Hypothesis Generation

Representation learning from medical code sequences in electronic health records and medical claims data has been successful in various clinical applications, such as those regarding disease prediction. However, significant challenges remain in extending this approach to the discovery of scientific hypotheses. One reason is that many existing BERT-based models fail to adequately capture the hierarchical structure of medical codes and the complex interactions between diagnoses and treatments. To address these limitations, we propose a new unified pre-training framework that explicitly integrates hierarchical sub-token aggregation, partial masking, and cross-reference mechanisms. The proposed model consistently outperformed existing methods on both pre-training objectives and downstream clinical event prediction tasks, including the onset of dementia and hospitalization. We also conducted an in silico drug repositioning case study targeting Alzheimer's disease. In the hypothesis generation step, our approach successfully rediscovered known promising drugs in a data-driven manner without relying on such external knowledge sources as the literature. Subsequently, in the hypothesis prioritization step, we introduced a Task-Adaptive Representation Approach to alleviate the over-encoding of historical prescription information within diagnostic vectors, enabling the robust prioritization of generated hypotheses. This study establishes an exploratory screening workflow for hypothesis generation and prioritization based on observational associations. Importantly, this framework is not intended to provide causal evidence, but rather to identify promising candidates for subsequent rigorous causal inference. Overall, this study demonstrates that domain-informed representation learning combined with task-adaptive representation control can enable a practical hypothesis discovery workflow.

Foundation models have progressed from learning and reasoning over existing knowledge, to increasingly learning through action, tool use, and outcome feedback. We argue that the next frontier is a further transition: from solving and acting within problems specified by humans to participating in the process by which new problems, representations, explanations, and knowledge are created. We refer to this capability as Discovery Intelligence. We formulate Discovery Foundation Models (DFMs) as general-purpose model systems for open-ended discovery. A DFM operates over a revisable research state and supports seven coupled capabilities spanning problem discovery, formulation, representation construction, hypothesis formation, intervention, evidence-grounded revision, and continual discovery improvement. We instantiate this framework with Zetema, which couples explicit research-state dynamics, verification and experimental gating, external grounding, and cross-task Discovery Skill evolution. We further ground the framework with GALILEO, a real therapeutic-discovery system in which Dry-Lab reasoning, robotic and hands-on Wet-Lab experimentation, external biological evidence, and iterative hypothesis and design revision form a closed physical discovery loop. We then formulate a unified approach to capability formation and process-centered evaluation, enabling discovery behavior to be trained, improved, and measured beyond final-answer performance. Together, these components establish discovery as a learnable, executable, and evaluable capability of foundation-model systems. We view this shift as a broader progression in intelligence scaling: from learning over existing knowledge, to learning from action outcomes, and ultimately to participating in the construction, testing, and revision of the structures through which new knowledge is discovered. Code: https://github.com/Gen-Verse/DFM-Plans

Scientific agents contribute to hypothesis discovery by synthesizing evidence, assessing proposals, and developing new explanations. Recent systems combine scientific agents with evolutionary search through critique, comparison, and revision. However, how different forms of agent collaboration affect hypothesis quality remains an open question. Answering this question requires separating the effects of agents' scientific capabilities from those of their collaboration. A framework must therefore preserve agents' scientific roles and support rules for combining, revising, and retaining hypotheses. Building on this view, we introduce HypoEvolve, which makes collaboration explicit through successive updates to a hypothesis population. Specifically, we propose a generational genetic algorithm to coordinate specialized large language model (LLM) agents that integrate mechanistic arguments, reconsider assumptions, and assess evidence and testability. Each generation specifies how scientific judgments and new proposals reshape the population, making collaboration effects on hypothesis quality directly testable. Moreover, we design our evaluation around scientifically meaningful hypotheses that explain how a proposed intervention could work. Drug repurposing links these explanations to target-level biological claims assessed against external evidence. Specifically, we adapt DepMap and Open Targets into complementary external measures grounded in experimental, genetic, and clinical evidence. Across 34 cancer types, HypoEvolve achieves the highest scores against six baselines on both measures. DepMap selectivity reaches 0.171, versus 0.115 for the strongest baseline. Gains over single-pass generation also generalize to held-out cancer types. HypoEvolve advances a vision of autonomous science in which AI research teams achieve a capacity for discovery beyond that of individual models.

Large language models (LLMs) can generate biomedical hypotheses, but it remains unclear whether they truly reason from scientific evidence or simply produce convincing-sounding ideas. To study this, we combine three major biological databases: the Kyoto Encyclopedia of Genes and Genomes (KEGG), Rhea, and UniProt, into a unified biochemical knowledge graph and construct a benchmark of 550 paths connecting enzyme sources to rare disease endpoints, yielding 13,200 hypotheses from six LLMs under four conditions varying the biological information each model receives: source enzyme only, full biological path, or source and disease endpoint only. Hypotheses are scored using an expert-derived five-criterion rubric on a 1-5 scale per criterion. We find that models given both the source and disease endpoint often produce the highest-scoring hypotheses, showing that LLMs can generate compelling ideas from minimal information. However, these hypotheses are less grounded in the evidence. In contrast, models given the full biological path generate hypotheses more consistent with known mechanistic relationships. We call this evidence-disciplined reasoning. To confirm this effect, we shuffled intermediate path steps while keeping endpoints fixed. Evidence grounding dropped significantly (delta = -0.793, p < 0.001), confirming models genuinely used path structure during reasoning. Our findings show that knowledge graphs support hypothesis generation in two ways: they identify biological endpoint pairs absent from the literature, and their mechanistic paths guide how LLMs reason between them.

