Daily Papers

Clinical trials are fundamental in developing new drugs, medical devices, and treatments. However, they are often time-consuming and have low success rates. Although there have been initial attempts to create large language models (LLMs) for clinical trial design and patient-trial matching, these models remain task-specific and not adaptable to diverse clinical trial tasks. To address this challenge, we propose a clinical trial foundation model named Panacea, designed to handle multiple tasks, including trial search, trial summarization, trial design, and patient-trial matching. We also assemble a large-scale dataset, named TrialAlign, of 793,279 trial documents and 1,113,207 trial-related scientific papers, to infuse clinical knowledge into the model by pre-training. We further curate TrialInstruct, which has 200,866 of instruction data for fine-tuning. These resources enable Panacea to be widely applicable for a range of clinical trial tasks based on user requirements. We evaluated Panacea on a new benchmark, named TrialPanorama, which covers eight clinical trial tasks. Our method performed the best on seven of the eight tasks compared to six cutting-edge generic or medicine-specific LLMs. Specifically, Panacea showed great potential to collaborate with human experts in crafting the design of eligibility criteria, study arms, and outcome measures, in multi-round conversations. In addition, Panacea achieved 14.42% improvement in patient-trial matching, 41.78% to 52.02% improvement in trial search, and consistently ranked at the top for five aspects of trial summarization. Our approach demonstrates the effectiveness of Panacea in clinical trials and establishes a comprehensive resource, including training data, model, and benchmark, for developing clinical trial foundation models, paving the path for AI-based clinical trial development.

Natural language processing (NLP) of clinical trial documents can be useful in new trial design. Here we identify entity types relevant to clinical trial design and propose a framework called CT-BERT for information extraction from clinical trial text. We trained named entity recognition (NER) models to extract eligibility criteria entities by fine-tuning a set of pre-trained BERT models. We then compared the performance of CT-BERT with recent baseline methods including attention-based BiLSTM and Criteria2Query. The results demonstrate the superiority of CT-BERT in clinical trial NLP.

Developing artificial intelligence (AI) for vertical domains requires a solid data foundation for both training and evaluation. In this work, we introduce TrialPanorama, a large-scale, structured database comprising 1,657,476 clinical trial records aggregated from 15 global sources. The database captures key aspects of trial design and execution, including trial setups, interventions, conditions, biomarkers, and outcomes, and links them to standard biomedical ontologies such as DrugBank and MedDRA. This structured and ontology-grounded design enables TrialPanorama to serve as a unified, extensible resource for a wide range of clinical trial tasks, including trial planning, design, and summarization. To demonstrate its utility, we derive a suite of benchmark tasks directly from the TrialPanorama database. The benchmark spans eight tasks across two categories: three for systematic review (study search, study screening, and evidence summarization) and five for trial design (arm design, eligibility criteria, endpoint selection, sample size estimation, and trial completion assessment). The experiments using five state-of-the-art large language models (LLMs) show that while general-purpose LLMs exhibit some zero-shot capability, their performance is still inadequate for high-stakes clinical trial workflows. We release TrialPanorama database and the benchmark to facilitate further research on AI for clinical trials.

Alzheimer's disease (AD) is a degenerative brain disease impairing a person's ability to perform day to day activities. The clinical manifestations of Alzheimer's disease are characterized by heterogeneity in age, disease span, progression rate, impairment of memory and cognitive abilities. Due to these variabilities, personalized care and treatment planning, as well as patient counseling about their individual progression is limited. Recent developments in machine learning to detect hidden patterns in complex, multi-dimensional datasets provides significant opportunities to address this critical need. In this work, we use unsupervised and supervised machine learning approaches for subtype identification and prediction. We apply machine learning methods to the extensive clinical observations available at the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set to identify patient subtypes and to predict disease progression. Our analysis depicts the progression space for the Alzheimer's disease into low, moderate and high disease progression zones. The proposed work will enable early detection and characterization of distinct disease subtypes based on clinical heterogeneity. We anticipate that our models will enable patient counseling, clinical trial design, and ultimately individualized clinical care.

Large Language Models (LLMs) have become integral components in various autonomous agent systems. In this study, we present an exploration-based trajectory optimization approach, referred to as ETO. This learning method is designed to enhance the performance of open LLM agents. Contrary to previous studies that exclusively train on successful expert trajectories, our method allows agents to learn from their exploration failures. This leads to improved performance through an iterative optimization framework. During the exploration phase, the agent interacts with the environment while completing given tasks, gathering failure trajectories to create contrastive trajectory pairs. In the subsequent training phase, the agent utilizes these trajectory preference pairs to update its policy using contrastive learning methods like DPO. This iterative cycle of exploration and training fosters continued improvement in the agents. Our experiments on three complex tasks demonstrate that ETO consistently surpasses baseline performance by a large margin. Furthermore, an examination of task-solving efficiency and potential in scenarios lacking expert trajectory underscores the effectiveness of our approach.

Most LLM-based agent frameworks adopt a top-down philosophy: humans decompose tasks, define workflows, and assign agents to execute each step. While effective on benchmark-style tasks, such systems rely on designer updates and overlook agents' potential to learn from experience. Recently, Silver and Sutton(2025) envision a shift into a new era, where agents could progress from a stream of experiences. In this paper, we instantiate this vision of experience-driven learning by introducing a bottom-up agent paradigm that mirrors the human learning process. Agents acquire competence through a trial-and-reasoning mechanism-exploring, reflecting on outcomes, and abstracting skills over time. Once acquired, skills can be rapidly shared and extended, enabling continual evolution rather than static replication. As more agents are deployed, their diverse experiences accelerate this collective process, making bottom-up design especially suited for open-ended environments. We evaluate this paradigm in Slay the Spire and Civilization V, where agents perceive through raw visual inputs and act via mouse outputs, the same as human players. Using a unified, game-agnostic codebase without any game-specific prompts or privileged APIs, our bottom-up agents acquire skills entirely through autonomous interaction, demonstrating the potential of the bottom-up paradigm in complex, real-world environments. Our code is available at https://github.com/AngusDujw/Bottom-Up-Agent.

In this study, a chair-type asymmetric tripedal low-rigidity robot was designed based on the three-legged chair character in the movie "Suzume" and its gait was generated. Its body structure consists of three legs that are asymmetric to the body, so it cannot be easily balanced. In addition, the actuator is a servo motor that can only feed-forward rotational angle commands and the sensor can only sense the robot's posture quaternion. In such an asymmetric and imperfect body structure, we analyzed how gait is generated in walking and stand-up motions by generating gaits with two different methods: a method using linear completion to connect the postures necessary for the gait discovered through trial and error using the actual robot, and a method using the gait generated by reinforcement learning in the simulator and reflecting it to the actual robot. Both methods were able to generate gait that realized walking and stand-up motions, and interesting gait patterns were observed, which differed depending on the method, and were confirmed on the actual robot. Our code and demonstration videos are available here: https://github.com/shin0805/Chair-TypeAsymmetricalTripedalRobot.git

Catalyzed by the popularity of blockchain technology, there has recently been a renewed interest in the design, implementation and evaluation of decentralized systems. Most of these systems are intended to be deployed at scale and in heterogeneous environments with real users and unpredictable workloads. Nevertheless, most research in this field evaluates such systems in controlled environments that poorly reflect the complex conditions of real-world environments. In this work, we argue that deployment is crucial to understanding decentralized mechanisms in a real-world environment and an enabler to building more robust and sustainable systems. We highlight the merits of deployment by comparing this approach with other experimental setups and show how our lab applied a deployment-first methodology. We then outline how we use Tribler, our peer-to-peer file-sharing application, to deploy and monitor decentralized mechanisms at scale. We illustrate the application of our methodology by describing a deployment trial in experimental tokenomics. Finally, we summarize four lessons learned from multiple deployment trials where we applied our methodology.

We initiate a formal investigation into the design and analysis of LLM-based algorithms, i.e. algorithms that contain one or multiple calls of large language models (LLMs) as sub-routines and critically rely on the capabilities of LLMs. While LLM-based algorithms, ranging from basic LLM calls with prompt engineering to complicated LLM-powered agent systems and compound AI systems, have achieved remarkable empirical success, the design and optimization of them have mostly relied on heuristics and trial-and-errors, which is largely due to a lack of formal and analytical study for these algorithms. To fill this gap, we start by identifying the computational-graph representation of LLM-based algorithms, the design principle of task decomposition, and some key abstractions, which then facilitate our formal analysis for the accuracy and efficiency of LLM-based algorithms, despite the black-box nature of LLMs. Through extensive analytical and empirical investigation in a series of case studies, we demonstrate that the proposed framework is broadly applicable to a wide range of scenarios and diverse patterns of LLM-based algorithms, such as parallel, hierarchical and recursive task decomposition. Our proposed framework holds promise for advancing LLM-based algorithms, by revealing the reasons behind curious empirical phenomena, guiding the choices of hyperparameters, predicting the empirical performance of algorithms, and inspiring new algorithm design. To promote further study of LLM-based algorithms, we release our source code at https://github.com/modelscope/agentscope/tree/main/examples/paper_llm_based_algorithm.

Large Language Models (LLMs) and multi-agent systems have shown impressive capabilities in natural language tasks but face challenges in clinical trial applications, primarily due to limited access to external knowledge. Recognizing the potential of advanced clinical trial tools that aggregate and predict based on the latest medical data, we propose an integrated solution to enhance their accessibility and utility. We introduce Clinical Agent System (ClinicalAgent), a clinical multi-agent system designed for clinical trial tasks, leveraging GPT-4, multi-agent architectures, LEAST-TO-MOST, and ReAct reasoning technology. This integration not only boosts LLM performance in clinical contexts but also introduces novel functionalities. The proposed method achieves competitive predictive performance in clinical trial outcome prediction (0.7908 PR-AUC), obtaining a 0.3326 improvement over the standard prompt Method. Publicly available code can be found at https://anonymous.4open.science/r/ClinicalAgent-6671.

In deep learning, performance is strongly affected by the choice of architecture and hyperparameters. While there has been extensive work on automatic hyperparameter optimization for simple spaces, complex spaces such as the space of deep architectures remain largely unexplored. As a result, the choice of architecture is done manually by the human expert through a slow trial and error process guided mainly by intuition. In this paper we describe a framework for automatically designing and training deep models. We propose an extensible and modular language that allows the human expert to compactly represent complex search spaces over architectures and their hyperparameters. The resulting search spaces are tree-structured and therefore easy to traverse. Models can be automatically compiled to computational graphs once values for all hyperparameters have been chosen. We can leverage the structure of the search space to introduce different model search algorithms, such as random search, Monte Carlo tree search (MCTS), and sequential model-based optimization (SMBO). We present experiments comparing the different algorithms on CIFAR-10 and show that MCTS and SMBO outperform random search. In addition, these experiments show that our framework can be used effectively for model discovery, as it is possible to describe expressive search spaces and discover competitive models without much effort from the human expert. Code for our framework and experiments has been made publicly available.

This paper defines and explores the design space for information extraction (IE) from layout-rich documents using large language models (LLMs). The three core challenges of layout-aware IE with LLMs are 1) data structuring, 2) model engagement, and 3) output refinement. Our study delves into the sub-problems within these core challenges, such as input representation, chunking, prompting, and selection of LLMs and multimodal models. It examines the outcomes of different design choices through a new layout-aware IE test suite, benchmarking against the state-of-art (SoA) model LayoutLMv3. The results show that the configuration from one-factor-at-a-time (OFAT) trial achieves near-optimal results with 14.1 points F1-score gain from the baseline model, while full factorial exploration yields only a slightly higher 15.1 points gain at around 36x greater token usage. We demonstrate that well-configured general-purpose LLMs can match the performance of specialized models, providing a cost-effective alternative. Our test-suite is freely available at https://github.com/gayecolakoglu/LayIE-LLM.

Clinical trials are crucial for drug development but are time consuming, expensive, and often burdensome on patients. More importantly, clinical trials face uncertain outcomes due to issues with efficacy, safety, or problems with patient recruitment. If we were better at predicting the results of clinical trials, we could avoid having to run trials that will inevitably fail more resources could be devoted to trials that are likely to succeed. In this paper, we propose Hierarchical INteraction Network (HINT) for more general, clinical trial outcome predictions for all diseases based on a comprehensive and diverse set of web data including molecule information of the drugs, target disease information, trial protocol and biomedical knowledge. HINT first encode these multi-modal data into latent embeddings, where an imputation module is designed to handle missing data. Next, these embeddings will be fed into the knowledge embedding module to generate knowledge embeddings that are pretrained using external knowledge on pharmaco-kinetic properties and trial risk from the web. Then the interaction graph module will connect all the embedding via domain knowledge to fully capture various trial components and their complex relations as well as their influences on trial outcomes. Finally, HINT learns a dynamic attentive graph neural network to predict trial outcome. Comprehensive experimental results show that HINT achieves strong predictive performance, obtaining 0.772, 0.607, 0.623, 0.703 on PR-AUC for Phase I, II, III, and indication outcome prediction, respectively. It also consistently outperforms the best baseline method by up to 12.4\% on PR-AUC.

The development and popularization of large language models (LLMs) have raised concerns that they will be used to create tailor-made, convincing arguments to push false or misleading narratives online. Early work has found that language models can generate content perceived as at least on par and often more persuasive than human-written messages. However, there is still limited knowledge about LLMs' persuasive capabilities in direct conversations with human counterparts and how personalization can improve their performance. In this pre-registered study, we analyze the effect of AI-driven persuasion in a controlled, harmless setting. We create a web-based platform where participants engage in short, multiple-round debates with a live opponent. Each participant is randomly assigned to one of four treatment conditions, corresponding to a two-by-two factorial design: (1) Games are either played between two humans or between a human and an LLM; (2) Personalization might or might not be enabled, granting one of the two players access to basic sociodemographic information about their opponent. We found that participants who debated GPT-4 with access to their personal information had 81.7% (p < 0.01; N=820 unique participants) higher odds of increased agreement with their opponents compared to participants who debated humans. Without personalization, GPT-4 still outperforms humans, but the effect is lower and statistically non-significant (p=0.31). Overall, our results suggest that concerns around personalization are meaningful and have important implications for the governance of social media and the design of new online environments.

Recruiting patients to participate in clinical trials can be challenging and time-consuming. Usually, participation in a clinical trial is initiated by a healthcare professional and proposed to the patient. Promoting clinical trials directly to patients via online recruitment might help to reach them more efficiently. In this study, we address the case where a patient is initiating their own recruitment process and wants to determine whether they are eligible for a given clinical trial, using their own language to describe their medical profile. To study whether this creates difficulties in the patient trial matching process, we design a new dataset and task, Natural Language Inference for Patient Recruitment (NLI4PR), in which patient language profiles must be matched to clinical trials. We create it by adapting the TREC 2022 Clinical Trial Track dataset, which provides patients' medical profiles, and rephrasing them manually using patient language. We also use the associated clinical trial reports where the patients are either eligible or excluded. We prompt several open-source Large Language Models on our task and achieve from 56.5 to 71.8 of F1 score using patient language, against 64.7 to 73.1 for the same task using medical language. When using patient language, we observe only a small loss in performance for the best model, suggesting that having the patient as a starting point could be adopted to help recruit patients for clinical trials. The corpus and code bases are all freely available on our Github and HuggingFace repositories.

RF/Analog design is essential for bridging digital technologies with real-world signals, ensuring the functionality and reliability of a wide range of electronic systems. However, analog design procedures are often intricate, time-consuming and reliant on expert intuition, and hinder the time and cost efficiency of circuit development. To overcome the limitations of the manual circuit design, we introduce MenTeR - a multiagent workflow integrated into an end-to-end analog design framework. By employing multiple specialized AI agents that collaboratively address different aspects of the design process, such as specification understanding, circuit optimization, and test bench validation, MenTeR reduces the dependency on frequent trial-and-error-style intervention. MenTeR not only accelerates the design cycle time but also facilitates a broader exploration of the design space, demonstrating robust capabilities in handling real-world analog systems. We believe that MenTeR lays the groundwork for future "RF/Analog Copilots" that can collaborate seamlessly with human designers.

