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Applications · Chemistry and Drug Discovery

YAN WANG, Lihao Wang, Yuning Shen, Yiqun Wang, Huizhuo Yuan, Yue Wu, Quanquan Gu

The conformational landscape of proteins is crucial to understanding their functionality in complex biological processes. Traditional physics-based computational methods, such as molecular dynamics (MD) simulations, suffer from rare event sampling and long equilibration time problems, hindering their applications in general protein systems. Recently, deep generative modeling techniques, especially diffusion models, have been employed to generate novel protein conformations. However, existing score-based diffusion methods cannot properly incorporate important physical prior knowledge to guide the generation process, causing large deviations in the sampled protein conformations from the equilibrium distribution. In this paper, to overcome these limitations, we propose a force-guided $\mathrm{SE}(3)$ diffusion model, ConfDiff, for protein conformation generation. By incorporating a force-guided network with a mixture of data-based score models, ConfDiff can generate protein conformations with rich diversity while preserving high fidelity. Experiments on a variety of protein conformation prediction tasks, including 12 fast-folding proteins and the Bovine Pancreatic Trypsin Inhibitor (BPTI), demonstrate that our method surpasses the state-of-the-art method.

Huijie Zhang, Jinfan Zhou, Yifu Lu, Minzhe Guo, Peng Wang, Liyue Shen, Qing Qu

In this work, we investigate an intriguing and prevalent phenomenon of diffusion models which we term as "consistent model reproducibility'': given the same starting noise input and a deterministic sampler, different diffusion models often yield remarkably similar outputs. We confirm this phenomenon through comprehensive experiments, implying that different diffusion models consistently reach the same data distribution and score function regardless of diffusion model frameworks, model architectures, or training procedures. More strikingly, our further investigation implies that diffusion models are learning *distinct distributions* influenced by the training data size. This is evident in two distinct training regimes: (I) "memorization regime,'' where the diffusion model overfits to the training data distribution, and (ii) "generalization regime,'' where the model learns the underlying data distribution. Our study also finds that this valuable property generalizes to many variants of diffusion models, including those for conditional generation and solving inverse problems. Lastly, we discuss how our findings connect to existing research and highlight the practical implications of our discoveries.

Applications · Chemistry and Drug Discovery

Xinyou Wang, Zaixiang Zheng, Fei YE, Dongyu Xue, Shujian Huang, Quanquan Gu

This paper introduces diffusion protein language model (DPLM), a versatile protein language model that demonstrates strong generative and predictive capabilities for protein sequences. We first pre-train scalable DPLMs from evolutionary-scale protein sequences within a generative self-supervised discrete diffusion probabilistic framework, which generalizes language modeling for proteins in a principled way. After pre-training, DPLM exhibits the ability to generate structurally plausible, novel and diverse protein sequences for unconditional generation. We further demonstrate the proposed diffusion generative pre-training make DPLM possess a better understanding of proteins, making it a superior representation learner, which can be fine-tuned for various predictive tasks, comparing favorably to ESM2. Moreover, DPLM can be tailored for various needs, which showcases its prowess of conditional generation in several ways: (1) conditioning on partial peptide sequences, e.g., generating scaffolds for functional motifs with high success rate; (2) incorporating other modalities as conditioners, e.g., structure-conditioned generation for inverse folding; and (3) steering sequence generation towards desired properties, e.g., satisfying specified secondary structures, through a plug-and-play classifier guidance.

Social Aspects · Trustworthy Machine Learning

Yiwei Lu, Matthew Yang, Zuoqiu Liu, Gautam Kamath, Yaoliang Yu

Copyright infringement may occur when a generative model produces samples substantially similar to some copyrighted data that it had access to during the training phase. The notion of access usually refers to including copyrighted samples directly in the training dataset, which one may inspect to identify an infringement. We argue that such visual auditing largely overlooks a concealed copyright infringement, where one constructs a disguise that looks drastically different from the copyrighted sample yet still induces the effect of training Latent Diffusion Models on it. Such disguises only require indirect access to the copyrighted material and cannot be visually distinguished, thus easily circumventing the current auditing tools. In this paper, we provide a better understanding of such disguised copyright infringement by uncovering the disguises generation algorithm, the revelation of the disguises, and importantly, how to detect them to augment the existing toolbox. Additionally, we introduce a broader notion of acknowledgment for comprehending such indirect access.