Scientific knowledge graphs organize entities and relations extracted from scientific literature, but they remain inherently incomplete. Missing typed links in such graphs can therefore represent plausible scientific hypotheses, such as unexplored associations between materials and applications. However, scientific hypothesis discovery is challenging because true discoveries are extremely sparse among typed candidate pairs: graph neural networks (GNNs) are efficient but unreliable for ambiguous cases, while large language models (LLMs) are knowledgeable but too costly to apply exhaustively and are not naturally grounded in graph structures. We propose HyGRAIL, a cost-aware and evidence-grounded framework that combines heterogeneous GNN triage with LLM-based hypothesis review. HyGRAIL first uses a GNN to score candidate hypotheses and identify a validation-calibrated ambiguous region, routing only graph-uncertain cases to LLM review. For each routed hypothesis, HyGRAIL retrieves node-level associations and multi-hop relational paths from the knowledge graph (KG), then converts this structured evidence into natural language through template-based or LLM-based naturalization. An LLM review agent finally judges each hard hypothesis using the naturalized evidence and validation-selected decision criteria. On MatKG, HyGRAIL achieves the best F1 score of 0.429, improving over the strongest prior baseline by 0.242 F1 points and over the GNN-only baseline by 0.322. Meanwhile, GNN triage reduces the LLM call rate by 54.36% on average. Ablation studies further show that retrieved graph evidence is crucial for reliable hypothesis verification and that compact, two-sided evidence is more effective than simply increasing retrieval quantity.

Predicting the answer to interventional ``what if'' questions --- the outcome of an action never taken --- requires a \emph{mechanistic}, causal model, not a curve fit; and learning such a model requires \emph{experiments}, because passive data leaves its mechanisms unidentified. Experiments are expensive, so the central problem is \emph{data efficiency}. We present the Model Discovery Agent (MDA), which couples a large language model (LLM), used as a \emph{proposer} of candidate structures, with standard Bayesian machinery --- sequential Monte Carlo (SMC) for parameter and structure posteriors, simulation-based inference (SBI) for intractable likelihoods, and value-of-information (VoI) for experiment design --- to discover latent mechanistic world models from few interventions. MDA operates in the M-open setting: when the truth lies outside the current hypothesis class, a predictive check flags the inadequacy and the proposer expands the hypothesis space with a new model whose parameters are then identified by designed experiments. We show that \emph{discovery and design reinforce}: the design step identifies the mechanism the discovery step proposes, and the identified mechanism improves predictions, enabling further discoveries from the remaining unexplained residuals. On three different benchmarks --- covering physics (\DPbench, \citep{wiemann2026discoverphysics}), chemistry (\CHEMbench, \citep{kabra2026autoscilab}) and biology (\HHbench, a new partially observed single-neuron electrophysiology benchmark we create) --- we show that MDA sets a new SOTA in terms of data-efficient model learning and reliable interventional prediction ability.

AI co-scientists can generate fluent materials-science hypotheses, but fluency does not show that an answer preserves a scientifically meaningful mechanism. We present a graph-to-answer mechanism-tracing case study for Graph-PRefLexOR-8B, a Qwen3-8B model adapted to expose distinct stages for brainstorming, graph construction, pattern extraction, and synthesis. We organize semantic backtracking, graph corruption, activation-based recovery measurements, and layer-by-token-region grids into a visual diagnostic workflow for inspecting this pathway. Across 100 open-ended materials-science questions, final answers remain closest to the model's own structured stages, especially synthesis. Under graph corruption, a full sweep over 37 residual-stream checkpoints, the embedding output and 36 transformer blocks, shows little mechanism recovery in the earlier transition region at layers 7--10, recovery instead concentrates in late synthesis and answer-start regions around layers 30 and 36. The workflow is intended to help scientists and model developers identify where a generated hypothesis loses or regains mechanism support before it is passed to downstream experimental planning.

Can scientific abduction occur without continuous sensorimotor embodiment? Recent arguments in AI and philosophy of science hold that genuine hypothesis generation requires an agent continuously coupled to the physical world. We defend a narrower claim: online embodiment is not necessary for every abductive scientific act. Our focus is identity abduction: the inference that two independently developed structures are one object under an explicit correspondence, reached through representational grounding rather than bodily interaction. An agent may acquire new inferential affordances not through physical interaction but through transformations into representations that expose latent invariants. Scientific diagrams are a practical substrate because they embody independently evolved conventions that partially canonicalize symmetry, topology, and operator structure across disciplines - a property we develop as convention space, which answers a hard retrieval problem: finding mathematically related work when two fields share no discriminating vocabulary. We operationalize the mechanism as an architecture, the Abduction Loop: representation generation, motif extraction, convention-space canonicalization, cross-domain retrieval, identity-hypothesis generation, and adversarial verification, with abstention as the designed default. A documented episode, in which a multimodal model given a figure of a gravitational-memory transport model generated and then verified the hypothesis that its central differential complex is equivalent to the spherical Kaiser-Squires mass-mapping complex of weak-lensing cosmology, serves as a motivating possibility witness from which the architecture is abstracted, not as evidence of general capability. We close with a falsifiable evaluation program, the DAB-30 benchmark. The contribution is a mechanistic proposal, an architecture, and a test program.

Security operations centers rely on anomaly detection systems to flag suspicious events. Feature-level explanations for anomaly detectors offer limited value for operational investigations. To effectively handle alerts, analysts need to know contextual relationships and need actionable understanding of the entities involved. This paper introduces an event-centric detector-agnostic approach for explaining cybersecurity alerts in small- to medium-sized enterprise networks. We present (EC)2, a multi-agent framework that performs structured, hypothesis-driven investigation to provide explanations grounded in verifiable evidence. Evaluation results show that the proposed framework improves post-detection analysis by generating operationally meaningful explanations, which also enhance event classification accuracy.