Designing neural networks typically relies on manual trial and error or a neural architecture search (NAS) followed by weight training. The former is time-consuming and labor-intensive, while the latter often discretizes architecture search and weight optimization. In this paper, we propose a fundamentally different approach that simultaneously optimizes both the architecture and the weights of a neural network. Our framework first trains a universal multi-scale autoencoder that embeds both architectural and parametric information into a continuous latent space, where functionally similar neural networks are mapped closer together. Given a dataset, we then randomly initialize a point in the embedding space and update it via gradient descent to obtain the optimal neural network, jointly optimizing its structure and weights. The optimization process incorporates sparsity and compactness penalties to promote efficient models. Experiments on synthetic regression tasks demonstrate that our method effectively discovers sparse and compact neural networks with strong performance.

Analog front-end design heavily relies on specialized human expertise and costly trial-and-error simulations, which motivated many prior works on analog design automation. However, efficient and effective exploration of the vast and complex design space remains constrained by the time-consuming nature of SPICE simulations, making effective design automation a challenging endeavor. In this paper, we introduce INSIGHT, a GPU-powered, technology-agnostic, effective universal neural simulator in the analog front-end design automation loop. INSIGHT accurately predicts the performance metrics of analog circuits across various technologies with just a few microseconds of inference time. Notably, its autoregressive capabilities enable INSIGHT to accurately predict simulation-costly critical transient specifications leveraging less expensive performance metric information. The low cost and high fidelity feature make INSIGHT a good substitute for standard simulators in analog front-end optimization frameworks. INSIGHT is compatible with any optimization framework, facilitating enhanced design space exploration for sample efficiency through sophisticated offline learning and adaptation techniques. Our experiments demonstrate that INSIGHT-M, a model-based batch reinforcement learning sizing framework with INSIGHT as the accurate surrogate, only requires < 20 real-time simulations with 100-1000x lower simulation costs and significant speedup over existing sizing methods.

Large Language Models (LLMs) show significant potential for automating Register-Transfer Level (RTL) code generation. However, current approaches face a critical challenge: they can not simultaneously optimize for functional correctness and hardware quality (Power, Performance, Area - PPA). Methods based on supervised fine-tuning often generate functionally correct but PPA-suboptimal code, lacking mechanisms to learn optimization principles. In contrast, post-processing techniques that attempt to improve PPA metrics after generation are often inefficient because they operate externally without updating the LLM's parameters, thus failing to enhance the model's intrinsic design capabilities. To bridge this gap, we introduce ChipSeek-R1, a hierarchical reward-driven reinforcement learning framework to train LLMs to generate RTL code that achieves both functional correctness and optimized PPA metrics. ChipSeek-R1 employs a hierarchical reward system, which incorporates direct feedback on syntax, functional correctness (from simulators) and PPA metrics (from synthesis tools) during reinforcement learning. This enables the model to learn complex hardware design trade-offs via trial-and-error, generating RTL code that is both functionally correct and PPA-optimized. Evaluating ChipSeek-R1 on standard benchmarks (VerilogEval, RTLLM), we achieve state-of-the-art results in functional correctness. Notably, on the RTLLM benchmark, ChipSeek-R1 generated 27 RTL designs surpassing the PPA metrics of the original human-written code. Our findings demonstrate the effectiveness of integrating toolchain feedback into LLM training and highlight the potential for reinforcement learning to enable automated generation of human-surpassing RTL code. We open-source our code in anonymous github.

Contrastive representation learning is crucial in medical time series analysis as it alleviates dependency on labor-intensive, domain-specific, and scarce expert annotations. However, existing contrastive learning methods primarily focus on one single data level, which fails to fully exploit the intricate nature of medical time series. To address this issue, we present COMET, an innovative hierarchical framework that leverages data consistencies at all inherent levels in medical time series. Our meticulously designed model systematically captures data consistency from four potential levels: observation, sample, trial, and patient levels. By developing contrastive loss at multiple levels, we can learn effective representations that preserve comprehensive data consistency, maximizing information utilization in a self-supervised manner. We conduct experiments in the challenging patient-independent setting. We compare COMET against six baselines using three diverse datasets, which include ECG signals for myocardial infarction and EEG signals for Alzheimer's and Parkinson's diseases. The results demonstrate that COMET consistently outperforms all baselines, particularly in setup with 10% and 1% labeled data fractions across all datasets. These results underscore the significant impact of our framework in advancing contrastive representation learning techniques for medical time series. The source code is available at https://github.com/DL4mHealth/COMET.

The ability to discover new materials with desirable properties is critical for numerous applications from helping mitigate climate change to advances in next generation computing hardware. AI has the potential to accelerate materials discovery and design by more effectively exploring the chemical space compared to other computational methods or by trial-and-error. While substantial progress has been made on AI for materials data, benchmarks, and models, a barrier that has emerged is the lack of publicly available training data and open pre-trained models. To address this, we present a Meta FAIR release of the Open Materials 2024 (OMat24) large-scale open dataset and an accompanying set of pre-trained models. OMat24 contains over 110 million density functional theory (DFT) calculations focused on structural and compositional diversity. Our EquiformerV2 models achieve state-of-the-art performance on the Matbench Discovery leaderboard and are capable of predicting ground-state stability and formation energies to an F1 score above 0.9 and an accuracy of 20 meV/atom, respectively. We explore the impact of model size, auxiliary denoising objectives, and fine-tuning on performance across a range of datasets including OMat24, MPtraj, and Alexandria. The open release of the OMat24 dataset and models enables the research community to build upon our efforts and drive further advancements in AI-assisted materials science.

We study the problem of using low computational cost to automate the choices of learners and hyperparameters for an ad-hoc training dataset and error metric, by conducting trials of different configurations on the given training data. We investigate the joint impact of multiple factors on both trial cost and model error, and propose several design guidelines. Following them, we build a fast and lightweight library FLAML which optimizes for low computational resource in finding accurate models. FLAML integrates several simple but effective search strategies into an adaptive system. It significantly outperforms top-ranked AutoML libraries on a large open source AutoML benchmark under equal, or sometimes orders of magnitude smaller budget constraints.

The omnipresence of NP-hard combinatorial optimization problems (COPs) compels domain experts to engage in trial-and-error heuristic design. The long-standing endeavor of design automation has gained new momentum with the rise of large language models (LLMs). This paper introduces Language Hyper-Heuristics (LHHs), an emerging variant of Hyper-Heuristics that leverages LLMs for heuristic generation, featuring minimal manual intervention and open-ended heuristic spaces. To empower LHHs, we present Reflective Evolution (ReEvo), a novel integration of evolutionary search for efficiently exploring the heuristic space, and LLM reflections to provide verbal gradients within the space. Across five heterogeneous algorithmic types, six different COPs, and both white-box and black-box views of COPs, ReEvo yields state-of-the-art and competitive meta-heuristics, evolutionary algorithms, heuristics, and neural solvers, while being more sample-efficient than prior LHHs.

Large language models (LLMs) have formulated a blueprint for the advancement of artificial general intelligence. Its primary objective is to function as a human-centric (helpful, honest, and harmless) assistant. Alignment with humans assumes paramount significance, and reinforcement learning with human feedback (RLHF) emerges as the pivotal technological paradigm underpinning this pursuit. Current technical routes usually include reward models to measure human preferences, Proximal Policy Optimization (PPO) to optimize policy model outputs, and process supervision to improve step-by-step reasoning capabilities. However, due to the challenges of reward design, environment interaction, and agent training, coupled with huge trial and error cost of large language models, there is a significant barrier for AI researchers to motivate the development of technical alignment and safe landing of LLMs. The stable training of RLHF has still been a puzzle. In the first report, we dissect the framework of RLHF, re-evaluate the inner workings of PPO, and explore how the parts comprising PPO algorithms impact policy agent training. We identify policy constraints being the key factor for the effective implementation of the PPO algorithm. Therefore, we explore the PPO-max, an advanced version of PPO algorithm, to efficiently improve the training stability of the policy model. Based on our main results, we perform a comprehensive analysis of RLHF abilities compared with SFT models and ChatGPT. The absence of open-source implementations has posed significant challenges to the investigation of LLMs alignment. Therefore, we are eager to release technical reports, reward models and PPO codes

Polymeric nano- and micro-scale particles have critical roles in tackling critical healthcare and energy challenges with their miniature characteristics. However, tailoring their synthesis process to meet specific design targets has traditionally depended on domain expertise and costly trial-and-errors. Recently, modeling strategies, particularly Bayesian optimization (BO), have been proposed to aid materials discovery for maximized/minimized properties. Coming from practical demands, this study for the first time integrates constrained and composite Bayesian optimization (CCBO) to perform efficient target value optimization under black-box feasibility constraints and limited data for laboratory experimentation. Using a synthetic problem that simulates electrospraying, a model nanomanufacturing process, CCBO strategically avoided infeasible conditions and efficiently optimized particle production towards predefined size targets, surpassing standard BO pipelines and providing decisions comparable to human experts. Further laboratory experiments validated CCBO capability to guide the rational synthesis of poly(lactic-co-glycolic acid) (PLGA) particles with diameters of 300 nm and 3.0 mum via electrospraying. With minimal initial data and unknown experiment constraints, CCBO reached the design targets within 4 iterations. Overall, the CCBO approach presents a versatile and holistic optimization paradigm for next-generation target-driven particle synthesis empowered by artificial intelligence (AI).

Cancer is a complex disease, the understanding and treatment of which are being aided through increases in the volume of collected data and in the scale of deployed computing power. Consequently, there is a growing need for the development of data-driven and, in particular, deep learning methods for various tasks such as cancer diagnosis, detection, prognosis, and prediction. Despite recent successes, however, designing high-performing deep learning models for nonimage and nontext cancer data is a time-consuming, trial-and-error, manual task that requires both cancer domain and deep learning expertise. To that end, we develop a reinforcement-learning-based neural architecture search to automate deep-learning-based predictive model development for a class of representative cancer data. We develop custom building blocks that allow domain experts to incorporate the cancer-data-specific characteristics. We show that our approach discovers deep neural network architectures that have significantly fewer trainable parameters, shorter training time, and accuracy similar to or higher than those of manually designed architectures. We study and demonstrate the scalability of our approach on up to 1,024 Intel Knights Landing nodes of the Theta supercomputer at the Argonne Leadership Computing Facility.

Reward engineering has long been a challenge in Reinforcement Learning (RL) research, as it often requires extensive human effort and iterative processes of trial-and-error to design effective reward functions. In this paper, we propose RL-VLM-F, a method that automatically generates reward functions for agents to learn new tasks, using only a text description of the task goal and the agent's visual observations, by leveraging feedbacks from vision language foundation models (VLMs). The key to our approach is to query these models to give preferences over pairs of the agent's image observations based on the text description of the task goal, and then learn a reward function from the preference labels, rather than directly prompting these models to output a raw reward score, which can be noisy and inconsistent. We demonstrate that RL-VLM-F successfully produces effective rewards and policies across various domains - including classic control, as well as manipulation of rigid, articulated, and deformable objects - without the need for human supervision, outperforming prior methods that use large pretrained models for reward generation under the same assumptions.

Optimization problems over dynamic networks have been extensively studied and widely used in the past decades to formulate numerous real-world problems. However, (1) traditional optimization-based approaches do not scale to large networks, and (2) the design of good heuristics or approximation algorithms often requires significant manual trial-and-error. In this work, we argue that data-driven strategies can automate this process and learn efficient algorithms without compromising optimality. To do so, we present network control problems through the lens of reinforcement learning and propose a graph network-based framework to handle a broad class of problems. Instead of naively computing actions over high-dimensional graph elements, e.g., edges, we propose a bi-level formulation where we (1) specify a desired next state via RL, and (2) solve a convex program to best achieve it, leading to drastically improved scalability and performance. We further highlight a collection of desirable features to system designers, investigate design decisions, and present experiments on real-world control problems showing the utility, scalability, and flexibility of our framework.

Multimodality-to-Multiaudio (MM2MA) generation faces significant challenges in synthesizing diverse and contextually aligned audio types (e.g., sound effects, speech, music, and songs) from multimodal inputs (e.g., video, text, images), owing to the scarcity of high-quality paired datasets and the lack of robust multi-task learning frameworks. Recently, multi-agent system shows great potential in tackling the above issues. However, directly applying it to MM2MA task presents three critical challenges: (1) inadequate fine-grained understanding of multimodal inputs (especially for video), (2) the inability of single models to handle diverse audio events, and (3) the absence of self-correction mechanisms for reliable outputs. To this end, we propose AudioGenie, a novel training-free multi-agent system featuring a dual-layer architecture with a generation team and a supervisor team. For the generation team, a fine-grained task decomposition and an adaptive Mixture-of-Experts (MoE) collaborative entity are designed for dynamic model selection, and a trial-and-error iterative refinement module is designed for self-correction. The supervisor team ensures temporal-spatial consistency and verifies outputs through feedback loops. Moreover, we build MA-Bench, the first benchmark for MM2MA tasks, comprising 198 annotated videos with multi-type audios. Experiments demonstrate that our AudioGenie outperforms state-of-the-art (SOTA) methods across 9 metrics in 8 tasks. User study further validate the effectiveness of the proposed method in terms of quality, accuracy, alignment, and aesthetic. The anonymous project website with samples can be found at https://audiogenie.github.io/.

The expanding computational costs and limited resources underscore the critical need for budgeted-iteration training, which aims to achieve optimal learning within predetermined iteration budgets.While learning rate schedules fundamentally govern the performance of different networks and tasks, particularly in budgeted-iteration scenarios, their design remains largely heuristic, lacking theoretical foundations.In addition, the optimal learning rate schedule requires extensive trial-and-error selection, making the training process inefficient.In this work, we propose the Unified Budget-Aware (UBA) schedule, a theoretically grounded learning rate schedule that consistently outperforms commonly-used schedules among diverse architectures and tasks under different constrained training budgets.First, we bridge the gap by constructing a novel training budget-aware optimization framework, which explicitly accounts for the robustness to landscape curvature variations.From this framework, we derive the UBA schedule, controlled by a single hyper-parameter varphi that provides a trade-off between flexibility and simplicity, eliminating the need for per-network numerical optimization. Moreover, we establish a theoretical connection between varphi and the condition number, adding interpretation and justification to our approach. Besides, we prove the convergence for different values of varphi.We offer practical guidelines for its selection via theoretical analysis and empirical results.xtensive experimental results show that UBA consistently surpasses the commonly-used schedules across diverse vision and language tasks, spanning network architectures (e.g., ResNet, OLMo) and scales, under different training-iteration budgets.

We study the problem of adaptively identifying patient subpopulations that benefit from a given treatment during a confirmatory clinical trial. This type of adaptive clinical trial has been thoroughly studied in biostatistics, but has been allowed only limited adaptivity so far. Here, we aim to relax classical restrictions on such designs and investigate how to incorporate ideas from the recent machine learning literature on adaptive and online experimentation to make trials more flexible and efficient. We find that the unique characteristics of the subpopulation selection problem -- most importantly that (i) one is usually interested in finding subpopulations with any treatment benefit (and not necessarily the single subgroup with largest effect) given a limited budget and that (ii) effectiveness only has to be demonstrated across the subpopulation on average -- give rise to interesting challenges and new desiderata when designing algorithmic solutions. Building on these findings, we propose AdaGGI and AdaGCPI, two meta-algorithms for subpopulation construction. We empirically investigate their performance across a range of simulation scenarios and derive insights into their (dis)advantages across different settings.

Understanding causality should be a core requirement of any attempt to build real impact through AI. Due to the inherent unobservability of counterfactuals, large randomised trials (RCTs) are the standard for causal inference. But large experiments are generically expensive, and randomisation carries its own costs, e.g. when suboptimal decisions are trialed. Recent work has proposed more sample-efficient alternatives to RCTs, but these are not adaptable to the downstream application for which the causal effect is sought. In this work, we develop a task-specific approach to experimental design and derive sampling strategies customised to particular downstream applications. Across a range of important tasks, real-world datasets, and sample sizes, our method outperforms other benchmarks, e.g. requiring an order-of-magnitude less data to match RCT performance on targeted marketing tasks.

