Edward De Brouwer

Hugues Van Assel, Edward De Brouwer, Saeed Saremi et al.

Generative modeling and self-supervised representation learning (SSL) optimize structurally different objectives: generative training rewards distributional fidelity, while SSL rewards semantic coherence. Yet recent work repeatedly finds that SSL features improve generative training, though the mechanism of this synergy remains unclear. Here, we study the benefits of SSL in generative modeling in the framework of one-step generation where the role of representation is explicit: frozen SSL features are used to match generated samples to real data. We use the Sinkhorn divergence in that feature space, providing a tractable surrogate for the Wasserstein distance, the population-level discrepancy approximated by Fréchet-style evaluation metrics (such as FID). We find that this objective becomes highly effective when computed in a semantically structured SSL feature space (a 39$\times$ reduction in ImageNet FID). We trace this behavior primarily to matching estimation: semantic SSL features that suppress nuisance reconstruction details induce a more compact geometry, making distribution matching more tractable. As a consequence, the best training SSL features need not match the features used by the evaluation metric. In particular, we show that using Inception as the feature extractor can improve FID while degrading matching stability and sample quality, revealing a form of metric hacking. Using extensive experiments on ImageNet, we identify which SSL feature families lead to best generation performance and show that matching stability is a quantitative criterion for selecting them. Code is available at https://github.com/Genentech/semantic-transport-generation.

Edward De Brouwer

Referred to as the third rung of the causal inference ladder, counterfactual queries typically ask the "What if ?" question retrospectively. The standard approach to estimate counterfactuals resides in using a structural equation model that accurately reflects the underlying data generating process. However, such models are seldom available in practice and one usually wishes to infer them from observational data alone. Unfortunately, the correct structural equation model is in general not identifiable from the observed factual distribution. Nevertheless, in this work, we show that under the assumption that the main latent contributors to the treatment responses are categorical, the counterfactuals can be still reliably predicted. Building upon this assumption, we introduce CounterFactual Query Prediction (CFQP), a novel method to infer counterfactuals from continuous observations when the background variables are categorical. We show that our method significantly outperforms previously available deep-learning-based counterfactual methods, both theoretically and empirically on time series and image data. Our code is available at https://github.com/edebrouwer/cfqp.

Martijn Oldenhof, Adam Arany, Yves Moreau et al.

Training object detection models usually requires instance-level annotations, such as the positions and labels of all objects present in each image. Such supervision is unfortunately not always available and, more often, only image-level information is provided, also known as weak supervision. Recent works have addressed this limitation by leveraging knowledge from a richly annotated domain. However, the scope of weak supervision supported by these approaches has been very restrictive, preventing them to use all available information. In this work, we propose ProbKT, a framework based on probabilistic logical reasoning that allows to train object detection models with arbitrary types of weak supervision. We empirically show on different datasets that using all available information is beneficial as our ProbKT leads to significant improvement on target domain and better generalization compared to existing baselines. We also showcase the ability of our approach to handle complex logic statements as supervision signal.

Dhananjay Bhaskar, Sumner Magruder, Edward De Brouwer et al.

Complex systems are characterized by intricate interactions between entities that evolve dynamically over time. Accurate inference of these dynamic relationships is crucial for understanding and predicting system behavior. In this paper, we propose Regulatory Temporal Interaction Network Inference (RiTINI) for inferring time-varying interaction graphs in complex systems using a novel combination of space-and-time graph attentions and graph neural ordinary differential equations (ODEs). RiTINI leverages time-lapse signals on a graph prior, as well as perturbations of signals at various nodes in order to effectively capture the dynamics of the underlying system. This approach is distinct from traditional causal inference networks, which are limited to inferring acyclic and static graphs. In contrast, RiTINI can infer cyclic, directed, and time-varying graphs, providing a more comprehensive and accurate representation of complex systems. The graph attention mechanism in RiTINI allows the model to adaptively focus on the most relevant interactions in time and space, while the graph neural ODEs enable continuous-time modeling of the system's dynamics. We evaluate RiTINI's performance on various simulated and real-world datasets, demonstrating its state-of-the-art capability in inferring interaction graphs compared to previous methods.

David R. Johnson, Joyce A. Chew, Edward De Brouwer et al.

