Evaluating representation learning on the protein structure universe

We introduce ProteinWorkshop, a comprehensive benchmark suite for representation learning on protein structures with Geometric Graph Neural Networks. We consider large-scale pre-training and downstream tasks on both experimental and predicted structures to enable the systematic evaluation of the quality of the learned structural representation and their usefulness in capturing functional relationships for downstream tasks. We find that: (1) large-scale pretraining on AlphaFold structures and auxiliary tasks consistently improve the performance of both rotation-invariant and equivariant GNNs, and (2) more expressive equivariant GNNs benefit from pretraining to a greater extent compared to invariant models. We aim to establish a common ground for the machine learning and computational biology communities to rigorously compare and advance protein structure representation learning. Our open-source codebase reduces the barrier to entry for working with large protein structure datasets by providing: (1) storage-efficient dataloaders for large-scale structural databases including AlphaFoldDB and ESM Atlas, as well as (2) utilities for constructing new tasks from the entire PDB. ProteinWorkshop is available at: github.com/a-r-j/ProteinWorkshop.

ZeroPur: Succinct Training-Free Adversarial Purification

Adversarial purification is a kind of defense technique that can defend various unseen adversarial attacks without modifying the victim classifier. Existing methods often depend on external generative models or cooperation between auxiliary functions and victim classifiers. However, retraining generative models, auxiliary functions, or victim classifiers relies on the domain of the fine-tuned dataset and is computation-consuming. In this work, we suppose that adversarial images are outliers of the natural image manifold and the purification process can be considered as returning them to this manifold. Following this assumption, we present a simple adversarial purification method without further training to purify adversarial images, called ZeroPur. ZeroPur contains two steps: given an adversarial example, Guided Shift obtains the shifted embedding of the adversarial example by the guidance of its blurred counterparts; after that, Adaptive Projection constructs a directional vector by this shifted embedding to provide momentum, projecting adversarial images onto the manifold adaptively. ZeroPur is independent of external models and requires no retraining of victim classifiers or auxiliary functions, relying solely on victim classifiers themselves to achieve purification. Extensive experiments on three datasets (CIFAR-10, CIFAR-100, and ImageNet-1K) using various classifier architectures (ResNet, WideResNet) demonstrate that our method achieves state-of-the-art robust performance. The code will be publicly available.

DEFT: Efficient Finetuning of Conditional Diffusion Models by Learning the Generalised $h$-transform

Generative modelling paradigms based on denoising diffusion processes have emerged as a leading candidate for conditional sampling in inverse problems. In many real-world applications, we often have access to large, expensively trained unconditional diffusion models, which we aim to exploit for improving conditional sampling. Most recent approaches are motivated heuristically and lack a unifying framework, obscuring connections between them. Further, they often suffer from issues such as being very sensitive to hyperparameters, being expensive to train or needing access to weights hidden behind a closed API. In this work, we unify conditional training and sampling using the mathematically well-understood Doob's h-transform. This new perspective allows us to unify many existing methods under a common umbrella. Under this framework, we propose DEFT (Doob's h-transform Efficient FineTuning), a new approach for conditional generation that simply fine-tunes a very small network to quickly learn the conditional $h$-transform, while keeping the larger unconditional network unchanged. DEFT is much faster than existing baselines while achieving state-of-the-art performance across a variety of linear and non-linear benchmarks. On image reconstruction tasks, we achieve speedups of up to 1.6$\times$, while having the best perceptual quality on natural images and reconstruction performance on medical images.

The Explanation Necessity for Healthcare AI

Explainability is often critical to the acceptable implementation of artificial intelligence (AI). Nowhere is this more important than healthcare where decision-making directly impacts patients and trust in AI systems is essential. This trust is often built on the explanations and interpretations the AI provides. Despite significant advancements in AI interpretability, there remains the need for clear guidelines on when and to what extent explanations are necessary in the medical context. We propose a novel categorization system with four distinct classes of explanation necessity, guiding the level of explanation required: patient or sample (local) level, cohort or dataset (global) level, or both levels. We introduce a mathematical formulation that distinguishes these categories and offers a practical framework for researchers to determine the necessity and depth of explanations required in medical AI applications. Three key factors are considered: the robustness of the evaluation protocol, the variability of expert observations, and the representation dimensionality of the application. In this perspective, we address the question: When does an AI medical application need to be explained, and at what level of detail?

Contrastive-Adversarial and Diffusion: Exploring pre-training and fine-tuning strategies for sulcal identification

In the last decade, computer vision has witnessed the establishment of various training and learning approaches. Techniques like adversarial learning, contrastive learning, diffusion denoising learning, and ordinary reconstruction learning have become standard, representing state-of-the-art methods extensively employed for fully training or pre-training networks across various vision tasks. The exploration of fine-tuning approaches has emerged as a current focal point, addressing the need for efficient model tuning with reduced GPU memory usage and time costs while enhancing overall performance, as exemplified by methodologies like low-rank adaptation (LoRA). Key questions arise: which pre-training technique yields optimal results - adversarial, contrastive, reconstruction, or diffusion denoising? How does the performance of these approaches vary as the complexity of fine-tuning is adjusted? This study aims to elucidate the advantages of pre-training techniques and fine-tuning strategies to enhance the learning process of neural networks in independent identical distribution (IID) cohorts. We underscore the significance of fine-tuning by examining various cases, including full tuning, decoder tuning, top-level tuning, and fine-tuning of linear parameters using LoRA. Systematic summaries of model performance and efficiency are presented, leveraging metrics such as accuracy, time cost, and memory efficiency. To empirically demonstrate our findings, we focus on a multi-task segmentation-classification challenge involving the paracingulate sulcus (PCS) using different 3D Convolutional Neural Network (CNN) architectures by using the TOP-OSLO cohort comprising 596 subjects.

