Phenotypes

Accurate 3D plant organ segmentation is fundamental to automated phenotyping. Existing approaches rely on annotated training data or species-specific model configurations. We present an annotation-free pipeline for 3D plant organ segmentation, combining text-prompted SAM3 segmentation with semantic neural radiance fields (NeRFs). Given only multi-view RGB images and a list of class names, our zero-shot pipeline produces semantically labeled 3D point clouds without manual annotation, per-species fine-tuning, or domain-specific preprocessing. Multi-view NeRF fusion acts as effective implicit consensus mechanism that lifts imperfect per-frame masks into accurate 3D labels. On a controlled Begonia maculata testbed the SAM3 pipeline achieves 92.6% mIoU, reaching 95.9% of the oracle upper bound established with perfect ground-truth masks. The pipeline was further evaluated on a new dataset spanning ten diverse plant point clouds reaching an average 0.856 mIoU, with leaf and pot IoU above 0.91 and 0.90 for every species, respectively. These results demonstrate that annotation-free 3D plant organ segmentation is now feasible and approaching the range of supervised methods.

Maize ear geometry (length, width, curvature, and volume) is closely tied to yield and grain-filling outcomes, but existing high-throughput phenotyping pipelines remain constrained by the cost, labor, and specialized hardware they require. We developed and validated a low-cost pipeline that reconstructs a watertight 3-D mesh of a maize ear from a single 20-second video captured with a consumer-grade DSLR on a motorized turntable under uniform LED illumination. Camera poses from a multi-seed COLMAP procedure initialize a Neural Radiance Field (NeRF), and a cylindrical holder of known diameter, visible in every frame, provides automatic metric scaling with downstream geometric quality control. Applied to 300 ears spanning a diverse maize inbred panel, 250 (83.3%) passed automated processing and quality control. Skeleton length agreed with manual caliper measurements across all 250 ears (R^2 = 0.964, RMSE = 4.68 mm), and convex-hull volume agreed with water-displacement volume on a 15-ear subset spanning the full size range (R^2 = 0.982, RMSE = 5.26 mL). Residual length error grew with ear curvature, whereas bounding-box height, which records the same straight-line chord as calipers, showed no such trend; the discrepancy therefore originates in the measurement definition, since calipers record the chord while skeleton length traces the geodesic arc. The capture hardware costs approximately 607 USD, and operator involvement fell from roughly five minutes to one minute per ear, with all downstream processing running unattended. The platform provides a foundation for breeding-scale 3-D ear phenotyping.

Medical foundation models learn latent representations of clinically meaningful phenotypes, yet their ability to support controllable image generation remains largely unexplored. We evaluate four retinal foundation models within the representation tokenizer framework and examine whether demographic and clinical information encoded in latent representations from foundation models is preserved during synthetic image generation. We show that generated representations and images faithfully inherit phenotype information when evaluated within their originating foundation models, consistently outperforming conventional latent diffusion on multiple downstream prediction tasks. However, these gains largely disappear when evaluated using classifiers trained on real images, revealing a previously uncharacterised synthetic-to-real representation gap. These findings demonstrate that foundation-model latent spaces provide a powerful substrate for controllable retinal synthesis while highlighting the need to better align synthetic representations with real-image distributions.

AI-assisted facial phenotyping supports rare genetic disorder prioritization by retrieving visually similar diagnosed cases from facial image reference databases such as the GestaltMatcher Database (GMDB). Existing GestaltMatcher-based retrieval frameworks compare each test image with individual gallery images in a facial phenotype embedding space. However, this pointwise formulation does not fully exploit available evidence, because patients may have multiple images and disorders may be represented by multiple diagnosed gallery patients. We propose an inference-time multi-level evidence aggregation framework that improves facial phenotype retrieval without modifying the underlying GestaltMatcher-Arc encoder. The framework combines embedding-level patient aggregation of multiple images from the same individual, patient-weighted disorder centroids, and hybrid individual-centroid scoring to integrate test-patient observations, disorder-level gallery evidence, and local nearest-neighbor evidence. We evaluated the approach on GMDB v1.1.4 across disorders represented during training (GMDB-Freq), unseen disorders (GMDB-Rare), and multi-image patient subsets, using a unified gallery containing both GMDB-Freq and GMDB-Rare disorders. Multi-level evidence aggregation improved mean per-disorder top-$N$ retrieval accuracy across all evaluation subsets. Top-1 accuracy increased from 38.52% to 48.82% on GMDB-Freq and from 19.38% to 23.79% on GMDB-Rare. On multi-image subsets, top-1 accuracy increased from 46.12% to 60.94% on GMDB-Multi-Freq and from 18.54% to 26.71% on GMDB-Multi-Rare. These findings show that inference-time aggregation can improve next-generation facial phenotype retrieval without retraining the encoder, supporting a shift from isolated single-image matching toward multi-level aggregation of patient and disorder evidence for rare-disorder prioritization.

Advances in crop breeding have introduced an increasing number of grain varieties, creating a growing demand for efficient variety recognition and quantitative analysis. However, existing methods are typically trained on a fixed variety set, and incorporating newly introduced varieties requires additional data collection and model retraining. To address this limitation, we propose GROW, a framework for Grain Recognition and quantitative analysis in Open sets Without retraining. GROW first performs class-agnostic grain localization, converting mixed-grain images into individual instances for variety-wise counting and phenotypic measurement. It then combines visual embeddings and morphological descriptors into fused grain descriptors stored in an extensible GrainBank. Query grains are recognized through rank-similarity weighted top-k retrieval, and newly introduced varieties are incorporated by appending their descriptors without updating the deployed models. Extensive experiments under progressive variety expansion, varying grain densities, and background domain shifts demonstrate the scalability, robustness, and adaptability of GROW. Compared with joint retraining, GROW reduced the average category-registration time from 4153 s to only 39 s while maintaining competitive recognition performance. These results demonstrate that GROW provides an efficient and maintainable solution for extensible grain recognition, counting, and phenotypic analysis without repeated model retraining.

Neuroimaging and genetic testing are two important clinical references for nervous system diseases, offering complementary diagnostic information. However, integrating genomic and neuroimaging data for precise disease diagnosis is challenging due to cross-modality heterogeneity. Existing imaging-genetics approaches mainly encode genetic information as hard-coded labels, which lose the local sequence context around disease-associated variants. To address this limitation, we propose GeneFuse, a multimodal learning framework that aligns genetic representations from pre-trained Genomic Language Models (GLMs) with features extracted from images. GeneFuse integrates two components: (1) Genotype-Conditioned Feature Modulation (GCFM), a FiLM-inspired module that uses genomic embeddings to modulate image feature maps; and (2) Uncertainty-aware Genomic Residual Fusion (U-GRF), a fusion strategy that uses imaging-derived predictive uncertainty to gate the contribution of genotypic features. We evaluate GeneFuse on early cognitive decline identification (NC vs. MCI) and dementia screening (NC vs. AD). In the APOE-centered setting, GeneFuse achieves AUROCs of 0.77 and 0.83, outperforming existing imaging-genetics fusion methods. These results indicate that GLM-derived genomic embeddings provide additional information to imaging.

Image-based profiling captures rich phenotypic signatures for drug discovery and functional genomics. Large public datasets like JUMP Cell Painting now provide millions of images for systematic study. However, JUMP alone occupies 115 TB, and fragmented evaluation practices make systematic comparisons of representation methods impractical for many researchers. Here we present Nahual, an open-source framework for reproducible model deployment, and JUMP-lite, a 92.0 GB subset of JUMP that is approximately 1,250-fold smaller, selected to cover genetic modalities and compound annotations and reduced via lossy JPEG XL compression. Using these resources, we benchmark five representation methods, including classical features (CellProfiler) and deep learning models (MorphEM, OpenPhenom, SubCell, DINOv2). Moderate compression broadly retains signal relative to uncompressed images. Standardized phenotypic activity and consistency metrics reveal meaningful performance differences across methods. Together, JUMP-lite and Nahual provide a foundation for accessible, reproducible benchmarking of image-based cell representations.

