Understanding cellular responses to external stimuli is critical for parsing biological mechanisms and advancing therapeutic development. High-content image-based assays provide a cost-effective approach to examine cellular phenotypes induced by diverse interventions, which offers valuable insights into biological processes and cellular states. We introduce MorphoDiff, a generative pipeline to predict high-resolution cell morphological responses under different conditions based on perturbation encoding. To the best of our knowledge, MorphoDiff is the first framework capable of producing guided, high-resolution predictions of cell morphology that generalize across both chemical and genetic interventions. The model integrates perturbation embeddings as guiding signals within a 2D latent diffusion model. The comprehensive computational, biological, and visual validations across three open-source Cell Painting datasets show that MorphoDiff can generate high-fidelity images and produce meaningful biology signals under various interventions. We envision the model will facilitate efficient in silico exploration of perturbational landscapes towards more effective drug discovery studies.

Chest X-rays (CXRs) play an integral role in driving critical decisions in disease management and patient care. While recent innovations have led to specialized models for various CXR interpretation tasks, these solutions often operate in isolation, limiting their practical utility in clinical practice. We present MedRAX, the first versatile AI agent that seamlessly integrates state-of-the-art CXR analysis tools and multimodal large language models into a unified framework. MedRAX dynamically leverages these models to address complex medical queries without requiring additional training. To rigorously evaluate its capabilities, we introduce ChestAgentBench, a comprehensive benchmark containing 2,500 complex medical queries across 7 diverse categories. Our experiments demonstrate that MedRAX achieves state-of-the-art performance compared to both open-source and proprietary models, representing a significant step toward the practical deployment of automated CXR interpretation systems. Data and code have been publicly available at https://github.com/bowang-lab/MedRAX

Unlocking deep and interpretable biological reasoning from complex genomic data remains a major AI challenge limiting scientific progress. While current DNA foundation models excel at representing sequences, they struggle with multi-step reasoning and lack transparent, biologically meaningful explanations. BioReason addresses this by tightly integrating a DNA foundation model with a large language model (LLM), enabling the LLM to directly interpret and reason over genomic information. Through supervised fine-tuning and reinforcement learning, BioReason learns to produce logical, biologically coherent deductions. It achieves major performance gains, boosting KEGG-based disease pathway prediction accuracy from 86% to 98% and improving variant effect prediction by an average of 15% over strong baselines. BioReason can reason over unseen biological entities and explain its decisions step by step, offering a transformative framework for interpretable, mechanistic AI in biology. All data, code, and checkpoints are available at [https://github.com/bowang-lab/BioReason](https://github.com/bowang-lab/BioReason).

The discovery and identification of molecules in biological and environmental samples is crucial for advancing biomedical and chemical sciences. Tandem mass spectrometry (MS/MS) is the leading technique for high-throughput elucidation of molecular structures. However, decoding a molecular structure from its mass spectrum is exceptionally challenging, even when performed by human experts. As a result, the vast majority of acquired MS/MS spectra remain uninterpreted, thereby limiting our understanding of the underlying (bio)chemical processes. Despite decades of progress in machine learning applications for predicting molecular structures from MS/MS spectra, the development of new methods is severely hindered by the lack of standard datasets and evaluation protocols. To address this problem, we propose MassSpecGym -- the first comprehensive benchmark for the discovery and identification of molecules from MS/MS data. Our benchmark comprises the largest publicly available collection of high-quality MS/MS spectra and defines three MS/MS annotation challenges: \textit{de novo} molecular structure generation, molecule retrieval, and spectrum simulation. It includes new evaluation metrics and a generalization-demanding data split, therefore standardizing the MS/MS annotation tasks and rendering the problem accessible to the broad machine learning community. MassSpecGym is publicly available at \url{https://github.com/pluskal-lab/MassSpecGym}.

