Generating Clinical Vignettes that Preserve Cognitive Formulations

Large language models can generate fluent clinical case vignettes, but fluency alone does not ensure fidelity to a specifiable clinical structure. We introduce FORMA, a theory-grounded framework that compiles a cognitive model of a disorder into a directed weighted graph, samples a person-specific configuration of that graph, and validates whether the generated vignette preserves the specified components and causal links. We instantiate FORMA on Posttraumatic Stress Disorder using the Ehlers and Clark cognitive model, generating 16,500 vignettes across 500 personas, 11 generation models, and three ablation conditions. Evaluation combines an external edge-recovery probe, two clinical experts, a scaled LLM judge, and a clinician user study with 100 licensed practitioners. The cognitive graph is recoverable from full-condition vignettes (MCC = +0.41, AUC = 0.70) but not from zero-shot generation (MCC = +0.01, AUC = 0.50). Experts rate full vignettes substantially higher than zero-shot alternatives, and clinicians perceive them to be human-written 85% of the time, compared with 22% for zero-shot. FORMA also reduces demographic disparity in perceived quality by 1.5-7x. These results show that cognitive formulation can serve as an auditable specification for scalable synthetic clinical text generation. A repository with the data and code is available online: https://github.com/Amit-Oren/FORMA.

KMGen: A Skill-based Approach for Synthetic Individual Patient Data Generation

Individual patient data (IPD) from clinical trials is the substrate for survival modeling, meta-analysis, and safety research, yet IPD is rarely released. Prior work has addressed only half of this gap: reconstructing Kaplan-Meier (KM) curves from published plots -- typically requiring manual digitization or human-in-the-loop correction -- while offering no mechanism for generating the adverse-event (AE) streams that constitute the other half of a patient record. We introduce KMGen, the first end-to-end framework that (i) fully automates KM curve extraction at accuracy competitive with human-guided tools, and (ii) generates synthetic per-patient AE trajectories from public trial registry records. The extraction stage is a fully automated agentic pipeline -- an agent generates code to extract each step in the KM curve -- achieving a mean Integrated Absolute Error (IAE) of 0.0151 on a 32-plot benchmark spanning clean, edge-case, and adversarial conditions. The IPD generation stage decouples patient archetype extraction from statistical sampling: an LLM distills the trial record into arm-specific statistics, adverse events, patient demographics, and risk multipliers. A mechanistic sampler generates patient events via clinical archetypes, bootstrap rank-correlation coupling to the empirical KM curve (preserving the marginal survival distribution exactly), and cycle-based AE scheduling with an induction/maintenance split. Across three held-out oncology trials spanning an order of magnitude in cohort size and 30 independent regenerations per trial, KMGen achieves mean integrated KM absolute difference $Δ_{\text{KM}}\,{\leq}\,0.051$, sex/ECOG JSD ${\leq}\,0.013$ on 5 of 6 demographic slots, and recovers ${\geq}\,71\%$ of the top-15 AEs by exact MedDRA term under a single fixed parameter set. The pipeline is released as open source at https://github.com/chufangao/kmgen.

Dissecting Neuro-Symbolic Quality Assurance for Synthetic Oncology Data Generation

Synthetic clinical data generation with large language models addresses the scarcity that limits cancer staging research, but oncology hallucinations are categorically harmful: one clinically impossible staging assignment contaminates every downstream model trained on it. Neuro-symbolic pipelines validate during generation, yet the contribution of individual quality-assurance components remains unclear. We report three controlled studies isolating gate necessity, constraint attribution, and retrieval conditionality, holding generation protocol, diversity thresholds, and fine-tuning hyperparameters constant across adapter conditions. The symbolic gate enforces schema completeness, ontology coverage against the Systematized Nomenclature of Medicine, and staging-logic consistency under American Joint Committee on Cancer eighth-edition rules. Ungated, 29.9% of records contain schema failures and 20.1% contain clinically invalid staging. Schema validation is the load-bearing filter: within the fully gated corpus it rejects 148 of 512 records, ontology grounding a further 24, and staging-logic validation none---the only generator producing logic violations is already excluded on schema, making clinical-logic validation a generator-conditional safeguard rather than the dominant filter. Retrieval augmentation is strongly model-dependent: it improves gate compliance for one generator by 12.5 percentage points, has no measurable effect for a second, and collapses output in a third. Across gated configurations ontology density is largely unchanged, indicating that symbolic validation improves clinical validity rather than vocabulary richness. Symbolic gating therefore buys corpus validity but no commensurate gain on real lung-cancer notes in this study; retrieval should be evaluated per model, and ontology density should not be reported as a proxy for corpus quality.

