Biomarker

Physical activity (PA) plays an important role in maintaining and improving health. Daily steps have been a key PA measure that is easily accessible with common wearable devices. However, methods are lacking to recommend a personalized optimal distribution of daily steps over a period of time for the best of certain health biomarkers. In this paper, we fill this void based on the data from the All of Us Research Program which includes months of step counts as well as repeated measurements of key health biomarkers. We develop a new offline reinforcement learning (RL) algorithm to learn personalized and optimal PA distributions associated with cardiometabolic risk, where the action is a function representing the daily step distribution over a period of time. Simulation studies demonstrate the advantage of the proposed approach over existing continuous-action RL methods. The learned optimal policy from the All of Us data generally suggests people take more daily steps and also follow a more consistent pattern of PA over time while offering tailored recommendations for subgroups in blood glucose level, body mass index, blood pressure, age, and sex.

Blood-based biomarkers underpin clinical diagnosis and management, yet their interpretation relies largely on fixed population reference intervals that ignore stable, intra-patient variability. As such, population-based interpretation can mask meaningful deviation from an individual's baseline, risking delayed disease detection. To remedy this, there have been increasing efforts to personalize blood biomarker interpretation using individual testing histories. However, these methods may overfit to sparse data, inflating false-positive rates and unnecessary follow-up, and can also unwittingly include unrecognized or subclinical disease. Here, we leverage nearly 2 billion longitudinal laboratory measurements from over 1.6 million individuals across North America, the Middle East, and East Asia, to show that while laboratory values are highly individual, purely personalized intervals routinely overfit, classifying up to 68% of measurements as abnormal, without corresponding associations with adverse clinical outcomes. We then introduce NORMA, a conditional transformer-based framework that generates reference intervals by conditioning on both a patient's history and population-level data about "normal" variation. NORMA-derived intervals achieve higher precision for predicting outcomes, including mortality, acute kidney injury, and chronic disease. These findings caution against over-personalization in laboratory medicine and demonstrate that anchoring individual trajectories to population-level priors outperforms either approach alone. To promote transparency, we publicly release the model, code, and an interactive user interface for accessible, individualized laboratory interpretation.

Time series classification (TSC) of biological signals has progressed from handcrafted, modality-specific approaches to deep architectures capable of representing the diverse waveform structures of underlying physiological processes (i.e., morphology). This review introduces a unified morphology--modality framework that connects waveform structure to a methodological design, revealing how spikes, bursts, oscillations, slow drift, and hierarchical rhythms inform model design. By analyzing electroencephalography, electromyography, electrocardiography, photoplethysmography, and ocular modalities (electrooculography, pupillometry, eye-tracking), the review demonstrates how morphology determines preprocessing and modeling strategies. Integrating evidence across these biological signals, the framework reveals that morphology, not model class, most strongly determines performance and interpretability. This provides insight into why deep models succeed when their inductive biases align with underlying waveform dynamics. This review also identifies future work including morphological data augmentation and evaluation metrics to improve generalization. Together, these insights position morphology-aware modeling as a unifying principle for developing generalizable, interpretable, and physiologically meaningful TSC models across biological signals.

Hospital readmission within 30 days of discharge is a leading driver of morbidity, mortality, and avoidable healthcare expenditure in congestive heart failure (CHF). Current clinical risk stratification tools rely primarily on non-imaging data and exhibit limited predictive performance. Point-of-care lung ultrasound (LUS) offers a sensitive, noninvasive window into the pulmonary congestion that characterizes CHF decompensation, yet its prognostic utility for readmission prediction remains largely unexplored. We present a pilot feasibility study, the first systematic machine learning study using B-mode LUS acquired during hospitalization to predict 30-day CHF readmission. Quantitative spatiotemporal embeddings are extracted from a pretrained Temporal Shift Module (TSM) ResNet-18 encoder, and interpretable biomarker features are separately evaluated. Through structured ablations over lung view, temporal representation, multi-view fusion, and cross-lung augmentation, we identify the key imaging factors driving readmission risk. Our findings reveal that (1) dependent lower-lung regions (Left-3, Right-3) carry the strongest prognostic signal, consistent with their greater susceptibility to hydrostatic congestion; (2) temporal difference features between sequential examinations substantially outperform single-timepoint representations, highlighting the importance of capturing disease trajectory; and (3) multi-view feature concatenation yields the best overall performance, with our top MLP model achieving an F1 score of 0.80 (95% CI: 0.62-0.96). Biomarker analysis further reveals that pleural-line abnormalities, including breaks and indentations, are as informative as the canonical A-line and B-line markers. These results support POCUS-derived biomarkers as practical, interpretable tools for noninvasive CHF risk stratification.