Social Aspects

Sayash Kapoor, Rishi Bommasani, Kevin Klyman, Shayne Longpre, Ashwin Ramaswami, Peter Cihon, Aspen Hopkins, Kevin Bankston, Stella Biderman, Miranda Bogen 等

Foundation models are powerful technologies: how they are released publicly directly shapes their societal impact. In this position paper, we focus on *open* foundation models, defined here as those with broadly available model weights (e.g., Llama 3, Stable Diffusion XL). We identify five distinctive properties (e.g., greater customizability, poor monitoring) that mediate their benefits and risks. Open foundation models present significant benefits, with some caveats, that span innovation, competition, the distribution of decision-making power, and transparency. To understand their risks of misuse, we design a risk assessment framework for analyzing their *marginal risk*. Across several misuse vectors (e.g., cyberattacks, bioweapons), we find that current research is insufficient to effectively characterize the marginal risk of open foundation models relative to pre-existing technologies. The framework helps explain why the marginal risk is low in some cases, clarifies disagreements about misuse risks by revealing that past work has focused on different subsets of the framework with different assumptions, and articulates a way forward for more constructive debate. Overall, our work helps support a more grounded assessment of the societal impact of open foundation models by outlining what research is needed to empirically validate their theoretical benefits and risks.

Deep Learning · Graph Neural Networks

Qitian Wu, Fan Nie, Chenxiao Yang, Junchi Yan

Real-world data generation often involves certain geometries (e.g., graphs) that induce instance-level interdependence. This characteristic makes the generalization of learning models more difficult due to the intricate interdependent patterns that impact data-generative distributions and can vary from training to testing. In this work, we propose a geometric diffusion model with learnable divergence fields for the challenging generalization problem with interdependent data. We generalize the diffusion equation with stochastic diffusivity at each time step, which aims to capture the multi-faceted information flows among interdependent data. Furthermore, we derive a new learning objective through causal inference, which can guide the model to learn generalizable patterns of interdependence that are insensitive across domains. Regarding practical implementation, we introduce three model instantiations that can be considered as the generalized versions of GCN, GAT, and Transformers, respectively, which possess advanced robustness against distribution shifts. We demonstrate their promising efficacy for out-of-distribution generalization on diverse real-world datasets. Source codes are available at https://github.com/fannie1208/GLIND.

Deep Learning · Generative Models and Autoencoders

Saeid Naderiparizi, Xiaoxuan Liang, Setareh Cohan, Berend Zwartsenberg, Frank Wood

Score-based diffusion models are a powerful class of generative models, widely utilized across diverse domains. Despite significant advancements in large-scale tasks such as text-to-image generation, their application to constrained domains has received considerably less attention. This work addresses model learning in a setting where, in addition to the training dataset, there further exists side-information in the form of an oracle that can label samples as being outside the support of the true data generating distribution. Specifically we develop a new denoising diffusion probabilistic modeling methodology, Gen-neG, that leverages this additional side-information. Gen-neG builds on classifier guidance in diffusion models to guide the generation process towards the positive support region indicated by the oracle. We empirically establish the utility of Gen-neG in applications including collision avoidance in self-driving simulators and safety-guarded human motion generation.

Reinforcement Learning · Batch/Offline

Chang Chen, Junyeob Baek, Fei Deng, Kenji Kawaguchi, Caglar Gulcehre, Sungjin Ahn

Despite the recent advancements in offline RL, no unified algorithm could achieve superior performance across a broad range of tasks. Offline *value function learning*, in particular, struggles with sparse-reward, long-horizon tasks due to the difficulty of solving credit assignment and extrapolation errors that accumulates as the horizon of the task grows. On the other hand, models that can perform well in long-horizon tasks are designed specifically for goal-conditioned tasks, which commonly perform worse than value function learning methods on short-horizon, dense-reward scenarios. To bridge this gap, we propose a hierarchical planner designed for offline RL called PlanDQ. PlanDQ incorporates a diffusion-based planner at the high level, named D-Conductor, which guides the low-level policy through sub-goals. At the low level, we used a Q-learning based approach called the Q-Performer to accomplish these sub-goals. Our experimental results suggest that PlanDQ can achieve superior or competitive performance on D4RL continuous control benchmark tasks as well as AntMaze, Kitchen, and Calvin as long-horizon tasks.