Large language models (LLMs) excel at answering pre-specified questions, yet their ability to navigate the open-ended, pre-conclusion stage of discovery remains largely unmeasured. We introduce Prospective Hypothesis Discovery (PHD), which asks models to autonomously construct grounded, discriminative, and testable hypothesis spaces from inconclusive evidence, including anomalous observations and fragmented records, to guide subsequent investigation. To evaluate this capability, we introduce HypoArena, comprising HypoData, a benchmark of 988 cases across six scientific and analytical domains, and HypoEval, an evaluation framework for open-ended hypothesis sets. To construct HypoData at scale, we propose Retrospective Context Regression, a Forge--Audit pipeline that reconstructs pre-conclusion contexts from completed expert documents by removing explicit conclusions, target hypotheses, and retrospective causal attributions while preserving the factual substrate. Because PHD admits multiple valid outputs, HypoEval combines bidirectional pairwise judgments with Bradley--Terry--Davidson aggregation for ranking and six-dimensional rubric scoring for diagnosis. Experiments on 15 frontier LLMs reveal clear capability stratification and model-dependent effects of structured analytical skills, with gains for several lower-performing models on HypoArena but regressions for other systems, including a top-performing model. Compared with absolute rubric scoring, arena evaluation resolves finer-grained differences among models, with aggregated rankings showing strong agreement with human experts and an independent judge. Together, these results support treating PHD as a distinct target for evaluating how LLMs formulate investigative directions when final conclusions are withheld. Our code and data are publicly available at github.com/SKYLENAGE-AI/HypoArena and github.com/SKYLENAGE-AI/HypoArena.

Discovering governing partial differential equations (PDEs) from noisy observational data is a fundamental challenge in scientific machine learning. Traditional symbolic regression (SR) methods often struggle to identify accurate equations within vast combinatorial search spaces, largely due to their inability to incorporate essential domain-specific prior knowledge. Furthermore, reliance on pointwise evaluations and discrete finite differences inherently amplifies high-frequency noise, creating deceptive fitness landscapes that derail the optimization process. To resolve these bottlenecks, we propose LLM-PDESR, a framework that integrates the structural hypothesis generation of Large Language Models (LLMs) with a mathematically rigorous evaluation environment. By employing C^4-continuous quintic splines for robust differentiation and subdomain weighted residuals as natural low-pass filters, our approach effectively mitigates the fitness landscape distortion that plagues existing methods. A Pareto-driven feedback loop then enables the LLM to iteratively refine candidate equations, balancing predictive accuracy with structural parsimony. We evaluate LLM-PDESR on 23 canonical PDEs and five structurally novel equations (including a multivariate system) specifically designed to preclude dataset memorization and test true discovery capabilities. Demonstrating real-world applicability, the framework successfully extracts a consistent structural skeleton for an interpretable 1D dynamical surrogate (1D-CACE) directly from noisy ERA5 reanalysis data. Extensive experiments and out-of-distribution testing confirm that LLM-PDESR significantly outperforms state-of-the-art methodologies in structural recovery, noise resilience, and the avoidance of spurious complexity and equation bloat.

Financial markets are noisy, non-stationary, and high-dimensional, making it difficult to discover predictive and robust trading signals. Alpha discovery has evolved from manual factor design to machine learning, evolutionary search, and recent LLM-based frameworks, improving the efficiency of factor generation, search, and evaluation. However, existing methods still mostly automate isolated steps, rather than functioning as end-to-end quant researchers that can absorb external knowledge, close the hypothesis-to-code validation loop, and learn from accumulated discovery feedback. To fill this gap, we introduce XAlpha, a memory-driven AI Quant Researcher for continuous hypothesis-to-code alpha discovery. XAlpha maintains a multi-source research memory system that integrates report-grounded financial knowledge with discovery feedback from prior generations and research cycles. Guided by this memory system, a Macro Brain plans research themes and selects suitable Archetypes; a Micro Brain transforms the planned hypothesis pool into executable factor code and verifies ex-ante tri-alignment among the hypothesis idea, code logic, and financial plausibility; and a Cross Brain consolidates empirical outcomes into generation-level feedback, cycle-level summaries, and archetype-level research cues for future exploration. In this way, XAlpha turns alpha mining from isolated factor generation into a closed-loop research process that continuously reads, hypothesizes, implements, validates, reflects, and evolves. Experiments on CSI300 show that XAlpha achieves stronger overall alpha discovery performance than representative baselines.

We consider an open-world planning setting in which service robots must operate in unknown environments with incomplete knowledge of objects and actions. Traditional closed-world approaches with pre-programmed knowledge bases fail when robots encounter unexpected situations and tasks, posing a fundamental challenge for autonomous knowledge expansion in human environments. In this work, we propose an open-world planning framework that enables robots to automatically generate, verify, and update hypotheses about their abstract world models. Our key insight is to explicitly maintain uncertainty-aware knowledge expansion and integrate hypothesis verification into goal-reaching planning. The framework leverages foundation models to generate initial hypotheses over states and transitions, and applies automated planning to produce action sequences that jointly address hypothesis verification and task execution. Through iterative execution and refinement, the robot expands its knowledge by incorporating verification feedback from the foundation models when hypotheses prove incorrect. Extensive experiments in simulated and real-world environments demonstrate that our framework enables autonomous knowledge expansion and effective operation in open-world settings. These results indicate that integrating uncertainty-aware model expansion from robot foundation models with planning advances the practical deployment of household service robots.

Scientific equation discovery must combine broad domain priors with strict numerical testing. Symbolic regression supplies numerical grounding but faces a combinatorial search space, whereas many language-model systems ask the model to propose or select formulas directly. We test a different division of labour. We compare role specifications in which the language model acts as equation author, candidate decider or search controller, alongside end-to-end language-model and purely numerical baselines. In the controller setting we propose here, implemented as LLM-PySR, language models specify variables, operators, transformations and search depth; symbolic regression enumerates and fits expressions; and deterministic metrics govern retention. Across 74 AI-Feynman equations and seven complex formula-recovery tasks, search control achieved the strongest observed balance of accuracy, complexity, stability and cost. On an independent battery dataset, LLM-PySR identified a compact piecewise-linear relation between early voltage-curve displacement and cycle life. The results suggest that language models should shape hypothesis exploration rather than decide which equations survive.