Pertussis booster vaccination produces immune responses that vary widely across individuals in both peak magnitude and long-term durability. These two phases are governed by partly distinct biological compartments:peak reflects acute B-cell activation and antibody secretion, while durability reflects the establishment of long-term humoral memory. Yet most computational models target only one, missing the full boost-and-wane trajectory. Jointly predicting both is non-trivial because the two endpoints are biologically dissociated rather than redundant; samples are small, modalities are heterogeneous with structured missingness, and the two tasks rely on different measurement windows. We propose a multi-task contrastive multimodal fusion architecture combining frozen TabPFN-v2 per-modality encoders, a dual-label supervised contrastive loss that treats two subjects as a positive pair if they agree on the Task 1 label or the Task 2 label, modality dropout calibrated to empirical missingness, and missingness-masked attention fusion. Applied to a curated subset of the CMI-PB pertussis booster dataset (n = 158 subjects, four modalities, 44.9% with at least one modality missing; Spearman r = -0.58 between peak and durability, n = 96), the model achieves test AUROC 0.797 (95% CI [0.621, 0.948]) for peak response and 0.755 (95% CI [0.519, 0.945]) for durability, with both significant under joint label permutation (N = 1000; p = 0.002 and p = 0.045). Across logistic regression, XGBoost, and MLP baselines on raw features and on TabPFN embeddings, the proposed model is the only one whose 95% CIs lie above chance on both tasks simultaneously. Per-modality contribution analyses recover task-specific modality contributions consistent with the underlying immunology: peak prediction is carried by cytokine signatures, while durability is carried by baseline antibody features.

Background: Radiogenomics allows identification of radiological biomarkers for genomic phenotypes. In glioblastoma, these biomarkers could potentially complement patient stratification strategies. We aim to develop and analytically validate radiological biomarkers that capture immune cell signatures within IDH-wildtype glioblastoma microenvironment using radiogenomic analysis. Methods: This was a retrospective multicenter study using curated open-access anonymized imaging and genomic data from TCGA-GBM, CPTAC, IvyGAP, REMBRANDT and CGGA datasets. Imaging data consisted of MRI-based radiomic features extracted from necrotic core, enhancing and edema regions of deep learning-based auto-segmented tumors. Radiomic feature selections were performed using nested cross-validated LASSO. Support vector machine and ensemble models were trained using seventeen immune and cell-specific score labels extracted from deconvoluted transcriptomic data using pan-cancer and glioblastoma immune signature matrices as reference standards. Seventeen classifier models trained in three cross-cohort strategies were validated on three held-out datasets assessing stability and generalizability. Results: One-hundred-and-seventy-six patients were included in the study. The immune-related radiomic signatures obtained after feature selection were shape, first order and higher order radiomic features. Models predicting macrophage subtype immune signature showed stable mean performance on balanced accuracy (0.67) and precision (0.89) metrics for three independent holdout datasets with ensemble model outperforming support vector machine model. Conclusion: Radiogenomic models non-invasively predicted the macrophage subtype M0 immune signature in IDH-wildtype glioblastoma. These biomarkers have the potential to stratify patients for immunotherapy within prospective glioblastoma clinical trials.

