Phenotypes

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.

Continuous Glucose Monitoring (CGM) can detect early metabolic subphenotypes (insulin resistance, IR; $β$-cell dysfunction), but population-scale deployment faces two coupled problems. First, the same physiological state appears through multiple views (CGM time series, venous OGTT, Glucodensity summaries), so single-view representations fail to transfer when deployment shifts the modality or setting. Second, baselines perform inconsistently across these shifts. Both problems point to one remedy: representations that abstract away from any single view to capture higher-level temporal and distributional structure. We propose CGM-JEPA, a self-supervised pretraining framework which predicts masked latent representations rather than raw values, yielding abstraction that transfers across modalities. X-CGM-JEPA adds a masked Glucodensity cross-view objective for complementary distributional information. We pretrain on $\sim$389k unlabeled CGM readings from 228 subjects and evaluate on two clinical cohorts ($N=27$ and $N=17$ public-release subsets) across three regimes (cohort generalization, venous-to-CGM transfer, home CGM) under 20-iteration $\times$ 2-fold cross-validation. X-CGM-JEPA ranks first or second on AUROC for both endpoints across all three regimes while no baseline does, exceeding the strongest baseline by up to $+6.5$ pp in cohort generalization and $+3.6$ pp in venous-to-CGM transfer (paired Wilcoxon, $p<0.001$). Under modality shift, it matches mean AUROC while redistributing toward weaker subgroups (ethnicity AUROC gap shrinks 25-54%); on sparse in-domain venous data, the distributional view lifts label-aware clustering (ARI $+39\%$, NMI $+40\%$). Code and weights: https://github.com/cruiseresearchgroup/CGM-JEPA

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.

Transfer learning is a critical technique that enables the application of knowledge gained from existing tasks or domains to improve performance on a new one, reducing the need for extensive data and training in each new context. Many existing transfer learning methods rely on leveraging information from source populations closely resembling the target population. However, this approach often overlooks valuable knowledge that may be present in different yet potentially related auxiliary samples. When dealing with a limited amount of target data and multiple source data, we introduce a novel approach, Guided Adversarial Robust Transfer (GART) learning, that breaks free from strict similarity constraints. GART is designed to optimize the most adversarial loss with respect to a collection of source mixture distributions that guarantee excellent prediction performances for the target data. We establish the closed form of the population GART and show that the GART estimator achieves a faster convergence rate than the model fitted with the target data. Our simulation studies suggest that GART outperforms existing transfer learning methods, attaining higher robustness and accuracy. We highlight GART's predictiveness and robustness by applying it to form genetic prediction models of high-density lipoprotein cholesterol using multi-institutional biobank-linked electronic health records data.