Large language models have recently been explored for scientific hypothesis generation, but most prior work relies on unstructured literature and free-form textual claims. We present a pipeline for Earth observation that grounds hypothesis generation directly in the NASA Earth Observation Knowledge Graph. A heterogeneous graph neural network trained on historical co-usage relations ranks candidate dataset pairings, and a three-agent LLM pipeline filters, generates, and evaluates structured research hypotheses. Applied to 1,475 NASA datasets, the system produces 160 hypotheses spanning multiple Earth-science domains, including ecohydrology, glaciology, aerosol--cloud interactions, vegetation phenology, and stratospheric chemistry. Model-predicted novel dataset pairings are rated nearly as plausible as held-out real co-usages from the literature, indicating that the pipeline surfaces scientifically coherent yet unexplored combinations. A 222 factorial experiment across GPT-5.2 and Claude Sonnet 4.6 shows that hypothesis rankings remain stable, while absolute scores depend strongly on judge identity, highlighting limitations of single-judge LLM evaluation.

Autonomous scientific discovery systems offer the potential to accelerate research by automating the process of hypothesis generation and validation. However, current systems operate within constrained search spaces or require predefined research questions, limiting their capacity for true open-ended inquiry. Furthermore, while they generate hypotheses iteratively, they largely lack the ability to explicitly synthesize their own accumulated findings to uncover complex, interconnected phenomena. We introduce DiscoPER, an autonomous large language model-powered framework that conducts open-ended research by dynamically generating and executing code to explore datasets without pre-specified research objectives. To ensure rigorous scientific validity, every proposed discovery must pass statistical testing. To overcome the limitations of isolated search, our framework introduces a second-order reasoning mechanism that periodically analyzes its own accumulated discoveries. By treating prior discoveries as empirical data, DiscoPER identifies structural patterns, confounds, and epistemic gaps, actively redirecting hypothesis exploration toward uncharted regions of the search space. The search space is further expanded by incorporating tool use, enabling the system to explore hypotheses beyond structured metadata by seamlessly processing and extracting useful information from multimodal sources like images. Evaluated on iNatDisco, a new multimodal ecological knowledge benchmark with pattern-level ground truth obtained from peer-reviewed literature, DiscoPER recovers 8 of 9 known patterns with a 72.7% hypothesis support rate, outperforming both classical causal discovery and LLM-guided baselines. Ablations show that DiscoPER scales with more data, and confirms the benefits of second-order meta-reflection.

Accelerating materials discovery requires AI systems that can generate scientifically valid hypotheses through multi-step, domain-grounded reasoning. Standard large language models often produce fluent but weakly traceable responses to open-ended materials design problems, making it difficult to determine whether final answers are supported by coherent intermediate reasoning. We develop Graph-PRefLexOR, a family of graph-native reasoning models fine-tuned with Group Relative Policy Optimization (GRPO) to organize reasoning into explicit phases for mechanism exploration, graph construction, pattern extraction, and hypothesis synthesis. This design links neural language generation with symbolic relational structure, enabling causal connections to be constructed, inspected, and reused. On 100 open-ended questions from materials science and mechanics literature, Graph-PRefLexOR achieves 40-65% improvements over corresponding base models, with the largest gains in reasoning traceability. Embedding analyses show broader semantic exploration and approximately 2-3 times greater semantic diversity than baselines. Semantic backtracking and layer-wise hidden-state analyses further show stronger alignment between structured reasoning and final answers. Finally, test-time graph expansion reveals that additional compute primarily increases long-range conceptual recombination within a bounded semantic space, rather than simply expanding semantic coverage. These results establish graph-native reinforcement learning as a pathway toward interpretable AI systems for scientific hypothesis generation in materials design and other scientific applications.

Autonomous scientific discovery systems increasingly use large language models (LLMs) to propose new hypotheses, but many such systems condition primarily on experimental memory: archives of high-scoring candidates or heuristic summaries of recent trials. We argue that discovery agents should instead maintain explicit, uncertainty-aware beliefs about hypothesis quality. We introduce BayesEvolve, a belief-guided discovery framework that converts experimental evidence into a predictive belief state and uses this belief to guide future experimentation. As a controlled testbed for belief-guided discovery, we evaluate BayesEvolve on shifted BBOB-style black-box optimization tasks, leaving program and laboratory discovery domains to future work. BayesEvolve improves sample efficiency over memory- and archive-guided LLM baselines under a fixed evaluation budget. We further show that the belief state is predictive on held-out candidate pools, that controlled decision-rule ablations favor belief-guided selection with an annealed uncertainty bonus, and that BayesEvolve exhibits productive late-stage concentration rather than unfocused exploration.

Scientific discovery saturates when new hypotheses cease to provide independent information, even if the nominal hypothesis space remains large. We study hybrid discovery systems that combine structured local search with LLM-generated non-local proposals and pose the Search Compression Hypothesis: non-local exploration helps only when three geometric conditions co-occur: spectral compression, orthogonal escape from the explored span, and residual signal alignment with the target. We formalize these conditions, derive necessary conditions for hybrid advantage, and test the mechanism in controlled synthetic environments, large-scale A-share factor discovery, and symbolic-regression benchmarks; a public tabular operational sanity check tests the associated budget-allocation implication. Signal-planting and directed-versus-random experiments show that novelty alone is insufficient: random orthogonal jumps expand coverage but do not improve yield without predictive alignment. Across compression sweeps, real factor archives, and LLM-SRBench tasks, hybrid gains concentrate in weakly represented but target-bearing directions and vanish as the hypothesis space approaches full rank. The framework turns LLM-guided discovery from generic novelty search into a diagnostic procedure for deciding when directed non-local exploration is warranted.