Large Language Models (LLMs) have accelerated drug discovery, particularly in the automated design of antimicrobial peptides (AMPs). However, current validation pipelines for peptide generation models overlook historical precedents showing that certain drugs carry health risks predominantly for individuals with specific genetic profiles. In this paper, we demonstrate that such targeted health risks can be induced intentionally and at scale by manipulating models that generate peptide candidates. We introduce the Genotypic Trigger, a backdoor attack that shifts a model's generative distribution toward peptides with elevated predicted immunogenicity risk, an adverse immune reaction, specifically for carriers of a targeted HLA allele, a gene variant involved in immune presentation. Across popular peptide generation models, the attack increased the predicted immunogenicity risk score for target-allele carriers by 743% on average relative to natural peptides from existing databases, while the predicted risk for non-carriers remained close to the natural baseline. Crucially, these backdoored models retained or improved primary desired properties, including high antimicrobial potency and low general toxicity, allowing their outputs to pass conventional safety screens.

Phenotypic drug discovery enables the discovery of functional relationships between molecular structures and cellular responses. However, existing multimodal representation learning methods often optimize cross-modal alignment without considering the intrinsic organization of chemical space, resulting in distorted molecular representations and loss of structural information. We propose \textbf{PhenMol}, a structure-preserving framework for phenotype-aware molecular representation learning. PhenMol disentangles molecular and cellular representations into shared and private components, enabling phenotype-guided alignment while preserving chemical structures through a dedicated molecular branch. This design integrates cellular phenotype information without disrupting molecular neighborhood organization. Experiments on approximately $3.04 \times 10^{4}$ molecule--cell morphology pairs demonstrate that PhenMol improves molecular property prediction across 270 bioactivity tasks, molecule--phenotype retrieval, and clinical trial outcome prediction. Moreover, ECFP4-based structural analysis shows that PhenMol better preserves molecular neighborhoods and reduces embedding distortion compared with existing multimodal alignment methods. These results highlight the importance of structure-aware constraints in multimodal molecular representation learning and provide an effective approach for integrating cellular phenotypes with chemical knowledge for drug discovery.

Digital phenotyping (DP) using smartphones and wearable devices has shown considerable potential for mental health monitoring. However, progress remains difficult to evaluate due to heterogeneous datasets, inconsistent preprocessing pipelines. In this work, we present a reproducible benchmark built upon the Neurai-VN dataset, a high-resolution, multimodal dataset comprising passive sensing and active assessment from wearable and smartphone devices, collected from 100 Vietnamese adults over two weeks. We define four binary classification tasks evaluated using standardized subject-wise cross-validation. Representative linear, tree-based, and neural baseline models are evaluated systematically across predefined feature-group configurations. Mean subject-level F1 scores across five cross-validation folds reached 0.71 for Healthy Control vs. Depression and Healthy Control vs. Clinical, while Healthy Control vs. Anxiety and Depression vs. Anxiety achieved 0.69 and 0.56, respectively. These baseline results provide reproducible baselines for future research on multimodal DP for mental health classification tasks.

Ethical governance of AI-driven systems is often expressed through high-level principles and static documentation, creating a gap between regulatory requirements and system-level verification. This challenge is particularly acute in digital phenotyping, where continuous behavioural data raises concerns around consent, privacy, and fairness. In this paper, we propose a computational ethical framework for AI-driven digital phenotyping system in which ethical requirements are formalised as deontic temporal logic constraints, alongside a conceptual ethical agent that oversees the system and ensures that any supervised system satisfies the specified constraints. Using a case study involving financial data and mental health, we model key ethical properties and verify them using the Z3 Satisfiability Modulo Theories (SMT) solver. Our evaluation shows that the framework is logically consistent and that violations of the specified ethical properties are ruled out within the formal model through counterexample-based verification. This presents early research enabling continuous, machine-verifiable ethical checking, moving beyond retrospective compliance based on static documentation. We discuss limitations, including the need for real-world verification with data, the challenge with subjectivity and contextual sensitivity, the need for human oversight, and outline how such approaches can support the development of digital phenotyping and AI systems with continuous and auditable ethical guarantees.

Phenotype-driven diagnostic benchmarks usually report the rank of the reference disease, but they rarely reveal which plausible alternatives are ranked above it or what evidence a tool-using model examines before making its decision. We introduce GraphRareBench, a provenance-preserving benchmark containing 2,365 ontology-derived cases and 18,093 target-confounder pairs. Each case includes a coarsened HPO query, a fixed candidate pool, graph-defined hard confounders, and source-linked evidence records. On the 237-case gene-component-disjoint test split, supervised rankers using a shared 21-feature interface achieved MRRs ranging from 0.640 to 0.740 and case-averaged target-over-confounder accuracies ranging from 0.898 to 0.916. Agents instantiated with Agents-A1 and DeepSeek-V4-Flash achieved MRRs of 0.746 and 0.718, respectively. Their paired MRR difference was not statistically significant, whereas their target-evidence coverage differed by 0.561. Together with the observation that 22.1% to 43.7% of selected Hit@10 successes still ranked at least one graph-defined hard confounder above the target, these results indicate that full-pool retrieval, hard-confounder discrimination, and observable evidence access capture complementary aspects of model behavior. GraphRareBench therefore provides a foundation for more transparent and evidence-aware evaluation of phenotype-driven diagnostic systems. Code and data are available at https://github.com/GUI0609/GraphRareBench.

The function of many genes is still unknown, and conventional driver-discovery methods, which rely on how frequently a gene is mutated, cannot assess genes that are only rarely affected. Here we pair Evo2-based genome analysis with routine clinical imaging to identify gene--phenotype associations at genome-wide scale. For every somatic mutation across three TCGA cohorts (cRCC=clear cell renal cell carcinoma, HCC=hepatocellular carcinoma, and BC=breast cancer; $n = 340$ total), Evo2 predicts a severity score, with no task-specific training. Per-gene severity summaries are then correlated with radiomic features extracted from paired tumor segmentations, controlling for total mutation burden. In TCGA-cRCC ($n = 162$), this sweep recovers established renal-cancer drivers and identifies 46 additional genes reaching false discovery rate (FDR) significance absent from curated cancer-gene panels, several of which are Mendelian ciliopathy and cytoskeletal-disease genes. These results demonstrate that pairing a genomic language model with widely available clinical imaging can serve as a hypothesis-free discovery tool for gene--imaging associations invisible to conventional approaches.

Vision-based automation is an excellent candidate for reducing manual labor in greenhouse crop production and phenotyping. However, progress is constrained by the lack of annotated training data. Recent advances in vision-based foundational models have shown promising results in zero-shot generalization to novel domains, but their performance drops in complex agricultural environments. In this work, we present a sim-to-real framework for tomato plant segmentation that combines synthetic data generation with fine-tuning of a foundation model. We model a commercial cherry tomato greenhouse and use it to generate a large-scale synthetic dataset under diverse viewpoints, lighting conditions, and plant morphology. Subsequently, we fine-tune the Segment Anything Model 3 (SAM 3) on the synthetic dataset, specializing its text-conditioned segmentation behavior for greenhouse crop organs while retaining the general visual prior that makes zero-shot transfer possible. By evaluating our framework on multiple real-world greenhouse datasets, we demonstrate that combining synthetic data with SAM 3 fine-tuning significantly improves segmentation performance and model confidence. To support community benchmarking, we publicly release the procedural model, the generated synthetic dataset, and our fine-tuned SAM 3 weights.

Gold-standard phenotype labels are often unavailable at scale in electronic health record (EHR) studies because they require manual chart review. Weakly supervised phenotyping methods instead use silver-standard labels, such as diagnosis-code counts, natural language processing (NLP) mentions, medication indicators, or laboratory thresholds. PheNorm is widely used for this purpose, but its original formulation was designed for count-valued silver labels and relies on log transformation, utilization normalization, and Gaussian mixture modeling. These steps are not directly suited to binary silver labels, which are common and may be highly informative. We propose Binary PheNorm, an extension that uses binary silver labels directly in the corruption-and-regression denoising step and produces a continuous phenotype score without EM calibration. We also consider a lasso-regularized version for high-dimensional EHR settings and combined models using both binary and count labels. In simulations, Binary PheNorm achieved strong discrimination using binary labels alone and often improved performance when combined with count labels. In anaphylaxis, AUC increased from 0.793 for an epinephrine-mention indicator to 0.891-0.892 after Binary PheNorm. In acute pancreatitis, AUC increased from 0.736 for a lipase-threshold indicator to 0.805-0.819. These results support Binary PheNorm as a practical weakly supervised approach when informative binary silver labels are available.

