CRISPR-GPT: An LLM Agent for Automated Design of Gene-Editing Experiments

The introduction of genome engineering technology has transformed biomedical research, making it possible to make precise changes to genetic information. However, creating an efficient gene-editing system requires a deep understanding of CRISPR technology, and the complex experimental systems under investigation. While Large Language Models (LLMs) have shown promise in various tasks, they often lack specific knowledge and struggle to accurately solve biological design problems. In this work, we introduce CRISPR-GPT, an LLM agent augmented with domain knowledge and external tools to automate and enhance the design process of CRISPR-based gene-editing experiments. CRISPR-GPT leverages the reasoning ability of LLMs to facilitate the process of selecting CRISPR systems, designing guide RNAs, recommending cellular delivery methods, drafting protocols, and designing validation experiments to confirm editing outcomes. We showcase the potential of CRISPR-GPT for assisting non-expert researchers with gene-editing experiments from scratch and validate the agent's effectiveness in a real-world use case. Furthermore, we explore the ethical and regulatory considerations associated with automated gene-editing design, highlighting the need for responsible and transparent use of these tools. Our work aims to bridge the gap between beginner biological researchers and CRISPR genome engineering techniques, and demonstrate the potential of LLM agents in facilitating complex biological discovery tasks.

Gradient Guidance for Diffusion Models: An Optimization Perspective

Diffusion models have demonstrated empirical successes in various applications and can be adapted to task-specific needs via guidance. This paper introduces a form of gradient guidance for adapting or fine-tuning diffusion models towards user-specified optimization objectives. We study the theoretic aspects of a guided score-based sampling process, linking the gradient-guided diffusion model to first-order optimization. We show that adding gradient guidance to the sampling process of a pre-trained diffusion model is essentially equivalent to solving a regularized optimization problem, where the regularization term acts as a prior determined by the pre-training data. Diffusion models are able to learn data's latent subspace, however, explicitly adding the gradient of an external objective function to the sample process would jeopardize the structure in generated samples. To remedy this issue, we consider a modified form of gradient guidance based on a forward prediction loss, which leverages the pre-trained score function to preserve the latent structure in generated samples. We further consider an iteratively fine-tuned version of gradient-guided diffusion where one can query gradients at newly generated data points and update the score network using new samples. This process mimics a first-order optimization iteration in expectation, for which we proved O(1/K) convergence rate to the global optimum when the objective function is concave.

An Overview of Diffusion Models: Applications, Guided Generation, Statistical Rates and Optimization

Diffusion models, a powerful and universal generative AI technology, have achieved tremendous success in computer vision, audio, reinforcement learning, and computational biology. In these applications, diffusion models provide flexible high-dimensional data modeling, and act as a sampler for generating new samples under active guidance towards task-desired properties. Despite the significant empirical success, theory of diffusion models is very limited, potentially slowing down principled methodological innovations for further harnessing and improving diffusion models. In this paper, we review emerging applications of diffusion models, understanding their sample generation under various controls. Next, we overview the existing theories of diffusion models, covering their statistical properties and sampling capabilities. We adopt a progressive routine, beginning with unconditional diffusion models and connecting to conditional counterparts. Further, we review a new avenue in high-dimensional structured optimization through conditional diffusion models, where searching for solutions is reformulated as a conditional sampling problem and solved by diffusion models. Lastly, we discuss future directions about diffusion models. The purpose of this paper is to provide a well-rounded theoretical exposure for stimulating forward-looking theories and methods of diffusion models.

Diffusion Model for Data-Driven Black-Box Optimization

Generative AI has redefined artificial intelligence, enabling the creation of innovative content and customized solutions that drive business practices into a new era of efficiency and creativity. In this paper, we focus on diffusion models, a powerful generative AI technology, and investigate their potential for black-box optimization over complex structured variables. Consider the practical scenario where one wants to optimize some structured design in a high-dimensional space, based on massive unlabeled data (representing design variables) and a small labeled dataset. We study two practical types of labels: 1) noisy measurements of a real-valued reward function and 2) human preference based on pairwise comparisons. The goal is to generate new designs that are near-optimal and preserve the designed latent structures. Our proposed method reformulates the design optimization problem into a conditional sampling problem, which allows us to leverage the power of diffusion models for modeling complex distributions. In particular, we propose a reward-directed conditional diffusion model, to be trained on the mixed data, for sampling a near-optimal solution conditioned on high predicted rewards. Theoretically, we establish sub-optimality error bounds for the generated designs. The sub-optimality gap nearly matches the optimal guarantee in off-policy bandits, demonstrating the efficiency of reward-directed diffusion models for black-box optimization. Moreover, when the data admits a low-dimensional latent subspace structure, our model efficiently generates high-fidelity designs that closely respect the latent structure. We provide empirical experiments validating our model in decision-making and content-creation tasks.

Embodied LLM Agents Learn to Cooperate in Organized Teams

Large Language Models (LLMs) have emerged as integral tools for reasoning, planning, and decision-making, drawing upon their extensive world knowledge and proficiency in language-related tasks. LLMs thus hold tremendous potential for natural language interaction within multi-agent systems to foster cooperation. However, LLM agents tend to over-report and comply with any instruction, which may result in information redundancy and confusion in multi-agent cooperation. Inspired by human organizations, this paper introduces a framework that imposes prompt-based organization structures on LLM agents to mitigate these problems. Through a series of experiments with embodied LLM agents and human-agent collaboration, our results highlight the impact of designated leadership on team efficiency, shedding light on the leadership qualities displayed by LLM agents and their spontaneous cooperative behaviors. Further, we harness the potential of LLMs to propose enhanced organizational prompts, via a Criticize-Reflect process, resulting in novel organization structures that reduce communication costs and enhance team efficiency.