Accurate segmentation of cellular images remains an elusive task due to the intrinsic variability in morphology of biological structures. Complete manual segmentation is unfeasible for large datasets, and while supervised methods have been proposed to automate segmentation, they often rely on manually generated ground truths which are especially challenging and time consuming to generate in biology due to the requirement of domain expertise. Furthermore, these methods have limited generalization capacity, requiring additional manual labels to be generated for each dataset and use case. We introduce MAESTER (Masked AutoEncoder guided Segmen'Iation at pixEl Resolution), a self-supervised method for accurate, subcellular structure segmentation at pixel resolution. MAESTER treats segmentation as a representation learning and clustering problem. Specifically, MAESTER learns semantically meaningful token representations of multi-pixel image patches while simultaneously maintaining a sufficiently large field of view for contextual learning. We also develop a cover-and-stride inference strategy to achieve pixel-level subcellular structure segmentation. We evaluated MAESTER on a publicly available volumetric electron microscopy (VEM) dataset of primary mouse pancreatic islets ß cells and achieved up-wards of 29.1 % improvement over state-of-the-art under the same evaluation criteria. Furthermore, our results are competitive against supervised methods trained on the same tasks, closing the gap between self-supervised and supervised approaches. MAESTER shows promise for alleviating the critical bottleneck of ground truth generation for imaging related data analysis and thereby greatly increasing the rate of biological discovery. Code available at https://github.com/bowang-lab/MAESTER.

Histology imaging is an important tool in medical diagnosis and research, enabling the examination of tissue structure and composition at the microscopic level. Understanding the underlying molecular mechanisms of tissue architecture is critical in uncovering disease mechanisms and developing effective treatments.Gene expression profiling provides insight into the molecular processes underlying tissue architecture, but the process can be time-consuming and expensive. We present BLEEP (Bi-modaL Embedding for Expression Prediction), a bi-modal embedding framework capable of generating spatially resolved gene expression profiles of whole-slide Hematoxylin and eosin (H&E) stained histology images. BLEEP uses contrastive learning to construct a low-dimensional joint embedding space from a reference dataset using paired image and expression profiles at micrometer resolution. With this approach, the gene expression of any query image patch can be imputed using the expression profiles from the reference dataset. We demonstrate BLEEP’s effectiveness in gene expression prediction by benchmarking its performance on a human liver tissue dataset captured using the 10x Visium platform, where it achieves significant improvements over existing methods. Our results demonstrate the potential of BLEEP to provide insights into the molecular mechanisms underlying tissue architecture, with important implications in diagnosis and research of various diseases. The proposed approach can significantly reduce the time and cost associated with gene expression profiling, opening up new avenues for high-throughput analysis of histology images for both research and clinical applications.

Training and evaluating language models increasingly requires the construction of meta-datasets -- diverse collections of curated data with clear provenance. Natural language prompting has recently lead to improved zero-shot generalization by transforming existing, supervised datasets into a variety of novel instruction tuning tasks, highlighting the benefits of meta-dataset curation. While successful in general-domain text, translating these data-centric approaches to biomedical language modeling remains challenging, as labeled biomedical datasets are significantly underrepresented in popular data hubs. To address this challenge, we introduce BigBio a community library of 126+ biomedical NLP datasets, currently covering 13 task categories and 10+ languages. BigBio facilitates reproducible meta-dataset curation via programmatic access to datasets and their metadata, and is compatible with current platforms for prompt engineering and end-to-end few/zero shot language model evaluation. We discuss our process for task schema harmonization, data auditing, contribution guidelines, and outline two illustrative use cases: zero-shot evaluation of biomedical prompts and large-scale, multi-task learning. BigBio is an ongoing community effort and is available at https://github.com/bigscience-workshop/biomedical