Generating Benchmark Health Data Using a Tabular Diffusion Transformer

Cross-Tabular Data Generation (CTDG) seeks to learn a generative model from multiple heterogeneous tables and produce new synthetic tabular datasets. However, existing synthetic tabular data generation methods are largely restricted to single-input-table scenarios and struggle to effectively handle multiple heterogeneous tables with diverse feature sets. To address this limitation, we propose a two-stage framework for cross-tabular data generation. In the first stage, each heterogeneous raw table is transformed into a standardized statistical table with the same set of columns across all tables. Each statistical table captures the marginal distributions of the original columns and the pairwise correlations among them. In the second stage, a diffusion transformer model is trained to capture structural patterns across these homogeneous statistical tables and to generate synthetic statistical tables. Synthetic raw tables are subsequently reconstructed from the generated statistical tables via multivariate Gaussian sampling followed by an inverse probability integral transform. This two-stage CTDG framework enables the learning of a unified generative model from multiple heterogeneous tables and supports the generation of an unlimited number of realistic synthetic heterogeneous tables. Experimental results demonstrate high fidelity in the learned statistical representations and a favorable fidelity-diversity trade-off in the generated synthetic data, validating the effectiveness of the proposed approach.

Novel Knowledge-Guided Generative Methods for Synthetic Transcriptomic Data

As biomedical research increasingly relies on data-intensive tools, the quality and utility of datasets are critical. Challenges such as imbalances, biases, and ethical or legal constraints often limit access to high-quality data. Synthetic data generation can help overcome these limitations. Here, we present a comparative analysis of generative models for transcriptomic data, investigating strategies to incorporate prior biological knowledge via gene graphs. This ensures that synthetic data capture real-world gene patterns, maintaining their usefulness for downstream tasks. In particular, we introduce and benchmark three variants of the Generative Adversarial Network. Among the alternatives, MK-TGAN - an innovative multi-kernel, Graph Neural Network-based model - stands out for its performance in terms of both the realism and utility of the generated data. Unlike other methods, MK-TGAN leverages prior knowledge graphs by exploiting graph neural networks. Our results show that prior knowledge integration strategies improve performance, and that MK-TGAN consistently produces synthetic samples with superior realism and biological plausibility.

CoMedBench: A Multi-Source Benchmark of Synthetic Medical Data Fidelity and Downstream Utility

Access to clinical data is essential for developing reliable healthcare machine learning systems, but direct use of electronic health records is constrained by privacy regulation, institutional review, data-use agreements, and the risk of re-identification. Synthetic data promises a practical alternative: it can preserve useful statistical and clinical structure while reducing exposure of sensitive patient records. Prior studies often evaluate a single generator, one dataset, or a narrow downstream task, making it difficult to know when synthetic data can support model development and when it fails to preserve task-critical signal. We introduce CoMedBench, a reproducible benchmark that evaluates a family of generators under a common clinical-validity framework and one shared training and evaluation engine, spanning static tabular and temporal downstream tasks on established critical-care datasets. In total the benchmark spans 37 dataset-task pairs across two modalities consists of 20 static tabular and 17 temporal ICU time-series-drawn from seven public data sources: three intensive-care databases (MIMIC-III, MIMIC-IV, and eICU) together with the UCI Machine Learning Repository, the CDC BRFSS diabetes cohort (2015), NHANES (1999-2014), and the pycox survival datasets (GBSG and METABRIC). The benchmark evaluates both statistical fidelity and task utility by comparing models trained and tested across real and synthetic data. In these settings, synthetic training data preserves most of the downstream signal: on tabular tasks the reference generator CoMed-CTGAN retains a mean AUROC utility (the synthetic-to-real performance ratio) of 90.6%, rising to 97.3% for the strongest generator, CoMed-TVAE. Temporal ICU tasks are harder and more generator-sensitive: CoMed-CTGAN retains 81.6% (AUROC) and only 64.0% under the imbalance-sensitive AUPRC, whereas CoMed-TVAE still retains ~95% (AUROC).

Improving the Realism of Synthetic Clinical Benchmarks Under Utility Constraints

Synthetic clinical benchmarks for enterprise AI agents can pass existing utility checks and still remain structurally unrealistic, especially in privacy-sensitive healthcare settings where operational data are hard to access. We study how to improve such benchmarks without breaking the downstream utility checks already used in practice. We formulate benchmark revision as utility-constrained realism improvement: dataset changes should increase realism while staying above an operational utility floor. We instantiate this idea on a care-gap benchmark derived from Synthea-generated patients exercised through demonstration electronic health record workflows and then processed by the same downstream pipeline as operational data. Realism is measured through missingness structure, simplicity, structural plausibility, and population alignment. The baseline benchmark is extremely thin: sampled-pair missingness is 79.44%, only 12.75% of rows are actionable, 38.94% of patients have zero actionable measures, and top-three token concentration reaches 100.0%. Two deterministic revisions improve these panels while remaining above the current utility floor, whereas a naive densification control preserves unrealistic templating. We further show that internal benchmark realism and source fidelity to an aggregate operational reference are related but distinct objectives. These results suggest that synthetic benchmark quality should be optimized explicitly, with utility treated as one constraint rather than as sufficient evidence of realism.