Large language models (LLMs) are on the rise for accelerating scientific discovery, most recently in advanced tasks such as generating valid scientific hypotheses. Yet in many discovery settings, the goal is not to identify a single best hypothesis since validation can be noisy and expensive, and scientists benefit from a set of high-quality alternative hypotheses that hedge against downstream uncertainty for the best solutions. Nevertheless, commonly used evolutionary search recipes tend to prioritize optimization over exploration in hypothesis generation, and the resulting selection pressure during the search process leads to diversity collapse. Motivated by these limitations, we formulate hypothesis search as a sampling problem, where the objective is to efficiently produce diverse, high-quality hypotheses under a fixed validation budget. Building on this perspective, we propose \ours, an evolutionary framework inspired by the classical parallel tempering algorithm that searches hypotheses at multiple temperature levels and enables principled information exchange across temperatures to improve exploration without disrupting convergence. Across domains including molecular discovery, equation discovery, and algorithm discovery, our approach consistently improves both hypothesis quality and diversity under the same validation budget, and produces candidates that remain robust under more expensive downstream computational validations.

Modern artificial intelligence excels at prediction but cannot explain. From large language models to AI-for-science systems, today's machines answer what by recombining patterns already present in the human literature, yet they cannot reason out why a phenomenon must arise from underlying principles even though explanation, not prediction, lies at the heart of scientific discovery. Here we ask whether the structure of scientific explanation can be operationalized to guide how a machine generates hypotheses. We introduce DN-Hypo-Pipeline, a hypothesis-generation framework that adopts a layered, explanation-theoretic scaffold: Hempel's deductive-nomological (DN) model supplies the output form and deductive validity of a hypothesis, Salmon's causal-process account supplies an organizing constraint on where to search for the governing laws, and Armstrong's view of laws as relations between universals supplies the bridge from a phenomenon's constituent processes to the laws that may be associated with it. Rather than searching the space of what has been written, the framework searches the space of what principles govern a phenomenon: given an explanandum, it abstracts the universals instantiated in the phenomenon's formation process, retrieves the laws relating those universals, and deductively reconstructs a new, testable explanation. Evaluated in data-science modeling and judged by both LLMs and human experts, hypotheses generated through this principled reasoning significantly outperform those from direct prompting. Crucially, we translated the two highest-scoring hypotheses into novel algorithms one that reduces the Transformer's theoretical complexity with only minimal performance loss, and another that achieves competitive accuracy with substantially fewer parameters.

Large language models (LLMs) are increasingly deployed as autonomous agents in scientific tasks. Yet whether these systems can effectively engage in forms of inductive reasoning relevant to scientific discovery remains an open question. In this work, we introduce FALSIFYBENCH, an evaluation framework for hypothesis-driven reasoning inspired by the classic Wason 2-4-6 task, in which agents must discover hidden semantic properties by iteratively proposing examples and receiving feedback. This task captures key elements of scientific reasoning: hypothesis generation, evidence gathering, and belief revision in response to both confirming and disconfirming evidence. Our evaluation of 12 LLMs across model families and scales shows that reasoning models are generally stronger scientific reasoners than instruction-tuned models, although no model comes close to optimal performance. The primary driver of success is the capacity for negative testing: models that actively seek to falsify their hypotheses consistently outperform those that primarily seek confirmation. Moreover, a fine-grained turn-level analysis, neglected in previous work, reveals that failure is tied to identifiable patterns in how models navigate the hypothesis space.

A core goal of computational social science is to discover interpretable differences in how language varies across outcomes of interest, such as political affiliation or instructional quality. Recent LLM-based hypothesis generation methods describe such differences in natural language, but select for globally discriminative patterns without accounting for covariates that shape the data based on researchers' domain knowledge. When covariates are ignored, selected patterns can reflect confounds rather than differences of substantive interest. We introduce conditional hypothesis generation, a framework that incorporates researcher-specified covariates to steer hypothesis discovery toward differences that hold within relevant subgroups. Two challenges arise: the target subgroup may be underrepresented (stratum imbalance), and the direction of a difference may reverse across subgroups (sign reversal). We propose two econometrics-inspired methods: one introduces feature--covariate interactions to detect sign reversals, and the other applies within-stratum demeaning and inverse-frequency reweighting to equalize underrepresented strata. Synthetic experiments show each method outperforms global baselines in its targeted setting, and expert evaluation on two real-world datasets confirms that covariate-aware generation surfaces more useful hypotheses within relevant subgroups.

Abductive reasoning over knowledge graphs aims to generate logical hypotheses that explain observed entities or facts. Existing controllable hypothesis generation methods allow users to guide this process with explicit conditions, but they remain limited in interactive settings: they struggle to ground evolving natural-language intents across multi-turn dialogues and provide little fine-grained diagnosis when generated hypotheses fail. To address these limitations, we propose HypoAgent, an Agentic framework for interactive abductive Hypothesis Generation over knowledge graphs. HypoAgent integrates three agents: an Intent Recognition Agent that grounds user utterances and dialogue history into executable KG conditions, a Hypothesis Generation Agent that performs controllable hypothesis generation according to the extracted user intention, and a Root Cause Analysis Agent that diagnoses unreliable hypothesis fragments and leverages KG neighborhood probing to identify supported refinements. Experiments on commonsense and biomedical domain-specific knowledge graphs demonstrate that HypoAgent achieves state-of-the-art semantic similarity under single-turn, multi-turn, and unconditional settings. Our code is available at https://github.com/HKUST-KnowComp/HypoAgent.

Consensus protocols form the backbone of distributed systems and blockchains, where implementation bugs can cause data corruption and financial losses. While LLM-based approaches show promise in code analysis, they struggle with deep protocol-level logic bugs involving complex state-dependent behaviors across multiple execution stages. We present Agora, a domain-aware multi-agent framework that integrates hypothesis-driven testing with LLM capabilities for systematic protocol verification. Agora employs specialized agents that collaboratively explore protocol state spaces, synthesize attack scenarios using domain-specific constraints, and validate findings through iterative refinement. This explicit role separation enables reasoning about global protocol invariants beyond single-function code analysis. We evaluate Agora on four consensus implementations (Raft, EPaxos, HotStuff, BullShark) using four state-of-the-art LLMs. Agora discovers 15 previously unknown protocol-level logic bugs that violate safety properties, while existing LLM-based agents fail to detect any such protocol-level logic bugs. Our results demonstrate that domain-aware multi-agent collaboration is essential for detecting deep logic bugs in complex protocols.

