Antonio Scardace, Francesco Guarnera, Sebastiano Battiato +1cs.CV
While deep generative models offer new opportunities for medical image synthesis and data sharing, their ability to memorize and reproduce training samples raises serious concerns about patient confidentiality. Detecting such memorization at scale remains challenging: traditional pixel-based metrics are sensitive to generation artifacts, whereas generic embedding-based metrics often lack the anatomical sensitivity required for medical data. To address this challenge, we introduce DeepSSIM++, a self-supervised similarity metric for scalable memorization auditing in medical generative models. By leveraging multi-scale feature aggregation and anatomy-preserving augmentations, DeepSSIM++ learns an embedding space where cosine similarity approximates the Structural Similarity Index (SSIM), eliminating the need for exact pixel-level registration. Compared with state-of-the-art baselines, DeepSSIM++ achieves an average Macro F1 improvement of 33 percentage points under ideal alignment and 46 percentage points under realistic spatial and intensity perturbations. Furthermore, it accelerates large-scale similarity computation by several orders of magnitude compared with analytical SSIM. By combining anatomical sensitivity and computational efficiency, DeepSSIM++ provides an open-source tool for scalable memorization auditing in medical generative AI. Code and data are publicly available at: https://github.com/brAIn-science/DeepSSIM.
Deep generative models have recently emerged as powerful priors for solving ill-posed inverse problems in CT, with diffusion-based approaches achieving state-of-the-art reconstruction performance. However, diffusion models typically rely on stochastic sampling procedures, long inference trajectories, and carefully tuned noise schedules, which can limit computational efficiency and numerical stability, especially at high spatial resolutions. In this work, we investigate Flow Matching as an alternative generative prior for CT reconstruction. We train a high-resolution Rectified Flow Matching model on 256x256 chest images from the Mayo Clinic Low-Dose CT dataset. To mitigate overfitting and limited anatomical variability, we employ a two-stage training strategy consisting of an initial phase with strong, anatomically informed data augmentation, followed by a fine-tuning phase with reduced or no augmentation to refine structural fidelity. The resulting model is capable of generating high-quality and anatomically coherent CT-like images, serving as a strong learned prior. We then evaluate multiple reconstruction methods specifically designed for Flow Matching models, including Plug-and-Play Flow, FlowDPS, Flower, and Flow-Priors (ICTM), and compare them against state-of-the-art diffusion-based reconstruction algorithms such as DDRM, DPS, and DiffPIR. Experimental results across several CT inverse problem settings show that Flow Matching-based approaches consistently outperform diffusion-based methods in terms of PSNR, SSIM, and perceptual quality, while requiring fewer sampling steps. Finally, we publicly release the trained Flow Matching model and accompanying code to facilitate reproducibility and future research. Overall, this work demonstrates that Flow Matching provides a stable, efficient, and effective alternative to diffusion models for high-resolution CT image reconstruction.
Generative models have shown strong potential for positron emission tomography (PET) image reconstruction. Although diffusion model-based reconstruction methods have demonstrated promising performance, they often require many reverse sampling steps with data-consistency updates incorporated into the sampling process. Flow matching offers an attractive alternative because it can directly estimate clean images from intermediate states, allowing data-consistency refinement to be separated from flow propagation. In this work, we proposed flow matching-based PET image reconstruction methods. We first established PET-FlowDPS by incorporating Poisson likelihood guidance with an expectation-maximization (EM)-based preconditioner into the FlowDPS framework. We then proposed a model-based PET reconstruction method that used a pretrained flow matching model as a prior, in which the flow-based prior, PET data refinement, and stochastic propagation were interpreted within an approximate Bayesian framework. Experimental results using [$^{\text{18}}\text{F}$]FDG brain PET datasets showed that the proposed method achieved better bias-variance trade-offs across different dose levels compared with other reference methods. These results demonstrated the potential of flow matching as a generative prior for quantitative PET image reconstruction.