Probabilistic Methods

Manuel Gloeckler, Michael Deistler, Christian Weilbach, Frank Wood, Jakob Macke

Amortized Bayesian inference trains neural networks to solve stochastic inference problems using model simulations, thereby making it possible to rapidly perform Bayesian inference for any newly observed data. However, current simulation-based amortized inference methods are simulation-hungry and inflexible: They require the specification of a fixed parametric prior, simulator, and inference tasks ahead of time. Here, we present a new amortized inference method---the Simformer---which overcomes these limitations. By training a probabilistic diffusion model with transformer architectures, the Simformer outperforms current state-of-the-art amortized inference approaches on benchmark tasks and is substantially more flexible: It can be applied to models with function-valued parameters, it can handle inference scenarios with missing or unstructured data, and it can sample arbitrary conditionals of the joint distribution of parameters and data, including both posterior and likelihood. We showcase the performance and flexibility of the Simformer on simulators from ecology, epidemiology, and neuroscience, and demonstrate that it opens up new possibilities and application domains for amortized Bayesian inference on simulation-based models.

Reinforcement Learning · Deep RL

Qianlan Yang, Yu-Xiong Wang

Training autonomous agents with sparse rewards is a long-standing problem in online reinforcement learning (RL), due to low data efficiency. Prior work overcomes this challenge by extracting useful knowledge from offline data, often accomplished through the learning of action distribution from offline data and utilizing the learned distribution to facilitate online RL. However, since the offline data are given and fixed, the extracted knowledge is inherently limited, making it difficult to generalize to new tasks. We propose a novel approach that leverages offline data to learn a generative diffusion model, coined as Adaptive Trajectory Diffuser (ATraDiff). This model generates synthetic trajectories, serving as a form of data augmentation and consequently enhancing the performance of online RL methods. The key strength of our diffuser lies in its adaptability, allowing it to effectively handle varying trajectory lengths and mitigate distribution shifts between online and offline data. Because of its simplicity, ATraDiff seamlessly integrates with a wide spectrum of RL methods. Empirical evaluation shows that ATraDiff consistently achieves state-of-the-art performance across a variety of environments, with particularly pronounced improvements in complicated settings. Our code and demo video are available at https://atradiff.github.io.

Probabilistic Methods · Bayesian Models and Methods

David Heurtel-Depeiges, Charles Margossian, Ruben Ohana, Bruno Régaldo-Saint Blancard

In recent years, denoising problems have become intertwined with the development of deep generative models. In particular, diffusion models are trained like denoisers, and the distribution they model coincide with denoising priors in the Bayesian picture. However, denoising through diffusion-based posterior sampling requires the noise level and covariance to be known, preventing *blind denoising*. We overcome this limitation by introducing Gibbs Diffusion (GDiff), a general methodology addressing posterior sampling of both the signal and the noise parameters. Assuming arbitrary parametric Gaussian noise, we develop a Gibbs algorithm that alternates sampling steps from a conditional diffusion model trained to map the signal prior to the class of noise distributions, and a Monte Carlo sampler to infer the noise parameters. Our theoretical analysis highlights potential pitfalls, guides diagnostic usage, and quantifies errors in the Gibbs stationary distribution caused by the diffusion model. We showcase our method for 1) blind denoising of natural images involving colored noises with unknown amplitude and exponent, and 2) a cosmology problem, namely the analysis of cosmic microwave background data, where Bayesian inference of "noise" parameters means constraining models of the evolution of the Universe.

Applications · Language, Speech and Dialog

Zeqian Ju, Yuancheng Wang, Kai Shen, Xu Tan, Detai Xin, Dongchao Yang, Eric Liu, Yichong Leng, Kaitao Song, Siliang Tang 等

While recent large-scale text-to-speech (TTS) models have achieved significant progress, they still fall shorts in speech quality, similarity, and prosody. Considering that speech intricately encompasses various attributes (e.g., content, prosody, timbre, and acoustic details) that pose significant challenges for generation, a natural idea is to factorize speech into individual subspaces representing different attributes and generate them individually. Motivated by it, we propose a TTS system with novel factorized diffusion models to generate natural speech in a zero-shot way. Specifically, 1) we design a neural codec with factorized vector quantization (FVQ) to disentangle speech waveform into subspaces of content, prosody, timbre, and acoustic details; 2) we propose a factorized diffusion model, which generates attributes in each subspace following its corresponding prompt. With this factorization design, our method can effectively and efficiently model the intricate speech with disentangled subspaces in a divide-and-conquer way. Experimental results show that our method outperforms the state-of-the-art TTS systems on quality, similarity, prosody, and intelligibility.

