Proteins are fundamental to biological processes, with their function determined by the complex interplay between the amino acid sequence and the three-dimensional structure. Developing generative models capable of understanding this intrinsically multi-modal relationship is crucial for fields like drug discovery and protein engineering. Existing models often rely on a multi-stage training process where autoencoders that tokenize data into latent representations are trained in a first stage. Secondly, a generative model is trained on the latent representation of the autoencoder(s), i.e., generative modeling in a latent space. We hypothesize that this multi-stage training is not necessary to obtain performant co-design models and thus present SimpleDesign, an effective multi-modal protein design model trained directly in the data space. SimpleDesign leverages a single-stage end-to-end objective that combines discrete cross-entropy for sequences and a regression objective for structures. In order to effectively model the difference in sequence and structure modalities, we develop a Mixture-of-Transformer architecture that allows modality-specific processing while keeping global self-attention over both modalities. We train SimpleDesign on over 2M sequence-structure pairs achieving strong performance across co-design and unconditional sequence/structure generation benchmarks.
Preoperative planning for total hip arthroplasty (THA) is commonly framed as selecting a single prosthesis configuration and placement for a patient's osseous anatomy. In practice, however, the same anatomy may admit several clinically reasonable solutions, making planning inherently a one-to-many problem that is better represented by a conditional probability distribution. We present THA-Flow, a conditional flow-matching model that generates three-dimensional prosthesis geometry directly from preoperative CT. Separate AutoencoderKL models compress preoperative bone anatomy and prosthesis geometry, while a three-dimensional UNet learns a rectified flow from Gaussian noise to the prosthesis latent space under spatial bone conditioning and optional structured prosthesis parameters. The retrospective cohort comprised 1,355 hips from 1,149 patients undergoing primary THA. Following rigid registration of postoperative CT to preoperative CT, the actual postoperative prostheses were transformed independently according to the pelvic and femoral registrations and represented as a dual-channel truncated signed distance field. The prosthesis autoencoder achieved a peak signal-to-noise ratio of 47.11 dB and a structural similarity index of 0.9964 on the validation set. Complete acetabular and femoral geometries were generated across seven major stem models representing 93.4% of the cohort. Repeated bone-conditioned sampling preserved component position, alignment, and the principal bone-prosthesis interfaces while allowing limited local geometric variation. To our knowledge, THA-Flow represents the first application of generative AI to three-dimensional surgical planning for THA.
Longitudinal electronic health records (EHRs) document patients' sequences of clinical visits over time, preserving the temporal evolution of disease progression and care delivery. However, real longitudinal EHRs are difficult to access because they contain large amounts of fine-grained, patient-specific information. Synthetic EHR generation therefore provides a valuable approach for preserving the statistical patterns and clinical structure of patient visit trajectories, enabling broader modeling and analysis when real records are limited. Although recent generative models have made progress in producing future visit sequences, they remain limited in explicitly integrating inter-visit irregular temporal evolution and intra-visit clinical event structures in EHRs, leading to clinically inconsistent and temporally unrealistic visit sequences. In this work, we propose SynEHR, a lightweight adaptive LLM-based framework for longitudinal EHR synthesis. There are two novel designs in SynEHR, i.e., a Temporal State Conditioning Module captures irregular temporal states across visits and a Temporal-Relational Adaptation Module combines these states with patient history to dynamically construct patient-specific relational representations. SynEHR then builds on a parameter-efficient LoRA-adapted language-model generator with next-visit generation capability to train the two modules for temporally and clinically informed generation. Extensive experiments on real-world EHR datasets across fidelity, privacy, and downstream utility evaluations demonstrate that SynEHR outperforms state-of-the-art models by generating more clinically coherent and temporally faithful longitudinal EHR data.