In order to better understand manifold neural networks (MNNs), we introduce Manifold Filter-Combine Networks (MFCNs). Our filter-combine framework parallels the popular aggregate-combine paradigm for graph neural networks (GNNs) and naturally suggests many interesting families of MNNs which can be interpreted as manifold analogues of various popular GNNs. We propose a method for implementing MFCNs on high-dimensional point clouds that relies on approximating an underlying manifold by a sparse graph. We then 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, and we numerically demonstrate its effectiveness on real-world and synthetic data sets.

Edward De Brouwer, Rahul G. Krishnan

Neural ordinary differential equations (Neural ODEs) are an effective framework for learning dynamical systems from irregularly sampled time series data. These models provide a continuous-time latent representation of the underlying dynamical system where new observations at arbitrary time points can be used to update the latent representation of the dynamical system. Existing parameterizations for the dynamics functions of Neural ODEs limit the ability of the model to retain global information about the time series; specifically, a piece-wise integration of the latent process between observations can result in a loss of memory on the dynamic patterns of previously observed data points. We propose PolyODE, a Neural ODE that models the latent continuous-time process as a projection onto a basis of orthogonal polynomials. This formulation enforces long-range memory and preserves a global representation of the underlying dynamical system. Our construction is backed by favourable theoretical guarantees and in a series of experiments, we demonstrate that it outperforms previous works in the reconstruction of past and future data, and in downstream prediction tasks.

Yukti Makhija, Edward De Brouwer, Rahul G. Krishnan

Checklists, while being only recently introduced in the medical domain, have become highly popular in daily clinical practice due to their combined effectiveness and great interpretability. Checklists are usually designed by expert clinicians that manually collect and analyze available evidence. However, the increasing quantity of available medical data is calling for a partially automated checklist design. Recent works have taken a step in that direction by learning predictive checklists from categorical data. In this work, we propose to extend this approach to accomodate learning checklists from continuous medical data using mixed-integer programming approach. We show that this extension outperforms a range of explainable machine learning baselines on the prediction of sepsis from intensive care clinical trajectories.

Charles Xu, Laney Goldman, Valentina Guo et al.

Graph neural networks (GNNs) have emerged as a powerful tool for tasks such as node classification and graph classification. However, much less work has been done on signal classification, where the data consists of many functions (referred to as signals) defined on the vertices of a single graph. These tasks require networks designed differently from those designed for traditional GNN tasks. Indeed, traditional GNNs rely on localized low-pass filters, and signals of interest may have intricate multi-frequency behavior and exhibit long range interactions. This motivates us to introduce the BLIS-Net (Bi-Lipschitz Scattering Net), a novel GNN that builds on the previously introduced geometric scattering transform. Our network is able to capture both local and global signal structure and is able to capture both low-frequency and high-frequency information. We make several crucial changes to the original geometric scattering architecture which we prove increase the ability of our network to capture information about the input signal and show that BLIS-Net achieves superior performance on both synthetic and real-world data sets based on traffic flow and fMRI data.

Namkyeong Lee, Edward De Brouwer, Ehsan Hajiramezanali et al.

Recent advances in large language models (LLMs) have shown great potential to accelerate drug discovery. However, the specialized nature of biochemical data often necessitates costly domain-specific fine-tuning, posing major challenges. First, it hinders the application of more flexible general-purpose LLMs for cutting-edge drug discovery tasks. More importantly, it limits the rapid integration of the vast amounts of scientific data continuously generated through experiments and research. Compounding these challenges is the fact that real-world scientific questions are typically complex and open-ended, requiring reasoning beyond pattern matching or static knowledge retrieval.To address these challenges, we propose CLADD, a retrieval-augmented generation (RAG)-empowered agentic system tailored to drug discovery tasks. Through the collaboration of multiple LLM agents, CLADD dynamically retrieves information from biomedical knowledge bases, contextualizes query molecules, and integrates relevant evidence to generate responses - all without the need for domain-specific fine-tuning. Crucially, we tackle key obstacles in applying RAG workflows to biochemical data, including data heterogeneity, ambiguity, and multi-source integration. We demonstrate the flexibility and effectiveness of this framework across a variety of drug discovery tasks, showing that it outperforms general-purpose and domain-specific LLMs as well as traditional deep learning approaches. Our code is publicly available at https://github.com/Genentech/CLADD.