Patient Pose Assessment Using a CT-Based Framework for Synthetic Data Generation

An adequate diagnostic quality of radiographs is essential for reliable diagnoses and treatment planning. The patient's pose during radiography is one of the most important factors determining the diagnostic quality. Since patient positioning is difficult and not standardized, an automated AI-based approach using depth images to automatically assess the patient's pose before the radiograph has been taken would be helpful. Due to regulatory hurdles, however, it is difficult in practice to acquire the required depth images and corresponding radiographs. In this paper, we present a framework that can generate such training data synthetically from Computed Tomography scans. We further show that by pretraining on our generated synthetic dataset consisting of 3077 image pairs of upper ankle joints, the pose assessment of real upper ankle joints can be improved by up to 11 percentage points.

Clinical Communication Processing with Models Trained on LLM-Generated Synthetic Data: A Structured Survey and Novel Application Case Studies

Much clinical value is conveyed not through structured records but through communication: exchanges in which patients describe symptoms, clinicians reason and give instructions, ambulances hand over to emergency departments, and nurses pass on a shift. Such language differs from tabular data because meaning depends on speaker role, intent, causality, uncertainty, omission, and channel noise. Healthcare natural language processing must therefore interpret information as conveyed rather than coded. This requires well-annotated corpora, which are scarce because authentic exchanges are private, fragmented, and costly to annotate. Large language models offer a way forward by transforming clinical sources, such as records, diagnostic labels, symptom lists, or care plans, into written and transcribed communication for downstream models. We present a structured narrative survey organized by source representation, communication form and participants, generation method, and downstream task, complemented by thirteen novel case studies. These build clinical NLP systems for communication channels and languages without labeled real-world data, including EMS pre-arrival reports, field-radio casualty documentation, nurse handoffs, patient-portal triage, and low-resource discharge communication. They show that synthetic communication can bootstrap such systems. Findings include the competitiveness of fine-tuned encoder models over evaluated zero-shot baselines and the value of deliberately degraded communication for robustness. The main limitation is that most studies evaluate on held-out synthetic communication, while train-on-synthetic, test-on-authentic evidence remains limited. We conclude that syn-thetic clinical communication is becoming a practical research resource; establishing it as reusable clinical infrastructure will require authentic-data transfer, safety and external validation.

Assessment of Conditional Diffusion Model for Synthetic Histopathology Image Generation

Synthetic histopathology image generation has emerged as an approach that may address data scarcity in computational pathology, yet current evaluation methodologies may not fully assess synthetic data quality for medical applications. This work investigates and addresses limitations in existing evaluation metrics, investigating an approach for assessing synthetic histopathology image quality through domain-specific metrics and downstream task validation. We show that conventional synthetic data evaluation metrics such as Frechet Inception Distance (FID) and Inception Score (IS) may have limitations when applied to histopathology images due to their reliance on ImageNet-pretrained feature extractors. To address these limitations, we propose for consideration modified FID and IS approaches utilizing foundation models pretrained on digital pathology datasets, supplemented by precision-recall based metrics as part of an additional quality assessment. Using conditional denoising diffusion models trained on four benchmark datasets, with a two-step training approach, we generated synthetic datasets with systematically varied quality characteristics. We also measured the correlation between the synthetic data quality metrics with downstream nuclei segmentation performance using common metrics including the aggregated Jaccard index (AJI+) and the Dice coefficient. The study results suggest that pathology-specific metrics may provide improved discriminative power. Specifically, the modified Inception Score indicates higher correlation with downstream task performance (r=0.6096 with AJI+, p=0.0122), compared to the original IS (r=0.0708, p=0.7944). Our observations indicate that increasing the variety of generated training data has a higher positive correlation with segmentation model performance than improving the visual fidelity of individual generated images.

SynPre-FL: Synthetic data-driven pretraining integrated Federated Learning training framework

Federated learning (FL) offers a promising approach to privacy-preserving clinical risk prediction, but its deployment remains limited by restricted data sharing, client heterogeneity, class imbalance, and the lack of realistic tabular electronic health record (EHR) benchmarks. Synthetic data generation may alleviate data scarcity, yet its integration with federated optimisation has received limited systematic study. We propose SynPre-FL, a unified framework combining high-fidelity synthetic EHR generation with synthetic-pretrained FL for robust prediction under non-IID conditions. A latent autoencoder-diffusion model generates privacy-preserving synthetic cohorts, which are used to warm-start federated training. This pretraining is followed by heterogeneity-aware optimisation using class-balanced local objectives, proximal regularisation, and adaptive server aggregation. Post-hoc calibration and federated-safe explainability support reliable and interpretable risk estimates. Experiments show that the synthetic generator preserves univariate, bivariate, and multivariate structure while protecting against membership-inference and reconstruction attacks. The generated data achieve strong downstream utility under TSTR, TRTS, and model-based evaluations. Across federated settings with 5, 10, and 15 heterogeneous clients, SynPre-FL consistently improves robustness and scalability over baseline methods, especially under severe non-IID fragmentation. Calibration improves probability reliability, while SHAP analysis produces stable and clinically coherent feature attributions across federation sizes. SynPre-FL therefore provides a practical and reproducible framework for combining synthetic data with FL to enable privacy-aware, interpretable, and robust clinical prediction from distributed tabular EHR data.