Patient recruitment is challenging for clinical trials. We introduce TrialGPT, an end-to-end framework for zero-shot patient-to-trial matching with large language models. TrialGPT comprises three modules: it first performs large-scale filtering to retrieve candidate trials (TrialGPT-Retrieval); then predicts criterion-level patient eligibility (TrialGPT-Matching); and finally generates trial-level scores (TrialGPT-Ranking). We evaluate TrialGPT on three cohorts of 183 synthetic patients with over 75,000 trial annotations. TrialGPT-Retrieval can recall over 90% of relevant trials using less than 6% of the initial collection. Manual evaluations on 1,015 patient-criterion pairs show that TrialGPT-Matching achieves an accuracy of 87.3% with faithful explanations, close to the expert performance. The TrialGPT-Ranking scores are highly correlated with human judgments and outperform the best-competing models by 43.8% in ranking and excluding trials. Furthermore, our user study reveals that TrialGPT can reduce the screening time by 42.6% in patient recruitment. Overall, these results have demonstrated promising opportunities for patient-to-trial matching with TrialGPT.

Clinical trial matching is a key process in health delivery and discovery. In practice, it is plagued by overwhelming unstructured data and unscalable manual processing. In this paper, we conduct a systematic study on scaling clinical trial matching using large language models (LLMs), with oncology as the focus area. Our study is grounded in a clinical trial matching system currently in test deployment at a large U.S. health network. Initial findings are promising: out of box, cutting-edge LLMs, such as GPT-4, can already structure elaborate eligibility criteria of clinical trials and extract complex matching logic (e.g., nested AND/OR/NOT). While still far from perfect, LLMs substantially outperform prior strong baselines and may serve as a preliminary solution to help triage patient-trial candidates with humans in the loop. Our study also reveals a few significant growth areas for applying LLMs to end-to-end clinical trial matching, such as context limitation and accuracy, especially in structuring patient information from longitudinal medical records.

Synthesizing clinical evidence largely relies on systematic reviews of clinical trials and retrospective analyses from medical literature. However, the rapid expansion of publications presents challenges in efficiently identifying, summarizing, and updating clinical evidence. Here, we introduce TrialMind, a generative artificial intelligence (AI) pipeline for facilitating human-AI collaboration in three crucial tasks for evidence synthesis: study search, screening, and data extraction. To assess its performance, we chose published systematic reviews to build the benchmark dataset, named TrialReviewBench, which contains 100 systematic reviews and the associated 2,220 clinical studies. Our results show that TrialMind excels across all three tasks. In study search, it generates diverse and comprehensive search queries to achieve high recall rates (Ours 0.711-0.834 v.s. Human baseline 0.138-0.232). For study screening, TrialMind surpasses traditional embedding-based methods by 30% to 160%. In data extraction, it outperforms a GPT-4 baseline by 29.6% to 61.5%. We further conducted user studies to confirm its practical utility. Compared to manual efforts, human-AI collaboration using TrialMind yielded a 71.4% recall lift and 44.2% time savings in study screening and a 23.5% accuracy lift and 63.4% time savings in data extraction. Additionally, when comparing synthesized clinical evidence presented in forest plots, medical experts favored TrialMind's outputs over GPT-4's outputs in 62.5% to 100% of cases. These findings show the promise of LLM-based approaches like TrialMind to accelerate clinical evidence synthesis via streamlining study search, screening, and data extraction from medical literature, with exceptional performance improvement when working with human experts.

Clinical trial matching is the task of identifying trials for which patients may be potentially eligible. Typically, this task is labor-intensive and requires detailed verification of patient electronic health records (EHRs) against the stringent inclusion and exclusion criteria of clinical trials. This process is manual, time-intensive, and challenging to scale up, resulting in many patients missing out on potential therapeutic options. Recent advancements in Large Language Models (LLMs) have made automating patient-trial matching possible, as shown in multiple concurrent research studies. However, the current approaches are confined to constrained, often synthetic datasets that do not adequately mirror the complexities encountered in real-world medical data. In this study, we present the first, end-to-end large-scale empirical evaluation of clinical trial matching using real-world EHRs. Our study showcases the capability of LLMs to accurately match patients with appropriate clinical trials. We perform experiments with proprietary LLMs, including GPT-4 and GPT-3.5, as well as our custom fine-tuned model called OncoLLM and show that OncoLLM, despite its significantly smaller size, not only outperforms GPT-3.5 but also matches the performance of qualified medical doctors. All experiments were carried out on real-world EHRs that include clinical notes and available clinical trials from a single cancer center in the United States.

We consider the task of evaluating policies of algorithmic resource allocation through randomized controlled trials (RCTs). Such policies are tasked with optimizing the utilization of limited intervention resources, with the goal of maximizing the benefits derived. Evaluation of such allocation policies through RCTs proves difficult, notwithstanding the scale of the trial, because the individuals' outcomes are inextricably interlinked through resource constraints controlling the policy decisions. Our key contribution is to present a new estimator leveraging our proposed novel concept, that involves retrospective reshuffling of participants across experimental arms at the end of an RCT. We identify conditions under which such reassignments are permissible and can be leveraged to construct counterfactual trials, whose outcomes can be accurately ascertained, for free. We prove theoretically that such an estimator is more accurate than common estimators based on sample means -- we show that it returns an unbiased estimate and simultaneously reduces variance. We demonstrate the value of our approach through empirical experiments on synthetic, semi-synthetic as well as real case study data and show improved estimation accuracy across the board.

Clinical trials or studies oftentimes require long-term and/or costly follow-up of participants to evaluate a novel treatment/drug/vaccine. There has been increasing interest in the past few decades in using short-term surrogate outcomes as a replacement of the primary outcome i.e., in using the surrogate outcome, which can potentially be observed sooner, to make inference about the treatment effect on the long-term primary outcome. Very few of the available statistical methods to evaluate a surrogate are applicable to settings where both the surrogate and the primary outcome are time-to-event outcomes subject to censoring. Methods that can handle this setting tend to require parametric assumptions or be limited to assessing only the restricted mean survival time. In this paper, we propose a non-parametric approach to evaluate a censored surrogate outcome, such as time to progression, when the primary outcome is also a censored time-to-event outcome, such as time to death, and the treatment effect of interest is the difference in overall survival. Specifically, we define the proportion of the treatment effect on the primary outcome that is explained (PTE) by the censored surrogate outcome in this context, and estimate this proportion by defining and deriving an optimal transformation of the surrogate information. Our approach provides the added advantage of relaxed assumptions to guarantee that the true PTE is within (0,1), along with being model-free. Finite sample performance of our estimators are illustrated via extensive simulation studies and a real data application examining progression-free survival as a surrogate for overall survival for patients with metastatic colorectal cancer.

Randomized controlled trials (RCTs) are considered the gold standard for estimating the average treatment effect (ATE) of interventions. One use of RCTs is to study the causes of global poverty -- a subject explicitly cited in the 2019 Nobel Memorial Prize awarded to Duflo, Banerjee, and Kremer "for their experimental approach to alleviating global poverty." Because the ATE is a population summary, anti-poverty experiments often seek to unpack the effect variation around the ATE by conditioning (CATE) on tabular variables such as age and ethnicity that were measured during the RCT data collection. Although such variables are key to unpacking CATE, using only such variables may fail to capture historical, geographical, or neighborhood-specific contributors to effect variation, as tabular RCT data are often only observed near the time of the experiment. In global poverty research, when the location of the experiment units is approximately known, satellite imagery can provide a window into such factors important for understanding heterogeneity. However, there is no method that specifically enables applied researchers to analyze CATE from images. In this paper, using a deep probabilistic modeling framework, we develop such a method that estimates latent clusters of images by identifying images with similar treatment effects distributions. Our interpretable image CATE model also includes a sensitivity factor that quantifies the importance of image segments contributing to the effect cluster prediction. We compare the proposed methods against alternatives in simulation; also, we show how the model works in an actual RCT, estimating the effects of an anti-poverty intervention in northern Uganda and obtaining a posterior predictive distribution over effects for the rest of the country where no experimental data was collected. We make all models available in open-source software.

Dynamic treatment regimes (DTRs) are personalized, adaptive, multi-stage treatment plans that adapt treatment decisions both to an individual's initial features and to intermediate outcomes and features at each subsequent stage, which are affected by decisions in prior stages. Examples include personalized first- and second-line treatments of chronic conditions like diabetes, cancer, and depression, which adapt to patient response to first-line treatment, disease progression, and individual characteristics. While existing literature mostly focuses on estimating the optimal DTR from offline data such as from sequentially randomized trials, we study the problem of developing the optimal DTR in an online manner, where the interaction with each individual affect both our cumulative reward and our data collection for future learning. We term this the DTR bandit problem. We propose a novel algorithm that, by carefully balancing exploration and exploitation, is guaranteed to achieve rate-optimal regret when the transition and reward models are linear. We demonstrate our algorithm and its benefits both in synthetic experiments and in a case study of adaptive treatment of major depressive disorder using real-world data.

We introduce Seed1.5-Thinking, capable of reasoning through thinking before responding, resulting in improved performance on a wide range of benchmarks. Seed1.5-Thinking achieves 86.7 on AIME 2024, 55.0 on Codeforces and 77.3 on GPQA, demonstrating excellent reasoning abilities in STEM and coding. Beyond reasoning tasks, the method demonstrates notable generalization across diverse domains. For instance, it surpasses DeepSeek R1 by 8% in win rate on non-reasoning tasks, indicating its broader applicability. Compared to other state-of-the-art reasoning models, Seed1.5-Thinking is a Mixture-of-Experts (MoE) model with a relatively small size, featuring 20B activated and 200B total parameters. As part of our effort to assess generalized reasoning, we develop two internal benchmarks, BeyondAIME and Codeforces, both of which will be publicly released to support future research. Model trial link: https://www.volcengine.com/experience/ark.

Reinforcement learning (RL) over text representations can be effective for finding high-value policies that can search over graphs. However, RL requires careful structuring of the search space and algorithm design to be effective in this challenge. Through extensive experiments, we explore how different design choices for text grammar and algorithmic choices for training can affect an RL policy's ability to generate molecules with desired properties. We arrive at a new RL-based molecular design algorithm (ChemRLformer) and perform a thorough analysis using 25 molecule design tasks, including computationally complex protein docking simulations. From this analysis, we discover unique insights in this problem space and show that ChemRLformer achieves state-of-the-art performance while being more straightforward than prior work by demystifying which design choices are actually helpful for text-based molecule design.

Indirect experiments provide a valuable framework for estimating treatment effects in situations where conducting randomized control trials (RCTs) is impractical or unethical. Unlike RCTs, indirect experiments estimate treatment effects by leveraging (conditional) instrumental variables, enabling estimation through encouragement and recommendation rather than strict treatment assignment. However, the sample efficiency of such estimators depends not only on the inherent variability in outcomes but also on the varying compliance levels of users with the instrumental variables and the choice of estimator being used, especially when dealing with numerous instrumental variables. While adaptive experiment design has a rich literature for direct experiments, in this paper we take the initial steps towards enhancing sample efficiency for indirect experiments by adaptively designing a data collection policy over instrumental variables. Our main contribution is a practical computational procedure that utilizes influence functions to search for an optimal data collection policy, minimizing the mean-squared error of the desired (non-linear) estimator. Through experiments conducted in various domains inspired by real-world applications, we showcase how our method can significantly improve the sample efficiency of indirect experiments.

Protein design, a grand challenge of the day, involves optimization on a fitness landscape, and leading methods adopt a model-based approach where a model is trained on a training set (protein sequences and fitness) and proposes candidates to explore next. These methods are challenged by sparsity of high-fitness samples in the training set, a problem that has been in the literature. A less recognized but equally important problem stems from the distribution of training samples in the design space: leading methods are not designed for scenarios where the desired optimum is in a region that is not only poorly represented in training data, but also relatively far from the highly represented low-fitness regions. We show that this problem of "separation" in the design space is a significant bottleneck in existing model-based optimization tools and propose a new approach that uses a novel VAE as its search model to overcome the problem. We demonstrate its advantage over prior methods in robustly finding improved samples, regardless of the imbalance and separation between low- and high-fitness training samples. Our comprehensive benchmark on real and semi-synthetic protein datasets as well as solution design for physics-informed neural networks, showcases the generality of our approach in discrete and continuous design spaces. Our implementation is available at https://github.com/sabagh1994/PGVAE.

Clinical trials drive improvements in cancer treatments and outcomes. However, most adults with cancer do not participate in trials, and trials often fail to enroll enough patients to answer their scientific questions. Artificial intelligence could accelerate matching of patients to appropriate clinical trials. Here, we describe the development and evaluation of the MatchMiner-AI pipeline for clinical trial searching and ranking. MatchMiner-AI focuses on matching patients to potential trials based on core criteria describing clinical "spaces," or disease contexts, targeted by a trial. It aims to accelerate the human work of identifying potential matches, not to fully automate trial screening. The pipeline includes modules for extraction of key information from a patient's longitudinal electronic health record; rapid ranking of candidate trial-patient matches based on embeddings in vector space; and classification of whether a candidate match represents a reasonable clinical consideration. Code and synthetic data are available at https://huggingface.co/ksg-dfci/MatchMiner-AI . Model weights based on synthetic data are available at https://huggingface.co/ksg-dfci/TrialSpace and https://huggingface.co/ksg-dfci/TrialChecker . A simple cancer clinical trial search engine to demonstrate pipeline components is available at https://huggingface.co/spaces/ksg-dfci/trial_search_alpha .

To effectively optimize and personalize treatments, it is necessary to investigate the heterogeneity of treatment effects. With the wide range of users being treated over many online controlled experiments, the typical approach of manually investigating each dimension of heterogeneity becomes overly cumbersome and prone to subjective human biases. We need an efficient way to search through thousands of experiments with hundreds of target covariates and hundreds of breakdown dimensions. In this paper, we propose a systematic paradigm for detecting, surfacing and characterizing heterogeneous treatment effects. First, we detect if treatment effect variation is present in an experiment, prior to specifying any breakdowns. Second, we surface the most relevant dimensions for heterogeneity. Finally, we characterize the heterogeneity beyond just the conditional average treatment effects (CATE) by studying the conditional distributions of the estimated individual treatment effects. We show the effectiveness of our methods using simulated data and empirical studies.

Scientific discovery relies on scientists generating novel hypotheses that undergo rigorous experimental validation. To augment this process, we introduce an AI co-scientist, a multi-agent system built on Gemini 2.0. The AI co-scientist is intended to help uncover new, original knowledge and to formulate demonstrably novel research hypotheses and proposals, building upon prior evidence and aligned to scientist-provided research objectives and guidance. The system's design incorporates a generate, debate, and evolve approach to hypothesis generation, inspired by the scientific method and accelerated by scaling test-time compute. Key contributions include: (1) a multi-agent architecture with an asynchronous task execution framework for flexible compute scaling; (2) a tournament evolution process for self-improving hypotheses generation. Automated evaluations show continued benefits of test-time compute, improving hypothesis quality. While general purpose, we focus development and validation in three biomedical areas: drug repurposing, novel target discovery, and explaining mechanisms of bacterial evolution and anti-microbial resistance. For drug repurposing, the system proposes candidates with promising validation findings, including candidates for acute myeloid leukemia that show tumor inhibition in vitro at clinically applicable concentrations. For novel target discovery, the AI co-scientist proposed new epigenetic targets for liver fibrosis, validated by anti-fibrotic activity and liver cell regeneration in human hepatic organoids. Finally, the AI co-scientist recapitulated unpublished experimental results via a parallel in silico discovery of a novel gene transfer mechanism in bacterial evolution. These results, detailed in separate, co-timed reports, demonstrate the potential to augment biomedical and scientific discovery and usher an era of AI empowered scientists.

Randomized controlled trials are susceptible to imbalance on covariates predictive of the outcome. Rerandomization and deterministic treatment assignment are two proposed solutions. This paper explores the relationship between rerandomization and deterministic assignment, showing how deterministic assignment is an extreme case of rerandomization. The paper argues that in small experiments, both fully randomized and fully deterministic assignment have limitations. Instead, the researcher should consider setting the rerandomization acceptance probability based on an analysis of covariates and assumptions about the data structure to achieve an optimal alignment between randomness and balance. This allows for the calculation of minimum p-values along with valid permutation tests and fiducial intervals. The paper also introduces tools, including a new, open-source R package named fastrerandomize, to implement rerandomization and explore options for optimal rerandomization acceptance thresholds.