MOTIVATION: Molecular carcinogenicity is a preventable cause of cancer, but systematically identifying carcinogenic compounds, which involves performing experiments on animal models, is expensive, time consuming and low throughput. As a result, carcinogenicity information is limited and building data-driven models with good prediction accuracy remains a major challenge. RESULTS: In this work, we propose CONCERTO, a deep learning model that uses a graph transformer in conjunction with a molecular fingerprint representation for carcinogenicity prediction from molecular structure. Special efforts have been made to overcome the data size constraint, such as multi-round pre-training on related but lower quality mutagenicity data, and transfer learning from a large self-supervised model. Extensive experiments demonstrate that our model performs well and can generalize to external validation sets. CONCERTO could be useful for guiding future carcinogenicity experiments and provide insight into the molecular basis of carcinogenicity. AVAILABILITY AND IMPLEMENTATION: The code and data underlying this article are available on github at https://github.com/bowang-lab/CONCERTO.

John Giorgi, Osvald Nitski, Bo Wang, Gary Bader. Proceedings of the 59th Annual Meeting of the Association for Computational Linguistics and the 11th International Joint Conference on Natural Language Processing (Volume 1: Long Papers). 2021.

Age estimation from facial images is typically cast as a label distribution learning or regression problem, since aging is a gradual progress. Its main challenge is the facial feature space w.r.t. ages is inhomogeneous, due to the large variation in facial appearance across different persons of the same age and the non-stationary property of aging. In this paper, we propose two Deep Differentiable Random Forests methods, Deep Label Distribution Learning Forest (DLDLF) and Deep Regression Forest (DRF), for age estimation. Both of them connect split nodes to the top layer of convolutional neural networks (CNNs) and deal with inhomogeneous data by jointly learning input-dependent data partitions at the split nodes and age distributions at the leaf nodes. This joint learning follows an alternating strategy: (1) Fixing the leaf nodes and optimizing the split nodes and the CNN parameters by Back-propagation; (2) Fixing the split nodes and optimizing the leaf nodes by Variational Bounding. Two Deterministic Annealing processes are introduced into the learning of the split and leaf nodes, respectively, to avoid poor local optima and obtain better estimates of tree parameters free of initial values. Experimental results show that DLDLF and DRF achieve state-of-the-art performance on three age estimation datasets.

Few-shot learning is a challenging task that aims at training a classifier for unseen classes with only a few training examples. The main difficulty of few-shot learning lies in the lack of intra-class diversity within insufficient training samples. To alleviate this problem, we propose a novel generative framework, Diversity Transfer Network (DTN), that learns to transfer latent diversities from known categories and composite them with support features to generate diverse samples for novel categories in feature space. The learning problem of the sample generation (i.e., diversity transfer) is solved via minimizing an effective meta-classification loss in a single-stage network, instead of the generative loss in previous works. Besides, an organized auxiliary task co-training over known categories is proposed to stabilize the meta-training process of DTN. We perform extensive experiments and ablation studies on three datasets, i.e., miniImageNet, CIFAR100 and CUB. The results show that DTN, with single-stage training and faster convergence speed, obtains the state-of-the-art results among the feature generation based few-shot learning methods. Code and supplementary material are available at: https://github.com/Yuxin-CV/DTN.

Recent anchor-based deep face detectors have achieved promising performance, but they are still struggling to detect hard faces, such as small, blurred and partially occluded faces. One reason is that they treat all images and faces equally, and ignore the imbalance between easy images and hard images; however large amounts of training images only contain easy faces, which are less helpful to learn robust detectors for hard faces. In this paper, we propose that the robustness of a face detector against hard faces can be improved by learning small faces on hard images. Our intuitions are (1) hard images are the images which contain at least one hard face, thus they facilitate training robust face detectors; (2) most hard faces are small faces and other types of hard faces can be easily shrunk to small faces. To this end, we build an anchor-based deep face detector, which only outputs a single high-resolution feature map with small anchors, to specifically learn small faces and train it by a novel hard image mining strategy which automatically adjusts training weights on images according to their difficulties. Extensive experiments have been conducted on WIDER FACE, FDDB, Pascal Faces, and AFW datasets and our method achieves APs of 95.7, 94.9 and 89.7 on easy, medium and hard WIDER FACE val dataset respectively, which verify the effectiveness of our methods, especially on detecting hard faces. Our detector is also lightweight and enjoys a fast inference speed. Code and model are available at https://github.com/bairdzhang/smallhardface.