Solving the enigma: Deriving optimal explanations of deep networks

The accelerated progress of artificial intelligence (AI) has popularized deep learning models across domains, yet their inherent opacity poses challenges, notably in critical fields like healthcare, medicine and the geosciences. Explainable AI (XAI) has emerged to shed light on these "black box" models, helping decipher their decision making process. Nevertheless, different XAI methods yield highly different explanations. This inter-method variability increases uncertainty and lowers trust in deep networks' predictions. In this study, for the first time, we propose a novel framework designed to enhance the explainability of deep networks, by maximizing both the accuracy and the comprehensibility of the explanations. Our framework integrates various explanations from established XAI methods and employs a non-linear "explanation optimizer" to construct a unique and optimal explanation. Through experiments on multi-class and binary classification tasks in 2D object and 3D neuroscience imaging, we validate the efficacy of our approach. Our explanation optimizer achieved superior faithfulness scores, averaging 155% and 63% higher than the best performing XAI method in the 3D and 2D applications, respectively. Additionally, our approach yielded lower complexity, increasing comprehensibility. Our results suggest that optimal explanations based on specific criteria are derivable and address the issue of inter-method variability in the current XAI literature.

Masked Attention is All You Need for Graphs

Graph neural networks (GNNs) and variations of the message passing algorithm are the predominant means for learning on graphs, largely due to their flexibility, speed, and satisfactory performance. The design of powerful and general purpose GNNs, however, requires significant research efforts and often relies on handcrafted, carefully-chosen message passing operators. Motivated by this, we propose a remarkably simple alternative for learning on graphs that relies exclusively on attention. Graphs are represented as node or edge sets and their connectivity is enforced by masking the attention weight matrix, effectively creating custom attention patterns for each graph. Despite its simplicity, masked attention for graphs (MAG) has state-of-the-art performance on long-range tasks and outperforms strong message passing baselines and much more involved attention-based methods on over 55 node and graph-level tasks. We also show significantly better transfer learning capabilities compared to GNNs and comparable or better time and memory scaling. MAG has sub-linear memory scaling in the number of nodes or edges, enabling learning on dense graphs and future-proofing the approach.

A framework for conditional diffusion modelling with applications in motif scaffolding for protein design

Many protein design applications, such as binder or enzyme design, require scaffolding a structural motif with high precision. Generative modelling paradigms based on denoising diffusion processes emerged as a leading candidate to address this motif scaffolding problem and have shown early experimental success in some cases. In the diffusion paradigm, motif scaffolding is treated as a conditional generation task, and several conditional generation protocols were proposed or imported from the Computer Vision literature. However, most of these protocols are motivated heuristically, e.g. via analogies to Langevin dynamics, and lack a unifying framework, obscuring connections between the different approaches. In this work, we unify conditional training and conditional sampling procedures under one common framework based on the mathematically well-understood Doob's h-transform. This new perspective allows us to draw connections between existing methods and propose a new variation on existing conditional training protocols. We illustrate the effectiveness of this new protocol in both, image outpainting and motif scaffolding and find that it outperforms standard methods.

A Hitchhiker's Guide to Geometric GNNs for 3D Atomic Systems

Recent advances in computational modelling of atomic systems, spanning molecules, proteins, and materials, represent them as geometric graphs with atoms embedded as nodes in 3D Euclidean space. In these graphs, the geometric attributes transform according to the inherent physical symmetries of 3D atomic systems, including rotations and translations in Euclidean space, as well as node permutations. In recent years, Geometric Graph Neural Networks have emerged as the preferred machine learning architecture powering applications ranging from protein structure prediction to molecular simulations and material generation. Their specificity lies in the inductive biases they leverage -- such as physical symmetries and chemical properties -- to learn informative representations of these geometric graphs. In this opinionated paper, we provide a comprehensive and self-contained overview of the field of Geometric GNNs for 3D atomic systems. We cover fundamental background material and introduce a pedagogical taxonomy of Geometric GNN architectures:(1) invariant networks, (2) equivariant networks in Cartesian basis, (3) equivariant networks in spherical basis, and (4) unconstrained networks. Additionally, we outline key datasets and application areas and suggest future research directions. The objective of this work is to present a structured perspective on the field, making it accessible to newcomers and aiding practitioners in gaining an intuition for its mathematical abstractions.

Incorporating LLM Priors into Tabular Learners

We present a method to integrate Large Language Models (LLMs) and traditional tabular data classification techniques, addressing LLMs challenges like data serialization sensitivity and biases. We introduce two strategies utilizing LLMs for ranking categorical variables and generating priors on correlations between continuous variables and targets, enhancing performance in few-shot scenarios. We focus on Logistic Regression, introducing MonotonicLR that employs a non-linear monotonic function for mapping ordinals to cardinals while preserving LLM-determined orders. Validation against baseline models reveals the superior performance of our approach, especially in low-data scenarios, while remaining interpretable.