Large language models (LLMs) show remarkable potential in scientific hypothesis discovery. However, existing approaches face two critical limitations: they treat divergent exploratory search and convergent fine-grained refinement as isolated tasks, and they operate autonomously with little to no human guidance. We present MOOSE-Copilot, the first unified framework to bridge this abstraction gap through a formalized human-AI interaction (HAII) protocol. Our system empowers scientists to steer the generative process via three explicit signals: initial blueprints, inter-stage routing, and intra-stage feedback. Using an oracle-simulated evaluation in which an LLM provides idealized expert signals, we show that injecting these structured signals significantly outperforms purely autonomous baselines, characterizing the gains achievable under high-quality guidance. Furthermore, we build a web-based interface that turns the framework into a no-code workflow: researchers pose a question, watch the hypothesis search unfold as an interactive tree, and steer it by selecting hypotheses, routing between stages, and injecting feedback-no command-line agents required. This makes end-to-end hypothesis discovery directly accessible to interdisciplinary researchers.

Knowledge graphs (KGs) can provide structured scientific context to language models, but it remains unclear which graph facts actually shape the generated hypotheses. We study KG-guided hypothesis generation for battery materials across Mistral-7B, Llama-3.1-70B, and Gemini 2.5 Flash. We perturb local KGs by varying density, ontology richness, topology, and control structure, and evaluate outputs with both provided-graph and fixed-reference metrics. Across models, KG utility is selective and model-dependent: graph context changes outputs, but no-KG outputs also recover substantial graph content from model priors. Compact top-k subgraphs often approximate full-KG behavior, including when claimed-outcome triples are held out. At the same time, compression is not unique to one semantic ranking rule, random and topology-based subsets can also recover much of the signal. These results support a redundancy-aware Compressive KG hypothesis: useful KG signal is often recoverable from compact, scientifically structured subgraphs rather than requiring the full local graph.

Biomedical discovery often requires connecting broad biomedical knowledge with specific experimental or clinical data. Background knowledge suggests relevant mechanisms but is usually too general to map directly onto dataset variables, while data-driven patterns can be dataset-specific and hard to interpret mechanistically. We study this missing link as knowledge contextualization: transforming broad biomedical knowledge into evidence-supported, scenario-grounded propositions that domain experts can inspect, replay, and validate. We propose SCENE, a bi-level multi-agent framework that treats knowledge contextualization as iterative search. The upper level converts broad knowledge into search directions and grounds them in the dataset schema. The lower level executes these directions through multi-objective optimization to identify concrete propositions that balance evidential strength and data support. Feedback between the two levels progressively refines the search. We evaluate SCENE in two settings: discovering patient subgroups with heterogeneous treatment benefits in clinical trial scenarios, and identifying context-specific biological responses in LINCS L1000 studies. In clinical trials, SCENE discovers specific, well-supported subgroups and outperforms existing baselines. In L1000 studies, SCENE identifies perturbational contexts with strong target-response matching and high positive rates. These results show that SCENE bridges broad knowledge and scenario-specific evidence, producing traceable, inspectable hypotheses for follow-up validation.

Real world decision-making requires constructing mental models under uncertainty over evidence, over the underlying causal rules, and over the state of the world itself. Which computational principles underpin human inference under such conditions, and do LLM-based agents exhibit similar behavior given matching constraints? We address these questions using an inductive inference Box Task in which participants, human children and LLM-based agents, infer a latent cause through sequential interaction with an uncertain environment. We formalize this task as program induction with Bayesian particle-based inference, admitting two complementary interpretations: (1) as a constraint satisfaction process over hypotheses, and (2) as a program synthesis problem in which hypotheses are executable programs evaluated against evidence. Using the constraint-based formulation, we show that children's behavior is best explained by a combination of subjective evidence reliability and online hypothesis generation, accounting for both their evidence-seeking patterns and their dissociation between task completion and rule generalization. Using the program synthesis formulation, we treat LLM-based agents as model organisms: controllable systems that allow systematic manipulation of task conditions. Across backends, LLM-based agents replicate children's responses to changes in evidence reliability and observability, including discounting unreliable evidence, seeking to resolve partial information, and dissociating between task completion and causal generalization. At the same time, LLM-based agents tend to over-observe and over-comply with instructions relative to children. These results suggest that while children and LLM-based agents adapt similarly to environmental structure, their information-seeking behavior exhibits distinct underlying costs and inductive biases.

Nanomedicine research spans delivery chemistry, immunology, imaging, biomaterials, and disease-specific translational science, yet its conceptual design space remains fragmented across a large and heterogeneous literature. To date, artificial intelligence in nanomedicine has focused primarily on property prediction and formulation optimization, with much less attention to evidence-grounded discovery support at the level of research direction selection. We introduce pArticleMap, a literature-mapping and research-hypothesis-generation system that combines article embeddings, similarity-graph analysis, sparse frontier extraction, structured evidence-pack retrieval, and an audited large-language-model (LLM) workflow for grounded ideation. Rather than forecasting future concept co-occurrence, pArticleMap targets low-density article-level bridge regions and cluster interfaces, then generates and scores citation-grounded hypotheses with large language models in an agentic setup. We evaluate the system with a retrospective realization benchmark (generate later literature under a historical cutoff) and a blinded human reader assessment layer across cue-conditioned nanomedicine tasks. Across 4 selected retrospective bundles, pArticleMap generated ideas and selected task-retained hypotheses (winner ideas) under the benchmark protocol. For task-level retained hypotheses, a pooled gold recovery rate of 10.8% was obtained, with a recall@10 of 15.9% and a future-neighborhood rate of 61.0%, indicating that the system often reached the correct forward-looking neighborhood (paper ideas) even without exact paper-level recovery. Human-agent agreement is modest overall, indicating that internal scoring is useful as a support signal but does not replace expert judgment. These results position pArticleMap as a conservative, evidence-grounded research assistant for nanomedicine.