Conventional unsupervised domain adaptation (UDA) assumes that training data are sampled from a single domain. This neglects the more practical scenario where training data are collected from multiple sources, requiring multi-source domain adaptation. We make three major contributions towards addressing this problem. First, we collect and annotate by far the largest UDA dataset, called DomainNet, which contains six domains and about 0.6 million images distributed among 345 categories, addressing the gap in data availability for multi-source UDA research. Second, we propose a new deep learning approach, Moment Matching for Multi-Source Domain Adaptation (M3SDA), which aims to transfer knowledge learned from multiple labeled source domains to an unlabeled target domain by dynamically aligning moments of their feature distributions. Third, we provide new theoretical insights specifically for moment matching approaches in both single and multiple source domain adaptation. Extensive experiments are conducted to demonstrate the power of our new dataset in benchmarking state-of-the-art multi-source domain adaptation methods, as well as the advantage of our proposed model. Dataset and Code are available at http://ai.bu.edu/M3SDA/.

Age estimation from facial images is typically cast as a nonlinear regression problem. The main challenge of this problem is the facial feature space w.r.t. ages is inhomogeneous, due to the large variation in facial appearance across different persons of the same age and the non-stationary property of aging patterns. In this paper, we propose Deep Regression Forests (DRFs), an end-to-end model, for age estimation. DRFs connect the split nodes to a fully connected layer of a convolutional neural network (CNN) and deal with inhomogeneous data by jointly learning input-dependant data partitions at the split nodes and data abstractions at the leaf nodes. This joint learning follows an alternating strategy: First, by fixing the leaf nodes, the split nodes as well as the CNN parameters are optimized by Back-propagation; Then, by fixing the split nodes, the leaf nodes are optimized by iterating a step-size free update rule derived from Variational Bounding. We verify the proposed DRFs on three standard age estimation benchmarks and achieve state-of-the-art results on all of them.

We propose a novel single shot object detection network named Detection with Enriched Semantics (DES). Our motivation is to enrich the semantics of object detection features within a typical deep detector, by a semantic segmentation branch and a global activation module. The segmentation branch is supervised by weak segmentation ground-truth, i.e., no extra annotation is required. In conjunction with that, we employ a global activation module which learns relationship between channels and object classes in a self-supervised manner. Comprehensive experimental results on both PASCAL VOC and MS COCO detection datasets demonstrate the effectiveness of the proposed method. In particular, with a VGG16 based DES, we achieve an mAP of 81.7 on VOC2007 test and an mAP of 32.8 on COCO test-dev with an inference speed of 31.5 milliseconds per image on a Titan Xp GPU. With a lower resolution version, we achieve an mAP of 79.7 on VOC2007 with an inference speed of 13.0 milliseconds per image.

Depth is one of the keys that make neural networks succeed in the task of large-scale image recognition. The state-of-the-art network architectures usually increase the depths by cascading convolutional layers or building blocks. In this paper, we present an alternative method to increase the depth. Our method is by introducing computation orderings to the channels within convolutional layers or blocks, based on which we gradually compute the outputs in a channel-wise manner. The added orderings not only increase the depths and the learning capacities of the networks without any additional computation costs, but also eliminate the overlap singularities so that the networks are able to converge faster and perform better. Experiments show that the networks based on our method achieve the state-of-the-art performances on CIFAR and ImageNet datasets.

