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 critical challenges. First, it hinders the application of more flexible general-purpose LLMs in cutting-edge drug discovery tasks. More importantly, it impedes the rapid integration of the vast amounts of scientific data continuously generated through experiments and research. To investigate 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.

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.

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.

Drawing causal inferences from observational studies (OS) requires unverifiable validity assumptions; however, one can falsify those assumptions by benchmarking the OS with experimental data from a randomized controlled trial (RCT). A major limitation of existing procedures is not accounting for censoring, despite the abundance of RCTs and OSes that report right-censored time-to-event outcomes. We consider two cases where censoring time (1) is independent of time-to-event and (2) depends on time-to-event the same way in OS and RCT. For the former, we adopt a censoring-doubly-robust signal for the conditional average treatment effect (CATE) to facilitate an equivalence test of CATEs in OS and RCT, which serves as a proxy for testing if the validity assumptions hold. For the latter, we show that the same test can still be used even though unbiased CATE estimation may not be possible. We verify the effectiveness of our censoring-aware tests via semi-synthetic experiments and analyze RCT and OS data from the Women's Health Initiative study.

We introduce a class of manifold neural networks (MNNs) that we call Manifold Filter-Combine Networks (MFCNs), which aims to further our understanding of MNNs, analogous to how the aggregate-combine framework helps with the understanding of graph neural networks (GNNs). This class includes a wide variety of subclasses that can be thought of as the manifold analog of various popular GNNs. We then consider a method, based on building a data-driven graph, for implementing such networks when one does not have global knowledge of the manifold, but merely has access to finitely many points sampled from some probability distribution on the manifold. We provide sufficient conditions for the network to provably converge to its continuum limit as the number of sample points tends to infinity. Unlike previous work (which focused on specific graph constructions and assumed that the data was drawn from the uniform distribution), our rate of convergence does not directly depend on the number of filters used. Moreover, it exhibits linear dependence on the depth of the network rather than the exponential dependence obtained previously. Additionally, we provide several examples of interesting subclasses of MFCNs and of the rates of convergence that are obtained under specific graph constructions.

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.

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).

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.

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. Time series are ubiquitous in many fields of science and as such, represent an important but challenging data modality for machine learning. Indeed, their temporal nature, along with the potentially high dimensionality makes them arduous to manipulate as mathematical objects. A long-standing line of research has thus focused on efforts in learning informative time series representations, such as simple vectors, that are capable of capturing local and global structure in such data (Franceschi et al., 2019; Gu et al., 2020). Such architectures include recurrent neural networks (Malhotra et al., 2017), temporal transformers (Zhou et al., 2021) and neural ordinary differential equations (neural ODEs) (Chen et al., 2018).

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.