The global cost of drug discovery and development exceeds $200 billion annually. The main results of drug discovery and development are the outcomes of clinical trials, which directly influence the regulatory approval of new drug candidates and ultimately affect patient outcomes. Despite their significance, large-scale, high-quality clinical trial outcome data are not readily available to the public. Suppose a large clinical trial outcome dataset is provided; machine learning researchers can potentially develop accurate prediction models using past trials and outcome labels, which could help prioritize and optimize therapeutic programs, ultimately benefiting patients. This paper introduces Clinical Trial Outcome (CTO) dataset, the largest trial outcome dataset with around 479K clinical trials, aggregating outcomes from multiple sources of weakly supervised labels, minimizing the noise from individual sources, and eliminating the need for human annotation. These sources include large language model (LLM) decisions on trial-related documents, news headline sentiments, stock prices of trial sponsors, trial linkages across phases, and other signals such as patient dropout rates and adverse events. CTO's labels show unprecedented agreement with supervised clinical trial outcome labels from test split of the supervised TOP dataset, with a 91 F1.

Building on developments in machine learning and prior work in the science of judicial prediction, we construct a model designed to predict the behavior of the Supreme Court of the United States in a generalized, out-of-sample context. To do so, we develop a time evolving random forest classifier which leverages some unique feature engineering to predict more than 240,000 justice votes and 28,000 cases outcomes over nearly two centuries (1816-2015). Using only data available prior to decision, our model outperforms null (baseline) models at both the justice and case level under both parametric and non-parametric tests. Over nearly two centuries, we achieve 70.2% accuracy at the case outcome level and 71.9% at the justice vote level. More recently, over the past century, we outperform an in-sample optimized null model by nearly 5%. Our performance is consistent with, and improves on the general level of prediction demonstrated by prior work; however, our model is distinctive because it can be applied out-of-sample to the entire past and future of the Court, not a single term. Our results represent an important advance for the science of quantitative legal prediction and portend a range of other potential applications.

When deploying machine learning models in high-stakes real-world environments such as health care, it is crucial to accurately assess the uncertainty concerning a model's prediction on abnormal inputs. However, there is a scarcity of literature analyzing this problem on medical data, especially on mixed-type tabular data such as Electronic Health Records. We close this gap by presenting a series of tests including a large variety of contemporary uncertainty estimation techniques, in order to determine whether they are able to identify out-of-distribution (OOD) patients. In contrast to previous work, we design tests on realistic and clinically relevant OOD groups, and run experiments on real-world medical data. We find that almost all techniques fail to achieve convincing results, partly disagreeing with earlier findings.

Next token prediction paradigm has been prevailing for autoregressive models in the era of LLMs. The current default sampling choice for popular LLMs is temperature scaling together with nucleus sampling to balance diversity and coherence. Nevertheless, such approach leads to inferior performance in various NLP tasks when the model is not certain about testing questions. To this end, we propose a brand new training-free decoding strategy, dubbed as Cautious Next Token Prediction (CNTP). In the decoding process, if the model has comparatively high prediction entropy at a certain step, we sample multiple trials starting from the step independently and stop when encountering any punctuation. Then we select the trial with the lowest perplexity score viewed as the most probable and reliable trial path given the model's capacity. The trial number is negatively correlated with the prediction confidence, i.e., the less confident the model is, the more trials it should sample. This is consistent with human beings' behaviour: when feeling uncertain or unconfident, one tends to think more creatively, exploring multiple thinking paths, to cautiously select the path one feels most confident about. Extensive experiments on both LLMs and MLLMs show that our proposed CNTP approach outperforms existing standard decoding strategies consistently by a clear margin. Moreover, the integration of CNTP with self consistency can further improve over vanilla self consistency. We believe our proposed CNTP has the potential to become one of the default choices for LLM decoding. Code is available at https://github.com/wyzjack/CNTP.

This article introduces Regression Discontinuity Design (RDD) with Distribution-Valued Outcomes (R3D), extending the standard RDD framework to settings where the outcome is a distribution rather than a scalar. Such settings arise when treatment is assigned at a higher level of aggregation than the outcome-for example, when a subsidy is allocated based on a firm-level revenue cutoff while the outcome of interest is the distribution of employee wages within the firm. Since standard RDD methods cannot accommodate such two-level randomness, I propose a novel approach based on random distributions. The target estimand is a "local average quantile treatment effect", which averages across random quantiles. To estimate this target, I introduce two related approaches: one that extends local polynomial regression to random quantiles and another based on local Fr\'echet regression, a form of functional regression. For both estimators, I establish asymptotic normality and develop uniform, debiased confidence bands together with a data-driven bandwidth selection procedure. Simulations validate these theoretical properties and show existing methods to be biased and inconsistent in this setting. I then apply the proposed methods to study the effects of gubernatorial party control on within-state income distributions in the US, using a close-election design. The results suggest a classic equality-efficiency tradeoff under Democratic governorship, driven by reductions in income at the top of the distribution.

With an increasing number of replication studies performed in psychological science, the question of how to evaluate the outcome of a replication attempt deserves careful consideration. Bayesian approaches allow to incorporate uncertainty and prior information into the analysis of the replication attempt by their design. The Replication Bayes Factor, introduced by Verhagen & Wagenmakers (2014), provides quantitative, relative evidence in favor or against a successful replication. In previous work by Verhagen & Wagenmakers (2014) it was limited to the case of t-tests. In this paper, the Replication Bayes Factor is extended to F-tests in multi-group, fixed-effect ANOVA designs. Simulations and examples are presented to facilitate the understanding and to demonstrate the usefulness of this approach. Finally, the Replication Bayes Factor is compared to other Bayesian and frequentist approaches and discussed in the context of replication attempts. R code to calculate Replication Bayes factors and to reproduce the examples in the paper is available at https://osf.io/jv39h/.

Recent advancements in large language models (LLMs) have sparked optimism about their potential to accelerate scientific discovery, with a growing number of works proposing research agents that autonomously generate and validate new ideas. Despite this, no evaluations have shown that LLM systems can take the very first step of producing novel, expert-level ideas, let alone perform the entire research process. We address this by establishing an experimental design that evaluates research idea generation while controlling for confounders and performs the first head-to-head comparison between expert NLP researchers and an LLM ideation agent. By recruiting over 100 NLP researchers to write novel ideas and blind reviews of both LLM and human ideas, we obtain the first statistically significant conclusion on current LLM capabilities for research ideation: we find LLM-generated ideas are judged as more novel (p < 0.05) than human expert ideas while being judged slightly weaker on feasibility. Studying our agent baselines closely, we identify open problems in building and evaluating research agents, including failures of LLM self-evaluation and their lack of diversity in generation. Finally, we acknowledge that human judgements of novelty can be difficult, even by experts, and propose an end-to-end study design which recruits researchers to execute these ideas into full projects, enabling us to study whether these novelty and feasibility judgements result in meaningful differences in research outcome.

Reward models are key in reinforcement learning from human feedback (RLHF) systems, aligning the model behavior with human preferences. Particularly in the math domain, there have been plenty of studies using reward models to align policies for improving reasoning capabilities. Recently, as the importance of reward models has been emphasized, RewardBench is proposed to understand their behavior. However, we figure out that the math subset of RewardBench has different representations between chosen and rejected completions, and relies on a single comparison, which may lead to unreliable results as it only see an isolated case. Therefore, it fails to accurately present the robustness of reward models, leading to a misunderstanding of its performance and potentially resulting in reward hacking. In this work, we introduce a new design for reliable evaluation of reward models, and to validate this, we construct RewardMATH, a benchmark that effectively represents the robustness of reward models in mathematical reasoning tasks. We demonstrate that the scores on RewardMATH strongly correlate with the results of optimized policy and effectively estimate reward overoptimization, whereas the existing benchmark shows almost no correlation. The results underscore the potential of our design to enhance the reliability of evaluation, and represent the robustness of reward model. We make our code and data publicly available.

We introduce DEsignBench, a text-to-image (T2I) generation benchmark tailored for visual design scenarios. Recent T2I models like DALL-E 3 and others, have demonstrated remarkable capabilities in generating photorealistic images that align closely with textual inputs. While the allure of creating visually captivating images is undeniable, our emphasis extends beyond mere aesthetic pleasure. We aim to investigate the potential of using these powerful models in authentic design contexts. In pursuit of this goal, we develop DEsignBench, which incorporates test samples designed to assess T2I models on both "design technical capability" and "design application scenario." Each of these two dimensions is supported by a diverse set of specific design categories. We explore DALL-E 3 together with other leading T2I models on DEsignBench, resulting in a comprehensive visual gallery for side-by-side comparisons. For DEsignBench benchmarking, we perform human evaluations on generated images in DEsignBench gallery, against the criteria of image-text alignment, visual aesthetic, and design creativity. Our evaluation also considers other specialized design capabilities, including text rendering, layout composition, color harmony, 3D design, and medium style. In addition to human evaluations, we introduce the first automatic image generation evaluator powered by GPT-4V. This evaluator provides ratings that align well with human judgments, while being easily replicable and cost-efficient. A high-resolution version is available at https://github.com/design-bench/design-bench.github.io/raw/main/designbench.pdf?download=

Offline reinforcement learning (RL) allows agents to learn effective, return-maximizing policies from a static dataset. Three popular algorithms for offline RL are Conservative Q-Learning (CQL), Behavior Cloning (BC), and Decision Transformer (DT), from the class of Q-Learning, Imitation Learning, and Sequence Modeling respectively. A key open question is: which algorithm is preferred under what conditions? We study this question empirically by exploring the performance of these algorithms across the commonly used D4RL and Robomimic benchmarks. We design targeted experiments to understand their behavior concerning data suboptimality, task complexity, and stochasticity. Our key findings are: (1) DT requires more data than CQL to learn competitive policies but is more robust; (2) DT is a substantially better choice than both CQL and BC in sparse-reward and low-quality data settings; (3) DT and BC are preferable as task horizon increases, or when data is obtained from human demonstrators; and (4) CQL excels in situations characterized by the combination of high stochasticity and low data quality. We also investigate architectural choices and scaling trends for DT on Atari and D4RL and make design/scaling recommendations. We find that scaling the amount of data for DT by 5x gives a 2.5x average score improvement on Atari.

How do we most effectively treat a disease or condition? Ideally, we could consult a database of evidence gleaned from clinical trials to answer such questions. Unfortunately, no such database exists; clinical trial results are instead disseminated primarily via lengthy natural language articles. Perusing all such articles would be prohibitively time-consuming for healthcare practitioners; they instead tend to depend on manually compiled systematic reviews of medical literature to inform care. NLP may speed this process up, and eventually facilitate immediate consult of published evidence. The Evidence Inference dataset was recently released to facilitate research toward this end. This task entails inferring the comparative performance of two treatments, with respect to a given outcome, from a particular article (describing a clinical trial) and identifying supporting evidence. For instance: Does this article report that chemotherapy performed better than surgery for five-year survival rates of operable cancers? In this paper, we collect additional annotations to expand the Evidence Inference dataset by 25\%, provide stronger baseline models, systematically inspect the errors that these make, and probe dataset quality. We also release an abstract only (as opposed to full-texts) version of the task for rapid model prototyping. The updated corpus, documentation, and code for new baselines and evaluations are available at http://evidence-inference.ebm-nlp.com/.

To generate evidence regarding the safety and efficacy of artificial intelligence (AI) enabled medical devices, AI models need to be evaluated on a diverse population of patient cases, some of which may not be readily available. We propose an evaluation approach for testing medical imaging AI models that relies on in silico imaging pipelines in which stochastic digital models of human anatomy (in object space) with and without pathology are imaged using a digital replica imaging acquisition system to generate realistic synthetic image datasets. Here, we release M-SYNTH, a dataset of cohorts with four breast fibroglandular density distributions imaged at different exposure levels using Monte Carlo x-ray simulations with the publicly available Virtual Imaging Clinical Trial for Regulatory Evaluation (VICTRE) toolkit. We utilize the synthetic dataset to analyze AI model performance and find that model performance decreases with increasing breast density and increases with higher mass density, as expected. As exposure levels decrease, AI model performance drops with the highest performance achieved at exposure levels lower than the nominal recommended dose for the breast type.

We introduce a gradient-based approach for the problem of Bayesian optimal experimental design to learn causal models in a batch setting -- a critical component for causal discovery from finite data where interventions can be costly or risky. Existing methods rely on greedy approximations to construct a batch of experiments while using black-box methods to optimize over a single target-state pair to intervene with. In this work, we completely dispose of the black-box optimization techniques and greedy heuristics and instead propose a conceptually simple end-to-end gradient-based optimization procedure to acquire a set of optimal intervention target-state pairs. Such a procedure enables parameterization of the design space to efficiently optimize over a batch of multi-target-state interventions, a setting which has hitherto not been explored due to its complexity. We demonstrate that our proposed method outperforms baselines and existing acquisition strategies in both single-target and multi-target settings across a number of synthetic datasets.

We introduce Multi-Objective Counterfactuals for Design (MCD), a novel method for counterfactual optimization in design problems. Counterfactuals are hypothetical situations that can lead to a different decision or choice. In this paper, the authors frame the counterfactual search problem as a design recommendation tool that can help identify modifications to a design, leading to better functional performance. MCD improves upon existing counterfactual search methods by supporting multi-objective queries, which are crucial in design problems, and by decoupling the counterfactual search and sampling processes, thus enhancing efficiency and facilitating objective tradeoff visualization. The paper demonstrates MCD's core functionality using a two-dimensional test case, followed by three case studies of bicycle design that showcase MCD's effectiveness in real-world design problems. In the first case study, MCD excels at recommending modifications to query designs that can significantly enhance functional performance, such as weight savings and improvements to the structural safety factor. The second case study demonstrates that MCD can work with a pre-trained language model to suggest design changes based on a subjective text prompt effectively. Lastly, the authors task MCD with increasing a query design's similarity to a target image and text prompt while simultaneously reducing weight and improving structural performance, demonstrating MCD's performance on a complex multimodal query. Overall, MCD has the potential to provide valuable recommendations for practitioners and design automation researchers looking for answers to their ``What if'' questions by exploring hypothetical design modifications and their impact on multiple design objectives. The code, test problems, and datasets used in the paper are available to the public at decode.mit.edu/projects/counterfactuals/.

Generalist foundation models such as GPT-4 have displayed surprising capabilities in a wide variety of domains and tasks. Yet, there is a prevalent assumption that they cannot match specialist capabilities of fine-tuned models. For example, most explorations to date on medical competency benchmarks have leveraged domain-specific training, as exemplified by efforts on BioGPT and Med-PaLM. We build on a prior study of GPT-4's capabilities on medical challenge benchmarks in the absence of special training. Rather than using simple prompting to highlight the model's out-of-the-box capabilities, we perform a systematic exploration of prompt engineering. We find that prompting innovation can unlock deeper specialist capabilities and show that GPT-4 easily tops prior leading results for medical benchmarks. The prompting methods we explore are general purpose, and make no specific use of domain expertise, removing the need for expert-curated content. Our experimental design carefully controls for overfitting during the prompt engineering process. We introduce Medprompt, based on a composition of several prompting strategies. With Medprompt, GPT-4 achieves state-of-the-art results on all nine of the benchmark datasets in the MultiMedQA suite. The method outperforms leading specialist models such as Med-PaLM 2 by a significant margin with an order of magnitude fewer calls to the model. Steering GPT-4 with Medprompt achieves a 27% reduction in error rate on the MedQA dataset over the best methods to date achieved with specialist models and surpasses a score of 90% for the first time. Beyond medical problems, we show the power of Medprompt to generalize to other domains and provide evidence for the broad applicability of the approach via studies of the strategy on exams in electrical engineering, machine learning, philosophy, accounting, law, nursing, and clinical psychology.