Current approaches to detecting depression and anxiety from speech primarily rely on machine learning techniques that utilize hand-engineered paralinguistic features and related acoustic descriptors derived from time- and frequency-domain representations of speech signals. Applying deep learning methods directly to raw speech signals has the potential to produce biomarker representations with substantially greater predictive power. However, these approaches typically require large volumes of carefully annotated data to learn robust and clinically meaningful representations of the underlying biomarkers. In this paper, we describe our efforts toward developing a deep learning model trained on a large-scale proprietary dataset comprising ~65,000 utterances collected from more than 23,000 subjects representative of relevant United States demographics. We present the techniques employed and analyze their impact on model performance. Our results demonstrate that the proposed models can extract content-agnostic biomarker information, which, when combined with lexical features extracted from audio, yields improved predictive performance in production settings. Our models are evaluated on ~5000 unique subjects and achieve performance of 71% in terms of sensitivity and specificity. To foster further research in mental health assessment from speech, we release the best-performing model described in this paper on HuggingFace.

Transforming neuroimaging data into clinically actionable biomarkers is a knowledge-intensive and labor-intensive process. Standardized workflows such as fMRIPrep have improved robustness and efficiency, but they are statically configured and cannot reason about downstream objectives, deliberate over alternative strategies, or close the loop between intermediate evidence and subsequent decisions in the way a human researcher would. This lack of closed-loop adaptation often leaves domain experts trapped in a cycle of manual trial-and-error to tune parameters and remediate pipeline failures, severely constraining the scalability of clinical biomarker development. To bridge this gap, we introduce NEXUS, an autonomous multi-agent framework that integrates neuroimaging workflow execution with scientific-objective understanding. Unlike conventional flat toolcalling agents, NEXUS adopts a code-centric execution paradigm where specialist agents collaboratively synthesize and optimize executable programs over composable domain-specific primitives. This design enables robust, long-horizon workflow construction that adapts dynamically to runtime observations. Furthermore, we propose a hierarchical verification framework for autonomous quality control, integrating cohort-level metric screening with agentic visual inspection to drive evidence-grounded workflow remediation. Experiments on ADHD-200 and ADNI demonstrate that NEXUS outperforms standard workflow-based baselines in predictive performance while exhibiting sophisticated agentic behaviors, including strategy exploration and adaptive refinement. The code is available at https://github.com/LearningKeqi/Virtual-Neuroscientist-NEXUS.

Early identification of individuals at elevated risk of Chlamydia trachomatis infection may enable optimal use of molecular testing in resource-aware screening. We evaluate the feasibility of pre-test risk stratification (PTRS) using machine-learning models trained on routinely available, non-invasive clinical data. A curated dataset of 93 urine samples with PCR reference labels was analyzed using three feature groups: patient-reported history and symptoms, urine biomarkers from standard urinalysis, and their combination. Five supervised classifiers were evaluated using stratified 5-fold cross-validation with out-of-fold probability estimates. Performance was assessed using area under the receiver operating characteristic curve (AUC) and threshold-dependent metrics, with uncertainty quantified via bootstrap confidence intervals. Models using only patient-reported data showed moderate discrimination (AUC up to 0.72). Urine biomarker-based models demonstrated slightly lower peak discrimination but more consistent performance, with ensemble methods yielding the strongest results. Combining feature groups marginally increased the peak AUC and reduced performance variability across models, indicating improved robustness. Findings indicate that urine biomarkers provide a reliable predictive signal for PTRS that is complementary to patient-reported information, while feature integration enhances robustness. This work supports the integration of non-invasive, routinely available information for PTRS into screening workflows, including decentralized or home-based PCR contexts, to optimize testing prioritization.