Sidi Mohamed Sid'El Moctar, Nicolas Vitry, Hélène Bouvraiscs.CV cs.LG q-bio.QM
Segmentation of curvilinear anatomical structures in 3D medical images remains challenging due to complex topology, severe class imbalance, weak contrast, and large variations in structure morphology. While deep learning approaches for 3D curvilinear segmentation have been proposed, they are often tailored to specific anatomies or modalities, limiting generalization across clinical settings and leaving room for improvement. Recent generative models have shown the benefits of iterative prediction for structured segmentation tasks, yet diffusion-based methods suffer from computationally expensive sampling, hindering their use on high-resolution 3D volumes. We present 3D-CurvSegFlow, a flow matching-based model for 3D curvilinear structure segmentation. The model learns a continuous transformation from a simple source distribution to the target vascular representation, enabling progressive refinement of complex curvilinear geometries with efficient inference. We evaluate our method on Three public challenging datasets covering distinct anatomies and modalities: portal vein, cerebral vessel, and coronary arteries. Using a common architecture and training strategy across all tasks, our method outperforms general-purpose and vessel-specific approaches, with strong preservation of thin branches and vascular continuity. This work not only advances the state-of-the-art in 3D curvilinear segmentation but also opens new avenues for efficient, generalizable, and clinically applicable methods in medical image analysis.
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.
Modern generative models increasingly produce distribution-valued outputs, such as predicted cellular responses to genetic perturbations in single-cell genomics. While these models provide valuable auxiliary information, they are inherently imperfect, creating a need for statistical methods that leverage their predictions without relying on their correctness. We propose generation-powered inference (GPI), a general framework for improving inference on distribution-valued parameters using auxiliary generative models. Focusing on Wasserstein barycenters and related distributional functionals, we introduce a function-valued bridge representation that transforms inference in the nonlinear Wasserstein space into estimation of a mean function in a Hilbert space, enabling an augmented estimation framework analogous to prediction-powered inference. We develop a family of GPI estimators with optimal information borrowing, establish consistency, asymptotic normality, and simultaneous confidence bands, and derive valid inference for linear functionals and Wasserstein distances. Simulation studies demonstrate efficiency gains over labeled-data-only methods and robust performance under generative model misspecification. We illustrate the proposed framework using a Perturb-seq study of K562 cells, where synthetic perturbation responses generated by the State foundation model are used to improve inference for pathway-level consensus gene expression distributions associated with perturbations of the 40S ribosome module.
Lisa K. Fischer, Mykhailo Riabets, Daniel Rueckert +3cs.CV cs.AI cs.LG
Large-scale multi-modal MRI datasets impose substantial storage and I/O costs, limiting the training of 3D generative models on commodity infrastructure. While lossy compression is known to preserve accuracy for discriminative segmentation networks, its effect on generative models, which must learn the full data distribution rather than a decision boundary, is unexplored. We study whether standard image codecs can effectively compress semantically rich brain tumor MRI while preserving the fidelity required to train and deploy a 3D MRI generative model. Each 3D volume is compressed with JPEG2000 or a near-lossless JPEG-LS pipeline. Next, a Wavelet Flow Matching model, conditioned on BraTS image sequences (T1n, T1c, T2, T2f), is trained on compressed data, and the resulting models are evaluated on the validation set. At a 20:1 compression ratio, synthesis quality is statistically equivalent to a model trained on uncompressed data within a pre-specified margin ($Δ$PSNR $<1$,dB, $Δ$SSIM $<0.02$; paired TOST $p=[[p]]$): mean PSNR is 27.3,dB vs. 27.0,dB and mean SSIM is 0.95 vs. 0.96 across modalities. Our results indicate that JPEG2000 compression is a practical step toward scalable 3D MRI generative modeling without degrading synthesis quality. The codebase is available at https://github.com/lisafis/MRIComp4Flow .