Biological networks entail important topological features and patterns critical to understanding interactions within complicated biological systems. Despite a great progress in understanding their structure, much more can be done to improve our inference and network analysis. Spectral methods play a key role in many network-based applications. Fundamental to spectral methods is the Laplacian, a matrix that captures the global structure of the network. Unfortunately, the Laplacian does not take into account intricacies of the network's local structure and is sensitive to noise in the network. These two properties are fundamental to biological networks and cannot be ignored. We propose an alternative matrix Vicus. The Vicus matrix captures the local neighborhood structure of the network and thus is more effective at modeling biological interactions. We demonstrate the advantages of Vicus in the context of spectral methods by extensive empirical benchmarking on tasks such as single cell dimensionality reduction, protein module discovery and ranking genes for cancer subtyping. Our experiments show that using Vicus, spectral methods result in more accurate and robust performance in all of these tasks.

Complex networks play an important role in a plethora of disciplines in natural sciences. Cleaning up noisy observed networks, poses an important challenge in network analysis Existing methods utilize labeled data to alleviate the noise effect in the network. However, labeled data is usually expensive to collect while unlabeled data can be gathered cheaply. In this paper, we propose an optimization framework to mine useful structures from noisy networks in an unsupervised manner. The key feature of our optimization framework is its ability to utilize local structures as well as global patterns in the network. We extend our method to incorporate multi-resolution networks in order to add further resistance to high-levels of noise. We also generalize our framework to utilize partial labels to enhance the performance. We specifically focus our method on multi-resolution Hi-C data by recovering clusters of genomic regions that co-localize in 3D space. Additionally, we use Capture-C-generated partial labels to further denoise the Hi-C network. We empirically demonstrate the effectiveness of our framework in denoising the network and improving community detection results.

MOTIVATION: Population low-coverage whole-genome sequencing is rapidly emerging as a prominent approach for discovering genomic variation and genotyping a cohort. This approach combines substantially lower cost than full-coverage sequencing with whole-genome discovery of low-allele frequency variants, to an extent that is not possible with array genotyping or exome sequencing. However, a challenging computational problem arises of jointly discovering variants and genotyping the entire cohort. Variant discovery and genotyping are relatively straightforward tasks on a single individual that has been sequenced at high coverage, because the inference decomposes into the independent genotyping of each genomic position for which a sufficient number of confidently mapped reads are available. However, in low-coverage population sequencing, the joint inference requires leveraging the complex linkage disequilibrium (LD) patterns in the cohort to compensate for sparse and missing data in each individual. The potentially massive computation time for such inference, as well as the missing data that confound low-frequency allele discovery, need to be overcome for this approach to become practical. RESULTS: Here, we present Reveel, a novel method for single nucleotide variant calling and genotyping of large cohorts that have been sequenced at low coverage. Reveel introduces a novel technique for leveraging LD that deviates from previous Markov-based models, and which is aimed at computational efficiency as well as accuracy in capturing LD patterns present in rare haplotypes. We evaluate Reveel's performance through extensive simulations as well as real data from the 1000 Genomes Project, and show that it achieves higher accuracy in low-frequency allele discovery and substantially lower computation cost than previous state-of-the-art methods. AVAILABILITY AND IMPLEMENTATION: http://reveel.stanford.edu/ CONTACT: : [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

With the increasing availability of high dimensional data and demand in sophisticated data analysis algorithms, manifold learning becomes a critical technique to perform dimensionality reduction, unraveling the intrinsic data structure. The real-world data however often come with noises and outliers, seldom, all the data live in a single linear subspace. Inspired by the recent advances in sparse subspace learning and diffusion-based approaches, we propose a new manifold denoising algorithm in which data neighborhoods are adaptively inferred via sparse subspace reconstruction, we then derive a new formulation to perform denoising to the original data. Experiments carried out on both toy and real applications demonstrate the effectiveness of our method, it is insensitive to parameter tuning and we show significant improvement over the competing algorithms.