OntoBook: Ontology-Grounded Synthetic Textbooks for Medical Encoder Pretraining

We present OntoBook, a method that converts medical ontology structure into pretraining signal for encoder language models. Our approach has three stages: random walks through ontology graphs capture hierarchical and causal relations between medical codes, a large language model reformulates these walks into fluent textbook-style prose, and the resulting text is used to train ModernCamemBERT, a 149M-parameter French encoder, with two objectives on the same data: masked language modeling and relation prediction between code pairs. On three French medical coding benchmarks (FRACCO, Cantemist-FR, Distemist-FR), OntoBook achieves significant improvements over MLM-only pretraining, with +2.5 micro-F1 on FRACCO and +8.0 micro-F1 on Distemist. We find that alignment between objectives is necessary: misaligned training, where each task uses different data, causes a 30-point degradation. We release 1.3 million LLM-reformulated medical textbooks across three French ontologies (CIM-10, CCAM, ATC) and pretrained model checkpoints.

Demographically-Conditioned Synthetic Medical Images for Bias Mitigation and Bias Detection in Disease Classifiers

Per-subgroup fairness audits of medical image classifiers face a sample-size problem: minority subgroups in held-out test sets have so few samples that the resulting confidence intervals on per-subgroup performance are wider than the bias the audit is meant to detect. We argue that a demographically-conditioned synthetic generator can do both: mitigate bias on the training side and detect bias on the evaluation side. Working on COVID-19 chest CT classification with an end-to-end fine-tuned Stable Diffusion 2.1 generator, we make two findings. For bias mitigation (training), a demographically-balanced synthetic cohort is most useful as a pretraining prior, not as joint augmentation: with the same fixed data, sequential pretraining followed by fine-tuning substantially outperforms joint augmentation, and the resulting classifier surpasses the full-real baseline at $\sim$$100\times$ real-data efficiency. For bias detection (evaluation), across five synthetic minority cohorts and five classifier seeds, the synthetic estimator reproduces the subgroup ranking of a well-powered real oracle (Spearman $ρ= 1.00$ on MCC and Recall) and gives the more reliable per-cell estimate where the small real test set runs out of samples. The synthetic cohort is therefore most useful in exactly the cells that fairness audits care about, as both a fix for and a measure of subgroup bias.

SYNRARE: Synthetic Rare Disease EHR Generation for ML Benchmarking

Motivation: Rare disease (RD) diagnosis is frequently delayed due to the similarities in symptoms to common disease variants. Machine Learning Algorithms applied to Electronic Health Records show promise for accelerating the diagnosis; however, legal and privacy concerns pose significant barriers. To address these issues, Synthetic Data Generation is an alternative method for obtaining Electronic Health Records and can be applied with any Machine Learning algorithm for benchmarking and development purposes. Despite the availability of Synthetic Data Generation algorithms, support for generating a subset of patients that differ in a definable degree from the majority to simulate patients with RD is often lacking. Results: We present SYNRARE, a graphical user interface based on the Synthea framework that enables easier modification and generation of synthetic Electronic Health Records of RD patients, which differ only to a definable degree from patients with common diseases, thereby enabling the benchmarking and testing of algorithms under controlled technical conditions. SYNRARE enables researchers to rapidly benchmark their Machine Learning algorithms across any scenario. Availability and implementation: SYNRARE, including detailed instructions for installing, is available at https://gitlab.sdu.dk/screen4care/synrare.

Explainable AI for Screening Abuse-Related Trauma in Bangladeshi Children: A Training-Free Multimodal Framework Evaluated on Noise-Aware Synthetic Data

Bangladesh has an estimated 1.17 mental-health professionals per 100,000 population and only six child psychiatrists nationwide. No Bengali-language, culturally adapted tool exists for early screening of abuse-related psychological trauma in children. We present ShishuRaksha AI, a decision-support (not diagnostic) framework that fuses four screening modalities: validated questionnaires (SDQ, CPSS), Bengali narrative text, House-Tree-Person (HTP) drawing features, and facial affect. The fusion is training-free and clinically weighted, uses cross-modal attention, and includes a single-modality override rule. Every risk score is explained through clinically weighted, perturbation-based additive attribution and rendered as a bilingual (Bangla/English) report with referral routing to national child-protection services (OCC, DSS, NMHH) under the Children Act 2013. No clinical dataset of abused children can be collected ethically at this stage, so we introduce a noise-aware synthetic benchmark (500 cases, 116 positive [23.2%], four deliberate noise layers, literature-grounded HTP priors) and evaluate tree-ensemble surrogates of the fusion design (facial channel excluded) under 5-fold stratified cross-validation. The fused model reaches an AUC of 0.874 [0.834-0.908], against 0.756 [0.705-0.803] for an SDQ-only baseline, with ablation, operating-point, subgroup, and calibration analyses. We state all limitations openly, including synthetic-only data, no held-out set, text-feature circularity, and an urban-rural subgroup gap. This work is a feasibility study and a design contribution toward ethically deployable child-protection screening in low-resource settings.

