arXiv subjects

Ehsan Hajiramezanali

Publications and source records attributed to Ehsan Hajiramezanali.

At least 19 recordsLinked to original sources

arXiv2026

AutoSciBench: Autonomous Benchmark Generation for Evaluating Scientific Agents

As agents rapidly evolve, existing benchmarks can become saturated, limiting their ability to distinguish capabilities and reveal remaining failure modes. Particularly in scientific domains, constructing and updating benchmarks requires substantial time, labor, and domain expertise, making it difficult to keep evaluation aligned with advances in agent capabilities. We address this challenge by investigating whether scientific-agent benchmarks can be automatically generated and iteratively adapted as agent capabilities evolve. We introduce AutoSciBench, a framework that represents each task as a high-level concept specifying the scientific domain, data modality, and required reasoning approach, together with a low-level recipe specifying how the question, environment, and ground-truth answer are constructed and verified. Agents attempt to solve each task, producing solver trajectories and corresponding judge feedback which AutoSciBench uses to revise the recipe or concept, closing observed shortcuts and shifting tasks toward raw-data re-examination, interpretation of intermediate results, and evidence integration. Experience distilled from completed refinement trajectories further guides new concept generation, allowing lessons from earlier task refinement to inform subsequent benchmark construction. Starting from existing benchmarks, we evaluate AutoSciBench across computational biology, materials science, and clinical imaging. Generated benchmarks reduce average solver accuracy by 22.4 and 25.5 percentage points relative to the human-curated benchmarks in computational biology and materials science, respectively, while generated tasks receive higher average quality ratings across all three domains, suggesting that scientific-agent evaluation can adapt as agent capabilities advance.

cs.AI↗

arXiv2026

Biology-in-the-loop: Amortized Adaptive Hit Discovery in CRISPR Screens

Many biological discovery problems require experiments to be selected sequentially under constrained budgets. CRISPR screening is a prominent example, as exhaustive perturbation testing is often infeasible and candidate perturbations must instead be prioritized over multiple experimental rounds. Despite the importance of this problem, existing benchmarks for adaptive hit discovery remain limited in scale and diversity. Here, we introduce AssayBench-Loop, a large-scale benchmark for adaptive hit discovery comprising 1,389 CRISPR screens across five phenotype categories. Beyond enabling systematic evaluation, its scale makes it possible to learn acquisition strategies across historical experiments. Building on this resource, we introduce AssayLoop, a sequential experimental design framework combining AssayFormer, a transformer-based amortized acquisition policy trained across historical screens to adapt from experimental feedback, with LLM-derived biological priors through an adaptive handoff. In this view, completed experiments become training data for learning how accumulated evidence should guide what to test next, while LLMs provide prior biological knowledge to seed the search. We further introduce AssayLLM, showing that the same principle can be extended directly to an LLM through task-specific post-training. On temporally held-out screens, AssayLoop achieves a 5.67-fold enrichment over random selection and recovers 27.7% of hits after assaying approximately 5% of the candidate library, outperforming existing adaptive-design methods and standalone LLMs, and AssayFormer alone. Performance improves with increasing historical training data and transfers to phenotype categories excluded from training. These results demonstrate the value of learning acquisition policies across historical experiments and combining them with broad biological priors for efficient adaptive hit discovery.

q-bio.QM↗

arXiv2026

Beyond Explainable AI (XAI): An Overdue Paradigm Shift and Post-XAI Research Directions

This study provides a cross-disciplinary examination of Explainable Artificial Intelligence (XAI) approaches-focusing on deep neural networks (DNNs) and large language models (LLMs)-and identifies empirical and conceptual limitations in current XAI. We discuss critical symptoms that stem from deeper root causes (i.e., two paradoxes, two conceptual confusions, and five false assumptions). These fundamental problems within the current XAI research field reveal three insights: experimentally, XAI exhibits significant flaws; conceptually, it is paradoxical; and pragmatically, further attempts to reform the paradoxical XAI might exacerbate its confusion-demanding fundamental shifts and new research directions. To move beyond XAI's limitations, we propose a four-pronged synthesized paradigm shift toward reliable and certified AI development. These four components include: verification-focused Interactive AI (IAI) to establish scientific community protocols for certifying AI system performance rather than attempting post-hoc explanations, AI Epistemology for rigorous scientific foundations, User-Sensible AI to create context-aware systems tailored to specific user communities, and Model-Centered Interpretability for faithful technical analysis-together offering comprehensive post-XAI research directions.

