SE(3) diffusion model with application to protein backbone generation

The design of novel protein structures remains a challenge in protein engineering for applications across biomedicine and chemistry. In this line of work, a diffusion model over rigid bodies in 3D (referred to as frames) has shown success in generating novel, functional protein backbones that have not been observed in nature. However, there exists no principled methodological framework for diffusion on SE(3), the space of orientation preserving rigid motions in R3, that operates on frames and confers the group invariance. We address these shortcomings by developing theoretical foundations of SE(3) invariant diffusion models on multiple frames followed by a novel framework, FrameDiff, for learning the SE(3) equivariant score over multiple frames. We apply FrameDiff on monomer backbone generation and find it can generate designable monomers up to 500 amino acids without relying on a pretrained protein structure prediction network that has been integral to previous methods. We find our samples are capable of generalizing beyond any known protein structure.

A Multi-Resolution Framework for U-Nets with Applications to Hierarchical VAEs

U-Net architectures are ubiquitous in state-of-the-art deep learning, however their regularisation properties and relationship to wavelets are understudied. In this paper, we formulate a multi-resolution framework which identifies U-Nets as finite-dimensional truncations of models on an infinite-dimensional function space. We provide theoretical results which prove that average pooling corresponds to projection within the space of square-integrable functions and show that U-Nets with average pooling implicitly learn a Haar wavelet basis representation of the data. We then leverage our framework to identify state-of-the-art hierarchical VAEs (HVAEs), which have a U-Net architecture, as a type of two-step forward Euler discretisation of multi-resolution diffusion processes which flow from a point mass, introducing sampling instabilities. We also demonstrate that HVAEs learn a representation of time which allows for improved parameter efficiency through weight-sharing. We use this observation to achieve state-of-the-art HVAE performance with half the number of parameters of existing models, exploiting the properties of our continuous-time formulation.

Causal Falsification of Digital Twins

Digital twins hold substantial promise in many applications, but rigorous procedures for assessing their accuracy are essential for their widespread deployment in safety-critical settings. By formulating this task within the framework of causal inference, we show it is not possible to certify that a twin is "correct" using real-world observational data unless potentially tenuous assumptions are made about the data-generating process. To avoid these assumptions, we propose an assessment strategy that instead aims to find cases where the twin is not correct, and present a general-purpose statistical procedure for doing so that may be used across a wide variety of applications and twin models. Our approach yields reliable and actionable information about the twin under only the assumption of an i.i.d. dataset of real-world observations, and in particular remains sound even in the presence of arbitrary unmeasured confounding. We demonstrate the effectiveness of our methodology via a large-scale case study involving sepsis modelling within the Pulse Physiology Engine, which we assess using the MIMIC-III dataset of ICU patients.

Continuous diffusion for categorical data

Diffusion models have quickly become the go-to paradigm for generative modelling of perceptual signals (such as images and sound) through iterative refinement. Their success hinges on the fact that the underlying physical phenomena are continuous. For inherently discrete and categorical data such as language, various diffusion-inspired alternatives have been proposed. However, the continuous nature of diffusion models conveys many benefits, and in this work we endeavour to preserve it. We propose CDCD, a framework for modelling categorical data with diffusion models that are continuous both in time and input space. We demonstrate its efficacy on several language modelling tasks.

Particle-Based Score Estimation for State Space Model Learning in Autonomous Driving

Multi-object state estimation is a fundamental problem for robotic applications where a robot must interact with other moving objects. Typically, other objects' relevant state features are not directly observable, and must instead be inferred from observations. Particle filtering can perform such inference given approximate transition and observation models. However, these models are often unknown a priori, yielding a difficult parameter estimation problem since observations jointly carry transition and observation noise. In this work, we consider learning maximum-likelihood parameters using particle methods. Recent methods addressing this problem typically differentiate through time in a particle filter, which requires workarounds to the non-differentiable resampling step, that yield biased or high variance gradient estimates. By contrast, we exploit Fisher's identity to obtain a particle-based approximation of the score function (the gradient of the log likelihood) that yields a low variance estimate while only requiring stepwise differentiation through the transition and observation models. We apply our method to real data collected from autonomous vehicles (AVs) and show that it learns better models than existing techniques and is more stable in training, yielding an effective smoother for tracking the trajectories of vehicles around an AV.

From Denoising Diffusions to Denoising Markov Models

Denoising diffusions are state-of-the-art generative models which exhibit remarkable empirical performance and come with theoretical guarantees. The core idea of these models is to progressively transform the empirical data distribution into a simple Gaussian distribution by adding noise using a diffusion. We obtain new samples whose distribution is close to the data distribution by simulating a "denoising" diffusion approximating the time reversal of this "noising" diffusion. This denoising diffusion relies on approximations of the logarithmic derivatives of the noised data densities, known as scores, obtained using score matching. Such models can be easily extended to perform approximate posterior simulation in high-dimensional scenarios where one can only sample from the prior and simulate synthetic observations from the likelihood. These methods have been primarily developed for data on $\mathbb{R}^d$ while extensions to more general spaces have been developed on a case-by-case basis. We propose here a general framework which not only unifies and generalizes this approach to a wide class of spaces but also leads to an original extension of score matching. We illustrate the resulting class of denoising Markov models on various applications.

Categorical SDEs with Simplex Diffusion

Diffusion models typically operate in the standard framework of generative modelling by producing continuously-valued datapoints. To this end, they rely on a progressive Gaussian smoothing of the original data distribution, which admits an SDE interpretation involving increments of a standard Brownian motion. However, some applications such as text generation or reinforcement learning might naturally be better served by diffusing categorical-valued data, i.e., lifting the diffusion to a space of probability distributions. To this end, this short theoretical note proposes Simplex Diffusion, a means to directly diffuse datapoints located on an n-dimensional probability simplex. We show how this relates to the Dirichlet distribution on the simplex and how the analogous SDE is realized thanks to a multi-dimensional Cox-Ingersoll-Ross process (abbreviated as CIR), previously used in economics and mathematical finance. Finally, we make remarks as to the numerical implementation of trajectories of the CIR process, and discuss some limitations of our approach.