A Filtered Mixture-of-Generators for Fully Synthetic Survival Training

Survival analysis models time-to-event data, but in clinical settings training data are costly and scarce: events accrue over years of follow-up, cohorts are small, and privacy regulations restrict sharing across institutions. Tabular generative models promise augmentation and privacy-preserving cohort sharing, yet are themselves data-hungry -- on the small cohorts typical of survival analysis, a single generator rarely characterizes the population well enough for downstream models trained on its output to match real-data performance. FoGS (Filtered Mixture-of-Generators for Survival analysis) reframes synthetic-data construction as sample selection rather than generation. A candidate pool is drawn from four architecturally distinct tabular generators, and each sample is scored by an ensemble of seven survival models trained on real data, using proper scoring rules as a per-sample plausibility proxy. A two-level pipeline optimizes, in its outer loop, a selection policy -- generator quotas, scorer weights, a random complement, and stratified balancing on event time and censoring -- against held-out downstream performance, while an inner loop tunes the downstream model (XGBoost-Cox). On 16 public datasets under train-on-synthetic, test-on-real (C-index and IBS, $0$--$100$ scale), FoGS yields mean improvements of $+2.17$ in C-index and $+0.67$ in IBS, improving both metrics on 9 of 16 datasets and at least one on 13 (one-sided Wilcoxon $p=0.039$ and $p=0.035$). It matches or exceeds real-data training on most cohorts, with no significant change in nearest-neighbour privacy margin relative to unfiltered sampling. Sample filtering over a heterogeneous generator pool is thus a viable substitute for real-data training in privacy-restricted clinical settings.

When Does Synthetic CT Transfer? A Label-Free Donor/Host Diagnostic for Medical Vision-Language Model Routing on Real Lung CT

A synthetic measurement of model competence is useful only if it survives the move to real data, yet the real labels that would verify it are exactly what medical imaging lacks. We ask whether transfer can be predicted in advance, label-free, and answer with a mechanism: on synthetic digital twins, competence that is donor-driven (a property of the transplanted nodule) survives the synthetic to real change of host, while host-driven competence (a property of the surrounding anatomy) need not. We test this on three lung CT vision-language tasks chosen to span that axis, across five public VLMs, four guidance conditions, and seven real datasets. The prediction holds in every case: presence and size orderings transfer (R2 >= 0.96), lobe does not; the split survives leave-source-out calibration, and the diagnostic names that boundary before any real label. TrialCouncil, a training-free council calibrated only on synthetic CT, confirms it by matching the best fixed model exactly where transfer is predicted. The contribution is not the router but the finding that transfer itself is predictable, label-free, from synthetic data alone.

A Neuroimaging Simulation Framework for Developing and Evaluating Causal AI

Causally linking disease-related factors to image-derived biomarkers provides a powerful pathway to understanding disease mechanisms. Despite growing interest in applying causal artificial intelligence (AI) approaches for this task, these methods still need to be adapted for complex medical images, and especially, neuroimaging. However, the lack of ground-truth data presents a barrier to development. To bridge this gap, we developed and tested a method for generating synthetic neuroimages, which adhere to a user-specified causal structure describing the non-image to image variable relationships, permitting the creation of ground-truth neuroimaging datasets. In the simulated T1-weighted magnetic resonance images, anatomical variability is modeled by sampling from a subspace estimated from real data and deforming a template image to create unique simulated subjects. Causal relationships are encoded via precise volumetric changes of any region-of-interest without unwanted global artifacts. We achieved relative volume errors of 0.3-2.66% for the targeted regions-of-interest and demonstrate their statistically significant causal relationships, while maintaining mean absolute errors for non-target brain regions between 0.034-0.397ml. An initial evaluation of causal discovery methods exposes their limited ability to suppress spurious connections, highlighting the need for image-appropriate methods. Our framework is the first to enable the generation of realistic synthetic 3D neuroimages with explicit causal control that can serve as the missing ground-truth data necessary for the objective benchmarking and development of causal AI methods.