Can evolutionary dynamics characteristic of biological development arise without a designer-specified fitness function? We present Genesis, a platform in which agents inhabit a Gray-Scott reaction-diffusion substrate and evolve under physical constraints alone. Three successive experimental cycles, each testing one falsifiable hypothesis, show: (1) constraint-driven selection sustains evolutionary activity after complete fitness removal but reaches a hard phenotypic complexity ceiling; (2) agent-mediated niche construction via chemical secretion is real but causally insufficient to break that ceiling; and (3) replacing the fixed-alphabet genome with a Compositional Pattern Producing Network (CPPN) indirect encoding, protected by NEAT-style speciation, produces the first evidence of progressive structural complexification in a fitness-free system. Null results are treated as precise, informative answers rather than failures, yielding reusable diagnostic tools and a sham-control protocol applicable to any open-ended evolution evaluation pipeline.

In this manuscript we release two datasets for visual sensing of tomato plants grown in commercial-like settings and acquired using a robot. The first is BUTom21 which consists of still images and manual annotations. The second is BUTom-ST21 which consists of video-based data and semi-automated annotations through AI-based methods, referred to as pseudo-labels. In both cases, we provide pixel-level labels for the ripeness of the fruit. The aim is to provide the research community a challenging set of real-world imagery to explore methods to sense and estimate the state of tomato plants and their fruit, which is an important horticultural crop. Importantly, the spatial-temporal dataset provides individual fruit count and ripeness information enabling researchers to push the boundaries of field-based phenotyping.

Comprehensive quantification of cardiac structures from computed tomography (CT) remains limited not by data availability but by the scalability of measurements, which makes routine use impractical. Here we present a unified framework for comprehensive cardiac CT segmentation and phenotyping that combines a human-in-the-loop annotation pipeline, a cardiac CT augmentation technique, and a self-supervised foundation model pre-trained on 60,000 unlabeled cardiac CT scans. Using this approach, we assembled the largest and most comprehensive expert-annotated cardiac CT segmentation dataset to date, comprising 1598 cases and 14 distinct cardiac structures (1000 for training, 598 for the external test set). Across five external datasets, the framework segmented all structures more accurately and comprehensively than existing open-source tools. Self-supervised pre-training improved labeling efficiency, with the most significant gains observed during external evaluation in the low-data regime. Benchmarking across convolutional, transformer, and state-space architectures showed comparable performance, indicating that data quality and pre-training, rather than architecture, drove accuracy. The framework was scaled to population-level phenotyping, with segmented anatomy that carries functionally relevant information about ventricular function and disease severity beyond demographic variables. By openly releasing the largest dataset with human labels, code, model weights, a CT augmentation library, and software, this work provides a reproducible foundation for opportunistic cardiac phenotyping from routinely acquired CT scans.

Tree crowns are a challenging target for resilient AI because they are not static objects: their spectral response, internal texture, translucency, and apparent boundaries change substantially across the growing season. We develop PhenoEmbed, a self-supervised crown-centric temporal embedding model trained with contrastive and masked reconstruction objectives on HeideBench, an 18-date UAV multispectral time-series benchmark for forest crown phenology in D{ö}lauer Heide. The model treats seasonal crown dynamics as phenological appearance change driven by leaf emergence, canopy closure, senescence, and leaf-off conditions. Segmented tree crown polygons are retained as object anchors to extract aligned crown-centered crops through time, allowing one 256-dimensional vector summarizing seasonal crown appearance to be learned per tree. On 5,885 crop-safe crowns, the exported embeddings show structured low-dimensional organization, with the first two principal components explaining 25.1% of variance and nearest-neighbor retrieval producing a median top-1 cosine similarity of 0.946. Compared with handcrafted temporal features and a learned mean-pooling baseline, PhenoEmbed yields substantially more compact nearest-neighbor structure, while ablations show that the contrastive loss, masked reconstruction loss, and explicit seasonal time features each affect the structure of the learned embedding space. These results support PhenoEmbed as a reusable forest crown representation learner and motivate future downstream tests of whether such features improve tree-level models under seasonal change.

Collecting annotated plant images for automated phenotyping is often slow and expensive. Plant models simulating growth and development can generate unlimited synthetic images with exact labels. However, previous work has established that whether incorporating synthetic data improves performance depends on the ratio of synthetic to real images and the label distribution of the synthetic dataset. To systematically quantify both factors, we train ResNet-18 models on a canola branch-counting task using a calibrated L-system plant model. We vary each factor independently. Synthetic-to-real ratios of 1:5 to 1:22 broadly improve performance; the best ratio (1:7) reduces mean absolute difference by 7.6% over real-only training. For label distribution, a uniform synthetic distribution is strongly suboptimal (abs. diff. of approximately 1.70); interpolating 90% toward the real distribution yields abs. diff. 0.927, whereas Gaussian smoothing of the real label distribution yields the best overall result (abs. diff. 0.912, a 14.7% improvement over real-only). A minimum of 10 synthetic images per label offers a simpler alternative with modest gains, while 100 per label over-corrects and hurts performance.

Understanding perceptual differences between autistic and neurotypical adults requires behavioral assays that are sensitive, reliable, and mechanistically informative. Facial emotion perception is a useful test case because group differences have been reported, but findings vary across studies. Here we show that this variability may reflect image-level sparsity: autistic-neurotypical differences in emotion judgments were concentrated in a small subset of diagnostic facial expressions rather than spread uniformly across stimuli. We trained population-specific artificial neural network models to predict image-level judgments for autistic and neurotypical participants, then used these models to select novel faces predicted to maximize group separation. In an independent cohort, model-selected images produced larger behavioral differences than matched random images. We then used the same models with a generative adversarial network to transform diagnostic images toward greater predicted group agreement. In phenotype-matched validation, synthesized images reduced behavioral separation relative to their matched originals. These results establish a model-guided framework for discovering and transforming stimuli that reveal population-specific perceptual differences. More broadly, they show how behavioral phenotyping can move beyond averaging across fixed stimulus sets toward optimized assays that identify the conditions under which neurodivergent perception diverges or converges.

Modelling psychological disorders in artificial agents offers both a testbed for computational psychiatry and a lens on the failure modes of affective control. Prior work induces one or two disorders in a reinforcement learning (RL) agent by hand-tuned reward shaping, labels the behaviour post hoc, and reports single runs. We recast disorder modelling as dose-controllable manipulation of cognitive appraisal signals in an appraisal-guided PPO agent, expressing seven disorders (anxiety, mania, obsessive-compulsive checking, depression, impulsivity, addiction, and post-traumatic stress) each as a single knob grounded in a computational psychiatry account, with each symptom measured by a preregistered assay mapped to a recognised paradigm. Across more than a thousand runs (10 seeds, four controls, 95% confidence intervals) every disorder shows a graded, monotone dose-response that no control reproduces. Beyond these induced effects, three findings emerge that were not written into the reward: the disorders self-organise into a two-dimensional affective space in which mania mirrors anxiety; removing a knob remits reward distortion disorders (mania, checking, addiction) but not avoidance disorders (anxiety, PTSD), which instead recover under a graded exposure curriculum; and two simultaneous knobs interact nonadditively, yielding testable comorbidity predictions. Appraisal weights thus parameterise a controllable space of affective phenotypes in which the same knobs that induce a disorder can model its treatment. We also show that three disorder knobs (depression, addiction, anxiety) transfer to a three-dimensional pixel environment (MiniWorld) with a standard convolutional agent and no appraisal critic, with cross-assay dissociation confirmed across both domains, indicating the framework is not specific to grid worlds or to PPO's appraisal critic.

FaceMesh2HPO is a framework for classifying facial phenotypic descriptors aligned with the Human Phenotype Ontology (HPO) to support clinical diagnosis. Using annotations from 124 clinicians across 10 disorders (107 HPO terms) combined with non-syndromic controls, we generated 3D facial meshes (478 landmarks) from 2D images and trained a hierarchical PointNet-based pipeline with cascading classification and feature elimination. The best models, incorporating 3D meshes, facial outline, and demographic metadata, achieved AUROCs between ~0.55 and ~0.89, with higher performance at parent nodes than leaf terms. External validation showed variable generalizability across disorders. Results demonstrate that hierarchical modeling of 3D facial geometry enables interpretable, ontology-linked phenotype classification, though performance on rare leaf terms remains limited. Improved data diversity and feature selection strategies are needed to enhance robustness and clinical utility.