cs.CY↗

arXiv2026

AssayBench: An Assay-Level Virtual Cell Benchmark for LLMs and Agents

Recent advances in machine learning and large-scale biological data collections have revived the prospect of building a virtual cell, a computational model of cellular behavior that could accelerate biological discovery. One of the most compelling promises of this vision is the ability to perform in silico phenotypic screens, in which a model predicts the effects of cellular perturbations in unseen biological contexts. This task combines heterogeneous textual inputs with diverse phenotypic outputs, making it particularly well-suited to LLMs and agentic systems. Yet, no standard benchmark currently exists for this task, as existing efforts focus on narrower molecular readouts that are only indirectly aligned with the phenotypic endpoints driving many real-world drug discovery workflows. In this work, we present AssayBench, a benchmark for phenotypic screen prediction, built from 1,920 publicly available CRISPR screens spanning five broad classes of cellular phenotypes. We formulate the screen prediction task as a gene rank prediction for each screen and introduce the adjusted nDCG, a continuous metric for comparing performance across heterogeneous assays. Our extensive evaluation shows that existing methods remain far from empirically estimated performance ceilings and zero-shot generalist LLMs outperform biology-specific LLMs and trainable baselines. Optimization techniques such as fine-tuning, ensembling, and prompt optimization can further improve LLM performance on this task. Overall, AssayBench offers a practical testbed for measuring progress toward in silico phenotypic screening and, more broadly, virtual cell models.

cs.LG↗

arXiv2026

DC-W2S: Dual-Consensus Weak-to-Strong Training for Reliable Process Reward Modeling in Biological Reasoning

In scientific reasoning tasks, the veracity of the reasoning process is as critical as the final outcome. While Process Reward Models (PRMs) offer a solution to the coarse-grained supervision problems inherent in Outcome Reward Models (ORMs), their deployment is hindered by the prohibitive cost of obtaining expert-verified step-wise labels. This paper addresses the challenge of training reliable PRMs using abundant but noisy "weak" supervision. We argue that existing Weak-to-Strong Generalization (W2SG) theories lack prescriptive guidelines for selecting high-quality training signals from noisy data. To bridge this gap, we introduce the Dual-Consensus Weak-to-Strong (DC-W2S) framework. By intersecting Self-Consensus (SC) metrics among weak supervisors with Neighborhood-Consensus (NC) metrics in the embedding space, we stratify supervision signals into distinct reliability regimes. We then employ a curriculum of instance-level balanced sampling and label-level reliability-aware masking to guide the training process. We demonstrate that DC-W2S enables the training of robust PRMs for complex reasoning without exhaustive expert annotation, proving that strategic data curation is more effective than indiscriminate training on large-scale noisy datasets.

cs.CL↗

arXiv2026

Iterative Distillation for Reward-Guided Fine-Tuning of Diffusion Models in Biomolecular Design

We address the problem of fine-tuning diffusion models for reward-guided generation in biomolecular design. While diffusion models have proven highly effective in modeling complex, high-dimensional data distributions, real-world applications often demand more than high-fidelity generation, requiring optimization with respect to potentially non-differentiable reward functions such as physics-based simulation or rewards based on scientific knowledge. Although RL methods have been explored to fine-tune diffusion models for such objectives, they often suffer from instability, low sample efficiency, and mode collapse due to their on-policy nature. In this work, we propose an iterative distillation-based fine-tuning framework that enables diffusion models to optimize for arbitrary reward functions. Our method casts the problem as policy distillation: it collects off-policy data during the roll-in phase, simulates reward-based soft-optimal policies during roll-out, and updates the model by minimizing the KL divergence between the simulated soft-optimal policy and the current model policy. Our off-policy formulation, combined with KL divergence minimization, enhances training stability and sample efficiency compared to existing RL-based methods. Empirical results demonstrate the effectiveness and superior reward optimization of our approach across diverse tasks in protein, small molecule, and regulatory DNA design. The source code is released at (https://divelab.github.io/VIDD/).