Clinical intelligence requires estimating a patient's underlying condition from incomplete observations rather than learning isolated mappings from scans to answers. Volumetric medical images provide dense observations of anatomy, attenuation, and lesions, whereas clinical language provides sparse but complementary semantic observations. We formulate CT-centered intelligence as inference over a shared latent patient state, under which readout, reconstruction, and simulation all become state-dependent prediction problems. To operationalize this view, we introduce HounsBench, a computed tomography (CT) centric patient-state benchmark that unifies these three task families with patient-disjoint splits and per-family metrics, and HounsWorld, a 3B multimodal world model that treats volumetric scans and language as observations of the shared state through Joint Understanding-Generation Learning. A shared transformer forms an implicit patient-state estimate and supports three outputs: query-conditioned answers that read out the state, reports and captions that reconstruct it in language, and condition-specific CT volumes for low-dose denoising, virtual contrast enhancement, and anatomy-constrained text-and-mask-to-volume generation. Zero-initialized CT adapters preserve pretrained multimodal mappings, while condition-explicit Hounsfield-unit window sampling exposes clinically meaningful density observations. HounsWorld shows strong performance across all three task families while consistently improving CT understanding through clinically structured completion. Our project is available at https://github.com/byhwhite/HounsWorld.git
Konstantinos Kevopoulos, Beatrice Moscoloni, Benjamin Alheit +4cs.LG cs.CV q-bio.QM q-bio.TO
Cardiac digital twin research is moving from subject-specific anatomical replicas toward virtual cohorts that represent clinically relevant population subgroups. Yet access to representative imaging-derived anatomy datasets remains limited by cohort size, subgroup sparsity, and data-sharing constraints. Conditional generative models could help address this gap, but virtual cohorts are useful only if they preserve realistic, metadata-dependent anatomical variability. Existing cardiac anatomy generators largely rely on conditional variational autoencoders (cVAEs), which couple representation learning and metadata conditioning through a shared regularized latent prior. We introduce CAN-FLOW, a two-step Conditional ANatomy generation framework based on normalizing FLOWs that first learns geometry-only latent representations of diffeomorphic cardiac shape momenta and then models their sex-, age-, and body-mass-index-dependent distribution with a conditional normalizing flow. We trained CAN-FLOW on 2,208 healthy UK Biobank subjects and compared it with cVAEs across regularization strengths. CAN-FLOW generated plausible stochastic biventricular anatomies that better reproduced clinical phenotype distributions, metadata-dependent trends, subgroup variability, point-cloud coverage, and high-dimensional shape variability. Together, these results establish CAN-FLOW as a shareable framework for generating realistic, stochastically varying, metadata-conditioned biventricular anatomies for virtual cohort construction and in silico clinical trial workflows.
Smriti Joshi, Apostolia Tsirikoglou, Daniel M. Lang +15cs.CV cs.AI
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is essential for breast cancer management, but reliance on gadolinium-based contrast agents (GBCAs) restricts use in contraindicated populations, prolongs scan protocols, and presents environmental toxicity concerns. Contrast synthesis offers a non-invasive alternative; however, existing approaches struggle to balance spatial realism with temporal continuity, suffer from slow iterative sampling, underutilize structural priors, and lack clinical validation. We propose a novel conditioned latent transport framework that predicts contrast enhancement in a single forward pass. By anchoring the latent trajectory to the pre-contrast anatomy and applying continuous time conditioning, the model synthesizes patient-specific contrast evolution at any acquisition time. The proposed approach outperforms baseline and the state-of-the-art models across spatial, perceptual, temporal, and distributional metrics. Evaluated on an independent external cohort, the method demonstrates robustness to domain shifts induced by scanner noise as well as differing acquisition protocol. Furthermore, our synthetic contrast enhancement significantly improved downstream tumor segmentation performance, yielding a 22.4% relative increase in Dice coefficient (0.60 vs. 0.49 baseline pre-contrast, p < 0.01), reducing boundary segmentation error by over 39%, while outperforming all other generative model baselines. Finally, a reader study involving four breast radiologists evaluated the image quality, kinetic fidelity, and diagnostic viability of our synthesized sequences across 40 randomly selected cases. The results demonstrated that in 70% of cases, synthesized images provided sufficient clinical information to support the same management decisions as real DCE-MRI, suggesting a path toward safer and faster contrast-free or contrast-reduced imaging workflows.
In X-ray CT, metallic objects cause beam hardening, photon starvation, and scattering, leading to projection inconsistency, streaks, dark bands, and structural distortions that compromise clinical diagnosis and quantitative analysis. Existing metal artifact reduction (MAR) methods remain limited: optimization-based methods may leave residual artifacts or blur structures, regression networks may generalize poorly across scenarios, and generative models without sample-specific structural guidance and physical constraints may produce anatomically inconsistent structures. Flow Matching learns a continuous-time velocity field that deterministically transports a source distribution to a target distribution, providing a flexible MAR prior. However, standard unconditional Flow Matching does not exploit sample-specific structure, spatially nonuniform metal-induced degradation, or measured projections. To address these limitations, we propose SCMA, a structure-conditioned and metal-aware Flow Matching framework. First, a linear-interpolation-corrected image is fed into the velocity network with the intermediate state as a sample-specific structural condition, guiding inference toward artifact-free CT images while preserving anatomy. Second, time-varying spatial weights from the metal mask and its distance transform are incorporated into the Flow Matching loss to emphasize severe degradation within and around metal regions. Finally, conditional Flow Matching updates alternate with projection-consistency correction during inference, allowing reliable measurements outside metal traces to constrain predictions. Experiments on simulated and real CT data demonstrate that SCMA more effectively suppresses metal artifacts, preserves local anatomical structures, and reduces hallucination-like structures inconsistent with projection measurements than representative MAR methods.