Temporally dense single-person "small data" have become widely available thanks to mobile apps and wearable sensors. Many caregivers and self-trackers want to use these data to help a specific person change their behavior to achieve desired health outcomes. Ideally, this involves discerning possible causes from correlations using that person's own observational time series data. In this paper, we estimate within-individual average treatment effects of physical activity on sleep duration, and vice-versa. We introduce the model twin randomization (MoTR; "motor") method for analyzing an individual's intensive longitudinal data. Formally, MoTR is an application of the g-formula (i.e., standardization, back-door adjustment) under serial interference. It estimates stable recurring effects, as is done in n-of-1 trials and single case experimental designs. We compare our approach to standard methods (with possible confounding) to show how to use causal inference to make better personalized recommendations for health behavior change, and analyze 222 days of Fitbit sleep and steps data for one of the authors.

Machine learning (ML) holds great potential for accurately forecasting treatment outcomes over time, which could ultimately enable the adoption of more individualized treatment strategies in many practical applications. However, a significant challenge that has been largely overlooked by the ML literature on this topic is the presence of informative sampling in observational data. When instances are observed irregularly over time, sampling times are typically not random, but rather informative -- depending on the instance's characteristics, past outcomes, and administered treatments. In this work, we formalize informative sampling as a covariate shift problem and show that it can prohibit accurate estimation of treatment outcomes if not properly accounted for. To overcome this challenge, we present a general framework for learning treatment outcomes in the presence of informative sampling using inverse intensity-weighting, and propose a novel method, TESAR-CDE, that instantiates this framework using Neural CDEs. Using a simulation environment based on a clinical use case, we demonstrate the effectiveness of our approach in learning under informative sampling.

Large language models (LLMs) hold great potential for many natural language applications but risk generating incorrect or toxic content. To probe when an LLM generates unwanted content, the current paradigm is to recruit a red team of human testers to design input prompts (i.e., test cases) that elicit undesirable responses from LLMs. However, relying solely on human testers is expensive and time-consuming. Recent works automate red teaming by training a separate red team LLM with reinforcement learning (RL) to generate test cases that maximize the chance of eliciting undesirable responses from the target LLM. However, current RL methods are only able to generate a small number of effective test cases resulting in a low coverage of the span of prompts that elicit undesirable responses from the target LLM. To overcome this limitation, we draw a connection between the problem of increasing the coverage of generated test cases and the well-studied approach of curiosity-driven exploration that optimizes for novelty. Our method of curiosity-driven red teaming (CRT) achieves greater coverage of test cases while mantaining or increasing their effectiveness compared to existing methods. Our method, CRT successfully provokes toxic responses from LLaMA2 model that has been heavily fine-tuned using human preferences to avoid toxic outputs. Code is available at https://github.com/Improbable-AI/curiosity_redteam

Benchmarking is seen as critical to assessing progress in NLP. However, creating a benchmark involves many design decisions (e.g., which datasets to include, which metrics to use) that often rely on tacit, untested assumptions about what the benchmark is intended to measure or is actually measuring. There is currently no principled way of analyzing these decisions and how they impact the validity of the benchmark's measurements. To address this gap, we draw on evidence-centered design in educational assessments and propose Evidence-Centered Benchmark Design (ECBD), a framework which formalizes the benchmark design process into five modules. ECBD specifies the role each module plays in helping practitioners collect evidence about capabilities of interest. Specifically, each module requires benchmark designers to describe, justify, and support benchmark design choices -- e.g., clearly specifying the capabilities the benchmark aims to measure or how evidence about those capabilities is collected from model responses. To demonstrate the use of ECBD, we conduct case studies with three benchmarks: BoolQ, SuperGLUE, and HELM. Our analysis reveals common trends in benchmark design and documentation that could threaten the validity of benchmarks' measurements.

Personalized treatment effect estimates are often of interest in high-stakes applications -- thus, before deploying a model estimating such effects in practice, one needs to be sure that the best candidate from the ever-growing machine learning toolbox for this task was chosen. Unfortunately, due to the absence of counterfactual information in practice, it is usually not possible to rely on standard validation metrics for doing so, leading to a well-known model selection dilemma in the treatment effect estimation literature. While some solutions have recently been investigated, systematic understanding of the strengths and weaknesses of different model selection criteria is still lacking. In this paper, instead of attempting to declare a global `winner', we therefore empirically investigate success- and failure modes of different selection criteria. We highlight that there is a complex interplay between selection strategies, candidate estimators and the data used for comparing them, and provide interesting insights into the relative (dis)advantages of different criteria alongside desiderata for the design of further illuminating empirical studies in this context.

We introduce a general, flexible, parametric survival modelling framework which encompasses key shapes of hazard function (constant, increasing, decreasing, up-then-down, down-then-up), various common survival distributions (log-logistic, Burr type XII, Weibull, Gompertz), and includes defective distributions (i.e., cure models). This generality is achieved using four basic distributional parameters: two scale-type parameters and two shape parameters. Generalising to covariate dependence, the scale-type regression components correspond to accelerated failure time (AFT) and proportional hazards (PH) models. Therefore, this general formulation unifies the most popular survival models which allows us to consider the practical value of possible modelling choices for survival data. Furthermore, in line with our proposed flexible baseline distribution, we advocate the use of multi-parameter regression in which more than one distributional parameter depends on covariates - rather than the usual convention of having a single covariate-dependent (scale) parameter. While many choices are available, we suggest introducing covariates through just one or other of the two scale parameters, which covers AFT and PH models, in combination with a `power' shape parameter, which allows for more complex non-AFT/non-PH effects, while the other shape parameter remains covariate-independent, and handles automatic selection of the baseline distribution. We explore inferential issues in simulations, both with and without a covariate, with particular focus on evidence concerning the need, or otherwise, to include both AFT and PH parameters. We illustrate the efficacy of our modelling framework by investigating differences between treatment groups using data from a lung cancer study and a melanoma study. Censoring is accommodated throughout.

Hypothesis ranking is a crucial component of automated scientific discovery, particularly in natural sciences where wet-lab experiments are costly and throughput-limited. Existing approaches focus on pre-experiment ranking, relying solely on large language model's internal reasoning without incorporating empirical outcomes from experiments. We introduce the task of experiment-guided ranking, which aims to prioritize candidate hypotheses based on the results of previously tested ones. However, developing such strategies is challenging due to the impracticality of repeatedly conducting real experiments in natural science domains. To address this, we propose a simulator grounded in three domain-informed assumptions, modeling hypothesis performance as a function of similarity to a known ground truth hypothesis, perturbed by noise. We curate a dataset of 124 chemistry hypotheses with experimentally reported outcomes to validate the simulator. Building on this simulator, we develop a pseudo experiment-guided ranking method that clusters hypotheses by shared functional characteristics and prioritizes candidates based on insights derived from simulated experimental feedback. Experiments show that our method outperforms pre-experiment baselines and strong ablations.

Safety performance evaluation is critical for developing and deploying connected and automated vehicles (CAVs). One prevailing way is to design testing scenarios using prior knowledge of CAVs, test CAVs in these scenarios, and then evaluate their safety performances. However, significant differences between CAVs and prior knowledge could severely reduce the evaluation efficiency. Towards addressing this issue, most existing studies focus on the adaptive design of testing scenarios during the CAV testing process, but so far they cannot be applied to high-dimensional scenarios. In this paper, we focus on the adaptive safety performance evaluation by leveraging the testing results, after the CAV testing process. It can significantly improve the evaluation efficiency and be applied to high-dimensional scenarios. Specifically, instead of directly evaluating the unknown quantity (e.g., crash rates) of CAV safety performances, we evaluate the differences between the unknown quantity and known quantity (i.e., control variates). By leveraging the testing results, the control variates could be well designed and optimized such that the differences are close to zero, so the evaluation variance could be dramatically reduced for different CAVs. To handle the high-dimensional scenarios, we propose the sparse control variates method, where the control variates are designed only for the sparse and critical variables of scenarios. According to the number of critical variables in each scenario, the control variates are stratified into strata and optimized within each stratum using multiple linear regression techniques. We justify the proposed method's effectiveness by rigorous theoretical analysis and empirical study of high-dimensional overtaking scenarios.

Researchers and developers increasingly rely on toxicity scoring to moderate generative language model outputs, in settings such as customer service, information retrieval, and content generation. However, toxicity scoring may render pertinent information inaccessible, rigidify or "value-lock" cultural norms, and prevent language reclamation processes, particularly for marginalized people. In this work, we extend the concept of algorithmic recourse to generative language models: we provide users a novel mechanism to achieve their desired prediction by dynamically setting thresholds for toxicity filtering. Users thereby exercise increased agency relative to interactions with the baseline system. A pilot study (n = 30) supports the potential of our proposed recourse mechanism, indicating improvements in usability compared to fixed-threshold toxicity-filtering of model outputs. Future work should explore the intersection of toxicity scoring, model controllability, user agency, and language reclamation processes -- particularly with regard to the bias that many communities encounter when interacting with generative language models.

In computer-aided engineering design, the goal of a designer is to find an optimal design on a given requirement using the numerical simulator in loop with an optimization method. In this design optimization process, a good design optimization process is one that can reduce the time from inception to design. In this work, we take a class of design problem, that is computationally cheap to evaluate but has high dimensional design space. In such cases, traditional surrogate-based optimization does not offer any benefits. In this work, we propose an alternative way to use ML model to surrogate the design process that formulates the search problem as an inverse problem and can save time by finding the optimal design or at least a good initial seed design for optimization. By using this trained surrogate model with the traditional optimization method, we can get the best of both worlds. We call this as Surrogate Assisted Optimization (SAO)- a hybrid approach by mixing ML surrogate with the traditional optimization method. Empirical evaluations of propeller design problems show that a better efficient design can be found in fewer evaluations using SAO.

The acceleration in the adoption of AI-based automated decision-making systems poses a challenge for evaluating the fairness of algorithmic decisions, especially in the absence of ground truth. When designing interventions, uplift modeling is used extensively to identify candidates that are likely to benefit from treatment. However, these models remain particularly susceptible to fairness evaluation due to the lack of ground truth on the outcome measure since a candidate cannot be in both treatment and control simultaneously. In this article, we propose a framework that overcomes the missing ground truth problem by generating surrogates to serve as a proxy for counterfactual labels of uplift modeling campaigns. We then leverage the surrogate ground truth to conduct a more comprehensive binary fairness evaluation. We show how to apply the approach in a comprehensive study from a real-world marketing campaign for promotional offers and demonstrate its enhancement for fairness evaluation.

A modified LAB algorithm is introduced in this paper. It builds upon the original LAB algorithm (Reddy et al. 2023), which is a socio-inspired algorithm that models competitive and learning behaviours within a group, establishing hierarchical roles. The proposed algorithm incorporates the roulette wheel approach and a reduction factor introducing inter-group competition and iteratively narrowing down the sample space. The algorithm is validated by solving the benchmark test problems from CEC 2005 and CEC 2017. The solutions are validated using standard statistical tests such as two-sided and pairwise signed rank Wilcoxon test and Friedman rank test. The algorithm exhibited improved and superior robustness as well as search space exploration capabilities. Furthermore, a Clustering-Based Search Space Reduction (C-SSR) method is proposed, making the algorithm capable to solve constrained problems. The C-SSR method enables the algorithm to identify clusters of feasible regions, satisfying the constraints and contributing to achieve the optimal solution. This method demonstrates its effectiveness as a potential alternative to traditional constraint handling techniques. The results obtained using the Modified LAB algorithm are then compared with those achieved by other recent metaheuristic algorithms.

Clinical diagnosis is critical in medical practice, typically requiring a continuous and evolving process that includes primary diagnosis, differential diagnosis, and final diagnosis. However, most existing clinical diagnostic tasks are single-step processes, which does not align with the complex multi-step diagnostic procedures found in real-world clinical settings. In this paper, we propose a multi-step diagnostic task and annotate a clinical diagnostic dataset (MSDiagnosis). This dataset includes primary diagnosis, differential diagnosis, and final diagnosis questions. Additionally, we propose a novel and effective framework. This framework combines forward inference, backward inference, reflection, and refinement, enabling the LLM to self-evaluate and adjust its diagnostic results. To assess the effectiveness of our proposed method, we design and conduct extensive experiments. The experimental results demonstrate the effectiveness of the proposed method. We also provide a comprehensive experimental analysis and suggest future research directions for this task.

OpenAI o1 represents a significant milestone in Artificial Inteiligence, which achieves expert-level performances on many challanging tasks that require strong reasoning ability.OpenAI has claimed that the main techinique behinds o1 is the reinforcement learining. Recent works use alternative approaches like knowledge distillation to imitate o1's reasoning style, but their effectiveness is limited by the capability ceiling of the teacher model. Therefore, this paper analyzes the roadmap to achieving o1 from the perspective of reinforcement learning, focusing on four key components: policy initialization, reward design, search, and learning. Policy initialization enables models to develop human-like reasoning behaviors, equipping them with the ability to effectively explore solution spaces for complex problems. Reward design provides dense and effective signals via reward shaping or reward modeling, which is the guidance for both search and learning. Search plays a crucial role in generating high-quality solutions during both training and testing phases, which can produce better solutions with more computation. Learning utilizes the data generated by search for improving policy, which can achieve the better performance with more parameters and more searched data. Existing open-source projects that attempt to reproduce o1 can be seem as a part or a variant of our roadmap. Collectively, these components underscore how learning and search drive o1's advancement, making meaningful contributions to the development of LLM.

This paper investigates prior prompt engineering (pPE) in the context of reinforcement fine-tuning (RFT), where language models (LMs) are incentivized to exhibit behaviors that maximize performance through reward signals. While existing RFT research has primarily focused on algorithms, reward shaping, and data curation, the design of the prior prompt--the instructions prepended to queries during training to elicit behaviors such as step-by-step reasoning--remains underexplored. We investigate whether different pPE approaches can guide LMs to internalize distinct behaviors after RFT. Inspired by inference-time prompt engineering (iPE), we translate five representative iPE strategies--reasoning, planning, code-based reasoning, knowledge recall, and null-example utilization--into corresponding pPE approaches. We experiment with Qwen2.5-7B using each of the pPE approaches, then evaluate performance on in-domain and out-of-domain benchmarks (e.g., AIME2024, HumanEval+, and GPQA-Diamond). Our results show that all pPE-trained models surpass their iPE-prompted counterparts, with the null-example pPE approach achieving the largest average performance gain and the highest improvement on AIME2024 and GPQA-Diamond, surpassing the commonly used reasoning approach. Furthermore, by adapting a behavior-classification framework, we demonstrate that different pPE strategies instill distinct behavioral styles in the resulting models. These findings position pPE as a powerful yet understudied axis for RFT.

Shojaee et al. (2025) report that Large Reasoning Models (LRMs) exhibit "accuracy collapse" on planning puzzles beyond certain complexity thresholds. We demonstrate that their findings primarily reflect experimental design limitations rather than fundamental reasoning failures. Our analysis reveals three critical issues: (1) Tower of Hanoi experiments systematically exceed model output token limits at reported failure points, with models explicitly acknowledging these constraints in their outputs; (2) The authors' automated evaluation framework fails to distinguish between reasoning failures and practical constraints, leading to misclassification of model capabilities; (3) Most concerningly, their River Crossing benchmarks include mathematically impossible instances for N > 5 due to insufficient boat capacity, yet models are scored as failures for not solving these unsolvable problems. When we control for these experimental artifacts, by requesting generating functions instead of exhaustive move lists, preliminary experiments across multiple models indicate high accuracy on Tower of Hanoi instances previously reported as complete failures. These findings highlight the importance of careful experimental design when evaluating AI reasoning capabilities.

DeepSeek-R1 has shown that long chain-of-thought (CoT) reasoning can naturally emerge through a simple reinforcement learning (RL) framework with rule-based rewards, where the training may directly start from the base models-a paradigm referred to as zero RL training. Most recent efforts to reproduce zero RL training have primarily focused on the Qwen2.5 model series, which may not be representative as we find the base models already exhibit strong instruction-following and self-reflection abilities. In this work, we investigate zero RL training across 10 diverse base models, spanning different families and sizes including LLama3-8B, Mistral-7B/24B, DeepSeek-Math-7B, Qwen2.5-math-7B, and all Qwen2.5 models from 0.5B to 32B. Leveraging several key design strategies-such as adjusting format reward and controlling query difficulty-we achieve substantial improvements in both reasoning accuracy and response length across most settings. However, by carefully monitoring the training dynamics, we observe that different base models exhibit distinct patterns during training. For instance, the increased response length does not always correlate with the emergence of certain cognitive behaviors such as verification (i.e., the "aha moment"). Notably, we observe the "aha moment" for the first time in small models not from the Qwen family. We share the key designs that enable successful zero RL training, along with our findings and practices. To facilitate further research, we open-source the code, models, and analysis tools.