Edward De Brouwer, Carl Edwards, Alexander Wu et al.

Recent advances in machine learning and large-scale biological data collections have revived the prospect of building a virtual cell, a computational model of cellular behavior that could accelerate biological discovery. One of the most compelling promises of this vision is the ability to perform in silico phenotypic screens, in which a model predicts the effects of cellular perturbations in unseen biological contexts. This task combines heterogeneous textual inputs with diverse phenotypic outputs, making it particularly well-suited to LLMs and agentic systems. Yet, no standard benchmark currently exists for this task, as existing efforts focus on narrower molecular readouts that are only indirectly aligned with the phenotypic endpoints driving many real-world drug discovery workflows. In this work, we present AssayBench, a benchmark for phenotypic screen prediction, built from 1,920 publicly available CRISPR screens spanning five broad classes of cellular phenotypes. We formulate the screen prediction task as a gene rank prediction for each screen and introduce the adjusted nDCG, a continuous metric for comparing performance across heterogeneous assays. Our extensive evaluation shows that existing methods remain far from empirically estimated performance ceilings and zero-shot generalist LLMs outperform biology-specific LLMs and trainable baselines. Optimization techniques such as fine-tuning, ensembling, and prompt optimization can further improve LLM performance on this task. Overall, AssayBench offers a practical testbed for measuring progress toward in silico phenotypic screening and, more broadly, virtual cell models.

Martijn Oldenhof, Edward De Brouwer, Adam Arany et al.

Identifying the chemical structure from a graphical representation, or image, of a molecule is a challenging pattern recognition task that would greatly benefit drug development. Yet, existing methods for chemical structure recognition do not typically generalize well, and show diminished effectiveness when confronted with domains where data is sparse, or costly to generate, such as hand-drawn molecule images. To address this limitation, we propose a new chemical structure recognition tool that delivers state-of-the-art performance and can adapt to new domains with a limited number of data samples and supervision. Unlike previous approaches, our method provides atom-level localization, and can therefore segment the image into the different atoms and bonds. Our model is the first model to perform OCSR with atom-level entity detection with only SMILES supervision. Through rigorous and extensive benchmarking, we demonstrate the preeminence of our chemical structure recognition approach in terms of data efficiency, accuracy, and atom-level entity prediction.

Chi-Min Chan, Ehsan Hajiramezanali, Xiner Li et al.

In scientific reasoning tasks, the veracity of the reasoning process is as critical as the final outcome. While Process Reward Models (PRMs) offer a solution to the coarse-grained supervision problems inherent in Outcome Reward Models (ORMs), their deployment is hindered by the prohibitive cost of obtaining expert-verified step-wise labels. This paper addresses the challenge of training reliable PRMs using abundant but noisy "weak" supervision. We argue that existing Weak-to-Strong Generalization (W2SG) theories lack prescriptive guidelines for selecting high-quality training signals from noisy data. To bridge this gap, we introduce the Dual-Consensus Weak-to-Strong (DC-W2S) framework. By intersecting Self-Consensus (SC) metrics among weak supervisors with Neighborhood-Consensus (NC) metrics in the embedding space, we stratify supervision signals into distinct reliability regimes. We then employ a curriculum of instance-level balanced sampling and label-level reliability-aware masking to guide the training process. We demonstrate that DC-W2S enables the training of robust PRMs for complex reasoning without exhaustive expert annotation, proving that strategic data curation is more effective than indiscriminate training on large-scale noisy datasets.

Yukti Makhija, Edward De Brouwer, Rahul G. Krishnan

Checklists have been widely recognized as effective tools for completing complex tasks in a systematic manner. Although originally intended for use in procedural tasks, their interpretability and ease of use have led to their adoption for predictive tasks as well, including in clinical settings. However, designing checklists can be challenging, often requiring expert knowledge and manual rule design based on available data. Recent work has attempted to address this issue by using machine learning to automatically generate predictive checklists from data, although these approaches have been limited to Boolean data. We propose a novel method for learning predictive checklists from diverse data modalities, such as images and time series. Our approach relies on probabilistic logic programming, a learning paradigm that enables matching the discrete nature of checklist with continuous-valued data. We propose a regularization technique to tradeoff between the information captured in discrete concepts of continuous data and permit a tunable level of interpretability for the learned checklist concepts. We demonstrate that our method outperforms various explainable machine learning techniques on prediction tasks involving image sequences, time series, and clinical notes.