The ability to generate variable-length proteins is crucial in protein design, where the optimal length is often unknown and tightly coupled to designability. Current diffusion- and flow-based generative models typically require the protein length to be specified before sampling, limiting their flexibility in exploring the feasible design space. To address this limitation, we introduce Generalized Poisson Flow (GPFlow), a variable-length generative framework that learns the rate function of an inhomogeneous generalized Poisson process by minimizing its negative log-likelihood. We establish population-level guarantees for recovering the joint multimodal distribution and derive an upper bound on the KL divergence between the data and generated distributions. We comprehensively evaluate GPFlow across structure and sequence design, motif scaffolding, and peptide co-design, spanning Euclidean, categorical, and Riemannian modalities to fully validate its variable-length generation quality. In unconditional design, GPFlow improves structural designability and achieves the best distributional fitness for sequence design compared to their corresponding fixed-length baselines, while perfectly recovering the length distribution. In conditional motif scaffolding, GPFlow ranks first on 10 of 16 structure-based design tasks with significantly more unique successes and also achieves more passed tasks in sequence-based design. In peptide co-design, GPFlow remains competitive even without access to a native-length oracle.
Spatial Transcriptomics (ST) measures gene expression while preserving spatial context, but its high cost and low throughput leave public datasets small. Inferring expression directly from widely available Hematoxylin and Eosin (H&E) stained histology offers a cost-effective alternative. However, existing approaches face several limitations: regression methods over-smooth toward the conditional mean, while generative methods are faithful but require slow multi-step inference; most methods treat genes as independent and equally important, ignoring inter-gene dependencies and heterogeneous gene informativeness; and most are tailored to a single resolution, either spot-level or cell-level. To address these issues, we propose DriftST, a unified framework for inferring spatially resolved gene expression from H&E images. DriftST builds on a Cellular Drifting generative model that learns a direct drift from a histology-conditioned source to the expression distribution, retaining generative expressiveness while enabling efficient one-step generation. To capture gene structure, we introduce the STransformer, which combines a co-expression attention module for inter-gene dependencies with a gene residual gate for differential gene importance. Operating on a generic gene-panel representation, DriftST applies directly to both spot-level and cell-level data in one framework, and extensive experiments across diverse tissues and platforms show that it achieves state-of-the-art performance at both resolutions.
Amirreza Dolatpour Fathkouhi, Justin Lee, Heman Shakerics.LG
Predicting a patient's physiological trajectory under a planned treatment sequence is a prospective interventional problem, not standard time-series extrapolation. We study this problem in glucose management, where insulin and carbohydrate records are policy-dependent: future drivers are coupled to patient state, behavior, and clinical decision rules, so observational forecasting accuracy alone does not guarantee correct responses to planned interventions. We introduce Interventional Flow Matching (IFM), a continuous-time generative framework for physiologically constrained prospective forecasting. IFM conditions a flow-matching velocity field on patient history and planned future drivers in a bounded latent glucose space. Rather than embedding strict mechanistic glucose--insulin ODE equations or enforcing causality through rollout-based simulations, IFM uses a solver-free regularization: it penalizes the Jacobian of the instantaneous velocity field with respect to smoothed treatment drivers. This imposes signed, dose-bounded local sensitivities directly on the learned dynamics: insulin lowers glucose, carbohydrates raise it, and both responses remain within plausible ranges. On a simulated UVA/Padova type 1 diabetes cohort, IFM achieves the strongest balance between observed-driver RMSE and interventional response metrics. Across experiments, it consistently produces physiologically correct responses to both insulin and carbohydrate drivers while maintaining high directional, and ranking consistency.