Hengyuan Cao, Shizhuo Cheng, Mingxuan Liu +5cs.LG q-bio.BM
The rapid evolution of generative models has unlocked new potentials in protein binder design, a pivotal task in structural biology, by facilitating end-to-end generation via joint sequence-structure modeling or hallucination. However, existing approaches are predominantly implemented under a single-target, single-state assumption, limiting their ability to model multi-target or multi-state interactions required for advanced function-oriented protein design. Here, we introduce Chamaileon, which unifies multi-target and multi-state binder design by formulating the problem as cross-context binding landscape modeling. The framework is underpinned by a training paradigm termed In-Context Complex Co-Design (I3CD) for context-aware sequence-structure co-modeling. During inference, we employ Mixture-of-Paths Sampling (MoPS), a scalable strategy that optimizes a single sequence across contexts while alleviating the scarcity of high-quality multi-conformational paired data. Extensive evaluation on our newly constructed benchmark, CROSS, demonstrates that Chamaileon effectively generates sequences adaptable to diverse conformational landscapes and multi-target requirements. The code is available on https://github.com/caohengyuan/Chamaileon.
Talha Meraj, Tom Flannery, Charlie Cummins +6cs.CV
Accurate tumour localization and diagnosis is a critical component of clinical care for brain cancers. Magnetic Resonance Imaging (MRI) is the most commonly used imaging modality due to its superior soft-tissue contrast. However, standard MRI often exhibits limited contrast and imaging artifacts, which necessitates the use of contrast agents to enhance lesion visibility. The administration of chemical contrast agents is not always feasible and may be contraindicated in patients with renal impairment or other health conditions. As a result, developing accurate and non-invasive contrast enhanced MRI (CEMRI) synthesis methods has clinical importance. In recent years, numerous approaches for CEMRI synthesis have been proposed, predominantly relying on generative artificial intelligence models. While these methods demonstrate promising performance, their dependence on implicit feature learning often limits their ability to preserve anatomical boundaries and tumour-specific fine structures. To address these challenges, we propose an anatomically aware frequency-and-structure-guided vision transformer (AA-ViT), for CEMRI synthesis using pre-contrast MRI modalities (T1, T2, and FLAIR). Experiments on the BraTS 2021 dataset demonstrate that the proposed method preserves anatomical and lesion boundaries, achieving higher PSNR and SSIM than state-of-the-art approaches. Clinical evaluation by three neuroradiologists and a neurosurgeon on 19 randomly selected cases across diverse gliomas yielded a mean score of 3.94/5, providing preliminary clinical validation rarely seen in prior studies. Synthetic post-contrast scans from our model could lower scanning costs, shorten imaging time, and avoid the potential risks of using gadolinium-based contrast agents.
While generative models enable encoding of complex neuroimaging data for feature generation and reconstruction, developing optimal architectural frameworks with appropriate encoding and latent space processes is crucial for studying structural and functional properties of the brain. We design a multimodal generative framework for structural and functional magnetic resonance imaging (MRI) features through systematic evaluation of encoding strategies, latent multimodal fusion, and generative model selection. Using structural gray matter volume (GMV) and static functional network connectivity (sFNC) features from a large neuroimaging dataset, we analyze generative frameworks involving variational autoencoders (VAEs), transformers, generative adversarial networks (GANs), and diffusion models. Architectures that employ modality-aware graph encoding of functional connectivity into a lower-dimensional latent space outperform vectorized encoders or direct data space approaches. The proposed multimodal graph VAE (gMMVAE) surpasses alternative generative variants across multiple metrics for generation fidelity, reconstruction quality, efficiency, and latent space discriminability, highlighting its potential for robust multimodal neuroimaging analysis.