cs.LG↗

arXiv2025

RAG-Enhanced Collaborative LLM Agents for Drug Discovery

Recent advances in large language models (LLMs) have shown great potential to accelerate drug discovery. However, the specialized nature of biochemical data often necessitates costly domain-specific fine-tuning, posing major challenges. First, it hinders the application of more flexible general-purpose LLMs for cutting-edge drug discovery tasks. More importantly, it limits the rapid integration of the vast amounts of scientific data continuously generated through experiments and research. Compounding these challenges is the fact that real-world scientific questions are typically complex and open-ended, requiring reasoning beyond pattern matching or static knowledge retrieval.To address these challenges, we propose CLADD, a retrieval-augmented generation (RAG)-empowered agentic system tailored to drug discovery tasks. Through the collaboration of multiple LLM agents, CLADD dynamically retrieves information from biomedical knowledge bases, contextualizes query molecules, and integrates relevant evidence to generate responses - all without the need for domain-specific fine-tuning. Crucially, we tackle key obstacles in applying RAG workflows to biochemical data, including data heterogeneity, ambiguity, and multi-source integration. We demonstrate the flexibility and effectiveness of this framework across a variety of drug discovery tasks, showing that it outperforms general-purpose and domain-specific LLMs as well as traditional deep learning approaches. Our code is publicly available at https://github.com/Genentech/CLADD.

cs.LG↗

arXiv2025

Adding Conditional Control to Diffusion Models with Reinforcement Learning

Diffusion models are powerful generative models that allow for precise control over the characteristics of the generated samples. While these diffusion models trained on large datasets have achieved success, there is often a need to introduce additional controls in downstream fine-tuning processes, treating these powerful models as pre-trained diffusion models. This work presents a novel method based on reinforcement learning (RL) to add such controls using an offline dataset comprising inputs and labels. We formulate this task as an RL problem, with the classifier learned from the offline dataset and the KL divergence against pre-trained models serving as the reward functions. Our method, $\textbf{CTRL}$ ($\textbf{C}$onditioning pre-$\textbf{T}$rained diffusion models with $\textbf{R}$einforcement $\textbf{L}$earning), produces soft-optimal policies that maximize the abovementioned reward functions. We formally demonstrate that our method enables sampling from the conditional distribution with additional controls during inference. Our RL-based approach offers several advantages over existing methods. Compared to classifier-free guidance, it improves sample efficiency and can greatly simplify dataset construction by leveraging conditional independence between the inputs and additional controls. Additionally, unlike classifier guidance, it eliminates the need to train classifiers from intermediate states to additional controls. The code is available at https://github.com/zhaoyl18/CTRL.

cs.LG↗

arXiv2024

MolCap-Arena: A Comprehensive Captioning Benchmark on Language-Enhanced Molecular Property Prediction

Bridging biomolecular modeling with natural language information, particularly through large language models (LLMs), has recently emerged as a promising interdisciplinary research area. LLMs, having been trained on large corpora of scientific documents, demonstrate significant potential in understanding and reasoning about biomolecules by providing enriched contextual and domain knowledge. However, the extent to which LLM-driven insights can improve performance on complex predictive tasks (e.g., toxicity) remains unclear. Further, the extent to which relevant knowledge can be extracted from LLMs also remains unknown. In this study, we present Molecule Caption Arena: the first comprehensive benchmark of LLM-augmented molecular property prediction. We evaluate over twenty LLMs, including both general-purpose and domain-specific molecule captioners, across diverse prediction tasks. To this goal, we introduce a novel, battle-based rating system. Our findings confirm the ability of LLM-extracted knowledge to enhance state-of-the-art molecular representations, with notable model-, prompt-, and dataset-specific variations. Code, resources, and data are available at github.com/Genentech/molcap-arena.

cs.CL↗

arXiv2024

Cell Morphology-Guided Small Molecule Generation with GFlowNets

High-content phenotypic screening, including high-content imaging (HCI), has gained popularity in the last few years for its ability to characterize novel therapeutics without prior knowledge of the protein target. When combined with deep learning techniques to predict and represent molecular-phenotype interactions, these advancements hold the potential to significantly accelerate and enhance drug discovery applications. This work focuses on the novel task of HCI-guided molecular design. Generative models for molecule design could be guided by HCI data, for example with a supervised model that links molecules to phenotypes of interest as a reward function. However, limited labeled data, combined with the high-dimensional readouts, can make training these methods challenging and impractical. We consider an alternative approach in which we leverage an unsupervised multimodal joint embedding to define a latent similarity as a reward for GFlowNets. The proposed model learns to generate new molecules that could produce phenotypic effects similar to those of the given image target, without relying on pre-annotated phenotypic labels. We demonstrate that the proposed method generates molecules with high morphological and structural similarity to the target, increasing the likelihood of similar biological activity, as confirmed by an independent oracle model.