In graph-based semi-supervised learning approaches, the classification rate is highly dependent on the size of the availabel labeled data, as well as the accuracy of the similarity measures. Here, we propose a semi-supervised multi-class/multi-label classification scheme, dynamic label propagation (DLP), which performs transductive learning through propagation in a dynamic process. Existing semi-supervised classification methods often have difficulty in dealing with multi-class/multi-label problems due to the lack in consideration of label correlation, our algorithm instead emphasizes dynamic metric fusion with label information. Significant improvement over the state-of-the-art methods is observed on benchmark datasets for both multi-class and multi-label tasks.

Metric learning is n fundamental problem in computer vision. Different features and algorithms may tackle a problem from different angles, and thus often provide complementary information. In this paper; we propose a fusion algorithm which outputs enhanced metrics by combining multiple given metrics (similarity measures). Unlike traditional co-training style algorithms where multi-view features or multiple data subsets are used for classification or regression, we focus on fusing multiple given metrics through diffusion process in an unsupervised way. Our algorithm has its particular advantage when the input similarity' matrices are the outputs from diverse algorithms. We provide both theoretical and empirical explanations to our method. Significant improvements over the state-of-the-art results have been observed on various benchmark datasets. For example, we have achieved 100% accuracy (no longer the bull's eye measure) on the MPEG-7 shape dataset. Our method has a wide range of applications in machine learning and computer vision.

Computing a faithful affinity map is essential to the clustering and segmentation tasks. In this paper, we propose a graph-based affinity (metric) learning method and show its application to image clustering and segmentation. Our method, self-diffusion (SD), performs a diffusion process by propagating the similarity mass along the intrinsic manifold of data points. Theoretical analysis is given to the SD algorithm and we provide a way of deriving the critical time stamp t. Our method therefore has nearly no parameter tuning and leads to significantly improved affinity maps, which help to greatly enhance the quality of clustering. In addition, we show that much improved image segmentation results can be obtained by combining SD with e.g. the normalized cuts algorithm. The proposed method can be used to deliver robust affinity maps for a range of problems.

In this paper, we propose a new shape/object retrieval algorithm, namely, co-transduction. The performance of a retrieval system is critically decided by the accuracy of adopted similarity measures (distances or metrics). In shape/object retrieval, ideally, intraclass objects should have smaller distances than interclass objects. However, it is a difficult task to design an ideal metric to account for the large intraclass variation. Different types of measures may focus on different aspects of the objects: for example, measures computed based on contours and skeletons are often complementary to each other. Our goal is to develop an algorithm to fuse different similarity measures for robust shape retrieval through a semisupervised learning framework. We name our method co-transduction, which is inspired by the co-training algorithm. Given two similarity measures and a query shape, the algorithm iteratively retrieves the most similar shapes using one measure and assigns them to a pool for the other measure to do a re-ranking, and vice versa. Using co-transduction, we achieved an improved result of 97.72% (bull's-eye measure) on the MPEG-7 data set over the state-of-the-art performance. We also present an algorithm called tri-transduction to fuse multiple-input similarities, and it achieved 99.06% on the MPEG-7 data set. Our algorithm is general, and it can be directly applied on input similarity measures/metrics; it is not limited to object shape retrieval and can be applied to other tasks for ranking/retrieval.

In this paper, we propose a diffusion-based approach to improve an input similarity metric. The diffusion process propagates similarity mass along the intrinsic manifold of data points. Our approach results in a global similarity metric which differs from the query-specific one for ranking produced by label propagation [26]. Unlike diffusion maps [7], our approach directly improves a given similarity metric without introducing any extra distance notions. We call our approach Self-Smoothing Operator (SSO). To demonstrate its wide applicability, experiments are reported on image retrieval, clustering, classification, and segmentation tasks. In most cases, using SSO results in significant performance gains over the original similarity metrics, with also very evident advantage over diffusion maps.

In this paper, we proposed a novel approach to shape classification. A new shape tree based on junction nodes can represent the global structure in a simple way. The statistic distribution of junctions can be learned by merging the shape trees. In the process of learning, context of a junction node is obtained to improve the rate of classification. We illustrate the utility of the proposed method on the problem of 2D shape classification using the new shape tree representation.