High-throughput plant phenotyping generates valuable data that often remains trapped in unstructured text and isolated RGB images. To bridge this semantic gap, we propose a framework for constructing a multimodal granular Knowledge Graph (KG) to monitor genotype-phenotype interactions across time and experiments. In this work, we focus on wheat Triticum aestivum as a representative target crop to validate our methodology across complex canopy environments. Our pipeline first distills noisy field notes to extract entities and relations, dynamically constructing the KG by converting unique instances into hierarchical class entities via RDF-typing. These graph nodes are then aligned with standardized ontologies (PO, RO, WTO) using PlantDeBERTa. To visually ground the constructed graph, a Vision-Language Model paired with a wheat-segmentation ViT generates attention-based softmaps, linking specific KG entities directly to image pixels. We introduce a central observation node Plant_Obs_Id to connect these multimodal subgraphs temporally. Evaluated on 500 curated WisWheat samples using Pointing Game accuracy, Visual Word Sense Disambiguation (VWSD), and rank-based metrics, our neuro-symbolic approach successfully maps complex field observations to a structured graph. This enables automated field note auditing, temporal stress monitoring, and precise spatial trait localization for wheat breeders.

Penile measurement is clinically relevant across male reproductive and urogenital health, including conditions such as micropenis, congenital and endocrine disorders, and sexual or urinary dysfunction. However, quantitative assessment of penile size has relied mainly on external length or circumference measurements, which are difficult to standardize, sensitive to measurement conditions, and unable to capture the internal portion of the penis. MRI enables volumetric assessment of the whole penis in vivo, but automated segmentation has not previously been established at population scale. Automated whole-organ volumetry would enable high-throughput phenotyping for multi-omics and clinical studies of male reproductive disease. Here, we present a deep learning framework for whole-penis segmentation in multi-channel DIXON MRI. Using a newly curated expert-annotated training dataset ($n = 145$ subjects; $13,050$ annotated slices) and a double-annotated independent test benchmark ($n = 24$ subjects; $2,160$ double-annotated slices), we optimized a 3D nnU-Net architecture. The model achieved a 5-fold cross-validation Dice score of $0.90$ and performed at observer-level accuracy on the independent test set (Dice: $0.92$; Hausdorff distance: $3.58$). We deployed the model in $34,412$ UK Biobank participants, enabling automated quantification of total penile tissue, including both external and internal components. Longitudinal evaluation in 2,282 men demonstrated high inter-session reproducibility ($r = 0.87$). This framework establishes a reproducible and population-scalable method for MRI-based assessment of penile anatomy and provides an open technical resource for future studies in urological imaging and male reproductive health. The trained model weights will be publicly released.

Classifying heterogeneous omics data remains a fundamental challenge in computational biology, particularly in high-dimensional, small-sample settings where nonlinear interactions dominate and class imbalance further complicates reliable prediction of minority phenotypes. While traditional kernel methods rely on feature abundance, they fail to leverage the known interaction landscapes of biological systems. In this work, we propose a structured Gaussian process classification framework that integrates graph-encoded biological pathways directly into the kernel construction. By propagating information along known interaction networks and combining this with abundance-derived features, the resulting classifier captures both quantitative measurements and topological context. We benchmark our proposed methodology on three publicly available gut and fecal microbiome datasets. To address severe class imbalance, we evaluate complementary strategies, including data-level resampling, threshold calibration, and confusion-matrix-based adjustments, and report minority-class performance alongside accuracy. The hybrid approach yields a performance gain over unstructured baselines and matches the performance of established benchmarks for similar datasets. Furthermore, the probabilistic nature of the framework naturally provides calibrated predictive uncertainty, enabling robust differentiation between confident predictions and ambiguous samples.

Wave Function Collapse (WFC) is a widely used procedural content generation method that learns local adjacency constraints from example inputs to generate larger outputs. In this paper, we explore combining WFC with evolutionary search by evolving the small input examples used by WFC rather than directly evolving complete levels. In this approach, WFC acts as a genotype-to-phenotype mapping. The generated levels are then evaluated through domain-specific fitness functions. We evaluate the method in two domains with different relationships between local and global structure: Maze connectivity maps and Zelda-style dungeon layouts. Our results show that evolutionary optimization over WFC inputs improves generation quality in domains where properties emerge from local relationships, while domains requiring global constraints remain challenging. These findings suggest that evolutionary search can effectively guide WFC generation when target objectives align with local structure.

3D plant phenotyping is notoriously known to be procedure-complicated and of low throughput due to the extensive multi-view imaging, the fragile 3D reconstruction pipeline, and the additional cost from reconstructed geometry to phenotypic extraction. These limitations are further amplified in low-cost data acquisition, where smartphone videos or sparsely sampled multi-view images provide limited view overlap and self-occlusion. In this work, we show that the conventional 3D plant phenotyping pipeline could be streamlined and significantly accelerated with 3D Foundation Models (3DFMs), and particularly, present one of the first cross-crop 3D phenotyping frameworks powered by 3DFMs. The framework replaces COLMAP-style sparse initialization with 3DFM-based feed-forward geometric recovery, combines geometry-constrained 3D Gaussian Splatting for dense reconstruction, enables few-view reconstruction through iterative view synthesis and refinement, and converts reconstructed geometry into measurable organs through 2D-to-3D semantic transfer, metric scale recovery, and organ instance separation. We further construct a cross-crop dataset with smartphone-based image acquisition, diverse plant morphologies, and manual annotations for segmentation and phenotypic evaluation. Experiments across 26 plant sequences show that 3D Foundation Models reduce the average reconstruction time from 6.52 minutes to 1.58 seconds while maintaining high reconstruction quality and phenotyping accuracy. These results suggest a fresh technical route for high-throughput 3D plant phenotyping, from low-cost image acquisition to fast reconstruction, perception, scale recovery, and phenotypic measurement.

Cardiac discharge phenotyping informs post-discharge treatment and follow-up, but real-world records are often incomplete and class-imbalanced, increasing the risk of missed high-risk phenotypes. We propose CW-B, a clinical risk-aligned class-weighted XGBoost pipeline for five-class cardiac discharge phenotyping under real-world class imbalance and missingness. CW-B combines fold-specific class-balanced instance weighting, missingness-indicator augmentation, and classwise error auditing to improve recognition of clinically prioritized phenotypes while preserving interpretable and auditable decision logic. In five-fold stratified cross-validation, CW-B achieves the best Accuracy, Macro-F1, Balanced Accuracy, and Prioritized F1 among tree-based, ensemble, and neural baselines. Overall, CW-B provides a practical and deployment-oriented approach for more reliable cardiac discharge phenotyping in real-world clinical settings.

Identifying robust associations between cardiac imaging phenotypes and clinical diseases is fundamental to population-scale cardiovascular research and reliable risk stratification. However, current phenome-wide association studies rely on pre-defined, single-variable phenotypes or expert-crafted features, which limits their ability to capture clinically meaningful non-linear effects and cross-phenotype interactions. To address this, we propose CPAgents, an iterative phenotype-Composition framework for cardiovascular Phenome-wide association study (PheWAS) that automatically constructs and validates interpretable composite phenotypes (e.g., polynomial, ratio, and interaction forms) from base imaging features. Specifically, our system coordinates three agents: (i) an Analyst that identifies statistical pathologies and nominates candidate transformations; (ii) a Proposer that generates constrained, medically and statistically motivated expressions under numerical safety rules; and (iii) a Verifier that evaluates candidates using multi-stage criteria and produces transparent evidence trails for accepted phenotypes. Evaluated on a population-scale cardiac imaging cohort, the discovered composite phenotypes markedly improve disease discrimination: across 72 classifier-disease-metric combinations, our variants achieve the top rank in 56 cases versus 18 for baselines, with gains observed across all nine clinical disease categories. Our framework yields compact, clinically interpretable phenotype formulas with transparent evidence trails, enabling scalable discovery of stronger phenotype-disease associations beyond expert-driven feature selection.

Understanding which genes control which traits in an organism remains one of the central challenges in biology. Despite significant advances in data collection technology, our ability to map genes to traits is still limited. This genome-to-phenome (G2P) challenge spans several problem domains, including plant breeding, and requires methods capable of reasoning over high-dimensional, heterogeneous, and biologically structured data. Current datasets and data repositories, however, are not well-equipped for this task. Current studies do not link gene expression and trait data, and most focus on very specific traits, limiting the breadth of possible correlations. To address this gap, we present the novel Gene-Graph Regression for Arabidopsis Functional Traits (GRAFT) dataset, a curated multi-modal dataset linking gene expression profiles with phenotypic trait measurements in Arabidopsis thaliana, a model organism in plant biology. GRAFT supports tasks such as phenotype prediction and interpretable graph learning. In addition, we benchmark conventional regression and explanatory baselines, including a biologically-informed hypergraph baseline, to validate gene-trait associations. To the best of our knowledge, this is the first dataset to provide multimodal gene information and heterogeneous trait or phenotype data for the same Arabidopsis thaliana specimens. With GRAFT, we aim to foster research to accurately understand the relationship between genotypes and phenotypes using gene information, higher-order gene pairings, and trait data from multiple sources.