Max Van Puyvelde, Ibrahim Gulluk, Wim Van Criekinge +1cs.AI cs.CV cs.LG
Three-dimensional (3D) brain MRI is central to clinical neurology and neuro-oncology, where generative models could augment under-represented cohorts, simulate disease trajectories, and support privacy-preserving data sharing. Latent diffusion has been the go-to solution for modeling imaging data, but it places two competing demands on the tokenizer: encoder embeddings must retain the clinical information that downstream tasks act on, and the decoder must reconstruct anatomically faithful volumes. Existing reconstruction-driven tokenizers achieve the second at the expense of the first. To address this, we introduce a fully volumetric masked-autoencoder (MAE) based tokenizer for 3D brain MRI latent diffusion, decoupling encoder and decoder: a frozen 3D MAE encoder produces clinically informative embeddings, while a dedicated CNN decoder reconstructs voxels from a linear projection of those embeddings. We pretrain the encoder on 35,309 volumes from 18 public cohorts spanning four modalities, ten disease categories, and 200+ acquisition sites, and demonstrate its dual utility in two settings. First, on a 23-task linear-probing benchmark, the encoder outperforms or matches SOTA models (i.e., BrainIAC, BrainSegFounder, and MedicalNet) on 21 of 23 tasks. Second, a conditional diffusion transformer (DiT) trained on these clinically informative embeddings supports both conditional generation across six variables and patient-specific longitudinal forecasting. Together these results establish a single 3D brain-MRI embedding space capable of both downstream clinical tasks and controllable generation.
Fabio De Sousa Ribeiro, Emma A. M. Stanley, Charles Jones +7cs.CV cs.AI cs.LG
We introduce the first generative foundation model for chest radiograph synthesis trained from scratch at the billion-parameter scale. Existing radiographic AI models often suffer from poor generalisation across patient subpopulations, institutions, and acquisition settings, resulting in limited real-world clinical utility. Controlled, high-fidelity synthesis of chest radiographs is a promising path toward diversifying clinical datasets and evaluating the robustness of diagnostic models. Therefore, we present the largest specialist generative foundation model for chest radiographs to date, with over 1.3B parameters, trained for 1.6T tokens on a curated, heterogeneous dataset comprising 1.2M radiographs and clinical expert-guided metadata. Our model supports controllable radiograph generation and editing across multiple demographic subgroups, acquisition views, and a dozen pathologies. Moreover, we significantly advance the state of the art in radiograph synthesis fidelity, producing images that are indistinguishable from real radiographs to clinical experts.
Jay Jung, Xiaohan Zhang, Shenghan Song +8q-bio.QM cs.AI cs.LG
Antimicrobial resistance causes to over a million deaths annually. Antimicrobial peptides (AMPs) are a promising solution, but generative AMP models are not yet ready to design peptides with non-natural amino acids and/or chemical modifications, which are essential for real-world peptide drugs. We present AMPGAN v3, a multi-objective conditional GAN that expands the generative vocabulary to D-amino acids and N/C-terminus modifications such as amidation. By separating adversarial and activity-aware supervision across two specialized discriminators, AMPGAN v3 substantially improves training stability and outperforms prior generative AMP models on external classifiers. We validated five candidates spanning three structural classes in vitro; two showed activity against Gram-positive strains, with the best candidate reaching MIC 8 μg/mL against B. subtilis. To support downstream curation, we further present PepCraft, a multi-agent framework for end-to-end AMP discovery in which a Planning Agent orchestrates specialized executors for generation, filtering, and verification. Its prioritization recommendations align with our in vitro outcomes. Together, these contributions let us examine, on a small but real scale, how generative and agentic AI compose in therapeutic peptide discovery. Code: https://github.com/marszzibros/AMPGANv3
Cyclic peptides represent a promising class of therapeutic compounds in modern drug discovery, often offering improved stability and binding affinity. However, the de novo design of cyclic peptides remains challenging because methods must identify pocket-adaptive cyclization patterns and linkage sites while simultaneously controlling drug-relevant properties. This challenge is particularly pronounced for recent generative models trained predominantly on linear peptide data, which may fail to capture cyclization-specific constraints. To address the limitation, we introduce APCyc, a target-aware de novo cyclic peptide generation framework that explicitly models cyclization and jointly optimizes multiple essential physicochemical properties. By using an expanded residue vocabulary and explicitly encoding cyclization-site and linkage-type information, APCyc learns cyclization-aware representations and leverages Bayesian posterior guidance to steer sampling toward cyclic peptides satisfying multiple property objectives. Experimental results demonstrate that our model learns target-dependent cyclization preferences, and enables effective and controllable multi-property optimization for cyclic peptide design. The source code of this paper is available at https://github.com/HKUSTGZ-ML4Health-Lab/APCyc.