A central aspect of machine learning research is experimentation, the process of designing and running experiments, analyzing the results, and iterating towards some positive outcome (e.g., improving accuracy). Could agents driven by powerful language models perform machine learning experimentation effectively? To answer this question, we introduce MLAgentBench, a suite of 13 tasks ranging from improving model performance on CIFAR-10 to recent research problems like BabyLM. For each task, an agent can perform actions like reading/writing files, executing code, and inspecting outputs. We then construct an agent that can perform ML experimentation based on ReAct framework. We benchmark agents based on Claude v1.0, Claude v2.1, Claude v3 Opus, GPT-4, GPT-4-turbo, Gemini-Pro, and Mixtral and find that a Claude v3 Opus agent is the best in terms of success rate. It can build compelling ML models over many tasks in MLAgentBench with 37.5% average success rate. Our agents also display highly interpretable plans and actions. However, the success rates vary considerably; they span from 100% on well-established older datasets to as low as 0% on recent Kaggle challenges created potentially after the underlying LM was trained. Finally, we identify several key challenges for LM-based agents such as long-term planning and reducing hallucination. Our code is released at https://github.com/snap-stanford/MLAgentBench.

Large Language Models (LLMs) have shown promise in accelerating the scientific research pipeline. A key capability for this process is the ability to generate novel research ideas, and prior studies have found settings in which LLM-generated research ideas were judged as more novel than human-expert ideas. However, a good idea should not simply appear to be novel, it should also result in better research after being executed. To test whether AI-generated ideas lead to better research outcomes, we conduct an execution study by recruiting 43 expert researchers to execute randomly-assigned ideas, either written by experts or generated by an LLM. Each expert spent over 100 hours implementing the idea and wrote a 4-page short paper to document the experiments. All the executed projects are then reviewed blindly by expert NLP researchers. Comparing the review scores of the same ideas before and after execution, the scores of the LLM-generated ideas decrease significantly more than expert-written ideas on all evaluation metrics (novelty, excitement, effectiveness, and overall; p < 0.05), closing the gap between LLM and human ideas observed at the ideation stage. When comparing the aggregated review scores from the execution study, we even observe that for many metrics there is a flip in rankings where human ideas score higher than LLM ideas. This ideation-execution gap highlights the limitations of current LLMs in generating truly effective research ideas and the challenge of evaluating research ideas in the absence of execution outcomes.

Usability testing is a fundamental yet challenging (e.g., inflexible to iterate the study design flaws and hard to recruit study participants) research method for user experience (UX) researchers to evaluate a web design. Recent advances in Large Language Model-simulated Agent (LLM-Agent) research inspired us to design UXAgent to support UX researchers in evaluating and reiterating their usability testing study design before they conduct the real human subject study. Our system features an LLM-Agent module and a universal browser connector module so that UX researchers can automatically generate thousands of simulated users to test the target website. The results are shown in qualitative (e.g., interviewing how an agent thinks ), quantitative (e.g., # of actions), and video recording formats for UX researchers to analyze. Through a heuristic user evaluation with five UX researchers, participants praised the innovation of our system but also expressed concerns about the future of LLM Agent-assisted UX study.

In this paper, we present a simulation system called AgentCourt that simulates the entire courtroom process. The judge, plaintiff's lawyer, defense lawyer, and other participants are autonomous agents driven by large language models (LLMs). Our core goal is to enable lawyer agents to learn how to argue a case, as well as improving their overall legal skills, through courtroom process simulation. To achieve this goal, we propose an adversarial evolutionary approach for the lawyer-agent. Since AgentCourt can simulate the occurrence and development of court hearings based on a knowledge base and LLM, the lawyer agents can continuously learn and accumulate experience from real court cases. The simulation experiments show that after two lawyer-agents have engaged in a thousand adversarial legal cases in AgentCourt (which can take a decade for real-world lawyers), compared to their pre-evolutionary state, the evolved lawyer agents exhibit consistent improvement in their ability to handle legal tasks. To enhance the credibility of our experimental results, we enlisted a panel of professional lawyers to evaluate our simulations. The evaluation indicates that the evolved lawyer agents exhibit notable advancements in responsiveness, as well as expertise and logical rigor. This work paves the way for advancing LLM-driven agent technology in legal scenarios. Code is available at https://github.com/relic-yuexi/AgentCourt.

Machine learning is a prevalent approach to tame the complexity of design space exploration for domain-specific architectures. Using ML for design space exploration poses challenges. First, it's not straightforward to identify the suitable algorithm from an increasing pool of ML methods. Second, assessing the trade-offs between performance and sample efficiency across these methods is inconclusive. Finally, lack of a holistic framework for fair, reproducible, and objective comparison across these methods hinders progress of adopting ML-aided architecture design space exploration and impedes creating repeatable artifacts. To mitigate these challenges, we introduce ArchGym, an open-source gym and easy-to-extend framework that connects diverse search algorithms to architecture simulators. To demonstrate utility, we evaluate ArchGym across multiple vanilla and domain-specific search algorithms in designing custom memory controller, deep neural network accelerators, and custom SoC for AR/VR workloads, encompassing over 21K experiments. Results suggest that with unlimited samples, ML algorithms are equally favorable to meet user-defined target specification if hyperparameters are tuned; no solution is necessarily better than another (e.g., reinforcement learning vs. Bayesian methods). We coin the term hyperparameter lottery to describe the chance for a search algorithm to find an optimal design provided meticulously selected hyperparameters. The ease of data collection and aggregation in ArchGym facilitates research in ML-aided architecture design space exploration. As a case study, we show this advantage by developing a proxy cost model with an RMSE of 0.61% that offers a 2,000-fold reduction in simulation time. Code and data for ArchGym is available at https://bit.ly/ArchGym.

The rapid advancement in capabilities of large language models (LLMs) raises a pivotal question: How can LLMs accelerate scientific discovery? This work tackles the crucial first stage of research, generating novel hypotheses. While recent work on automated hypothesis generation focuses on multi-agent frameworks and extending test-time compute, none of the approaches effectively incorporate transparency and steerability through a synergistic Human-in-the-loop (HITL) approach. To address this gap, we introduce IRIS: Interactive Research Ideation System, an open-source platform designed for researchers to leverage LLM-assisted scientific ideation. IRIS incorporates innovative features to enhance ideation, including adaptive test-time compute expansion via Monte Carlo Tree Search (MCTS), fine-grained feedback mechanism, and query-based literature synthesis. Designed to empower researchers with greater control and insight throughout the ideation process. We additionally conduct a user study with researchers across diverse disciplines, validating the effectiveness of our system in enhancing ideation. We open-source our code at https://github.com/Anikethh/IRIS-Interactive-Research-Ideation-System

Despite the recent success of representation learning in sequential decision making, the study of the pure exploration scenario (i.e., identify the best option and minimize the sample complexity) is still limited. In this paper, we study multi-task representation learning for best arm identification in linear bandits (RepBAI-LB) and best policy identification in contextual linear bandits (RepBPI-CLB), two popular pure exploration settings with wide applications, e.g., clinical trials and web content optimization. In these two problems, all tasks share a common low-dimensional linear representation, and our goal is to leverage this feature to accelerate the best arm (policy) identification process for all tasks. For these problems, we design computationally and sample efficient algorithms DouExpDes and C-DouExpDes, which perform double experimental designs to plan optimal sample allocations for learning the global representation. We show that by learning the common representation among tasks, our sample complexity is significantly better than that of the native approach which solves tasks independently. To the best of our knowledge, this is the first work to demonstrate the benefits of representation learning for multi-task pure exploration.

Finding relevant literature underpins the practice of evidence-based medicine. From 2014 to 2016, TREC conducted a clinical decision support track, wherein participants were tasked with finding articles relevant to clinical questions posed by physicians. In total, 87 teams have participated over the past three years, generating 395 runs. During this period, each team has trialled a variety of methods. While there was significant overlap in the methods employed by different teams, the results were varied. Due to the diversity of the platforms used, the results arising from the different techniques are not directly comparable, reducing the ability to build on previous work. By using a stable platform, we have been able to compare different document and query processing techniques, allowing us to experiment with different search parameters. We have used our system to reproduce leading teams runs, and compare the results obtained. By benchmarking our indexing and search techniques, we can statistically test a variety of hypotheses, paving the way for further research.

RNA design is the search for a sequence or set of sequences that will fold into predefined structures, also known as the inverse problem of RNA folding. While numerous RNA design methods have been invented to find sequences capable of folding into a target structure, little attention has been given to the identification of undesignable structures according to the minimum free energy (MFE) criterion under the Turner model. In this paper, we address this gap by first introducing mathematical theorems outlining sufficient conditions for recognizing undesignable structures, then proposing efficient algorithms, guided by these theorems, to verify the undesignability of RNA structures. Through the application of these theorems and algorithms to the Eterna100 puzzles, we demonstrate the ability to efficiently establish that 15 of the puzzles indeed fall within the category of undesignable structures. In addition, we provide specific insights from the study of undesignability, in the hope that it will enable more understanding of RNA folding and RNA design.

We consider the problem of performing Bayesian inference in probabilistic models where observations are accompanied by uncertainty, referred to as "uncertain evidence." We explore how to interpret uncertain evidence, and by extension the importance of proper interpretation as it pertains to inference about latent variables. We consider a recently-proposed method "distributional evidence" as well as revisit two older methods: Jeffrey's rule and virtual evidence. We devise guidelines on how to account for uncertain evidence and we provide new insights, particularly regarding consistency. To showcase the impact of different interpretations of the same uncertain evidence, we carry out experiments in which one interpretation is defined as "correct." We then compare inference results from each different interpretation illustrating the importance of careful consideration of uncertain evidence.

Clinical evidence, derived from rigorous research and data analysis, provides healthcare professionals with reliable scientific foundations for informed decision-making. Integrating clinical evidence into real-time practice is challenging due to the enormous workload, complex professional processes, and time constraints. This highlights the need for tools that automate evidence synthesis to support more efficient and accurate decision making in clinical settings. This study introduces Quicker, an evidence-based clinical decision support system powered by large language models (LLMs), designed to automate evidence synthesis and generate clinical recommendations modeled after standard clinical guideline development processes. Quicker implements a fully automated chain that covers all phases, from questions to clinical recommendations, and further enables customized decision-making through integrated tools and interactive user interfaces. To evaluate Quicker's capabilities, we developed the Q2CRBench-3 benchmark dataset, based on clinical guideline development records for three different diseases. Experimental results highlighted Quicker's strong performance, with fine-grained question decomposition tailored to user preferences, retrieval sensitivities comparable to human experts, and literature screening performance approaching comprehensive inclusion of relevant studies. In addition, Quicker-assisted evidence assessment effectively supported human reviewers, while Quicker's recommendations were more comprehensive and logically coherent than those of clinicians. In system-level testing, collaboration between a single reviewer and Quicker reduced the time required for recommendation development to 20-40 minutes. In general, our findings affirm the potential of Quicker to help physicians make quicker and more reliable evidence-based clinical decisions.

Purpose: With advancements in Large Language Models (LLMs) for healthcare, the need arises for competitive open-source models to protect the public interest. This work contributes to the field of open medical LLMs by optimizing key stages of data preprocessing and training, while showing how to improve model safety (through DPO) and efficacy (through RAG). The evaluation methodology used, which includes four different types of tests, defines a new standard for the field. The resultant models, shown to be competitive with the best private alternatives, are released with a permisive license. Methods: Building on top of strong base models like Llama 3.1 and Qwen 2.5, Aloe Beta uses a custom dataset to enhance public data with synthetic Chain of Thought examples. The models undergo alignment with Direct Preference Optimization, emphasizing ethical and policy-aligned performance in the presence of jailbreaking attacks. Evaluation includes close-ended, open-ended, safety and human assessments, to maximize the reliability of results. Results: Recommendations are made across the entire pipeline, backed by the solid performance of the Aloe Family. These models deliver competitive performance across healthcare benchmarks and medical fields, and are often preferred by healthcare professionals. On bias and toxicity, the Aloe Beta models significantly improve safety, showing resilience to unseen jailbreaking attacks. For a responsible release, a detailed risk assessment specific to healthcare is attached to the Aloe Family models. Conclusion: The Aloe Beta models, and the recipe that leads to them, are a significant contribution to the open-source medical LLM field, offering top-of-the-line performance while maintaining high ethical requirements. This work sets a new standard for developing and reporting aligned LLMs in healthcare.

Recent advances in LegalAI have primarily focused on individual case judgment analysis, often overlooking the critical appellate process within the judicial system. Appeals serve as a core mechanism for error correction and ensuring fair trials, making them highly significant both in practice and in research. To address this gap, we present the AppealCase dataset, consisting of 10,000 pairs of real-world, matched first-instance and second-instance documents across 91 categories of civil cases. The dataset also includes detailed annotations along five dimensions central to appellate review: judgment reversals, reversal reasons, cited legal provisions, claim-level decisions, and whether there is new information in the second instance. Based on these annotations, we propose five novel LegalAI tasks and conduct a comprehensive evaluation across 20 mainstream models. Experimental results reveal that all current models achieve less than 50% F1 scores on the judgment reversal prediction task, highlighting the complexity and challenge of the appeal scenario. We hope that the AppealCase dataset will spur further research in LegalAI for appellate case analysis and contribute to improving consistency in judicial decision-making.

Recently, large language models (LLMs) have shown promising abilities to generate novel research ideas in science, a direction which coincides with many foundational principles in computational creativity (CC). In light of these developments, we present an idea generation system named Spark that couples retrieval-augmented idea generation using LLMs with a reviewer model named Judge trained on 600K scientific reviews from OpenReview. Our work is both a system demonstration and intended to inspire other CC researchers to explore grounding the generation and evaluation of scientific ideas within foundational CC principles. To this end, we release the annotated dataset used to train Judge, inviting other researchers to explore the use of LLMs for idea generation and creative evaluations.

Model-Based Reinforcement Learning (RL) is widely believed to have the potential to improve sample efficiency by allowing an agent to synthesize large amounts of imagined experience. Experience Replay (ER) can be considered a simple kind of model, which has proved extremely effective at improving the stability and efficiency of deep RL. In principle, a learned parametric model could improve on ER by generalizing from real experience to augment the dataset with additional plausible experience. However, owing to the many design choices involved in empirically successful algorithms, it can be very hard to establish where the benefits are actually coming from. Here, we provide theoretical and empirical insight into when, and how, we can expect data generated by a learned model to be useful. First, we provide a general theorem motivating how learning a model as an intermediate step can narrow down the set of possible value functions more than learning a value function directly from data using the Bellman equation. Second, we provide an illustrative example showing empirically how a similar effect occurs in a more concrete setting with neural network function approximation. Finally, we provide extensive experiments showing the benefit of model-based learning for online RL in environments with combinatorial complexity, but factored structure that allows a learned model to generalize. In these experiments, we take care to control for other factors in order to isolate, insofar as possible, the benefit of using experience generated by a learned model relative to ER alone.

Medical systematic reviews can be very costly and resource intensive. We explore how Large Language Models (LLMs) can support and be trained to perform literature screening when provided with a detailed set of selection criteria. Specifically, we instruction tune LLaMA and Guanaco models to perform abstract screening for medical systematic reviews. Our best model, Bio-SIEVE, outperforms both ChatGPT and trained traditional approaches, and generalises better across medical domains. However, there remains the challenge of adapting the model to safety-first scenarios. We also explore the impact of multi-task training with Bio-SIEVE-Multi, including tasks such as PICO extraction and exclusion reasoning, but find that it is unable to match single-task Bio-SIEVE's performance. We see Bio-SIEVE as an important step towards specialising LLMs for the biomedical systematic review process and explore its future developmental opportunities. We release our models, code and a list of DOIs to reconstruct our dataset for reproducibility.