Birth defects are a major cause of fetal loss, neonatal morbidity and long-term disability. In the subset with suspected genetic etiologies, exome and genome sequencing have moved many cases from variant detection to post-sequencing interpretation: clinicians must rank patient-specific candidate variants under incomplete fetal or infant phenotypes and heterogeneous evidence from population genetics, variant-effect prediction, gene-disease validity, phenotype ontologies, cellular and pathway context, protein structure and clinical literature. We present DeepBD, a grounded agentic workflow for variant prioritization and diagnostic interpretation of genetic birth defects. DeepBD organizes the workflow into LLM-assisted case structuring, a pretrained evidence engine, specialist evidence modules and a grounded diagnostic review layer. The evidence engine learns patient-specific variant scores from structured rule evidence, sequence and variant-effect representations and phenotype-conditioned biological context, whereas specialist modules and the agentic layer provide tool-based refinement, candidate-pool review and diagnosis-oriented synthesis from ranked candidates. Developed using an in-house fetal and infant cohort comprising 18,622 cases, DeepBD achieved Recall@1/3/5/10 of 0.658/0.882/0.912/0.929 on an internal held-out solved-case benchmark, outperforming standalone Exomiser, DeepRare and prompted LLM reranking baselines evaluated on Exomiser-derived top-20 candidate variants. Ablation and overlap analyses show that rule evidence, mechanistic context, and specialist refinement provide complementary signals. These findings support a grounded agentic workflow that separates evidence integration, tool-based refinement, and LLM-assisted diagnostic review for retrospective variant prioritization in genetic birth defects.

Dementia diagnosis requires integrating multi-modal clinical assessments from diverse informants and clinicians under incomplete and heterogeneous data conditions. Yet most AI-driven approaches remain Alzheimer's disease (AD)-centric, framing the problem as binary AD detection or three-stage AD progression modeling within well-curated research settings. This pathology-driven paradigm overlooks the broader, syndrome-level nature of dementia, which spans multiple stages, phenotypes, and etiologies. In this paper, we propose Dementia-Agents, a clinically aligned multi-agent framework for real-world dementia staging and phenotyping. The framework follows a three-step workflow: (1) a data agent translates structured clinical records into semantically faithful textual representations that preserve missing-data signals and routes them to domain-aligned experts; (2) five fine-tuned expert agents generate domain-level predictions; and (3) a coordinator agent performs probabilistic aggregation to produce final staging and phenotyping decisions. We develop and evaluate Dementia-Agents on a real-world clinical cohort of 1,066 patients from two cognitive neurology services. Compared with monolithic multi-modal large language models (MLLMs) and prior medical multi-agent systems, our approach achieves consistent improvements in diagnostic performance for real-world syndrome-level dementia staging and phenotyping, while preserving domain-level interpretability.

The retina offers a noninvasive window into neurodegenerative disease, capturing subtle structural patterns associated with a risk of future cognitive decline. Vision-language alignment frameworks such as REVEAL have shown that pairing retinal fundus images with structured clinical risk narratives improves early prediction of Alzheimer's disease (AD). A key design choice in these approaches is the use of phenotypic grouping, where individuals with similar risk profiles are treated as multi-positive pairs during contrastive learning. However, existing methods operationalize phenotypic similarity as a discrete construct, relying on hard group assignments that impose rigid supervision and decouple group formation from representation learning. We propose a continuous formulation of phenotypic structure within contrastive learning. Rather than assigning samples to fixed clusters, we model inter-subject similarity as a differentiable weighting function derived from intra-modality embedding similarities in both retinal images and risk profiles. These weights define soft multi-positive relationships through a continuous aggregation operator, enabling graded supervision that reflects the spectrum nature of disease risk. We further introduce a soft-target contrastive objective that jointly learns cross-modal alignment and phenotypic structure in an end-to-end manner. Evaluated on UK Biobank retinal imaging data for incident AD prediction, the proposed framework consistently outperforms discrete group-based contrastive learning and standard vision-language baselines. By treating phenotypic similarity as a learnable, continuous signal rather than a fixed grouping rule, our approach provides a principled and robust foundation for population-scale neurodegenerative risk modeling from multi-modal retinal and clinical data.

Label-free, image-based cellular mechanophenotyping in microfluidic devices provides a high-throughput method for single-cell profiling. However, while complex microchannels (e.g., hyperbolic geometries) reveal transient deformation dynamics under continuous extensional stress, the resulting high-dimensional feature spaces are highly susceptible to hydrodynamic artifacts. Flow rate variations often distort discriminative boundaries, linking feature distributions to fluid conditions rather than intrinsic biology. To overcome this, we introduce a stability-guided analytical framework that decouples flow-induced noise from authentic mechanobiological signatures. We tracked the morphodynamic, kinematic, and intracellular optical-density trajectories of healthy and malignant ovarian cells to build a 93-dimensional feature space. Using a cross-flow screening strategy based on structural consistency and statistical persistence, we isolated robust descriptors, creating task-adapted subsets (20 features for binary classification; 25 for cancer subtyping). Variance-attribution analysis confirmed the neutralization of flow-conditioned artifacts; notably, flow-associated variance in the primary principal component fell from 69.9% to 9.3% in the subtyping task. We also found that macroscopic binary discrimination depends on bulk kinematic transitions, while clonal subtyping requires localized intracellular optical heterogeneity. These optimized subsets maintained diagnostic fidelity across multiple machine learning architectures and restricted sampling conditions. This framework establishes a robust, flow-independent foundation for continuous dynamic phenotyping.

This short paper introduces a stylometric interpretation method inspired by genome-wide association studies (GWAS). Each "gene" token's association with "phenotype" authorship is tested using logistic regression with multiple-comparison correction. Applied to English, German, and Russian corpora, the method detects statistically significant lexical markers distinctive of individual authors.

In this study, UAV multispectral imagery is used to segment the severity of bacterial leaf blight (BLB) in rice using convolutional neural networks (CNNs) and transformer-based models. The evaluated architectures include U-Net with a ResNet- 101 encoder, U-Net++ with EfficientNet-B3 and EfficientNetB7, DeepLabV3+, and SegFormer, all trained under a common pipeline with three input configurations (multispectral only, multispectral+NDVI, and multispectral+NDRE). Experiments are conducted using the publicly available BLB dataset with performance reported using mean IoU (mIoU), mean F1 (mF1), mean accuracy (mAcc), precision, and recall. U-Net++ with EfficientNet-B3 achieved the highest performance, with an mIoU of 97.62%. SegFormer obtained lower segmentation accuracy but comparable inference speed. Overall, the results indicate that lightweight CNN backbones remain more reliable for operational BLB monitoring while integration of vegetation indices provides small and consistent improvements. The study also highlights the value of standardised UAV datasets to compare disease mapping methods and encourages the use of CNN architectures for field implementation.

Identifying subtypes of complex conditions, such as Inflammatory Bowel Disease (IBD), often requires capturing latent patterns in longitudinal omics data. However, these data are typically high-dimensional, sparsely sampled, and irregularly observed over time, posing substantial challenges for conventional (bi)clustering and functional data analysis methods. We propose Tri-SfSVD, a unified sparse functional Singular Value Decomposition framework for discovering biclusters and triclusters in longitudinal data. Unlike existing functional biclustering methods that rely on ad hoc imputation or enforce restrictive shape-homogeneity assumptions, Tri-SfSVD integrates continuous trajectory estimation with simultaneous subject, feature, and temporal selection within a single optimization framework. By imposing sparse penalties across subjects, variables, and temporal subregions, the proposed method works directly on observed data to uncover localized structures at the subject, subject-feature, and subject-feature-time levels. Extensive simulations demonstrate that Tri-SfSVD outperforms existing approaches in high-dimensional settings. Applied to IBD multi-omics data, the method identified three biclusters linking sample clusters with distinct IBD-related clinical characteristics to microbial pathway groups associated with specific bacterial taxa, providing interpretable subject-pathway associations for characterizing disease heterogeneity. Applied to multi-channel EEG data, the method identified three triclusters linking sample clusters with distinct alcohol-related phenotypes to localized brain activity patterns, including subgroup differences separated by temporal subregions within the same spatial region.