Zeqian Ju, Yuancheng Wang, Kai Shen, Xu Tan, Detai Xin, Dongchao Yang, Eric Liu, Yichong Leng, Kaitao Song, Siliang Tang 等

While recent large-scale text-to-speech (TTS) models have achieved significant progress, they still fall shorts in speech quality, similarity, and prosody. Considering that speech intricately encompasses various attributes (e.g., content, prosody, timbre, and acoustic details) that pose significant challenges for generation, a natural idea is to factorize speech into individual subspaces representing different attributes and generate them individually. Motivated by it, we propose a TTS system with novel factorized diffusion models to generate natural speech in a zero-shot way. Specifically, 1) we design a neural codec with factorized vector quantization (FVQ) to disentangle speech waveform into subspaces of content, prosody, timbre, and acoustic details; 2) we propose a factorized diffusion model, which generates attributes in each subspace following its corresponding prompt. With this factorization design, our method can effectively and efficiently model the intricate speech with disentangled subspaces in a divide-and-conquer way. Experimental results show that our method outperforms the state-of-the-art TTS systems on quality, similarity, prosody, and intelligibility.

Deep Learning · Graph Neural Networks

Puja Trivedi, Ryan A Rossi, David Arbour, Tong Yu, Franck Dernoncourt, Sungchul Kim, Nedim Lipka, Namyong Park, Nesreen Ahmed, Danai Koutra

Most real-world networks are noisy and incomplete samples from an unknown target distribution. Refining them by correcting corruptions or inferring unobserved regions typically improves downstream performance. Inspired by the impressive generative capabilities that have been used to correct corruptions in images, and the similarities between "in-painting" and filling in missing nodes and edges conditioned on the observed graph, we propose a novel graph generative framework, SGDM, which is based on subgraph diffusion. Our framework not only improves the scalability and fidelity of graph diffusion models, but also leverages the reverse process to perform novel, conditional generation tasks. In particular, through extensive empirical analysis and a set of novel metrics, we demonstrate that our proposed model effectively supports the following refinement tasks for partially observable networks: (T1) denoising extraneous subgraphs, (T2) expanding existing subgraphs and (T3) performing ``style" transfer by regenerating a particular subgraph to match the characteristics of a different node or subgraph.

Deep Learning · Generative Models and Autoencoders

Amirmojtaba Sabour, Sanja Fidler, Karsten Kreis

Diffusion models (DMs) have established themselves as the state-of-the-art generative modeling approach in the visual domain and beyond. A crucial drawback of DMs is their slow sampling speed, relying on many sequential function evaluations through large neural networks. Sampling from DMs can be seen as solving a differential equation through a discretized set of noise levels known as the sampling schedule. While past works primarily focused on deriving efficient solvers, little attention has been given to finding optimal sampling schedules, and the entire literature relies on hand-crafted heuristics. In this work, for the first time, we propose a general and principled approach to optimizing the sampling schedules of DMs for high-quality outputs, called Align Your Steps. We leverage methods from stochastic calculus and find optimal schedules specific to different solvers, trained DMs and datasets. We evaluate our novel approach on several image, video as well as 2D toy data synthesis benchmarks, using a variety of different samplers, and observe that our optimized schedules outperform previous hand-crafted schedules in almost all experiments. Our method demonstrates the untapped potential of sampling schedule optimization, especially in the few-step synthesis regime.

Deep Learning · Generative Models and Autoencoders

Wei Deng, Weijian Luo, Yixin Tan, Marin Biloš, Yu Chen, Yuriy Nevmyvaka, Ricky T. Q. Chen

Schrödinger bridge (SB) has emerged as the go-to method for optimizing transportation plans in diffusion models. However, SB requires estimating the intractable forward score functions, inevitably resulting in the (costly) implicit training loss based on simulated trajectories. To improve the scalability while preserving efficient transportation plans, we leverage variational inference to linearize the forward score functions (variational scores) of SB and restore *simulation-free* properties in training backward scores. We propose the variational Schrödinger diffusion model (VSDM), where the forward process is a multivariate diffusion and the variational scores are adaptively optimized for efficient transport. Theoretically, we use stochastic approximation to prove the convergence of the variational scores and show the convergence of the adaptively generated samples based on the optimal variational scores. Empirically, we test the algorithm in simulated examples and observe that VSDM is efficient in generations of anisotropic shapes and yields straighter sample trajectories compared to the single-variate diffusion. We also verify the scalability of the algorithm in real-world data and achieve competitive unconditional generation performance in CIFAR10 and conditional generation in time series modeling. Notably, VSDM no longer depends on warm-up initializations required by SB.