David R. Johnson, Joyce Chew, Siddharth Viswanath et al.

In order to better understand manifold neural networks (MNNs), we introduce Manifold Filter-Combine Networks (MFCNs). The filter-combine framework 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.

Guillaume Huguet, Alexander Tong, Edward De Brouwer et al.

Diffusion-based manifold learning methods have proven useful in representation learning and dimensionality reduction of modern high dimensional, high throughput, noisy datasets. Such datasets are especially present in fields like biology and physics. While it is thought that these methods preserve underlying manifold structure of data by learning a proxy for geodesic distances, no specific theoretical links have been established. Here, we establish such a link via results in Riemannian geometry explicitly connecting heat diffusion to manifold distances. In this process, we also formulate a more general heat kernel based manifold embedding method that we call heat geodesic embeddings. This novel perspective makes clearer the choices available in manifold learning and denoising. Results show that our method outperforms existing state of the art in preserving ground truth manifold distances, and preserving cluster structure in toy datasets. We also showcase our method on single cell RNA-sequencing datasets with both continuum and cluster structure, where our method enables interpolation of withheld timepoints of data. Finally, we show that parameters of our more general method can be configured to give results similar to PHATE (a state-of-the-art diffusion based manifold learning method) as well as SNE (an attraction/repulsion neighborhood based method that forms the basis of t-SNE).

Edward De Brouwer, Javier González Hernández, Stephanie Hyland

Predicting the impact of treatments from observational data only still represents a majorchallenge despite recent significant advances in time series modeling. Treatment assignments are usually correlated with the predictors of the response, resulting in a lack of data support for counterfactual predictions and therefore in poor quality estimates. Developments in causal inference have lead to methods addressing this confounding by requiring a minimum level of overlap. However,overlap is difficult to assess and usually notsatisfied in practice. In this work, we propose Counterfactual ODE (CF-ODE), a novel method to predict the impact of treatments continuously over time using Neural Ordinary Differential Equations equipped with uncertainty estimates. This allows to specifically assess which treatment outcomes can be reliably predicted. We demonstrate over several longitudinal data sets that CF-ODE provides more accurate predictions and more reliable uncertainty estimates than previously available methods.

Jonghyeon Lee, Edward De Brouwer, Boumediene Hamzi et al.

A simple and interpretable way to learn a dynamical system from data is to interpolate its vector-field with a kernel. In particular, this strategy is highly efficient (both in terms of accuracy and complexity) when the kernel is data-adapted using Kernel Flows (KF)\cite{Owhadi19} (which uses gradient-based optimization to learn a kernel based on the premise that a kernel is good if there is no significant loss in accuracy if half of the data is used for interpolation). Despite its previous successes, this strategy (based on interpolating the vector field driving the dynamical system) breaks down when the observed time series is not regularly sampled in time. In this work, we propose to address this problem by directly approximating the vector field of the dynamical system by incorporating time differences between observations in the (KF) data-adapted kernels. We compare our approach with the classical one over different benchmark dynamical systems and show that it significantly improves the forecasting accuracy while remaining simple, fast, and robust.

Michael F. Adamer, Edward De Brouwer, Leslie O'Bray et al.

The magnitude of a finite metric space has recently emerged as a novel invariant quantity, allowing to measure the effective size of a metric space. Despite encouraging first results demonstrating the descriptive abilities of the magnitude, such as being able to detect the boundary of a metric space, the potential use cases of magnitude remain under-explored. In this work, we investigate the properties of the magnitude on images, an important data modality in many machine learning applications. By endowing each individual images with its own metric space, we are able to define the concept of magnitude on images and analyse the individual contribution of each pixel with the magnitude vector. In particular, we theoretically show that the previously known properties of boundary detection translate to edge detection abilities in images. Furthermore, we demonstrate practical use cases of magnitude for machine learning applications and propose a novel magnitude model that consists of a computationally efficient magnitude computation and a learnable metric. By doing so, we address the computational hurdle that used to make magnitude impractical for many applications and open the way for the adoption of magnitude in machine learning research.