Cell Painting combines multiplexed fluorescent staining, high-content imaging, and quantitative analysis to generate high-dimensional phenotypic readouts to support diverse downstream tasks such as mechanism-of-action (MoA) inference, toxicity prediction, and construction of drug-disease atlases. However, existing workflows are slow, costly and difficult to interpret. Approaches for drug screening modeling predominantly focus on molecular representation learning, while neglecting actual experimental context (e.g., cell line, dosing schedule, etc.), limiting generalization and MoA resolution. We introduce CP-Agent, an agentic multimodal large language model (MLLM) capable of generating mechanism-relevant, human-interpretable rationales for cell morphological changes under drug perturbations. At its core, CP-Agent leverages a context-aware alignment module, CP-CLIP, that jointly embeds high-content images and experimental metadata to enable robust treatment and MoA discrimination (achieving a maximum F1-score of 0.896). By integrating CP-CLIP outputs with agentic tool usage and reasoning, CP-Agent compiles rationales into a structured report to guide experimental design and hypothesis refinement. These capabilities highlight CP-Agent's potential to accelerate drug discovery by enabling more interpretable, scalable, and context-aware phenotypic screening -- streamlining iterative cycles of hypothesis generation in drug discovery.

Purpose: To compare dual-energy X-ray absorptiometry (DXA)-derived hip skeletal phenotypes in relation to hip fracture risk using prespecified confounder adjustment and to assess whether phenotypes ranked by their backdoor-adjusted average treatment effects (ATEs) improve risk stratification. Methods: We analyzed 21,098 UK Biobank participants with linked health records, hip DXA-derived skeletal measures, and prespecified covariates. Sixteen phenotypes spanning bone mineral content (BMC), bone mineral density (BMD), and T-score across hip-related regions were evaluated. Confounder selection was guided by a prespecified directed acyclic graph (DAG). Backdoor-adjusted ATEs were estimated on the absolute risk-difference scale per standard deviation (SD) increase. Effect heterogeneity was evaluated for total femur BMD, and downstream prediction was assessed using clinical variables combined with phenotypes ranked by ATE magnitude. Results: Among 21,098 participants, 115 had hip fractures. All 16 phenotypes showed negative backdoor-adjusted ATEs per SD increase. The largest ATEs were observed for total femur BMC and total femur BMD, each with a risk difference of -0.0047, corresponding to approximately 4.7 fewer hip fractures per 1,000 participants per SD higher phenotype value. Conditional effects of total femur BMD were stronger among older participants and those with lower BMI. In prediction, clinical variables plus the top 11 ATE-ranked phenotypes achieved higher AUC than FRAX with femoral neck BMD (0.842 vs. 0.709), with higher sensitivity (0.748 vs. 0.443) and similar specificity (0.793 vs. 0.777). Conclusion: DXA-derived hip skeletal phenotypes differed in their backdoor-adjusted ATEs. Phenotype-level causal evaluation may help identify informative DXA measures for risk stratification.

Linking free-text phenotype descriptions to ontology terms, typically referred to as phenotype annotation, is essential for the cross-study integration of comparative morphological data. This labor intensive process has heavily relied on highly trained human experts, which makes it challenging to scale and thus a key bottleneck. Dahdul et al. (2018) established a Gold Standard (GS) of Entity-Quality (EQ) annotations across seven phylogenetic studies and used it to evaluate three human curators and the Semantic CharaParser NLP tool with ontology-based semantic similarity metrics; they reported that machine-human consistency was significantly lower than inter-curator (human-human) consistency. Here we revisit that benchmark with five frontier hosted LLMs from Anthropic and OpenAI, each operating as an "agentic curator" within a self-contained workspace that supplies the source publication PDF, the same annotation guide used by the original human curators, the four project ontologies (UBERON, PATO, BSPO, GO), and a validation script. Evaluated against the same Gold Standard, every agent fell within the range of inter-curator variability of the three trained human biocurators of the original study; the best performing agents approached but did not reach the best performing human curator. Agents substantially outperformed Semantic CharaParser on all four metrics.

Small-molecule drug discovery requires simultaneous optimization of numerous properties of candidate molecules. These properties can be investigated through the analysis of high-dimensional biological signatures, such as cell morphology and transcriptomic perturbations, which provide a rich perspective on the underlying biological mechanisms. However, existing generative methods, which use those signatures for optimization, fail to meet two key requirements: providing precise guidance toward desired phenotypic signatures while maintaining structural proximity to a known hit. We introduce PhAME (Phenotype-Aware Molecular Editing), a latent diffusion framework that overcomes this challenge by recasting molecular optimization as editing in the latent space of a pretrained graph-based VAE. Our central contribution is a compositional classifier-free guidance scheme with two independent scales, one for the phenotype-conditioning and one for similarity to the seed structure, allowing practitioners to control the tradeoff between these two objectives. Empirical evaluations across diverse benchmarks, including docking score optimization and multimodal phenotypic generation, demonstrate that PhAME achieves state-of-the-art results while maintaining high chemical validity and novelty.

Behavioral phenotyping of genetic animal models currently requires labor-intensive manual feature engineering that limits reproducibility and scalability. We present GEESE, an end-to-end deep learning framework that learns behavioral representations directly from 3D pose dynamics without hand-crafted features. Using a pretrained time series foundation model, we encode movement sequences into a behavioral manifold that supports both behavior classification and genotype prediction. Evaluated across three autism-associated genetic models (CNTNAP2, CHD8, FMR1), our deep learning approach surpasses hand-crafted feature baselines in both tasks, revealing that learned representations capture genotype-specific behavioral signatures. The framework generalizes across genetic backgrounds, and an all-cohort model identifies both genetic background and genotype from movement patterns alone. We further provide HONK, an interactive intelligent tool enabling researchers without programming expertise to perform behavioral phenotyping from pose data through natural language interaction.

Computed tomography (CT) is a central to three-dimensional medical imaging, yet CT-based artificial intelligence remains fragmented across task-specific models for segmentation, classification, registration, and report analysis. Here we present FlexiCT, a family of CT foundation models trained by agglomerative continual pretraining on 266,227 CT volumes from 56 publicly available datasets, forming a large-scale public resource for CT representation learning. FlexiCT uses agglomerative pretraining across three stages: two-dimensional axial pretraining, three-dimensional anatomical pretraining and report-guided semantic alignment. This training strategy supports slice-level, volume-level and vision-language analysis. Across five downstream task families (segmentation, classification, registration, vision-language understanding and clinical retrieval), FlexiCT matches or exceeds prior task-specific approaches on multiple benchmarks. Its embeddings further organize CT scans along gradients associated with various tumor stages, suggesting that CT foundation models can capture imaging features relevant to disease phenotype characterization. Project page and code are available at: https://ricklisz.github.io/flexict.github.io and https://github.com/ricklisz/FlexiCT.

Label-free single-cell imaging offers a scalable, non-invasive alternative to fluorescence-based cytometry, yet inferring molecular phenotypes directly from bright-field morphology remains challenging. We present a unified Deep Learning (DL) framework that jointly performs White Blood Cell (WBC) classification and continuous protein-expression regression from label-free Differential Phase Contrast (DPC) images. Our model employs a Hybrid architecture that fuses convolutional fine-grained texture features with transformer-based global representations through a learnable cross-branch gating module, enabling robust morpho-molecular inference from DPC images. To support downstream interpretability, we further incorporate a Large Language Model (LLM) that generates concise, biologically grounded summaries of the predicted cell states. Experiments on the Berkeley Single Cell Computational Microscopy (BSCCM) and Blood Cells Image benchmarks demonstrate strong performance, achieving a 91.3% WBC classification accuracy and a 0.72 Pearson correlation for CD16 expression regression on BSCCM. These results underscore the promise of label-free single-cell imaging for cost-effective hematological profiling, enabling simultaneous phenotype identification and quantitative biomarker estimation without fluorescent staining. The source code is available at https://github.com/saqibnaziir/Single-Cell-Phenotyping.