Neta Shaul, Uriel Singer, Ricky T. Q. Chen, Matthew Le, Ali Thabet, Albert Pumarola, Yaron Lipman

This paper introduces Bespoke Non-Stationary (BNS) Solvers, a solver distillation approach to improve sample efficiency of Diffusion and Flow models. BNS solvers are based on a family of non-stationary solvers that provably subsumes existing numerical ODE solvers and consequently demonstrate considerable improvement in sample approximation (PSNR) over these baselines. Compared to model distillation, BNS solvers benefit from a tiny parameter space ($<$200 parameters), fast optimization (two orders of magnitude faster), maintain diversity of samples, and in contrast to previous solver distillation approaches nearly close the gap from standard distillation methods such as Progressive Distillation in the low-medium NFE regime. For example, BNS solver achieves 45 PSNR / 1.76 FID using 16 NFE in class-conditional ImageNet-64. We experimented with BNS solvers for conditional image generation, text-to-image generation, and text-2-audio generation showing significant improvement in sample approximation (PSNR) in all.

Applications · Chemistry and Drug Discovery

Benjamin Kurt Miller, Ricky T. Q. Chen, Anuroop Sriram, Brandon Wood

Crystalline materials are a fundamental component in next-generation technologies, yet modeling their distribution presents unique computational challenges. Of the plausible arrangements of atoms in a periodic lattice only a vanishingly small percentage are thermodynamically stable, which is a key indicator of the materials that can be experimentally realized. Two fundamental tasks in this area are to (a) predict the stable crystal structure of a known composition of elements and (b) propose novel compositions along with their stable structures. We present FlowMM, a pair of generative models that achieve state-of-the-art performance on both tasks while being more efficient and more flexible than competing methods. We extend Riemannian Flow Matching to suit the symmetries inherent to crystals: translation, rotation, permutation, and periodic boundary conditions. Our framework enables the freedom to choose the flow base distributions, drastically simplifying the problem of learning crystal structures compared with diffusion models. In addition to standard benchmarks, we validate FlowMM's generated structures with quantum chemistry calculations, demonstrating that it is $\sim$3x more efficient, in terms of integration steps, at finding stable materials compared to previous open methods.

Deep Learning · Generative Models and Autoencoders

Zach Evans, CJ Carr, Josiah Taylor, Scott Hawley, Jordi Pons

Generating long-form 44.1kHz stereo audio from text prompts can be computationally demanding. Further, most previous works do not tackle that music and sound effects naturally vary in their duration. Our research focuses on the efficient generation of long-form, variable-length stereo music and sounds at 44.1kHz using text prompts with a generative model. It is based on latent diffusion, with its latent defined by a fully-convolutional variational autoencoder. The generative model is conditioned on text prompts as well as timing embeddings, allowing for fine control over both the content and length of the generated music and sounds. It is capable of rendering stereo signals of up to 95 sec at 44.1kHz in 8 sec on an A100 GPU. Despite its compute efficiency and fast inference, the proposed model is one of the best in two public text-to-music and -audio benchmarks and, differently from state-of-the-art models, can generate music with structure and stereo sounds.

Deep Learning · Generative Models and Autoencoders

Taehong Moon, Moonseok Choi, EungGu Yun, Jongmin Yoon, Gayoung Lee, Jaewoong Cho, Juho Lee

Diffusion models have shown remarkable performance in generation problems over various domains including images, videos, text, and audio. A practical bottleneck of diffusion models is their sampling speed, due to the repeated evaluation of score estimation networks during the inference. In this work, we propose a novel framework capable of adaptively allocating compute required for the score estimation, thereby reducing the overall sampling time of diffusion models. We observe that the amount of computation required for the score estimation may vary along the time step for which the score is estimated. Based on this observation, we propose an early-exiting scheme, where we skip the subset of parameters in the score estimation network during the inference, based on a time-dependent exit schedule. Using the diffusion models for image synthesis, we show that our method could significantly improve the sampling throughput of the diffusion models without compromising image quality. Furthermore, we also demonstrate that our method seamlessly integrates with various types of solvers for faster sampling, capitalizing on their compatibility to enhance overall efficiency.