Unveil Conditional Diffusion Models with Classifier-free Guidance: A Sharp Statistical Theory

Conditional diffusion models serve as the foundation of modern image synthesis and find extensive application in fields like computational biology and reinforcement learning. In these applications, conditional diffusion models incorporate various conditional information, such as prompt input, to guide the sample generation towards desired properties. Despite the empirical success, theory of conditional diffusion models is largely missing. This paper bridges this gap by presenting a sharp statistical theory of distribution estimation using conditional diffusion models. Our analysis yields a sample complexity bound that adapts to the smoothness of the data distribution and matches the minimax lower bound. The key to our theoretical development lies in an approximation result for the conditional score function, which relies on a novel diffused Taylor approximation technique. Moreover, we demonstrate the utility of our statistical theory in elucidating the performance of conditional diffusion models across diverse applications, including model-based transition kernel estimation in reinforcement learning, solving inverse problems, and reward conditioned sample generation.

Offline Multitask Representation Learning for Reinforcement Learning

We study offline multitask representation learning in reinforcement learning (RL), where a learner is provided with an offline dataset from different tasks that share a common representation and is asked to learn the shared representation. We theoretically investigate offline multitask low-rank RL, and propose a new algorithm called MORL for offline multitask representation learning. Furthermore, we examine downstream RL in reward-free, offline and online scenarios, where a new task is introduced to the agent that shares the same representation as the upstream offline tasks. Our theoretical results demonstrate the benefits of using the learned representation from the upstream offline task instead of directly learning the representation of the low-rank model.

Data is all you need: Finetuning LLMs for Chip Design via an Automated design-data augmentation framework

Recent advances in large language models have demonstrated their potential for automated generation of hardware description language (HDL) code from high-level prompts. Researchers have utilized fine-tuning to enhance the ability of these large language models (LLMs) in the field of Chip Design. However, the lack of Verilog data hinders further improvement in the quality of Verilog generation by LLMs. Additionally, the absence of a Verilog and Electronic Design Automation (EDA) script data augmentation framework significantly increases the time required to prepare the training dataset for LLM trainers. This paper proposes an automated design-data augmentation framework, which generates high-volume and high-quality natural language aligned with Verilog and EDA scripts. For Verilog generation, it translates Verilog files to an abstract syntax tree and then maps nodes to natural language with a predefined template. For Verilog repair, it uses predefined rules to generate the wrong verilog file and then pairs EDA Tool feedback with the right and wrong verilog file. For EDA Script generation, it uses existing LLM(GPT-3.5) to obtain the description of the Script. To evaluate the effectiveness of our data augmentation method, we finetune Llama2-13B and Llama2-7B models using the dataset generated by our augmentation framework. The results demonstrate a significant improvement in the Verilog generation tasks with LLMs. Moreover, the accuracy of Verilog generation surpasses that of the current state-of-the-art open-source Verilog generation model, increasing from 58.8% to 70.6% with the same benchmark. Our 13B model (ChipGPT-FT) has a pass rate improvement compared with GPT-3.5 in Verilog generation and outperforms in EDA script (i.e., SiliconCompiler) generation with only 200 EDA script data.

Regularized DeepIV with Model Selection

In this paper, we study nonparametric estimation of instrumental variable (IV) regressions. While recent advancements in machine learning have introduced flexible methods for IV estimation, they often encounter one or more of the following limitations: (1) restricting the IV regression to be uniquely identified; (2) requiring minimax computation oracle, which is highly unstable in practice; (3) absence of model selection procedure. In this paper, we present the first method and analysis that can avoid all three limitations, while still enabling general function approximation. Specifically, we propose a minimax-oracle-free method called Regularized DeepIV (RDIV) regression that can converge to the least-norm IV solution. Our method consists of two stages: first, we learn the conditional distribution of covariates, and by utilizing the learned distribution, we learn the estimator by minimizing a Tikhonov-regularized loss function. We further show that our method allows model selection procedures that can achieve the oracle rates in the misspecified regime. When extended to an iterative estimator, our method matches the current state-of-the-art convergence rate. Our method is a Tikhonov regularized variant of the popular DeepIV method with a non-parametric MLE first-stage estimator, and our results provide the first rigorous guarantees for this empirically used method, showcasing the importance of regularization which was absent from the original work.

Theoretical Insights for Diffusion Guidance: A Case Study for Gaussian Mixture Models

Diffusion models benefit from instillation of task-specific information into the score function to steer the sample generation towards desired properties. Such information is coined as guidance. For example, in text-to-image synthesis, text input is encoded as guidance to generate semantically aligned images. Proper guidance inputs are closely tied to the performance of diffusion models. A common observation is that strong guidance promotes a tight alignment to the task-specific information, while reducing the diversity of the generated samples. In this paper, we provide the first theoretical study towards understanding the influence of guidance on diffusion models in the context of Gaussian mixture models. Under mild conditions, we prove that incorporating diffusion guidance not only boosts classification confidence but also diminishes distribution diversity, leading to a reduction in the differential entropy of the output distribution. Our analysis covers the widely adopted sampling schemes including DDPM and DDIM, and leverages comparison inequalities for differential equations as well as the Fokker-Planck equation that characterizes the evolution of probability density function, which may be of independent theoretical interest.