Many real-world optimization problems are not naturally homogeneous vectors but composite design objects with heterogeneous parameters: integers, real values, Booleans, categoricals, complex-valued descriptors, and embedding vectors. Standard evolutionary algorithms flatten these into a single chromosome and apply generic operators with rounding and repair, sacrificing representational fidelity. We introduce the Geno-Synthetic Algorithm (GSA), a type-factored coevolutionary framework in which gene families are partitioned by representational type, evolved in parallel with type-native operators, and assembled into executable phenotypes for joint fitness evaluation. GSA is formalized as a typed product-space search procedure with an explicit assembly operator. An open-source reference implementation (gsa-experiments, MIT-licensed) is released. A focused empirical study compares eight GSA variants against five baselines across seven benchmark problems (six synthetic plus the external COCO BBOB-MixInt suite) at budgets from 5,000 to 100,000 evaluations. The headline finding is architectural: GSA is the only method that operates when gene families include complex-valued descriptors or embedding vectors. On smooth synthetic multi-family problems, well-tuned flattened differential evolution remains the strongest baseline; on BBOB-MixInt at 100,000 evaluations, GSA_DIRECT becomes statistically indistinguishable from FLATTENED_DE while FLATTENED_EA drops from second to fifth rank, an asymptotic crossover. Ablations confirm that type-native operators are essential, elite credit dominates ensemble credit, and active assembly outperforms passive concatenation on gated benchmarks. The framework extends naturally to prompt and embedding optimization for large language model systems.

Cerebral Palsy (CP) is a neurological disorder of movement and the most common cause of lifelong physical disability in childhood. Approximately 75% of children with CP are ambulatory, and accurate gait assessment is central to preserving walking function, which deteriorates by mid-adulthood in a quarter to half of adults with CP. The Rodda and Graham classification system quantifies sagittal-plane gait deviations using ankle and knee z-scores derived from 3D Instrumented Gait Analysis (3D-IGA), but 3D-IGA is expensive and limited to specialized centers, while observational assessment shows only moderate inter-rater agreement. We developed a markerless gait analysis pipeline that quantifies Rodda and Graham knee and ankle z-scores directly from single-view clinical gait videos. Across 1,058 bilateral limb samples from 529 trials of 152 children (88 male, 63 female; age 12.1 $\pm$ 4.0 years; 60 distinct primary diagnoses, cerebral palsy the most common at $n=54$), the sagittal-view model achieved $R^2 = 0.80 \pm 0.02$ and CCC $= 0.89 \pm 0.02$ for knee z-scores and $R^2 = 0.57 \pm 0.02$ and CCC $= 0.72 \pm 0.02$ for ankle z-scores against 3D-IGA. Binary screening for excess knee flexion achieves AUROC $= 0.88$, correctly identifying 83% of affected children, and applying Rodda and Graham rules yields $43 \pm 1$% 7-class accuracy with macro-AUROC $= 0.78 \pm 0.01$, ankle prediction error remaining the primary bottleneck. Beyond cross-sectional screening, continuous z-scores support longitudinal trajectory tracking across visits, providing a quantitative substrate for monitoring disease progression and treatment response unavailable from observational scales. These results demonstrate the feasibility of video-based z-score estimation, excess-flexion screening, and longitudinal trajectory tracking as a path toward scalable, objective gait assessment in low-resource clinical settings.

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

In this retrospective multi-institutional study, a quantitative phenotyping framework, CT-IDP (CT Image-Derived Phenotypes) was developed on the MERLIN abdominal CT benchmark (training, validation, and test sets- 15,175, 5,018, and 5,082 studies, respectively) and externally evaluated on two independent dataset: Duke-Abdomen (2,000) and AMOS (1,107). Multi-organ segmentations were generated with TotalSegmentator and used to derive over 900 organ and compartment-level descriptors spanning morphometry, attenuation, and contextual/burden findings. Sparse disease-specific logistic regression with elastic-net regularization was trained on MERLIN and externally validated under a frozen specification. Performance was compared against a DINOv3-based vision-transformer baseline using AUC and average precision (AP), supported by phenotype-stratified audits and coefficient-level inspection. Macro-AUC for CT-IDP versus the baseline was 0.897 versus 0.880 on MERLIN, 0.877 versus 0.857 on the Duke-Abdomen dataset, and 0.780 versus 0.756 on AMOS.

Robust genotype-to-phenotype (G2P) prediction is essential for accelerating breeding decisions and genetic gain. However, it remains challenging to measure complex traits under variable field conditions and across years. In this study, we propose a linear-Transformer approach, LiT-G2P (Linear-Transformer Genotype-to-Phenotype), an automated predictive framework that integrates additive genetic variance effects with Transformer-based nonlinear interactions using genome-wide single-nucleotide polymorphisms (SNPs) data. We evaluated LiT-G2P on a panel of diverse grape accessions, genotyped with SNP markers and measured for phenotypes across two consecutive years. Target phenotypic traits include leaf hair density and trichome density of grapevines. Across both single-year and cross-year testing scenarios, LiT-G2P consistently improves prediction performance compared with baseline models. For hair density, LiT-G2P achieves the lowest error in both single-year and cross-year evaluations, with RMSEs of 0.469 and 0.454, respectively, while maintaining strong tolerance accuracies of 79.2% and 74.6%, respectively. For trichome density, LiT-G2P also presents the best overall G2P performance. In addition, we extract model-prioritized SNPs from attention weights and apply genotype-stratified analysis to provide interpretable candidate marker for downstream validation. These results demonstrate that integrating stable additive effects with learned interaction patterns can enhance cross-year robustness and support practical SNP-based predictive modeling for genomic selection.

Plant breeding underpins global food security through incremental, accumulating improvements in crop yield, quality and sustainability, achieved via repeated cycles of crop ranking, selection and crossing. Climate change disrupts this process by altering local growing conditions, thereby shifting the relative performance of crop genotypes. Predicting these relative changes in yield is critical for food security. Yet, this problem remains an open challenge in plant breeding, and relatively unexplored within the AI community. We propose MixINN, an approach that first isolates high-quality genotype-environment interaction labels using mixed models, and then predicts these interactions for new crop varieties in future environmental conditions with a deep neural network. We evaluate our method on a corn multi-environment trial across the continental United States and show improved prediction of genotype ranking over current plant breeding methods. MixINN demonstrated superior performance in identifying the 20% most productive corn genotypes, leading to a 5.8% higher average yield, which further improved to 7.2% when targeting specific growing environments. These are competitive results for real-world breeding programs, demonstrating the potential of AI research in accelerating the development of climate-adapted crops, and improving future food security under climate change.

We present a method for finding hierarchy-aware embeddings of knowledge graphs (KGs) using graph neural networks (GNNs) enriched with a semantic loss derived from underlying ontologies. This method yields embeddings that better reflect domain knowledge. To demonstrate their utility, we predict and interpret the effects of gene deletions in the yeast Saccharomyces cerevisiae and learn box embeddings for KGs in the absence of a prediction task. We further show how box embeddings can serve as the basis for evaluating KG revisions. Our yeast KG is constructed from community databases and ontology terms. Low-dimensional box embeddings combined with GNNs are used to predict cell growth for double gene knockouts. Over 10-fold cross validation, these predictions have a mean $R^2$scoreof~0.360, significantly higher than baseline comparisons, demonstrating that high-level qualitative knowledge is informative about experimental outcomes. Incorporating semantic loss terms in the training of the models improves their predictive performance ($R^2$=0.377) by aligning embeddings with ontology structure. This shows that class hierarchies from ontologies can be exploited for quantitative prediction. We also test the trained models on triple gene knockouts, showing they generalise to data beyond those seen in training. Additionally, by identifying co-occurring relations in the yeast KG important for the cell-growth predictions, we construct hypotheses about interacting traits in yeast. A biological experiment validates one such finding, revealing an association between inositol utilisation and osmotic stress resistance, highlighting the model's potential to guide biological discovery.

Predicting complex human traits from genetic data is challenging because different genetic, clinical, and molecular data sources often contain different parts of the signal. Here, we present EFGPP, a reproducible framework for generating, ranking, and combining multiple types of data for genotype-to-phenotype prediction. We applied EFGPP to migraine prediction using UK Biobank data from 733 individuals. The framework combined genotype-derived features, principal components, clinical and metabolomic covariates, and polygenic risk scores generated from migraine and depression GWAS using PLINK, PRSice-2, AnnoPred, and LDAK-GWAS. The best single data type achieved a test AUC of 0.644, while combining multiple data types improved performance to 0.688 using migraine-focused inputs and 0.663 using cross-trait depression-derived inputs. Genetic features alone did not outperform the covariates-only baseline, but genotype-derived features performed better than PRS alone, and depression-derived PRS showed useful predictive signal. Overall, EFGPP provides a practical proof-of-concept framework for prioritising and integrating heterogeneous genetic data sources for complex phenotype prediction.