Medium-horizon Alzheimer's disease progression prediction is difficult because future clinical scores can remain tied to baseline severity, while biomarker histories are irregular and incompletely observed. We develop an anchor-based analysis of 24-month Clinical Dementia Rating Sum of Boxes (CDR-SB) change using harmonized Alzheimer's Disease Neuroimaging Initiative (ADNI) tables. Each labeled sample is anchored at a mild cognitive impairment visit, uses only clinical and biomarker history observed at or before that anchor, and defines the response as CDR-SB at the future visit closest to 24 months within an 18--30 month window minus anchor CDR-SB. The analytic cohort contains 2,600 labeled anchors from 858 participants and 7,276 longitudinal rows. We propose a residual gap-aware transformer that combines a mixed-effects statistical reference with transformer-based residual learning from pre-anchor clinical and biomarker histories. The model uses participant-level random intercepts in the mixed-effects reference, observation-level triplet tokenization for irregular histories, and a learned nonnegative time-gap penalty inside self-attention. We compare the proposed model with a Bayesian-information-criterion-selected linear mixed-effects baseline, GRU-D, and STraTS under repeated participant-level train--test splits. Across five participant-level random seeds, the proposed model achieves the best mean test performance across all reported metrics, reducing MSE by 13.1% and increasing prediction--observation correlation by 26.4% relative to the mixed-effects baseline. It also improves over both GRU-D and STraTS in mean error and correlation. These results show that statistical anchoring and gap-aware residual learning provide a useful structure for medium-horizon Alzheimer's disease progression prediction.

Brain MRI foundation models learn rich representations of anatomy, but interpreting what clinical information they encode remains an open problem. Standard sparse autoencoders (SAEs) suffer from severe feature collapse in deep transformer layers, and in Alzheimer's disease (AD) research, aging confounds nearly every clinical variable, making naive annotation unreliable. We propose GeoSAE, a geometry-guided SAE framework that uses the foundation model's learned manifold structure to prevent feature collapse and annotates each surviving feature via age-deconfounded partial correlations. Applied to ~14k T1-weighted MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Australian Imaging biomarkers and Lifestyle (AIBL) datasets, GeoSAE identifies a compact, fully interpretable feature set that predicts mild cognitive impairment (MCI)-to-AD conversion (AUC 0.746) using only 2% of the embedding dimensions, while comorbidity-annotated features achieve only chance-level performance. The identified features replicate across cohorts without retraining (r=0.97) and localize to neuroanatomically distinct regions consistent with Braak staging. This shows that geometry-guided SAEs can extract interpretable, biomarkers from frozen brain MRI foundation models.

We propose a novel method of understanding disease transformation from a healthy baseline with biomarker-level explainability. By modeling the biomarker covariance matrices of healthy controls and disease states, the perturbation can be individually characterized to accomplish mechanistic explanations of disease trajectories, both at a molecular level and for individual patients. Given a cohort of n patients each measured on p biomarkers, we define the biomarker "Hamiltonian" H = X^T X / n \in R^{p \times p}, where X \in R^{n \times p} is the covariant biomarker matrix. The eigenvectors of H define a set of normal modes of biomarker coordination, and the eigenvalues quantify the energy carried by each mode. In the healthy state, the reference Hamiltonian H_0 governs this structure where disease perturbs H_0 by an additive operator ΔH, thus shifting eigenvalues and rotating eigenvectors in proportion to the severity of pathological disruption. We formalize this framework, derive the spectral change given a disease perturbation, and demonstrate that the projection of a newly diagnosed patient's cumulative biomarker covariance structure onto disease-discriminant eigenmodes constitutes an optimal prognostic statistic for greater precision in disease prognosis. This work serves as a veritable white paper with application across a panoply of disease frameworks from cancer to neurodegenerative disorders.