Traditional scientific modeling typically begins with fixed, instance-wise effective equations and then carries out equation-specific analysis and computation, a procedure that becomes exceptionally challenging in complex applications such as multiscale systems. We propose an alternative paradigm by learning mesoscopic dynamics within a mathematically constrained hypothesis class. Building upon a generalized Onsager principle, we introduce a unified framework encompassing both dissipative and conservative mesoscopic dynamics. We establish uniform and a priori theoretical guarantees, including global well-posedness, asymptotic stability, unique factorization identifiability, and discrete energy dissipation, applicable to all spatio-temporal evolution equations within this hypothesis class prior to all learning stages. Data from each problem instance is then used to guide the identification of members within our hypothesis class, giving rise to accurate, robust and interpretable dynamical models. We empirically validate this framework on both data from continuum PDE models as a check, and on data arising from microscopic chain models for which exact meso-scale models are unknown. The proposed approach not only acts as an effective dynamics learner, but also offers vital interpretable diagnostics of the underlying physics.

Current AI-powered research systems adopt a direct search-then-summarize paradigm that treats hypotheses as end products of scientific discovery. We argue this leaves a critical gap: hypotheses can serve a far more powerful role as organizational instruments that structure the research process itself. We propose the Hypothesis-Driven Deep Research (HDRI) methodology - the first framework using hypotheses to organize general-purpose deep research across arbitrary domains, rather than merely validating claims within specific domains. This transforms research from reactive information retrieval into proactive, verifiable, and iterative knowledge discovery. HDRI is formalized with six core principles and an eight-stage pipeline. A central innovation is the gap-driven iterative research mechanism - a closed-loop quality assurance system that automatically identifies informational and logical gaps, triggering targeted supplementary investigation. We further introduce a fact reasoning framework with traceable reasoning chains and quantified confidence propagation, a subject locking mechanism to prevent entity confusion, and a multi-dimensional quality assessment scheme. The methodology is realized in the INFOMINER system. Experiments demonstrate improvements of 22.4% in fact density, 90% subject matching accuracy, 0.92 multi-source verification confidence, and 14% completeness gain from gap-driven supplementation. Five case studies validate its practical applicability, achieving an average quality rating of 4.46/5.0.

A growing body of work pursues AI scientists capable of end-to-end autonomous scientific discovery. This position paper argues that although they already function as co-scientists, agentic AI scientists are not built for autonomous scientific discovery. We identify the following challenges in building and deploying autonomous AI scientists: (1) Problem selection is influenced by the McNamara fallacy; (2) Agents are built on large language models (LLMs) whose training corpora omit tacit procedural and failure knowledge of laboratory practice; (3) Preference optimisation during post-training compresses output diversity toward consensus; and (4) Most scientific benchmarks measure single-turn prediction accuracy and lack feedback from physical experiments back to the computational model. These challenges are not just questions of scale and scaffolding; they require revisiting fundamental design choices. To build truly autonomous AI scientists, we recommend the use of scientific simulations as verifiers for training, the design of persistent world models that represent the shifting objectives governing real investigations, the establishment of a centralized preregistration repository for all AI-generated hypotheses, and application driven by scientific need rather than tool affordance.

Clinical decision-making in emergency medicine demands rapid, accurate diagnoses under uncertainty. Despite benchmark progress, evidence for LLMs as interactive aids in live physician workflows remains sparse. MedSyn lets physicians iteratively query an LLM provided with the full clinical record while initially viewing only the chief complaint. Seven physicians (three seniors, four residents) completed baseline and AI-assisted sessions across 52 MIMIC-IV cases stratified by difficulty. Blinded evaluation showed residents' Hard-case correctness rose from 0.589 to 0.734; difficulty-standardised completely-correct rates confirmed a medium effect (Δ = 0.092; p = 0.071; d = 0.47). Automated metrics corroborated these gains: standardised any-match accuracy improved by 0.156 (p < 0.0001), and residents showed the largest F1 gain (Δ = 0.138; p < 0.0001). Dialogue analysis revealed expertise-dependent strategies (seniors asked targeted, hypothesis-driven questions; residents relied on broader queries) and cross-expertise concordance increased (Δ = 0.145; p < 0.0001). Interactive LLM support meaningfully enhances diagnostic reasoning.

Autonomous experimentation has transformed microscopy and materials discovery by enabling closed-loop optimization including imaging and spectroscopy tuning, strucutre property relationship discovery, and exploration of combinatorial libraries. However, most current workflows remain limited to selecting measurements within fixed objective or hypothesis spaces, rather than generating new physical models from experimental data. Here, we introduce an open hypothesis-learning framework that combines symbolic regression with large-language-model-based physical evaluation and implement it for autonomous scanning probe microscopy. Symbolic regression generates candidate analytical relationships directly from sparse measurements, while the language-model evaluator ranks these candidates according to physical plausibility, scaling behavior, and consistency with known mechanisms. We demonstrate the approach on autonomous piezoresponse force microscopy measurements of ferroelectric domain switching in a PZT thin film. Starting from five seed measurements, the workflow evolves from physically incomplete candidate expressions toward interpretable voltage-time growth laws consistent with kinetic domain-wall motion. This work extends autonomous microscopy from closed-loop optimization toward open hypothesis discovery, where candidate physical laws emerge from the experiment itself rather than being specified in advance. More broadly, the framework establishes a route for integrating symbolic regression, physical reasoning, and adaptive experimentation into hierarchical autonomous scientific workflows.