The proliferation of agentic artificial intelligence has outpaced the conceptual tools needed to characterize agency in computational systems. Prevailing definitions mainly rely on autonomy and goal-directedness. Here, we argue for a minimal notion open to principled inspection given three criteria: intentionality as action grounded in beliefs and desires, rationality as normatively coherent action entailed by a world model, and explainability as action causally traceable to internal states; we subsequently instantiate these as a partially observable Markov decision process under a variational framework wherein posterior beliefs, prior preferences, and the minimization of expected free energy jointly constitute an agentic action chain. Using a canonical T-maze paradigm, we evidence how empowerment, formulated as the channel capacity between actions and anticipated observations, serves as an operational metric that distinguishes zero-, intermediate-, and high-agency phenotypes through structural manipulations of the generative model. We conclude by arguing that as agents engage in epistemic foraging to resolve ambiguity, the governance controls that remain effective must shift systematically from external constraints to the internal modulation of prior preferences, offering a principled, variational bridge from computational phenotyping to AI governance strategy

We previously introduced a training-free method for dysarthria severity assessment based on d-prime separability of phonological feature subspaces in frozen self-supervised speech representations, validated on 890 speakers across 5 languages with HuBERT-base. Here, we scale the analysis to 3,374 speakers from 25 datasets spanning 12 languages and 5 aetiologies (Parkinson's disease, cerebral palsy, ALS, Down syndrome, and stroke), plus healthy controls, using 6 SSL backbones. We report three findings. First, aetiology-specific degradation profiles are distinguishable at the group level: 10 of 13 features yield large effect sizes (epsilon-squared > 0.14, Holm-corrected p < 0.001), with Parkinson's disease separable from the articulatory execution group at Cohen's d = 0.83; individual-level classification remains limited (22.6% macro F1). Second, profiles show cross-lingual profile-shape stability: cosine similarity of 5-dimensional consonant d-prime profiles exceeds 0.95 across the languages available for each aetiology. Absolute d-prime magnitudes are not cross-lingually calibrated, so the method supports language-independent phenotyping of degradation patterns but requires within-corpus calibration for absolute severity interpretation. Third, the method is architecture-independent: all 6 backbones produce monotonic severity gradients with inter-model agreement exceeding rho = 0.77. Fixed-token d-prime estimation preserves the severity correlation (rho = -0.733 at 200 tokens per class), confirming that the signal is not a token-count artefact. These results support phonological subspace analysis as a robust, training-free framework for aetiology-aware dysarthria characterisation, with evidence of cross-lingual profile-shape stability and cross-backbone robustness in the represented sample.

Microscopy-based phenotypic profiling is scalable for drug discovery but lacks the mechanistic depth of transcriptomics, which remains costly and scarce. Existing multimodal approaches either use images to support other modalities or naively align representations by sample identity, ignoring cell-type and dose variations in weakly paired data-limiting generalization to unseen interventions. In this paper, we introduce an intervention-aware distillation framework that leverages perturbational transcriptomics to guide image representation learning. A transcriptome-conditioned teacher integrates gene expression and intervention metadata to produce soft distributions over a chemistry-aware codebook organized by drug similarity. The teacher employs a fine-tuned single-cell foundation model to encode cell-type context and disentangle dose effects. An image-only student learns to predict these distributions from microscopy alone, distilling mechanistic knowledge while operating independently at test time. This design emphasizes intervention semantics rather than identity alignment and explicitly handles dose and cell-type mismatches. We provide theoretical guarantees showing that transcriptomic guidance tightens the risk bound for image-based prediction. On Cell Painting and RxRx datasets paired with L1000, our method significantly improves one-shot transfer to unseen interventions and drug-target gene discovery compared to self-supervised and alignment baselines.

Current knowledge graph (KG) construction methods are confirmatory, focusing on recovering known relationships rather than identifying novel or context-dependent nodes. This paper proposes a phenotype-driven and evidence-governed framework that shifts the paradigm toward structured hypothesis discovery and controlled KG expansion. The approach integrates graph neural networks (GNNs) for phenotype discovery, causal inference, probabilistic reasoning and large language models (LLMs) for hypothesis generation and claim extraction within a unified pipeline. The framework prioritizes relationships that are both structurally supported by data and underexplored in the literature. KG expansion is formulated as a multi-objective optimization problem, where candidate claims are jointly evaluated in terms of relevance, structural validation and novelty. Pareto-optimal selection enables the identification of non-dominated claims that balance confirmation and discovery, avoiding trivial or redundant knowledge inclusion. Experiments on heterogeneous population datasets demonstrate that the proposed framework produces more interpretable phenotypes, reveals context-dependent causal structures and generates high-quality claims that align with both data and scientific evidence. Compared to rule-based and LLM-only baselines, the method achieves the best trade-off across plausibility, novelty, validation and relevance. In retrieval-augmented settings, it significantly improves performance (Recall@5=0.98) while reducing hallucination rates (0.05), highlighting its effectiveness in grounding LLM outputs.

Accurate extraction of Alzheimer's Disease and Related Dementias (ADRD) phenotypes from electronic health records (EHR) is critical for early-stage detection and disease staging. However, this information is usually embedded in unstructured textual data rather than tabular data, making it difficult to be extracted accurately. We therefore propose LLM-MINE, a Large Language Model-based phenotype mining framework for automatic extraction of ADRD phenotypes from clinical notes. Using two expert-defined phenotype lists, we evaluate the extracted phenotypes by examining their statistical significance across cohorts and their utility for unsupervised disease staging. Chi-square analyses confirm statistically significant phenotype differences across cohorts, with memory impairment being the strongest discriminator. Few-shot prompting with the combined phenotype lists achieves the best clustering performance (ARI=0.290, NMI=0.232), substantially outperforming biomedical NER and dictionary-based baselines. Our results demonstrate that LLM-based phenotype extraction is a promising tool for discovering clinically meaningful ADRD signals from unstructured notes.

Cardiac Magnetic Resonance (CMR) imaging provides a comprehensive assessment of cardiac structure and function but remains constrained by high acquisition costs and reliance on expert annotations, limiting the availability of large-scale labeled datasets. In contrast, electrocardiograms (ECGs) are inexpensive, widely accessible, and offer a promising modality for conditioning the generative synthesis of cine CMR. To this end, we propose ECGFlowCMR, a novel ECG-to-CMR generative framework that integrates a Phase-Aware Masked Autoencoder (PA-MAE) and an Anatomy-Motion Disentangled Flow (AMDF) to address two fundamental challenges: (1) the cross-modal temporal mismatch between multi-beat ECG recordings and single-cycle CMR sequences, and (2) the anatomical observability gap due to the limited structural information inherent in ECGs. Extensive experiments on the UK Biobank and a proprietary clinical dataset demonstrate that ECGFlowCMR can generate realistic cine CMR sequences from ECG inputs, enabling scalable pretraining and improving performance on downstream cardiac disease classification and phenotype prediction tasks.

Individuals with suspected rare genetic disorders often undergo multiple clinical evaluations, imaging studies, laboratory tests, and genetic tests over a prolonged period of time, a process commonly described as the diagnostic odyssey. Addressing this odyssey has substantial clinical, psychosocial, and economic benefits. Many rare genetic diseases have distinctive facial features that artificial intelligence algorithms can use to facilitate clinical diagnosis, to prioritize candidate diseases for further laboratory or genetic testing, and to support the phenotype-driven reinterpretation of genome or exome sequencing data. Existing methods that use frontal facial photographs were built on conventional convolutional neural networks, rely exclusively on facial images, and cannot capture non-facial phenotypic traits or demographic information that are essential for accurate diagnosis. Here we introduce GestaltMML, a multimodal machine learning approach based solely on the Transformer architecture. It integrates facial images, demographic information (age, sex, ethnicity), and clinical notes (optionally a list of Human Phenotype Ontology terms) to improve prediction accuracy. We evaluate GestaltMML on 528 diseases from the GestaltMatcher Database and on several in-house and published cohorts, including Beckwith-Wiedemann syndrome, Sotos syndrome, NAA10-related neurodevelopmental syndrome, Cornelia de Lange syndrome, and KBG syndrome. GestaltMML improves on the state-of-the-art image-only ensembled model, narrows the diagnostic accuracy gap for patients from under-represented ancestries, and clarifies when multimodal fusion is beneficial and when image-only inference is preferable. The results suggest that GestaltMML can greatly narrow the candidate diagnoses of rare diseases and may facilitate the reinterpretation of sequencing data.