Cyclic peptides are emerging as promising molecular scaffolds in drug discovery due to their high binding affinity and structural stability. However, extending generative models from linear to cyclic peptide design remains challenging, as cyclization sharply restricts the feasible design space through coupled geometric and biophysical constraints. Moreover, limited training data has led existing approaches to rely largely on zero-shot generation or post hoc filtering, resulting in low yields of feasible designs and limited control over multi-objective trade-offs. To address these limitations, we propose FAR-DPO (Feasibility-Aware and Robust Direct Preference Optimization), an architecture-agnostic framework that steers generative models toward structurally and biophysically feasible cyclic peptide designs, particularly for challenging targets. FAR-DPO integrates feasibility-aware preference construction with difficulty-aware group-robust optimization. Specifically, it constructs within-target preference pairs through feasibility-gated multi-objective dominance and adaptively reweights predefined difficulty groups according to their current preference losses. On the CPSea LNR benchmark, under a fixed generation budget, FAR-DPO increases overall success rate from 46.89% to 57.79% on PepGLAD and from 47.96% to 49.57% on PepFlow. These gains also extend to the hardest target quartile and are accompanied by more favorable best-per-target binding scores. Together, these results demonstrate FAR-DPO's effectiveness in improving feasibility and target-wise robustness.
Reliable medical image understanding requires models to connect clinical language and visual reasoning with pixel-level grounding. Yet medical vision-language models often lack precise localization, whereas medical segmenters typically rely on explicit target categories or precise spatial prompts. This divide is reinforced by a supervision mismatch: segmentation datasets provide precise masks but little language supervision, whereas medical vision-language data rarely pair language with dense spatial annotations. To address this gap, we present MedPixel, a unified medical pixel-language model built around a shared language--mask interface. To provide scalable supervision, we introduce MedPLG-440K, comprising approximately 440K pixel-language task samples constructed through a clinically motivated synthesis process without external LLM annotation. MedPixel is trained with joint multi-task supervised fine-tuning followed by Pixel-Level Preference Optimization, which uses ground-truth masks as offline verifiers to derive response preferences from mask quality. MedPixel supports a broad spectrum of tasks spanning explicit grounding, implicit reasoning, spatial interaction, grounded explanation, and medical VQA. Across this task spectrum, MedPixel achieves strong performance in both pixel-level prediction and response generation, together with effective zero-shot transfer to external grounding benchmarks and robustness to imperfect spatial prompts. Code and model checkpoints will be released at https://github.com/yhy-whu/Medpixel.
Despite significant advances in Medical Report Generation (MRG), the reliability remains constrained by the prevalence of factual errors. While Direct Preference Optimization (DPO) has emerged as a promising post-training paradigm to enhance the performance of Supervised Fine-Tuned (SFT) MRG models, existing DPO-based MRG methods typically adopt a naive preference construction that directly pairs model-generated reports with ground truth reports. This strategy inadvertently entangles critical clinical findings with clinically irrelevant linguistic characteristics, and fundamentally lacks explicit vision-language alignment. To address these challenges, we propose DPO-Clin, a novel post-training framework that focuses preference optimization on clinical findings and cross-modal alignment. First, we introduce the Entity-level Clinical Diagnostic (ECD) module to perform a precise entity-level factual diagnosis. ECD guides the generation of linguistically-aligned report preference pairs, isolating clinical discrepancies from linguistic variations. Second, to achieve fine-grained cross-modal alignment, we develop M2DPO, a retrieval-augmented multi-modal DPO variant that enforces textual preference inversion triggered by visual context switches. Third, we locate correct yet highly uncertain predicted entities and apply counterfactual modifications to construct targeted preference data for latent risk mitigation, thereby further enhancing the model reliability. Extensive experiments on two public chest X-ray datasets (MIMIC-CXR and IU X-Ray) and an in-house endoscopy dataset demonstrate that DPO-Clin significantly improves the SFT baselines on clinical-aware metrics. Furthermore, it achieves superior performance over existing DPO-based MRG methods, exhibiting robust generalizability across distinct baseline architectures and diverse medical imaging modalities.
Yuta Kobayashi, Pradyun Ramesh, Muhammad Ahmed Chaudhry +5cs.CV cs.LG
Vision-Language Models (VLMs) for radiology report generation are typically trained on retrospective clinical reports, which suffer from omission noise: clinically present findings are left unreported due to the omission of subtle findings. For example, prior studies show that cardiomegaly may be omitted from ICU chest X-ray reports when the imaging request is focused on monitoring support device placement. As a result, models trained with standard approaches inherit these omissions, learning to under-report findings themselves. We propose PU-DPO, a preference optimization framework to prevent omission noise from corrupting the preference signal. We reformulate the objective under a positive-unlabeled (PU) learning framework, treating absent mentions as unlabeled rather than truly negative. Our framework provides preference supervision using constructed contrastive pairs, generated using edits to model responses, producing variants that explicitly mention or omit a specific finding. Generated responses that mention the finding are naturally preferred in the context of visual evidence. Across semi-synthetic experiments and analyses on real-world chest radiograph benchmarks where adjudicated labels are available, PU-DPO yields consistent gains in detection rates and recovery of hidden positives across multiple pathologies, and is more robust to omission noise than prior approaches.