High-content imaging assays quantify cellular responses to chemical and genetic perturbations, yet continuous trajectories of individual cells are unobservable because cells are chemically fixed at acquisition. Perturbation modeling therefore reduces to inferring stochastic transport between control and treated populations observed only as separate marginals. While recent generative models achieve strong end-point alignment, boundary consistency does not determine intermediate evolution: multiple stochastic processes may connect identical marginals while traversing regions unsupported by observed single-cell morphologies. We introduce \textbf{FreeBridge}, a Schrödinger Bridge formulation for single-cell transition modeling under endpoint-only supervision. FreeBridge defines atomic states as instance-segmented single-cell representations, establishing a fixed cellular manifold, and learns stochastic transport constrained within this geometry via empirical latent support regularization. Across BBBC021, RxRx1, and JUMP, FreeBridge maintains competitive or improved endpoint fidelity and mechanism-of-action retention under a unified evaluation protocol; on BBBC021, it further reduces intermediate support violations. These findings highlight the importance of geometric grounding for biologically interpretable perturbation dynamics. Project page: https://y-research-sbu.github.io/FreeBridge/.
The generation of high-fidelity synthetic Electronic Health Records (EHR) is crucial for advancing medical research while preserving patient privacy. However, head-to-head comparison of existing generative models is hindered by disjointed codebases, incompatible data loaders, conflicting library dependencies, and inconsistent evaluation protocols. To address these gaps, we introduce a lightweight, end-to-end benchmarking framework for reproducible synthetic EHR evaluation, organized as a unified pipeline spanning data ingestion, standardized model training, and architecture-agnostic evaluation. Our current implementation targets the generation of longitudinal ICD diagnosis codes -- the most commonly studied modality in this literature -- and is built on the community-maintained PyHealth library. We reimplement and unify strong baselines (MedGAN, CorGAN, PromptEHR, HALO) under full ICD-9 vocabulary granularity, and add a lightweight GPT-2 baseline from the general-purpose sequence-modeling literature. We contribute a rigorous, architecture-agnostic privacy-utility evaluation suite that applies identically to GAN- and transformer-based generators, and report bootstrapped confidence intervals across all metrics. We further analyze the poor long-tailed performance of existing models and discuss the extensibility of our framework beyond diagnosis codes. By lowering the engineering barrier to running, extending, and evaluating under a single pipeline, we introduce a starting point for community-driven reproducibility and benchmarking synthetic EHR models.
While generative AI models have demonstrated remarkable success in structure-based drug design, they predominantly rely on deep binding pockets and struggle to sample effective ligands for challenging low-pocketability targets, such as the historically "undruggable" oncology targets KRAS and MYC. To address this gap, we introduce ShallowBench, a strictly curated benchmark of 5,780 shallow-pocket targets extracted from CrossDocked2020. By computing the difference between an Alpha Shape "lid" volume and the underlying protein atom voxel volume, we successfully isolated targets with low concavity while ensuring sufficient surface area for binding. Evaluating various state-of-the-art generative models reveals weaker predicted binding affinity on these low-concavity interfaces. ShallowBench therefore provides a rigorous benchmark for generative biology models and highlights the necessity of new architectural innovations or loss functions capable of navigating these challenging targets.
Biomolecules such as proteins and small-molecule ligands play a central role in biological systems, arising from the tight interplay between sequence and three-dimensional structure. Recent generative models for biomolecular co-design aim to capture this interplay by jointly modeling coupled modalities. However, existing approaches largely adopt a parallel execution of marginal generative processes, implicitly enforcing fixed synchronous coupling. We argue that a critical but overlooked degree of freedom lies in how these marginal processes are temporally coupled during training and generation, where inappropriate coupling can introduce high-variance supervision and inconsistent intermediate states, affecting modality consistency. To address this, we introduce GeoCoupling, a systematic framework that optimizes for temporal couplings between heterogeneous modalities. Empirical results across structure-based drug design and unconditional protein design demonstrate the learned couplings consistently outperform synchronous and randomly coupled baselines, yielding biomolecules with improved physical validity and diversity.