In biomechanical systems, observable performance is often used as a proxy for underlying organization, although similar outputs may arise from different adaptive configurations. This study considers the vertical dimension of occlusion (VDO) as a constraint applied to an adaptive neuromechanical system. A single-case design in a patient with Parkinson's disease enabled repeated intra-individual gait observations under six occlusal probes. Three complementary analytical levels were examined: (i) an aggregated scalar score of observable performance, (ii) a conceptual dynamical systems framework, and (iii) an exploratory UMAP representation of 55 standardized biomechanical variables from 270 M1 observations. The revised Level 1 analysis showed that the relative ranking of OC2.5 and OC3 depended on score construction, while their scalar distributions remained close. The Level 3 embedding showed substantial overlap among all six probes and did not identify independently separated condition-specific clusters. OC2.5 and OC3 displayed limited centroid displacement but broad observation-level overlap. The principal result is therefore representational non-identifiability: neither the aggregated score nor the selected low-dimensional embedding uniquely identifies an occlusal-condition-specific system state. VDO is interpreted as a constraint parameter rather than a causal determinant. The findings are exploratory, model dependent, and non causal. They do not establish distinct physiological states, an optimal VDO, clinical thresholds, or diagnostic, predictive, mechanistic, or prescriptive validity.

The systemic, metabolic, lifestyle factors have established associations with Alzheimer's Disease (AD) through epidemiologic and AD-specific biomarker studies. Whether colored fundus photography (CFP) contains retinal structural signatures corresponding to these AD-related risk domains remains unclear. To determine whether deep learning (DL) models can predict 12 AD-related risk factors from CFP and to characterize the retinal structures underlying these predictions, thereby assessing whether CFP reflects pathways to AD vulnerability. Using 62,876 CFPs from 44,501 unique participants from the UK Biobank, DL models were trained to predict 12 factors linked to AD incidence: 6 categorical (sex, smoking, sleeplessness, economic status, alcohol use, depression) and 6 continuous (age, age at completing education, BMI, systolic, diastolic blood pressure, HbA1c). Model performance, model saliency, and saliency-derived scores (CAM-Score) were evaluated and compared to retinal morphometry. The scores were also compared between incident-AD cases (average 8.55 years before onset) and matched controls. Performance of DL ranged from AUROC= 0.5654-0.9480 for categorical and R2=-0.0291-0.7620 for continuous factors, outperforming most of the morphometry-machine learning models. Saliency-based score consistently highlighted biologically meaningful regions, particularly the optic nerve head and retinal vasculature. It also aligned with present morphometric variations. Several saliency-based scores differed significantly between incident AD and matched controls, suggesting potential overlap between retinal correlates of risk factors and preclinical AD-associated changes. CFP encodes retinal signatures linked to AD risk factors. Although not diagnostic, DL-derived retinal representations may uncover biologically meaningful risk-related structural changes mirroring the potential AD vulnerability.

To provide a structured and interpretable assessment, we decompose the image-based diagnosis into components following the Toulmin model of argumentation. This model consists of a claim, grounds, warrant, qualifier, rebuttal, and backing. Consider a claim generated by a machine learning (ML) model for retinal diagnosis. Rather than accepting this claim at face value, one could either apply explainable AI (XAI) methods or adopt an argumentation-based approach. In our framework, a model specialized in biomarker extraction from images provides the grounds. The warrant-linking the grounds to the claim - is analyzed by an agent equipped with medical knowledge; in our architecture, this role is fulfilled by a MedGemma agent. The qualifier is determined based on the overall quantitative evaluation of both the warrant and grounds models. Finally, a rebuttal is constructed using image similarity measures computed with MedSigLip. All these components are presented to the human expert, enabling a more informed and critical assessment of the ML-generated diagnosis.

Learning meaningful representations from medical time series (MedTS) such as ECG or EEG signals is a critical challenge. These signals are often high-dimensional, variable-length and rife with noise. Existing self-supervised approaches, such as Masked Autoencoders (MAEs) are highly effective for pre-training general-purpose encoders. However, they do not explicitly learn compact and semantically interpretable latent representations, typically relying on heuristic aggregation strategies such as global average pooling or a designated [CLS] token. We propose a novel framework that compresses a variable-length MedTS into a fixed-size set of $k$ latent Fingerprint Tokens. Our architecture employs a cross-attention bottleneck to generate these tokens and is trained with a dual-objective function. The first objective is a reconstruction loss, which ensures the tokens are \textit{sufficient statistics} for the original data. The second, a diversity penalty based on the Total Coding Rate (TCR), explicitly minimizes the redundancy between tokens, encouraging them to become statistically \textit{disentangled} representations. We present the theoretical justification for our method, framing it as a novel \textbf{Disentangled Rate-Distortion} problem. This approach produces a low-dimensional, interpretable, and sample-efficient representation, where each token is encouraged to capture an independent factor of variation, paving the way for more robust digital biomarkers.