Large language models (LLMs) increasingly help people solve problems, from debugging code to repairing machinery. This process requires generating plausible hypotheses from partial descriptions, then updating them as more information arrives. Yet how LLMs perform this form of inference, and how close it is to optimal, remains unclear. We study this question in the number game, a controlled setting in which a learner infers the hypothesis supported by a few positive integers, such as $\{16, 8, 2, 64\}$: a rule like powers of 2 or an interval like numbers near 20. We measure the posterior over hypotheses using three complementary probes: posterior prediction, hypothesis evaluation, and hypothesis generation. We then compare LLM behavior with an optimal Bayesian model and human behavior, and test whether the same posterior is expressed across probes. LLMs are often well described by a two-parameter Bayesian fit, but with systematic offsets: by default they show a strong-sampling assumption that creates an implicit Occam's razor, favoring narrower hypotheses, while thinking mode shifts them toward greater prior reliance. We also find a robust evaluation--generation gap: LLMs select more correct hypotheses during hypothesis evaluation but generate simpler, more rule-like hypotheses. Finally, this Bayesian-with-bias pattern does not extrapolate. Models can behave as if they hold rule-like hypotheses over observed examples, yet generalize poorly to parts of the hypothesis domain not covered by those examples. Our results highlight a limitation of LLMs as general problem solvers, especially for scientific inference, where hypotheses must go beyond the data.

Drug-induced liver injury (DILI) remains a leading cause of late-stage clinical trial attrition. However, existing computational predictors primarily rely on binary classification, a framing that limits generalization and yields no mechanistic insight to guide translational decisions. We argue that DILI prediction is better posed as an explainable hypothesis-generation problem. To support this shift, we introduce the DILER Benchmark, a dataset that extends beyond binary labels by augmenting a curated set of molecules with mechanistic hepatotoxicity hypotheses derived from biomedical literature. We further present HADES, an agentic system designed to generate transparent and auditable reasoning traces. By combining molecular-level predictions, metabolite decomposition, structural understanding, and toxicity pathway evidence, HADES mechanistically assesses DILI risk. Evaluated on the DILER Benchmark, HADES outperforms existing models in binary classification, achieving a ROC-AUC of 0.68 on the Test Set and 0.59 on the challenging Post-2021 Set, compared with 0.63 and 0.50 for DILI-Predictor, respectively. More importantly, we establish a baseline for mechanistic hypothesis generation, where HADES achieves a Hypothesis Alignment Fuzzy Jaccard Index of 0.16. This result underscores the inherent complexity of the task while highlighting the need for advanced explainable approaches in predictive toxicology.

Current knowledge graph (KG) construction methods are confirmatory, focusing on recovering known relationships rather than identifying novel or context-dependent nodes. This paper proposes a phenotype-driven and evidence-governed framework that shifts the paradigm toward structured hypothesis discovery and controlled KG expansion. The approach integrates graph neural networks (GNNs) for phenotype discovery, causal inference, probabilistic reasoning and large language models (LLMs) for hypothesis generation and claim extraction within a unified pipeline. The framework prioritizes relationships that are both structurally supported by data and underexplored in the literature. KG expansion is formulated as a multi-objective optimization problem, where candidate claims are jointly evaluated in terms of relevance, structural validation and novelty. Pareto-optimal selection enables the identification of non-dominated claims that balance confirmation and discovery, avoiding trivial or redundant knowledge inclusion. Experiments on heterogeneous population datasets demonstrate that the proposed framework produces more interpretable phenotypes, reveals context-dependent causal structures and generates high-quality claims that align with both data and scientific evidence. Compared to rule-based and LLM-only baselines, the method achieves the best trade-off across plausibility, novelty, validation and relevance. In retrieval-augmented settings, it significantly improves performance (Recall@5=0.98) while reducing hallucination rates (0.05), highlighting its effectiveness in grounding LLM outputs.

Identifying promising research directions in fast-moving subareas is one of the most cognitively expensive tasks in modern AI research. Existing LLM-driven scientific discovery systems are typically limited to one-shot prompting on static literature snapshots and are validated only against contemporary judges such as human reviewers, agent peer review, wet-lab assays, or self-evaluation, leaving open whether they can anticipate future trends. We present Continuous Knowledge Metabolism (CKM), an AI workflow for hypothesis generation with three key capabilities: (i) continuous literature metabolism via sliding windows that maintain an evolving knowledge state; (ii) predictive evaluation, which grades hypotheses against papers published after the generation window; and (iii) practitioner-grade failure detection that diagnoses workflow failure modes from its outputs. On a 50-topic machine learning benchmark, CKM-Lite produces at least one validated hypothesis on 72% of topics (36 out of 50), more than doubling a one-shot baseline (30%) at approximately 3 dollars per topic and achieving 91% lower token cost. Validated hypotheses precede their matched papers by an average of 404 days (55 hits across 36 topics; median 399 days, range 66-757 days). Broadly, predictive validation against future literature provides a falsifiable, low-cost alternative to contemporary-judge evaluation protocols and can be applied wherever a corpus has dated publication records.

Social scientists are increasingly turning to unstructured datasets to unlock new empirical insights, e.g., estimating descriptive statistics of or causal effects on quantitative measures derived from text, audio, or video data. In many settings, unsupervised analysis is of primary interest, in that the researcher does not want to (or cannot) manually pre-specify all important aspects of the unstructured data to measure; they are interested in "discovery." This paper proposes a general and flexible framework for pursuing such discovery from unstructured data in a statistically principled way. The framework leverages recent methods from the literature on AI interpretability to map unstructured data points to high-dimensional, sparse, and interpretable "concept embeddings"; computes statistics from these concept embeddings for testing interpretable, concept-by-concept hypotheses; performs selective inference on these hypotheses using algorithms validated by new results in high-dimensional central limit theory, producing a selected set ("discoveries"); and both generates and evaluates human-interpretable natural language descriptions of these discoveries. The proposed framework has few researcher degrees of freedom, is robust to data snooping and other post-selection inference concerns, and facilitates fast and inexpensive sensitivity analysis and replication. Applications to recent descriptive and causal analyses of unstructured data in empirical economics are explored.