Yogesh Verma, Dani Korpela, Harri Lähdesmäki +1cs.LG cs.AI cs.ET q-bio.QM
Designing functional biological sequences requires navigating vast discrete spaces under strict evolutionary and biophysical constraints. Discrete Flow Matching (DFM) offers a generative framework over such spaces, but existing approaches rely on biologically uninformative couplings and offer limited flexibility for variable-length sequence generation and fine-grained control. We propose a structured coupling that encodes domain-specific preferences among sequence elements, biasing the source distribution toward plausible regions without modifying the flow objective or training procedure. Building on this, we introduce a latent edit-based rate parameterization that models variable-length generation via edit operations conditioned on a shared global latent, akin to a latent variable model, while remaining tractable. We further introduce a latent classifier-free guidance mechanism that steers generation coherently in continuous latent space, along with Dirichlet-prior temperature scaling for test-time control over edit operations. Our method achieves state-of-the-art performance across diverse biological sequence tasks, including density estimation, unconditional and conditional DNA sequence generation, and peptide sequence generation.
Stanislav R. Kirpichenko, Andrei V. Konstantinov, Lev V. Utkincs.LG cs.AI stat.CO stat.ML
Survival analysis aims to estimate a time-to-event distribution from data with censored observations. Many existing methods either impose structural assumptions on the hazard function or discretize the time axis, which may limit flexibility and introduce approximation errors. We propose the Survival Diffusion Probabilistic Model (SDPM), a generative approach to continuous-time survival analysis. SDPM models the conditional distribution of the survival outcome, represented by the pair of observed time and censoring indicator, $\mathbb{P}(T,δ\mid \mathbf{x})$, using a denoising diffusion model. Under the assumption of conditionally independent censoring, conditional samples generated by the model can be transformed into survival function estimates using the Kaplan-Meier estimator. This formulation avoids parametric assumptions on the event-time distribution and does not require a discretization of the output time space. The model operates in a transformed target space, using standardized log-times and a continuous Gaussian-mixture representation of the censoring indicator. We evaluate SDPM on ten real survival datasets and compare it with five strong baselines, including tree-based, boosting-based, and neural survival models. Results show that SDPM achieves competitive predictive performance across C-index, integrated time-dependent AUC, and integrated Brier score. A study on synthetic Cox-Weibull data demonstrates that SDPM can recover the shape of an underlying continuous survival distribution more accurately than a strong nonparametric baseline when sufficiently many samples are generated. An ablation study confirms the importance of the proposed target-space transformations, which improve event-rate calibration, reduce invalid generated times, and provide consistent gains in predictive discrimination. Codes implementing the proposed model are publicly available.
Single-cell RNA sequencing (scRNA-seq) provides high-dimensional profiles of cellular states, enabling data-driven modeling of cellular dynamics over time. In practice, time-resolved scRNA-seq is collected at only a few discrete time points as unpaired snapshot populations, leaving substantial temporal gaps. This motivates trajectory inference at unmeasured time points. Existing methods mainly follow two directions, optimal-transport (OT) alignment provides distribution-level matching between observed snapshots, while continuous-time generative models support forecasting via learned dynamics. However, two challenges remain: (i) unpaired snapshots render local transitions between adjacent time points ambiguous, leading to unstable supervision; and (ii) long-horizon prediction relies on repeated integration, where small modeling errors compound and cause distribution drift. To address these challenges, we propose single-cell Flow Matching (scFM), a latent generative framework based on coupling-conditioned flow matching. First, we compute entropically regularized OT couplings between adjacent snapshots and use them to construct soft, weighted flow-matching targets for learning time-dependent velocity fields. Second, we learn bidirectional velocity fields and leverage their consistency to refine couplings and improve temporal coherence under sparse supervision. Third, we introduce distribution-level alignment and latent dynamic regularization to anchor long rollouts and mitigate drift. Experiments on real-world time-series scRNA-seq datasets show that scFM consistently improves distributional prediction performance for both temporal interpolation and extrapolation. Moreover, scFM yields more accurate trajectory reconstruction and temporally coherent visualizations where intermediate time points are absent, indicating a more faithful recovery of underlying temporal gene expression dynamics.