cs.LG↗

arXiv2024

Feedback Efficient Online Fine-Tuning of Diffusion Models

Diffusion models excel at modeling complex data distributions, including those of images, proteins, and small molecules. However, in many cases, our goal is to model parts of the distribution that maximize certain properties: for example, we may want to generate images with high aesthetic quality, or molecules with high bioactivity. It is natural to frame this as a reinforcement learning (RL) problem, in which the objective is to fine-tune a diffusion model to maximize a reward function that corresponds to some property. Even with access to online queries of the ground-truth reward function, efficiently discovering high-reward samples can be challenging: they might have a low probability in the initial distribution, and there might be many infeasible samples that do not even have a well-defined reward (e.g., unnatural images or physically impossible molecules). In this work, we propose a novel reinforcement learning procedure that efficiently explores on the manifold of feasible samples. We present a theoretical analysis providing a regret guarantee, as well as empirical validation across three domains: images, biological sequences, and molecules.

cs.LG↗

arXiv2024

Bridging Model-Based Optimization and Generative Modeling via Conservative Fine-Tuning of Diffusion Models

AI-driven design problems, such as DNA/protein sequence design, are commonly tackled from two angles: generative modeling, which efficiently captures the feasible design space (e.g., natural images or biological sequences), and model-based optimization, which utilizes reward models for extrapolation. To combine the strengths of both approaches, we adopt a hybrid method that fine-tunes cutting-edge diffusion models by optimizing reward models through RL. Although prior work has explored similar avenues, they primarily focus on scenarios where accurate reward models are accessible. In contrast, we concentrate on an offline setting where a reward model is unknown, and we must learn from static offline datasets, a common scenario in scientific domains. In offline scenarios, existing approaches tend to suffer from overoptimization, as they may be misled by the reward model in out-of-distribution regions. To address this, we introduce a conservative fine-tuning approach, BRAID, by optimizing a conservative reward model, which includes additional penalization outside of offline data distributions. Through empirical and theoretical analysis, we demonstrate the capability of our approach to outperform the best designs in offline data, leveraging the extrapolation capabilities of reward models while avoiding the generation of invalid designs through pre-trained diffusion models.

cs.LG↗

arXiv2024

Fine-Tuning of Continuous-Time Diffusion Models as Entropy-Regularized Control

Diffusion models excel at capturing complex data distributions, such as those of natural images and proteins. While diffusion models are trained to represent the distribution in the training dataset, we often are more concerned with other properties, such as the aesthetic quality of the generated images or the functional properties of generated proteins. Diffusion models can be finetuned in a goal-directed way by maximizing the value of some reward function (e.g., the aesthetic quality of an image). However, these approaches may lead to reduced sample diversity, significant deviations from the training data distribution, and even poor sample quality due to the exploitation of an imperfect reward function. The last issue often occurs when the reward function is a learned model meant to approximate a ground-truth "genuine" reward, as is the case in many practical applications. These challenges, collectively termed "reward collapse," pose a substantial obstacle. To address this reward collapse, we frame the finetuning problem as entropy-regularized control against the pretrained diffusion model, i.e., directly optimizing entropy-enhanced rewards with neural SDEs. We present theoretical and empirical evidence that demonstrates our framework is capable of efficiently generating diverse samples with high genuine rewards, mitigating the overoptimization of imperfect reward models.