The assessment of safety performance plays a pivotal role in the development and deployment of connected and automated vehicles (CAVs). A common approach involves designing testing scenarios based on prior knowledge of CAVs (e.g., surrogate models), conducting tests in these scenarios, and subsequently evaluating CAVs' safety performances. However, substantial differences between CAVs and the prior knowledge can significantly diminish the evaluation efficiency. In response to this issue, existing studies predominantly concentrate on the adaptive design of testing scenarios during the CAV testing process. Yet, these methods have limitations in their applicability to high-dimensional scenarios. To overcome this challenge, we develop an adaptive testing environment that bolsters evaluation robustness by incorporating multiple surrogate models and optimizing the combination coefficients of these surrogate models to enhance evaluation efficiency. We formulate the optimization problem as a regression task utilizing quadratic programming. To efficiently obtain the regression target via reinforcement learning, we propose the dense reinforcement learning method and devise a new adaptive policy with high sample efficiency. Essentially, our approach centers on learning the values of critical scenes displaying substantial surrogate-to-real gaps. The effectiveness of our method is validated in high-dimensional overtaking scenarios, demonstrating that our approach achieves notable evaluation efficiency.

Posterior sampling allows the exploitation of prior knowledge of the environment's transition dynamics to improve the sample efficiency of reinforcement learning. The prior is typically specified as a class of parametric distributions, a task that can be cumbersome in practice, often resulting in the choice of uninformative priors. In this work, we propose a novel posterior sampling approach in which the prior is given as a (partial) causal graph over the environment's variables. The latter is often more natural to design, such as listing known causal dependencies between biometric features in a medical treatment study. Specifically, we propose a hierarchical Bayesian procedure, called C-PSRL, simultaneously learning the full causal graph at the higher level and the parameters of the resulting factored dynamics at the lower level. For this procedure, we provide an analysis of its Bayesian regret, which explicitly connects the regret rate with the degree of prior knowledge. Our numerical evaluation conducted in illustrative domains confirms that C-PSRL strongly improves the efficiency of posterior sampling with an uninformative prior while performing close to posterior sampling with the full causal graph.

Online medical consultation (OMC) restricts doctors to gathering patient information solely through inquiries, making the already complex sequential decision-making process of diagnosis even more challenging. Recently, the rapid advancement of large language models has demonstrated a significant potential to transform OMC. However, most studies have primarily focused on improving diagnostic accuracy under conditions of relatively sufficient information, while paying limited attention to the "inquiry" phase of the consultation process. This lack of focus has left the relationship between "inquiry" and "diagnosis" insufficiently explored. In this paper, we first extract real patient interaction strategies from authentic doctor-patient conversations and use these strategies to guide the training of a patient simulator that closely mirrors real-world behavior. By inputting medical records into our patient simulator to simulate patient responses, we conduct extensive experiments to explore the relationship between "inquiry" and "diagnosis" in the consultation process. Experimental results demonstrate that inquiry and diagnosis adhere to the Liebig's law: poor inquiry quality limits the effectiveness of diagnosis, regardless of diagnostic capability, and vice versa. Furthermore, the experiments reveal significant differences in the inquiry performance of various models. To investigate this phenomenon, we categorize the inquiry process into four types: (1) chief complaint inquiry; (2) specification of known symptoms; (3) inquiry about accompanying symptoms; and (4) gathering family or medical history. We analyze the distribution of inquiries across the four types for different models to explore the reasons behind their significant performance differences. We plan to open-source the weights and related code of our patient simulator at https://github.com/LIO-H-ZEN/PatientSimulator.

The mathematical study of voting, social choice theory, has traditionally only been applicable to choices among a few predetermined alternatives, but not to open-ended decisions such as collectively selecting a textual statement. We introduce generative social choice, a design methodology for open-ended democratic processes that combines the rigor of social choice theory with the capability of large language models to generate text and extrapolate preferences. Our framework divides the design of AI-augmented democratic processes into two components: first, proving that the process satisfies representation guarantees when given access to oracle queries; second, empirically validating that these queries can be approximately implemented using a large language model. We apply this framework to the problem of summarizing free-form opinions into a proportionally representative slate of opinion statements; specifically, we develop a democratic process with representation guarantees and use this process to portray the opinions of participants in a survey about abortion policy. In a trial with 100 representative US residents, we find that 84 out of 100 participants feel "excellently" or "exceptionally" represented by the slate of five statements we extracted.

Exposure to large language model output is rapidly increasing. How will seeing AI-generated ideas affect human ideas? We conducted an experiment (800+ participants, 40+ countries) where participants viewed creative ideas that were from ChatGPT or prior experimental participants and then brainstormed their own idea. We varied the number of AI-generated examples (none, low, or high exposure) and if the examples were labeled as 'AI' (disclosure). Our dynamic experiment design -- ideas from prior participants in an experimental condition are used as stimuli for future participants in the same experimental condition -- mimics the interdependent process of cultural creation: creative ideas are built upon prior ideas. Hence, we capture the compounding effects of having LLMs 'in the culture loop'. We find that high AI exposure (but not low AI exposure) did not affect the creativity of individual ideas but did increase the average amount and rate of change of collective idea diversity. AI made ideas different, not better. There were no main effects of disclosure. We also found that self-reported creative people were less influenced by knowing an idea was from AI, and that participants were more likely to knowingly adopt AI ideas when the task was difficult. Our findings suggest that introducing AI ideas into society may increase collective diversity but not individual creativity.

Understanding the world and explaining it with scientific theories is a central aspiration of artificial intelligence research. Proposing theories, designing experiments to test them, and then revising them based on data are fundamental to scientific discovery. Despite the significant promise of LLM-based scientific agents, no benchmarks systematically test LLM's ability to propose scientific models, collect experimental data, and revise them in light of new data. We introduce BoxingGym, a benchmark with 10 environments for systematically evaluating both experimental design (e.g. collecting data to test a scientific theory) and model discovery (e.g. proposing and revising scientific theories). To enable tractable and quantitative evaluation, we implement each environment as a generative probabilistic model with which a scientific agent can run interactive experiments. These probabilistic models are drawn from various real-world scientific domains ranging from psychology to ecology. To quantitatively evaluate a scientific agent's ability to collect informative experimental data, we compute the expected information gain (EIG), an information-theoretic quantity which measures how much an experiment reduces uncertainty about the parameters of a generative model. A good scientific theory is a concise and predictive explanation. Therefore, to quantitatively evaluate model discovery, we ask a scientific agent to explain their model and then assess whether this explanation enables another scientific agent to make reliable predictions about this environment. In addition to this explanation-based evaluation, we compute standard model evaluation metrics such as prediction errors. We find that current LLMs, such as GPT-4o, struggle with both experimental design and model discovery. We find that augmenting the LLM-based agent with an explicit statistical model does not reliably improve these results.

Legal practitioners, particularly those early in their careers, face complex, high-stakes tasks that require adaptive, context-sensitive reasoning. While AI holds promise in supporting legal work, current datasets and models are narrowly focused on isolated subtasks and fail to capture the end-to-end decision-making required in real-world practice. To address this gap, we introduce LawFlow, a dataset of complete end-to-end legal workflows collected from trained law students, grounded in real-world business entity formation scenarios. Unlike prior datasets focused on input-output pairs or linear chains of thought, LawFlow captures dynamic, modular, and iterative reasoning processes that reflect the ambiguity, revision, and client-adaptive strategies of legal practice. Using LawFlow, we compare human and LLM-generated workflows, revealing systematic differences in structure, reasoning flexibility, and plan execution. Human workflows tend to be modular and adaptive, while LLM workflows are more sequential, exhaustive, and less sensitive to downstream implications. Our findings also suggest that legal professionals prefer AI to carry out supportive roles, such as brainstorming, identifying blind spots, and surfacing alternatives, rather than executing complex workflows end-to-end. Building on these findings, we propose a set of design suggestions, rooted in empirical observations, that align AI assistance with human goals of clarity, completeness, creativity, and efficiency, through hybrid planning, adaptive execution, and decision-point support. Our results highlight both the current limitations of LLMs in supporting complex legal workflows and opportunities for developing more collaborative, reasoning-aware legal AI systems. All data and code are available on our project page (https://minnesotanlp.github.io/LawFlow-website/).

Building upon our previous investigations of O1 replication (Part 1: Journey Learning [Qin et al., 2024] and Part 2: Distillation [Huang et al., 2024]), this work explores the potential of inference-time scaling in large language models (LLMs) for medical reasoning tasks, ranging from diagnostic decision-making to treatment planning. Through extensive experiments on medical benchmarks of varying complexity (MedQA, Medbullets, and JAMA Clinical Challenges), our investigation reveals several key insights: (1) Increasing inference time does lead to improved performance. With a modest training set of 500 samples, our model yields substantial performance improvements of 6%-11%. (2) Task complexity directly correlates with the required length of reasoning chains, confirming the necessity of extended thought processes for challenging problems. (3) The differential diagnoses generated by our model adhere to the principles of the hypothetico-deductive method, producing a list of potential conditions that may explain a patient's symptoms and systematically narrowing these possibilities by evaluating the evidence. These findings demonstrate the promising synergy between inference-time scaling and journey learning in advancing LLMs' real-world clinical reasoning capabilities.

Can foundation models be guided to execute tasks involving legal reasoning? We believe that building a benchmark to answer this question will require sustained collaborative efforts between the computer science and legal communities. To that end, this short paper serves three purposes. First, we describe how IRAC-a framework legal scholars use to distinguish different types of legal reasoning-can guide the construction of a Foundation Model oriented benchmark. Second, we present a seed set of 44 tasks built according to this framework. We discuss initial findings, and highlight directions for new tasks. Finally-inspired by the Open Science movement-we make a call for the legal and computer science communities to join our efforts by contributing new tasks. This work is ongoing, and our progress can be tracked here: https://github.com/HazyResearch/legalbench.

In modern recommendation systems, the standard pipeline involves training machine learning models on historical data to predict user behaviors and improve recommendations continuously. However, these data training loops can introduce interference in A/B tests, where data generated by control and treatment algorithms, potentially with different distributions, are combined. To address these challenges, we introduce a novel approach called weighted training. This approach entails training a model to predict the probability of each data point appearing in either the treatment or control data and subsequently applying weighted losses during model training. We demonstrate that this approach achieves the least variance among all estimators that do not cause shifts in the training distributions. Through simulation studies, we demonstrate the lower bias and variance of our approach compared to other methods.

We explore the potential of ChatGPT (3.5-turbo and 4) to generate conversations focused on self-care strategies for African-American heart failure patients -- a domain with limited specialized datasets. To simulate patient-health educator dialogues, we employed four prompting strategies: domain, African American Vernacular English (AAVE), Social Determinants of Health (SDOH), and SDOH-informed reasoning. Conversations were generated across key self-care domains of food, exercise, and fluid intake, with varying turn lengths (5, 10, 15) and incorporated patient-specific SDOH attributes such as age, gender, neighborhood, and socioeconomic status. Our findings show that effective prompt design is essential. While incorporating SDOH and reasoning improves dialogue quality, ChatGPT still lacks the empathy and engagement needed for meaningful healthcare communication.

We employ an audit design to investigate biases in state-of-the-art large language models, including GPT-4. In our study, we prompt the models for advice involving a named individual across a variety of scenarios, such as during car purchase negotiations or election outcome predictions. We find that the advice systematically disadvantages names that are commonly associated with racial minorities and women. Names associated with Black women receive the least advantageous outcomes. The biases are consistent across 42 prompt templates and several models, indicating a systemic issue rather than isolated incidents. While providing numerical, decision-relevant anchors in the prompt can successfully counteract the biases, qualitative details have inconsistent effects and may even increase disparities. Our findings underscore the importance of conducting audits at the point of LLM deployment and implementation to mitigate their potential for harm against marginalized communities.

Graphic designs are an effective medium for visual communication. They range from greeting cards to corporate flyers and beyond. Off-late, machine learning techniques are able to generate such designs, which accelerates the rate of content production. An automated way of evaluating their quality becomes critical. Towards this end, we introduce Design-o-meter, a data-driven methodology to quantify the goodness of graphic designs. Further, our approach can suggest modifications to these designs to improve its visual appeal. To the best of our knowledge, Design-o-meter is the first approach that scores and refines designs in a unified framework despite the inherent subjectivity and ambiguity of the setting. Our exhaustive quantitative and qualitative analysis of our approach against baselines adapted for the task (including recent Multimodal LLM-based approaches) brings out the efficacy of our methodology. We hope our work will usher more interest in this important and pragmatic problem setting.

We consider the problem of automatically generating a narrative biomedical evidence summary from multiple trial reports. We evaluate modern neural models for abstractive summarization of relevant article abstracts from systematic reviews previously conducted by members of the Cochrane collaboration, using the authors conclusions section of the review abstract as our target. We enlist medical professionals to evaluate generated summaries, and we find that modern summarization systems yield consistently fluent and relevant synopses, but that they are not always factual. We propose new approaches that capitalize on domain-specific models to inform summarization, e.g., by explicitly demarcating snippets of inputs that convey key findings, and emphasizing the reports of large and high-quality trials. We find that these strategies modestly improve the factual accuracy of generated summaries. Finally, we propose a new method for automatically evaluating the factuality of generated narrative evidence syntheses using models that infer the directionality of reported findings.

Sampling is ubiquitous in machine learning methodologies. Due to the growth of large datasets and model complexity, we want to learn and adapt the sampling process while training a representation. Towards achieving this grand goal, a variety of sampling techniques have been proposed. However, most of them either use a fixed sampling scheme or adjust the sampling scheme based on simple heuristics. They cannot choose the best sample for model training in different stages. Inspired by "Think, Fast and Slow" (System 1 and System 2) in cognitive science, we propose a reward-guided sampling strategy called Adaptive Sample with Reward (ASR) to tackle this challenge. To the best of our knowledge, this is the first work utilizing reinforcement learning (RL) to address the sampling problem in representation learning. Our approach optimally adjusts the sampling process to achieve optimal performance. We explore geographical relationships among samples by distance-based sampling to maximize overall cumulative reward. We apply ASR to the long-standing sampling problems in similarity-based loss functions. Empirical results in information retrieval and clustering demonstrate ASR's superb performance across different datasets. We also discuss an engrossing phenomenon which we name as "ASR gravity well" in experiments.

Toxicity remains a leading cause of early-stage drug development failure. Despite advances in molecular design and property prediction, the task of molecular toxicity repair - generating structurally valid molecular alternatives with reduced toxicity - has not yet been systematically defined or benchmarked. To fill this gap, we introduce ToxiMol, the first benchmark task for general-purpose Multimodal Large Language Models (MLLMs) focused on molecular toxicity repair. We construct a standardized dataset covering 11 primary tasks and 560 representative toxic molecules spanning diverse mechanisms and granularities. We design a prompt annotation pipeline with mechanism-aware and task-adaptive capabilities, informed by expert toxicological knowledge. In parallel, we propose an automated evaluation framework, ToxiEval, which integrates toxicity endpoint prediction, synthetic accessibility, drug-likeness, and structural similarity into a high-throughput evaluation chain for repair success. We systematically assess nearly 30 mainstream general-purpose MLLMs and design multiple ablation studies to analyze key factors such as evaluation criteria, candidate diversity, and failure attribution. Experimental results show that although current MLLMs still face significant challenges on this task, they begin to demonstrate promising capabilities in toxicity understanding, semantic constraint adherence, and structure-aware molecule editing.

Evaluating user interface (UI) design effectiveness extends beyond aesthetics to influencing user behavior, a principle central to Design Persuasiveness. A/B testing is the predominant method for determining which UI variations drive higher user engagement, but it is costly and time-consuming. While recent Vision-Language Models (VLMs) can process automated UI analysis, current approaches focus on isolated design attributes rather than comparative persuasiveness-the key factor in optimizing user interactions. To address this, we introduce WiserUI-Bench, a benchmark designed for Pairwise UI Design Persuasiveness Assessment task, featuring 300 real-world UI image pairs labeled with A/B test results and expert rationales. Additionally, we propose G-FOCUS, a novel inference-time reasoning strategy that enhances VLM-based persuasiveness assessment by reducing position bias and improving evaluation accuracy. Experimental results show that G-FOCUS surpasses existing inference strategies in consistency and accuracy for pairwise UI evaluation. Through promoting VLM-driven evaluation of UI persuasiveness, our work offers an approach to complement A/B testing, propelling progress in scalable UI preference modeling and design optimization. Code and data will be released publicly.