Xiaoliang Shi, Zichen Wang, Runze Ma +2q-bio.BM cs.LG
Antibodies are essential proteins that play a central role in immune recognition by binding specific antigen molecules. Although recent protein language models have enabled progress in single-chain protein modeling and generation, they often fall short in antigen-specific antibody design, where effective modeling requires explicit pairing between antibody and antigen, particularly at the epitope level. To address these limitations, we introduce AAMFM, an Antigen-specific Antibody Multimodal Foundation Model that learns unified representations of antibody sequences and structures conditioned on antigen context. AAMFM incorporates rich antigen information including geometric interfaces and epitope annotations via a cross-modal adapter, enabling joint modeling of antibody-antigen interactions in a shared latent space. To further guide the model toward functional relevance, we fine-tune AAMFM using Calibrated Direct Preference Optimization (Cal-DPO), leveraging preference signals extracted from a strong structural prior to align learning with binding-specific objectives. Extensive experiments demonstrate that AAMFM achieves state-of-the-art performance in functional antibody design, revealing its potential for antigen-specific antibody engineering. Our code is available at https://github.com/XL-S224/AAMFM.
The sycophancy of large language models can increase the safety risk in intervention dialogue for autistic children. Supervised fine-tuning can somewhat reduce sycophancy, but relying solely on positive examples is often insufficient to identify and correct failure patterns. We observe that sycophancy behaviors can often be localized to a limited span within the model response. In this regime, sequence-level preference optimization can over-update preference-irrelevant tokens and degrade intervention ability. To address this, we propose the \textbf{M}inimal \textbf{E}dit \textbf{D}ata \textbf{A}ugmentation (MEDA) strategy to construct controlled, stable, minimal edit preference pairs and \textbf{T}oken-level \textbf{D}ifference \textbf{D}irect \textbf{P}reference \textbf{O}ptimization (TD-DPO), which upweights difference tokens between chosen and rejected responses while downweighting shared tokens to suppress background drift. Extensive experiments across multiple backbones and evaluators show that TD-DPO achieves a better trade-off between sycophancy mitigation and intervention ability retention in our offline settings, highlighting its potential as a practical alignment approach for autism intervention.
Motivation: Patient-generated text contains critical information on patients' lived experiences, social context, and care engagement, but remains largely unstructured, limiting its use in patient-centered outcomes research. Prior work introduced the PV-Miner benchmark and PVMinerLLM models for structured extraction. However, supervised fine-tuning (SFT) alone struggles with rare, fine-grained, and unevenly distributed errors, particularly in token-critical structured outputs. Results: We present PVminerLLM2, an improved set of LLMs for structured patient voice extraction that applies preference optimization to address token-critical errors beyond the reach of supervised fine-tuning. Our method introduces (i) a preference objective with token-level gated stabilization term that prevents degradation of absolute token likelihood under preference optimization, and (ii) confusion-aware preference pair construction to better capture low-separation distinctions. We further incorporate token-importance weighting and inverse-frequency reweighing to address token imbalance and class skew. Across multiple model sizes, PVMinerLLM2 consistently outperforms strong baselines, achieving gains of up to 4.43% (Code), 3.50% (Sub-code), and 1.55% (Span), and outperforms baseline LLM trained with existing preference optimization methods. Availability and Implementation: The supplementary material, code, evaluation scripts, and trained models for PVminerLLM2 are publicly available at: https://github.com/Data-Mining-Lab-Yale/PVminerLLM2
Macrocyclic peptides are promising therapeutic candidates for intracellular targets, but their design requires simultaneous control over non-natural monomer chemistry, ring topology, membrane permeability, and target binding. Existing SMILES- or HELM-string generative models either operate in long atom-level sequence spaces or treat monomers as symbolic tokens with limited chemical grounding. We introduce PepALD, an Autoregressive Latent Diffusion (ALD) foundation model for \textit{de novo} macrocyclic peptide generation. The model represents HELM monomers with structured chemical embeddings, generates each residue through context-conditioned diffusion in chemically informed latent space, predicts R-group-aware ring closures during autoregressive generation, and aligns the denoiser to affinity rewards using winner-protected diffusion-adapted preference optimization. In silico experiments demonstrate PepALD's generation quality and reward-optimization performance against representative peptide generation baselines.
Shayan Mohammadizadehsamakosh, Pritam Sarkar, Leonid Sigal +2cs.CV cs.AI
Large Vision-Language Models (LVLMs) have achieved strong performance across medical imaging tasks, yet they remain prone to factual inconsistencies, poor visual grounding, and misalignment with clinically meaningful feedback. Existing post-training alignment approaches, including Direct Preference Optimization (DPO) and its variants, face three critical limitations in the medical domain: (1) sequence-level reward signals treat clinically critical tokens identically to generic filler text; (2) reliance on static supervised fine-tuning references as preferred responses introduces an off-policy distribution shift, steering optimization toward stylistic artifacts over clinical correctness; and (3) alignment objectives lack explicit visual grounding constraints, leaving models insensitive to subtle yet diagnostically decisive pathological features. Our method leverages a bidirectional token-wise KL regularizer alongside a visual-contrastive grounding objective that pairs clean and lesion-corrupted images to penalize responses generated without adequate visual evidence. Together, these components form a fine-grained, on-policy alignment framework that constructs preference pairs by minimally editing model-generated outputs, correcting only clinically erroneous spans while preserving the original linguistic style. Extensive experiments across medical imaging tasks and clinical text generation benchmarks validate the effectiveness of our approach.