cs.LG↗

arXiv2024

Toward the Identifiability of Comparative Deep Generative Models

Deep Generative Models (DGMs) are versatile tools for learning data representations while adequately incorporating domain knowledge such as the specification of conditional probability distributions. Recently proposed DGMs tackle the important task of comparing data sets from different sources. One such example is the setting of contrastive analysis that focuses on describing patterns that are enriched in a target data set compared to a background data set. The practical deployment of those models often assumes that DGMs naturally infer interpretable and modular latent representations, which is known to be an issue in practice. Consequently, existing methods often rely on ad-hoc regularization schemes, although without any theoretical grounding. Here, we propose a theory of identifiability for comparative DGMs by extending recent advances in the field of non-linear independent component analysis. We show that, while these models lack identifiability across a general class of mixing functions, they surprisingly become identifiable when the mixing function is piece-wise affine (e.g., parameterized by a ReLU neural network). We also investigate the impact of model misspecification, and empirically show that previously proposed regularization techniques for fitting comparative DGMs help with identifiability when the number of latent variables is not known in advance. Finally, we introduce a novel methodology for fitting comparative DGMs that improves the treatment of multiple data sources via multi-objective optimization and that helps adjust the hyperparameter for the regularization in an interpretable manner, using constrained optimization. We empirically validate our theory and new methodology using simulated data as well as a recent data set of genetic perturbations in cells profiled via single-cell RNA sequencing.

cs.LG↗

arXiv2023

Conformalized Deep Splines for Optimal and Efficient Prediction Sets

Uncertainty estimation is critical in high-stakes machine learning applications. One effective way to estimate uncertainty is conformal prediction, which can provide predictive inference with statistical coverage guarantees. We present a new conformal regression method, Spline Prediction Intervals via Conformal Estimation (SPICE), that estimates the conditional density using neural-network-parameterized splines. We prove universal approximation and optimality results for SPICE, which are empirically validated by our experiments. SPICE is compatible with two different efficient-to-compute conformal scores, one oracle-optimal for marginal coverage (SPICE-ND) and the other asymptotically optimal for conditional coverage (SPICE-HPD). Results on benchmark datasets demonstrate SPICE-ND models achieve the smallest average prediction set sizes, including average size reductions of nearly 50% for some datasets compared to the next best baseline. SPICE-HPD models achieve the best conditional coverage compared to baselines. The SPICE implementation is made available.

cs.LG↗

arXiv2023

Towards Understanding and Improving GFlowNet Training

Generative flow networks (GFlowNets) are a family of algorithms that learn a generative policy to sample discrete objects $x$ with non-negative reward $R(x)$. Learning objectives guarantee the GFlowNet samples $x$ from the target distribution $p^*(x) \propto R(x)$ when loss is globally minimized over all states or trajectories, but it is unclear how well they perform with practical limits on training resources. We introduce an efficient evaluation strategy to compare the learned sampling distribution to the target reward distribution. As flows can be underdetermined given training data, we clarify the importance of learned flows to generalization and matching $p^*(x)$ in practice. We investigate how to learn better flows, and propose (i) prioritized replay training of high-reward $x$, (ii) relative edge flow policy parametrization, and (iii) a novel guided trajectory balance objective, and show how it can solve a substructure credit assignment problem. We substantially improve sample efficiency on biochemical design tasks.

cs.LG↗

arXiv2022

Conditional Diffusion with Less Explicit Guidance via Model Predictive Control

How much explicit guidance is necessary for conditional diffusion? We consider the problem of conditional sampling using an unconditional diffusion model and limited explicit guidance (e.g., a noised classifier, or a conditional diffusion model) that is restricted to a small number of time steps. We explore a model predictive control (MPC)-like approach to approximate guidance by simulating unconditional diffusion forward, and backpropagating explicit guidance feedback. MPC-approximated guides have high cosine similarity to real guides, even over large simulation distances. Adding MPC steps improves generative quality when explicit guidance is limited to five time steps.

cs.LG↗

arXiv2022

Parameter Averaging for Feature Ranking

Neural Networks are known to be sensitive to initialisation. The methods that rely on neural networks for feature ranking are not robust since they can have variations in their ranking when the model is initialized and trained with different random seeds. In this work, we introduce a novel method based on parameter averaging to estimate accurate and robust feature importance in tabular data setting, referred as XTab. We first initialize and train multiple instances of a shallow network (referred as local masks) with "different random seeds" for a downstream task. We then obtain a global mask model by "averaging the parameters" of local masks. We show that although the parameter averaging might result in a global model with higher loss, it still leads to the discovery of the ground-truth feature importance more consistently than an individual model does. We conduct extensive experiments on a variety of synthetic and real-world data, demonstrating that the XTab can be used to obtain the global feature importance that is not sensitive to sub-optimal model initialisation.

cs.LG↗