Tractography-Driven Synthetic Data Generation for Fiber Bundle Segmentation in Tracer Histology

Diffusion MRI (dMRI) tractography enables non-invasive reconstruction of white-matter pathways, but its accuracy is fundamentally limited by indirect, low-resolution measurements of axonal organization. Tracer injection studies in non-human primates provide a gold standard for validating dMRI tractography. This, however, requires time-consuming manual annotation of fiber bundles in histology sections. We propose a synthetic-data augmented framework for automated fiber bundle segmentation in macaque tracer histology. Our approach uses ex vivo dMRI tractography as a generative prior to synthesize 2D image patches for training. This provides us with sufficiently realistic foreground texture, which we compose with backgrounds from blockface photos and diversify via domain randomization. A 2D U-Net is trained on mixed real and synthetic patches. Experiments on held-out brains demonstrate improved generalization across brains and fiber bundle densities compared to training with real data only. Training with synthetic data only leads to poor performance, underscoring the need for real supervision. Overall, our approach achieves performance comparable to the state-of-the-art while requiring 3x less manually annotated data.

A Pipeline for Generating Longitudinal Synthetic Clinical Notes Using Large Language Models

Synthetic data is increasingly used to enable the development and evaluation of AI systems in domains where access to real-world data is restricted. In healthcare, clinical documentation presents particular challenges due to its sensitivity. This work introduces a synthetic clinical notes pipeline and dataset designed to support the development of clinical AI tools while avoiding the privacy risks associated with real patient data. The dataset is generated using a modular pipeline that combines structured patient generation, semi-structured patient journey simulation, and unstructured clinical note generation using large language models. The pipeline is designed to prioritise internal consistency across longitudinal patient records, while also capturing variation in writing style, note structure, and clinical detail. Additional mechanisms, including LLM-based validation and augmentation steps, are used to improve faithfulness, realism, and diversity of the generated notes. We release a dataset of 70 synthetic patients, each associated with 20-50 clinical notes spanning a full hospital journey. The dataset is provided at multiple levels of validation, enabling users to balance realism and scalability depending on their use case. This dataset supports the development, testing, and evaluation of clinical AI systems, including summarisation tools, coding models, and decision support systems, without reliance on real patient data.

OncoSynth: Synthetic data generation for treatment effect estimation in oncology

In oncology, access to patient-level data is often restricted. Synthetic data provides an alternative for analyzing treatment effectiveness, but existing methods for synthetic data generation fail to preserve the causal relationships between covariates, treatments, and outcomes, thereby leading to biased estimates of treatment effects. Here, we introduce OncoSynth, a generative, causally-aware machine learning framework designed to produce synthetic cohorts that enable accurate estimation of population- and patient-level treatment effects. OncoSynth uses a diffusion-based sequential approach to model how covariates influence treatment assignment and how treatment affects survival. We evaluate OncoSynth using large lung (N = 37,128) and breast cancer (N = 17,046) cohorts. Our results show that OncoSynth generates high-fidelity synthetic patient cohorts that preserve real-world patient, treatment, and outcome distributions. Notably, OncoSynth improves treatment effect estimation over existing approaches, by reducing population-level treatment effect error by up to 66%, and patient-level treatment effect error by up to 58%. Thereby, OncoSynth supports reliable evidence generation for precision oncology in settings where data sharing is restricted.

A specialized reasoning large language model for accelerating rare disease diagnosis: a randomized AI physician assistance trial

Rare diseases affect millions of individuals worldwide, yet timely diagnosis remains a major public health challenge due to scarcity of specialized clinical expertise. While large language models (LLMs) show promise to support rare disease diagnosis, current models are constrained by insufficient clinical deployability, limited clinically grounded evidence, and scarcity of training data. Here we present RaDaR (Rare Disease navigatoR), an open-source, compact reasoning LLM (32B parameters) for rare disease diagnosis. RaDaR was trained with 49,170 publicly available free-text cases and 104,666 synthetic cases with reasoning-enhanced training. RaDaR showed the strongest performance among evaluated open-source models, including the 671B DeepSeek-R1, across public benchmarks and four external validation centers. In a retrospective cohort, RaDaR prioritized the final diagnosis before documented clinical suspicion in 61.06 percent of cases, corresponding to a potential lead time of 1.87 months and 50.18 percent of the within-center interval. In a randomized physician-assistance trial, RaDaR assistance improved physicians' rare-disease diagnostic accuracy by 21.44 percentage points compared with internet search alone. Synthetic-data ablations suggested that phenotype-anchored narratives provide useful training signal for long-tail rare diseases, with a monotonic scaling trend within the tested data range. Together, RaDaR and its development and validation framework provide a deployable rare-disease reasoning model and a reproducible development framework for diagnostic AI under data scarcity.

