language models (LLMs) trained mainly in the text domain. In this work, we explore whether DL can extract meaningful concepts from less human-interpretable scientific data, such as vision foundation models trained on cell microscopy images, where limited prior knowledge exists about which high-level concepts should arise. We propose a novel combination of a sparse DL algorithm, Iterative Codebook Feature Learning (ICFL), with a PCA whitening pre-processing step derived from control data. Using this combined approach, we successfully retrieve biologically meaningful concepts, such as cell types and genetic perturbations. Moreover, we demonstrate how our method reveals subtle morphological changes arising from human-interpretable interventions, offering a promising new direction for scientific discovery via mechanistic interpretability in bioimaging.

Kian Kenyon-Dean, Edward Newell, Jackie Chi Kit Cheung

Word embeddings are reliable feature representations of words used to obtain high quality results for various NLP applications. Uncontextualized word embeddings are used in many NLP tasks today, especially in resource-limited settings where high memory capacity and GPUs are not available. Given the historical success of word embeddings in NLP, we propose a retrospective on some of the most well-known word embedding algorithms. In this work, we deconstruct Word2vec, GloVe, and others, into a common form, unveiling some of the common conditions that seem to be required for making performant word embeddings. We believe that the theoretical findings in this paper can provide a basis for more informed development of future models.

Jingyi He, KC Tsiolis, Kian Kenyon-Dean et al.

Word embeddings are trained to predict word cooccurrence statistics, which leads them to possess different lexical properties (syntactic, semantic, etc.) depending on the notion of context defined at training time. These properties manifest when querying the embedding space for the most similar vectors, and when used at the input layer of deep neural networks trained to solve downstream NLP problems. Meta-embeddings combine multiple sets of differently trained word embeddings, and have been shown to successfully improve intrinsic and extrinsic performance over equivalent models which use just one set of source embeddings. We introduce word prisms: a simple and efficient meta-embedding method that learns to combine source embeddings according to the task at hand. Word prisms learn orthogonal transformations to linearly combine the input source embeddings, which allows them to be very efficient at inference time. We evaluate word prisms in comparison to other meta-embedding methods on six extrinsic evaluations and observe that word prisms offer improvements in performance on all tasks.

Edward Newell, Kian Kenyon-Dean, Jackie Chi Kit Cheung

Uncontextualized word embeddings are reliable feature representations of words used to obtain high quality results for various NLP applications. Given the historical success of word embeddings in NLP, we propose a retrospective on some of the most well-known word embedding algorithms. In this work, we deconstruct Word2vec, GloVe, and others, into a common form, unveiling some of the necessary and sufficient conditions required for making performant word embeddings. We find that each algorithm: (1) fits vector-covector dot products to approximate pointwise mutual information (PMI); and, (2) modulates the loss gradient to balance weak and strong signals. We demonstrate that these two algorithmic features are sufficient conditions to construct a novel word embedding algorithm, Hilbert-MLE. We find that its embeddings obtain equivalent or better performance against other algorithms across 17 intrinsic and extrinsic datasets.

Kian Kenyon-Dean

Word embedding algorithms produce very reliable feature representations of words that are used by neural network models across a constantly growing multitude of NLP tasks. As such, it is imperative for NLP practitioners to understand how their word representations are produced, and why they are so impactful. The present work presents the Simple Embedder framework, generalizing the state-of-the-art existing word embedding algorithms (including Word2vec (SGNS) and GloVe) under the umbrella of generalized low rank models. We derive that both of these algorithms attempt to produce embedding inner products that approximate pointwise mutual information (PMI) statistics in the corpus. Once cast as Simple Embedders, comparison of these models reveals that these successful embedders all resemble a straightforward maximum likelihood estimate (MLE) of the PMI parametrized by the inner product (between embeddings). This MLE induces our proposed novel word embedding model, Hilbert-MLE, as the canonical representative of the Simple Embedder framework. We empirically compare these algorithms with evaluations on 17 different datasets. Hilbert-MLE consistently observes second-best performance on every extrinsic evaluation (news classification, sentiment analysis, POS-tagging, and supersense tagging), while the first-best model depends varying on the task. Moreover, Hilbert-MLE consistently observes the least variance in results with respect to the random initialization of the weights in bidirectional LSTMs. Our empirical results demonstrate that Hilbert-MLE is a very consistent word embedding algorithm that can be reliably integrated into existing NLP systems to obtain high-quality results.

Kian Kenyon-Dean, Andre Cianflone, Lucas Page-Caccia et al.

The standard loss function used to train neural network classifiers, categorical cross-entropy (CCE), seeks to maximize accuracy on the training data; building useful representations is not a necessary byproduct of this objective. In this work, we propose clustering-oriented representation learning (COREL) as an alternative to CCE in the context of a generalized attractive-repulsive loss framework. COREL has the consequence of building latent representations that collectively exhibit the quality of natural clustering within the latent space of the final hidden layer, according to a predefined similarity function. Despite being simple to implement, COREL variants outperform or perform equivalently to CCE in a variety of scenarios, including image and news article classification using both feed-forward and convolutional neural networks. Analysis of the latent spaces created with different similarity functions facilitates insights on the different use cases COREL variants can satisfy, where the Cosine-COREL variant makes a consistently clusterable latent space, while Gaussian-COREL consistently obtains better classification accuracy than CCE.

Kian Kenyon-Dean, Jackie Chi Kit Cheung, Doina Precup

We present an approach to event coreference resolution by developing a general framework for clustering that uses supervised representation learning. We propose a neural network architecture with novel Clustering-Oriented Regularization (CORE) terms in the objective function. These terms encourage the model to create embeddings of event mentions that are amenable to clustering. We then use agglomerative clustering on these embeddings to build event coreference chains. For both within- and cross-document coreference on the ECB+ corpus, our model obtains better results than models that require significantly more pre-annotated information. This work provides insight and motivating results for a new general approach to solving coreference and clustering problems with representation learning.