Systematic literature review is essential for evidence-based medicine, requiring comprehensive analysis of clinical trial publications. However, the application of artificial intelligence (AI) models for medical literature mining has been limited by insufficient training and evaluation across broad therapeutic areas and diverse tasks. Here, we present LEADS, an AI foundation model for study search, screening, and data extraction from medical literature. The model is trained on 633,759 instruction data points in LEADSInstruct, curated from 21,335 systematic reviews, 453,625 clinical trial publications, and 27,015 clinical trial registries. We showed that LEADS demonstrates consistent improvements over four cutting-edge generic large language models (LLMs) on six tasks. Furthermore, LEADS enhances expert workflows by providing supportive references following expert requests, streamlining processes while maintaining high-quality results. A study with 16 clinicians and medical researchers from 14 different institutions revealed that experts collaborating with LEADS achieved a recall of 0.81 compared to 0.77 experts working alone in study selection, with a time savings of 22.6%. In data extraction tasks, experts using LEADS achieved an accuracy of 0.85 versus 0.80 without using LEADS, alongside a 26.9% time savings. These findings highlight the potential of specialized medical literature foundation models to outperform generic models, delivering significant quality and efficiency benefits when integrated into expert workflows for medical literature mining.

Interference is ubiquitous when conducting causal experiments over networks. Except for certain network structures, causal inference on the network in the presence of interference is difficult due to the entanglement between the treatment assignments and the interference levels. In this article, we conduct causal inference under interference on an observed, sparse but connected network, and we propose a novel design of experiments based on an independent set. Compared to conventional designs, the independent-set design focuses on an independent subset of data and controls their interference exposures through the assignments to the rest (auxiliary set). We provide a lower bound on the size of the independent set from a greedy algorithm , and justify the theoretical performance of estimators under the proposed design. Our approach is capable of estimating both spillover effects and treatment effects. We justify its superiority over conventional methods and illustrate the empirical performance through simulations.

Medical large language models (LLMs) research often makes bold claims, from encoding clinical knowledge to reasoning like a physician. These claims are usually backed by evaluation on competitive benchmarks; a tradition inherited from mainstream machine learning. But how do we separate real progress from a leaderboard flex? Medical LLM benchmarks, much like those in other fields, are arbitrarily constructed using medical licensing exam questions. For these benchmarks to truly measure progress, they must accurately capture the real-world tasks they aim to represent. In this position paper, we argue that medical LLM benchmarks should (and indeed can) be empirically evaluated for their construct validity. In the psychological testing literature, "construct validity" refers to the ability of a test to measure an underlying "construct", that is the actual conceptual target of evaluation. By drawing an analogy between LLM benchmarks and psychological tests, we explain how frameworks from this field can provide empirical foundations for validating benchmarks. To put these ideas into practice, we use real-world clinical data in proof-of-concept experiments to evaluate popular medical LLM benchmarks and report significant gaps in their construct validity. Finally, we outline a vision for a new ecosystem of medical LLM evaluation centered around the creation of valid benchmarks.

The efficient exploration of chemical space to design molecules with intended properties enables the accelerated discovery of drugs, materials, and catalysts, and is one of the most important outstanding challenges in chemistry. Encouraged by the recent surge in computer power and artificial intelligence development, many algorithms have been developed to tackle this problem. However, despite the emergence of many new approaches in recent years, comparatively little progress has been made in developing realistic benchmarks that reflect the complexity of molecular design for real-world applications. In this work, we develop a set of practical benchmark tasks relying on physical simulation of molecular systems mimicking real-life molecular design problems for materials, drugs, and chemical reactions. Additionally, we demonstrate the utility and ease of use of our new benchmark set by demonstrating how to compare the performance of several well-established families of algorithms. Surprisingly, we find that model performance can strongly depend on the benchmark domain. We believe that our benchmark suite will help move the field towards more realistic molecular design benchmarks, and move the development of inverse molecular design algorithms closer to designing molecules that solve existing problems in both academia and industry alike.

Reward design is a fundamental, yet challenging aspect of practical reinforcement learning (RL). For simple tasks, researchers typically handcraft the reward function, e.g., using a linear combination of several reward factors. However, such reward engineering is subject to approximation bias, incurs large tuning cost, and often cannot provide the granularity required for complex tasks. To avoid these difficulties, researchers have turned to reinforcement learning from human feedback (RLHF), which learns a reward function from human preferences between pairs of trajectory sequences. By leveraging preference-based reward modeling, RLHF learns complex rewards that are well aligned with human preferences, allowing RL to tackle increasingly difficult problems. Unfortunately, the applicability of RLHF is limited due to the high cost and difficulty of obtaining human preference data. In light of this cost, we investigate learning reward functions for complex tasks with less human effort; simply by ranking the importance of the reward factors. More specifically, we propose a new RL framework -- HERON, which compares trajectories using a hierarchical decision tree induced by the given ranking. These comparisons are used to train a preference-based reward model, which is then used for policy learning. We find that our framework can not only train high performing agents on a variety of difficult tasks, but also provide additional benefits such as improved sample efficiency and robustness. Our code is available at https://github.com/abukharin3/HERON.

Artificial intelligence (AI)-driven methods can vastly improve the historically costly drug design process, with various generative models already in widespread use. Generative models for de novo drug design, in particular, focus on the creation of novel biological compounds entirely from scratch, representing a promising future direction. Rapid development in the field, combined with the inherent complexity of the drug design process, creates a difficult landscape for new researchers to enter. In this survey, we organize de novo drug design into two overarching themes: small molecule and protein generation. Within each theme, we identify a variety of subtasks and applications, highlighting important datasets, benchmarks, and model architectures and comparing the performance of top models. We take a broad approach to AI-driven drug design, allowing for both micro-level comparisons of various methods within each subtask and macro-level observations across different fields. We discuss parallel challenges and approaches between the two applications and highlight future directions for AI-driven de novo drug design as a whole. An organized repository of all covered sources is available at https://github.com/gersteinlab/GenAI4Drug.

Over the last decades, excellent computational chemistry tools have been developed. Their full potential has not yet been reached as most are challenging to learn and exist in isolation. Recently, large-language models (LLMs) have shown strong performance in tasks across domains, but struggle with chemistry-related problems. Moreover, these models lack access to external knowledge sources, limiting their usefulness in scientific applications. In this study, we introduce ChemCrow, an LLM chemistry agent designed to accomplish tasks across organic synthesis, drug discovery, and materials design. By integrating 17 expert-designed tools, ChemCrow augments the LLM performance in chemistry, and new capabilities emerge. Our agent autonomously planned the syntheses of an insect repellent, three organocatalysts, as well as other relevant molecules. Our evaluation, including both LLM and expert assessments, demonstrates ChemCrow's effectiveness in automating a diverse set of chemical tasks. Surprisingly, we find that GPT-4 as an evaluator cannot distinguish between clearly wrong GPT-4 completions and Chemcrow's performance. There is a significant risk of misuse of tools like ChemCrow, and we discuss their potential harms. Employed responsibly, our work not only aids expert chemists and lowers barriers for non-experts, but also fosters scientific advancement by bridging the gap between experimental and computational chemistry. A subset of the code is publicly available at https://github.com/ur-whitelab/chemcrow-public.

Predicting how different interventions will causally affect a specific individual is important in a variety of domains such as personalized medicine, public policy, and online marketing. There are a large number of methods to predict the effect of an existing intervention based on historical data from individuals who received it. However, in many settings it is important to predict the effects of novel interventions (e.g., a newly invented drug), which these methods do not address. Here, we consider zero-shot causal learning: predicting the personalized effects of a novel intervention. We propose CaML, a causal meta-learning framework which formulates the personalized prediction of each intervention's effect as a task. CaML trains a single meta-model across thousands of tasks, each constructed by sampling an intervention, along with its recipients and nonrecipients. By leveraging both intervention information (e.g., a drug's attributes) and individual features~(e.g., a patient's history), CaML is able to predict the personalized effects of novel interventions that do not exist at the time of training. Experimental results on real world datasets in large-scale medical claims and cell-line perturbations demonstrate the effectiveness of our approach. Most strikingly, CaML's zero-shot predictions outperform even strong baselines trained directly on data from the test interventions.

Reward design in reinforcement learning (RL) is challenging since specifying human notions of desired behavior may be difficult via reward functions or require many expert demonstrations. Can we instead cheaply design rewards using a natural language interface? This paper explores how to simplify reward design by prompting a large language model (LLM) such as GPT-3 as a proxy reward function, where the user provides a textual prompt containing a few examples (few-shot) or a description (zero-shot) of the desired behavior. Our approach leverages this proxy reward function in an RL framework. Specifically, users specify a prompt once at the beginning of training. During training, the LLM evaluates an RL agent's behavior against the desired behavior described by the prompt and outputs a corresponding reward signal. The RL agent then uses this reward to update its behavior. We evaluate whether our approach can train agents aligned with user objectives in the Ultimatum Game, matrix games, and the DealOrNoDeal negotiation task. In all three tasks, we show that RL agents trained with our framework are well-aligned with the user's objectives and outperform RL agents trained with reward functions learned via supervised learning

Medical language models (MLMs) have become pivotal in advancing medical natural language processing. However, prior models that rely on pre-training or supervised fine-tuning often exhibit low data efficiency and limited practicality in real-world clinical applications. While OpenAIs O1 highlights test-time scaling in mathematics, attempts to replicate this approach in medicine typically distill responses from GPT-series models to open-source models, focusing primarily on multiple-choice tasks. This strategy, though straightforward, neglects critical concerns like data privacy and realistic deployment in clinical settings. In this work, we present a deployable, small-scale medical language model, \mone, designed for long-chain reasoning in clinical tasks using a self-evolution paradigm. Starting with a seed dataset of around 8,000 instances spanning five domains and 16 datasets, we prompt a base policy model to perform Monte Carlo Tree Search (MCTS) to construct verifiable reasoning chains. Each reasoning step is assigned an evolution rollout value, allowing verified trajectories to train the policy model and the reward model. During inference, the policy model generates multiple responses, and the reward model selects the one with the highest reward score. Experiments on eleven evaluation datasets demonstrate that \mone outperforms prior open-source models by 2 points, with the addition of the reward model further boosting performance (sim13 points), surpassing GPT-4o-mini. Code and data are available at https://github.com/pixas/MedSSS.

Traditional direct estimation methods are not efficient for domains of a survey population with small sample sizes. To estimate the domain proportions, we combine the direct estimators and the regression-synthetic estimators based on domain-level auxiliary information. For the case of small true proportions, we introduce the design-based linear combination that is a robust alternative to the empirical best linear unbiased predictor (EBLUP) based on the Fay--Herriot model. We also consider an adaptive procedure optimizing a sample-size-dependent composite estimator, which depends on a single parameter for all domains. We imitate the Lithuanian Labor Force Survey, where we estimate the proportions of the unemployed and employed in municipalities. We show where the considered design-based compositions and estimators of their mean square errors are competitive for EBLUP and its accuracy estimation.

Deep research agents, powered by Large Language Models (LLMs), are rapidly advancing; yet, their performance often plateaus when generating complex, long-form research reports using generic test-time scaling algorithms. Drawing inspiration from the iterative nature of human research, which involves cycles of searching, reasoning, and revision, we propose the Test-Time Diffusion Deep Researcher (TTD-DR). This novel framework conceptualizes research report generation as a diffusion process. TTD-DR initiates this process with a preliminary draft, an updatable skeleton that serves as an evolving foundation to guide the research direction. The draft is then iteratively refined through a "denoising" process, which is dynamically informed by a retrieval mechanism that incorporates external information at each step. The core process is further enhanced by a self-evolutionary algorithm applied to each component of the agentic workflow, ensuring the generation of high-quality context for the diffusion process. This draft-centric design makes the report writing process more timely and coherent while reducing information loss during the iterative search process. We demonstrate that our TTD-DR achieves state-of-the-art results on a wide array of benchmarks that require intensive search and multi-hop reasoning, significantly outperforming existing deep research agents.

Model selection/optimization in conformal inference is challenging, since it may break the exchangeability between labeled and unlabeled data. We study this problem in the context of conformal selection, which uses conformal p-values to select ``interesting'' instances with large unobserved labels from a pool of unlabeled data, while controlling the FDR in finite sample. For validity, existing solutions require the model choice to be independent of the data used to construct the p-values and calibrate the selection set. However, when presented with many model choices and limited labeled data, it is desirable to (i) select the best model in a data-driven manner, and (ii) mitigate power loss due to sample splitting. This paper presents OptCS, a general framework that allows valid statistical testing (selection) after flexible data-driven model optimization. We introduce general conditions under which OptCS constructs valid conformal p-values despite substantial data reuse and handles complex p-value dependencies to maintain finite-sample FDR control via a novel multiple testing procedure. We instantiate this general recipe to propose three FDR-controlling procedures, each optimizing the models differently: (i) selecting the most powerful one among multiple pre-trained candidate models, (ii) using all data for model fitting without sample splitting, and (iii) combining full-sample model fitting and selection. We demonstrate the efficacy of our methods via simulation studies and real applications in drug discovery and alignment of large language models in radiology report generation.

Many cellular processes involve information processing and decision making. We can probe these processes at increasing molecular detail. The analysis of heterogeneous data remains a challenge that requires new ways of thinking about cells in quantitative, predictive, and mechanistic ways. We discuss the role of mathematical models in the context of cell-fate decision making systems across the tree of life. Complex multi-cellular organisms have been a particular focus, but single celled organisms also have to sense and respond to their environment. We center our discussion around the idea of design principles which we can learn from observations and modeling, and exploit in order to (re)-design or guide cellular behavior.

Binding precedents (S\'umulas Vinculantes) constitute a juridical instrument unique to the Brazilian legal system and whose objectives include the protection of the Federal Supreme Court against repetitive demands. Studies of the effectiveness of these instruments in decreasing the Court's exposure to similar cases, however, indicate that they tend to fail in such a direction, with some of the binding precedents seemingly creating new demands. We empirically assess the legal impact of five binding precedents, 11, 14, 17, 26 and 37, at the highest court level through their effects on the legal subjects they address. This analysis is only possible through the comparison of the Court's ruling about the precedents' themes before they are created, which means that these decisions should be detected through techniques of Similar Case Retrieval. The contributions of this article are therefore twofold: on the mathematical side, we compare the uses of different methods of Natural Language Processing -- TF-IDF, LSTM, BERT, and regex -- for Similar Case Retrieval, whereas on the legal side, we contrast the inefficiency of these binding precedents with a set of hypotheses that may justify their repeated usage. We observe that the deep learning models performed significantly worse in the specific Similar Case Retrieval task and that the reasons for binding precedents to fail in responding to repetitive demand are heterogeneous and case-dependent, making it impossible to single out a specific cause.

In this work, we study the issue of reward hacking on the response length, a challenge emerging in Reinforcement Learning from Human Feedback (RLHF) on LLMs. A well-formatted, verbose but less helpful response from the LLMs can often deceive LLMs or even human evaluators to achieve high scores. The same issue also holds for some reward models in RL. To address the challenges in both training and evaluation, we establish a more reliable evaluation protocol for comparing different training configurations, which inspects the trade-off between LLM evaluation score and response length obtained by varying training hyperparameters. Based on this evaluation, we conduct large-scale studies, where the results shed insights into the efficacy of hyperparameters and tricks used in RL on mitigating length bias. We further propose to improve the reward model by jointly training two linear heads on shared feature representations to predict the rewards, one trained to correlate with length, and the other trained to decorrelate with length and therefore focus more on the actual content. We then discard the length head in RL to prevent reward hacking on length. Experiments demonstrate that our approach almost eliminates the reward correlation with length, and improves the obtained policy by a significant margin.