BAC-JEPA: Label-Efficient Breast Arterial Calcification Segmentation via Synthetic Mammography-Guided Supervision

Breast arterial calcification (BAC) on screening mammograms is an emerging cardiovascular risk biomarker, but quantitative use requires reproducible segmentation and expert pixel-level labels are costly. We present BAC-JEPA, a label-efficient segmentation framework trained on procedurally generated arterial calcification inserted into real mammographic backgrounds with exact masks. Candidate backgrounds were selected from model-screened mammograms with low predicted BAC response; the generator samples arterial structure, disease burden, radiographic appearance, and hard-negative distractors including nonarterial calcifications and metallic objects. Synthetic masks are paired with mammography self-supervised Vision Transformer encoders and a high-resolution convolutional decoder to produce full-resolution segmentation maps. The study used 75,472 mammography studies from 34,956 patients for background selection and representation learning, trained on synthetic images from 10,000 backgrounds, selected checkpoints with 1,000 development backgrounds, and evaluated transfer on all 1,000 human-labeled BacSeg synthetic 2D mammograms. On held-out synthetic validation data, the larger backbone achieved IoU 0.5325 and Dice 0.6357. On BacSeg, image-level classification from segmentation probability maps reached AUROC 0.8719, with 0.8547 for the smaller backbone. Four-view inference required 110.68--213.63 ms on an RTX 5090 GPU, and severe-preset synthetic image generation averaged 2.7071 s per image on a multicore workstation. These results indicate that BAC-specific synthetic supervision can produce useful image-level transfer without human pixel-level training masks, while expert-reviewed real-mammogram segmentation remains necessary for clinical validation and calibration.

Low-Cost Neuromorphic Fall Detection Using Synthetic Event Data and Hybrid SNNs

This work presents the development of hybrid models that integrate spiking neural networks (SNNs) with components of convolutional neural networks (CNNs) to learn from simulated event-based camera data (Dynamic Vision Sensor, DVS) generated from conventional smartphone videos. Aimed primarily at human fall detection, the approach leverages the energy efficiency and spatio-temporal processing capabilities of SNNs by converting video frames into event-based data. The proposed models are evaluated through simulations on multiple datasets, comparing their performance to that of traditional machine learning models. Results demonstrate significant gains in efficiency without sacrificing accuracy, underscoring the potential of combining SNNs and DVS technology for complex tasks in real-world environments.

PSyGenTAB: A Privacy-Preserving Framework for Synthetic Clinical Tabular Data Generation via Constrained Optimization

The development of medical AI is constrained by limited access to high-quality clinical data due to institutional silos and strict privacy regulations such as HIPAA and GDPR. Synthetic data generation offers a potential solution, but existing methods lack principled mechanisms to explicitly manage the privacy-utility trade-off, often degrading clinically meaningful patterns or risking patient re-identification. We present PSyGenTAB, a privacy-preserving generative framework that formulates synthetic healthcare data generation as a constrained optimization problem solved using the Augmented Lagrangian Method. By embedding configurable privacy constraints directly into model training, PSyGenTAB enforces minimum privacy thresholds while maximizing clinical data utility. Across multiple clinically motivated benchmarks, PSyGenTAB preserves inter-feature clinical relationships and minority-class diagnostic patterns essential for reliable health AI. Downstream evaluation using Train-on-Synthetic, Test-on-Real and Train-on-Real, Test-on-Synthetic protocols shows that models trained on synthetic data achieve performance comparable to those trained on real patient records. Privacy auditing further demonstrates reduced exact record reproduction and strong resilience to membership inference attacks. These results establish PSyGenTAB as a principled framework for balancing privacy protection and clinical utility in synthetic healthcare data, supporting secure cross-institutional AI development.

Boosting ECG Classification Performance by Pre-training with Synthesized Data

Deep Neural Networks (DNNs) typically require extensive datasets for effective training. In the medical domain, acquiring large-scale data is often challenging due to privacy concerns and the rarity of certain diseases. To address this data scarcity, we investigate the efficacy of training DNN models using synthetic data, generated based on domain-specific medical knowledge. Specifically, we develop a knowledge-driven Gaussian-composition synthesis algorithm for single-lead II ECGs, in which each heartbeat is represented by Gaussian-shaped P, Q, R, S, and T wave components. Using this simulator, we generate synthetic data for four abnormal electrocardiogram (ECG) classes: atrial fibrillation (AF), atrial flutter (AFLT), premature ventricular complex (PVC), and Wolff-Parkinson-White Syndrome (WPW). We evaluate the utility of this synthetic data by conducting abnormal ECG classification using ten different DNN architectures. Our results demonstrate that synthetic-to-real training improves classification performance for three of the four target abnormalities, with the largest architecture-averaged gain of $33.2\%$ observed for AFLT. Further analysis reveals that the performance enhancement from synthetic data is more pronounced with smaller real-world datasets. These findings suggest that domain-knowledge-based synthetic ECGs can serve as a useful pre-training resource, particularly in scenarios where real-world data are limited or difficult to obtain.