Max Horn, Edward De Brouwer, Michael Moor et al.

Graph neural networks (GNNs) are a powerful architecture for tackling graph learning tasks, yet have been shown to be oblivious to eminent substructures such as cycles. We present TOGL, a novel layer that incorporates global topological information of a graph using persistent homology. TOGL can be easily integrated into any type of GNN and is strictly more expressive (in terms the Weisfeiler--Lehman graph isomorphism test) than message-passing GNNs. Augmenting GNNs with TOGL leads to improved predictive performance for graph and node classification tasks, both on synthetic data sets, which can be classified by humans using their topology but not by ordinary GNNs, and on real-world data.

Edward De Brouwer, Thijs Becker, Yves Moreau et al.

Research in Multiple Sclerosis (MS) has recently focused on extracting knowledge from real-world clinical data sources. This type of data is more abundant than data produced during clinical trials and potentially more informative about real-world clinical practice. However, this comes at the cost of less curated and controlled data sets. In this work, we address the task of optimally extracting information from longitudinal patient data in the real-world setting with a special focus on the sporadic sampling problem. Using the MSBase registry, we show that with machine learning methods suited for patient trajectories modeling, such as recurrent neural networks and tensor factorization, we can predict disability progression of patients in a two-year horizon with an ROC-AUC of 0.86, which represents a 33% decrease in the ranking pair error (1-AUC) compared to reference methods using static clinical features. Compared to the models available in the literature, this work uses the most complete patient history for MS disease progression prediction.

Jaak Simm, Adam Arany, Edward De Brouwer et al.

Applying machine learning to molecules is challenging because of their natural representation as graphs rather than vectors.Several architectures have been recently proposed for deep learning from molecular graphs, but they suffer from informationbottlenecks because they only pass information from a graph node to its direct neighbors. Here, we introduce a more expressiveroute-based multi-attention mechanism that incorporates features from routes between node pairs. We call the resulting methodGraph Informer. A single network layer can therefore attend to nodes several steps away. We show empirically that the proposedmethod compares favorably against existing approaches in two prediction tasks: (1) 13C Nuclear Magnetic Resonance (NMR)spectra, improving the state-of-the-art with an MAE of 1.35 ppm and (2) predicting drug bioactivity and toxicity. Additionally, wedevelop a variant called injective Graph Informer that isprovablyas powerful as the Weisfeiler-Lehman test for graph isomorphism.Furthermore, we demonstrate that the route information allows the method to be informed about thenonlocal topologyof the graphand, thus, even go beyond the capabilities of the Weisfeiler-Lehman test.

Edward De Brouwer, Jaak Simm, Adam Arany et al.

Modeling real-world multidimensional time series can be particularly challenging when these are sporadically observed (i.e., sampling is irregular both in time and across dimensions)-such as in the case of clinical patient data. To address these challenges, we propose (1) a continuous-time version of the Gated Recurrent Unit, building upon the recent Neural Ordinary Differential Equations (Chen et al., 2018), and (2) a Bayesian update network that processes the sporadic observations. We bring these two ideas together in our GRU-ODE-Bayes method. We then demonstrate that the proposed method encodes a continuity prior for the latent process and that it can exactly represent the Fokker-Planck dynamics of complex processes driven by a multidimensional stochastic differential equation. Additionally, empirical evaluation shows that our method outperforms the state of the art on both synthetic data and real-world data with applications in healthcare and climate forecast. What is more, the continuity prior is shown to be well suited for low number of samples settings.

Edward De Brouwer, Jaak Simm, Adam Arany et al.

We present a generative approach to classify scarcely observed longitudinal patient trajectories. The available time series are represented as tensors and factorized using generative deep recurrent neural networks. The learned factors represent the patient data in a compact way and can then be used in a downstream classification task. For more robustness and accuracy in the predictions, we used an ensemble of those deep generative models to mimic Bayesian posterior sampling. We illustrate the performance of our architecture on an intensive-care case study of in-hospital mortality prediction with 96 longitudinal measurement types measured across the first 48-hour from admission. Our combination of generative and ensemble strategies achieves an AUC of over 0.85, and outperforms the SAPS-II mortality score and GRU baselines.