GenEyePose: Patient-Free, Knowledge-Based Saccadic Eye Movement Modeling for Digital Neurophysiologic Biomarker Development

Eye movements, including saccades, are widely regarded as highly sensitive and objective biomarkers of neurophysiologic states. Detecting saccadic signatures in neurologic diseases offers a rapid, portable alternative to brain imaging, avoiding access and cost barriers. Currently, there are no robust AI-enabled video-oculographic solutions (e.g., digital biomarkers) for screening, triaging, or localizing brain abnormalities due to privacy issues and scarce datasets. In this work, we propose the first fully synthetic, patient-free, multimodal eye movement generation pipeline for generalizable saccade analysis. Using this synthetic dataset, we trained a deep learning classifier to distinguish between normal and abnormal (hypometria and hypermetria) saccadic accuracies and evaluated its performance on real-world clinical data. The model achieved an AUROC of 0.76 and a sensitivity of 0.71, showing that the synthetic data has strong potential to generalize for clinical applications, including as a screening tool in at-home and emergency room settings or a tool for precise neuroanatomic localization.

Synthetic but Not Realistic: The Evaluation Challenge in Generative Modelling for Structured Electronic Medical Records

Synthetic healthcare data are widely proposed as privacy-preserving substitutes for real patient data, yet their evaluation remains dominated by statistical similarity and predictive performance that do not reflect clinical validity. We introduce a multi-dimensional evaluation framework grounded in epidemiology, assessing descriptive fidelity, clinical utility, and structural validity, corresponding to descriptive, predictive, and causal questions. We evaluate four representative generative paradigms - GAN-based, VAE-boosted, diffusion-based, and masked modelling - using PRIME-CVD, a 50,000-person cohort with known ground-truth structure. While all models reproduce marginal distributions, none simultaneously preserve subgroup structure, effect estimates, and dependency structure. Notably, models with strong distributional fidelity can exhibit poor calibration and distorted relationships, leading to unreliable inference. These results show that current evaluation practices can overestimate synthetic data quality and motivate domain-informed assessment based on the ability to support valid clinical and scientific conclusions.

Impact of Synthetic Lesional MR Images in Automated Focal Cortical Dysplasia Detection in Low-Data Scenarios

Background and Purpose: Automated detection of focal cortical dysplasia (FCD) requires large volumes of voxelwise lesion-delineated MRI data, which are difficult to acquire. This study aims to generate synthetic MRI data exhibiting FCD, assess their realism, and evaluate their impact on automated FCD detection, particularly in reducing the need for manual annotations. Methods: T1-weighted (T1w) and T2-weighted Fluid-Attenuated Inversion Recovery (FLAIR) MRI scans from 131 FCD patients and 90 healthy controls from multiple (3) sites were retrospectively studied. Synthetic MRIs were generated by conditioning a generative network on binary FCD masks. Two neuroradiologists identified real images from a random set of 14 real and 14 synthetic scans. Three nnU-Net models were trained to detect FCD using: (i) real-only (35 FCD / 35 controls), (ii) real (35 FCD / 35 controls) plus synthetic augmentation, and (iii) expanded real data (70 FCD / 70 controls). Results: Experts showed limited ability to distinguish real from synthetic images, with classification accuracy of 60% for T1w and 70% for FLAIR (inter-rater agreement kappa = 0.86). Augmenting automated FCD detection with synthetic data increased sensitivity by 8.14% (p = 0.12) and improved model confidence at true lesion sites (0.83 +/- 0.11 to 0.89 +/- 0.12; p = 0.02). The expanded real-data model further improved sensitivity to 73.8% (p < 0.001) and confidence to 0.90 +/- 0.14 (p = 0.01). Conclusion: Conditional generative networks can generate realistic synthetic FCD-MRIs, reducing labeled data needs by approximately 20% while maintaining equivalent sensitivity. Equivalent amounts of real data, when available, remain more effective than synthetic augmentation.

Cell Phantom Video Generation in Elliptical Fourier Descriptor Domain

Training Deep Neural Networks for tracking individual cells in biomedical videos requires a large amount of annotated data. The annotation of videos for cell tracking is very time consuming and often requires domain expertise; this explains the limited availability of public annotated data to address important medical problems like tissue repair or cancer treatment. Generating synthetic videos along with their Ground Truth annotations is a promising solution that relies, as a foundational first step, on the synthesis of single cell annotations (or phantoms). Phantoms need to be time consistent, as they have to replicate biological processes that are specific to the cell types. In this work, we propose a novel framework for generating videos of cell phantoms in the Elliptical Fourier Descriptors (EFDs) domain, a compact and geometrically interpretable representation for 2D closed contours. We represent the cell phantom evolution as a multivariate time series of EFD coefficients, introducing a strong prior for cell morphology and enabling the efficient generation of sequences that evolve coherently in time. Our experimental validation proves that modelling the temporal evolution in EFD space enables the generation of biologically plausible phantom videos. Our method can be used in generative pipelines for synthesizing annotated data for cell tracking, thus strongly mitigating the annotation effort for creating new datasets. Our code is available for download here: https://github.com/FrancescoBenedetto99/efd-cell-video-gen.