Digital biomarkers for depression have largely relied on static acoustic descriptors, pooled summary statistics, or conventional machine learning representations. Such approaches may miss nonlinear temporal organization embedded in conversational vocal dynamics. We hypothesized that depression is associated with altered recurrence structure in vocal state trajectories, reflecting changes in how the vocal system revisits acoustic states over time. Using the depression subset of the DAIC-WOZ corpus with 142 labeled participants, we modeled frame-level COVAREP trajectories as nonlinear dynamical systems and derived recurrence-based biomarkers from 74 vocal channels. Logistic regression with feature selection and stratified cross-validation evaluated classification performance. Recurrence-based biomarkers achieved a mean cross-validated AUC of 0.689, exceeding static acoustic baselines, entropy-dynamics features, Hurst exponent features, determinism features, and Lyapunov-like instability proxies. Permutation testing indicated statistical significance with $p=0.004$. Pooled cross-validated predictions yielded AUC 0.665 with a 95% bootstrap confidence interval of [0.568, 0.758]. These findings suggest that depression may be characterized by altered recurrence structure in conversational vocal dynamics and support nonlinear state-space analysis as a promising direction for digital psychiatric biomarkers.

Automated depression detection often relies on static aggregation of conversational signals, potentially obscuring clinically meaningful behavioral dynamics. We investigated whether entropy-driven temporal biomarkers improve depression detection beyond standard pooled features using the DAIC-WOZ corpus. Using 142 labeled participants, we reconstructed utterance-level acoustic trajectories and compared pooled temporal baselines, trajectory dynamics, Shannon entropy biomarkers, recurrence quantification, sample entropy, fractal complexity, and coupling biomarkers under leakage-aware validation. Static pooling achieved an AUC of 0.593, trajectory dynamics improved performance to 0.637, and entropy biomarkers produced the strongest statistically significant improvement over pooled baselines (AUC 0.646; nested cross-validated AUC 0.615; permutation p = 0.017). Entropy biomarkers outperformed recurrence, coupling, sample entropy, and fractalbased features, with several biomarkers stable across folds. These findings suggest depression-related signal may lie less in average acoustic levels than in entropy of conversational dynamics, supporting temporally informed digital phenotypes for mental-health assessment.

Developing robust and clinically reliable EEG biomarkers requires evaluation frameworks that explicitly address cross population generalization in multi site settings such as Parkinsons disease (PD) detection. Models trained under i.i.d. assumptions often capture population specific artifacts rather than disease relevant neural structure, leading to poor generalization across clinical cohorts. EEG further amplifies this challenge due to low signal to noise ratio and heterogeneous acquisition conditions. We propose a population aware evaluation framework to assess the robustness and clinical reliability of EEG biomarkers under distribution shift. Using an n gram expansion strategy, we enumerate all cross population train test configurations across five independent cohorts, resulting in 75 directional evaluations. A nested cross validation design with integrated channel selection ensures prospective biomarker identification without population leakage. Results show that cross population transfer is asymmetric and that both accuracy and biomarker stability improve with increasing training population diversity, achieving up to 94.1% accuracy on held out cohorts. A theoretical analysis based on mixture risk optimization and hypothesis space contraction explains these trends, showing that multi population training promotes population robust representations. This work establishes a principled framework for learning robust, generalizable, and clinically reliable EEG biomarkers for multi site biomedical applications.

Event-Based Models (EBMs) infer biomarker progression from cross-sectional data but typically only as ordinal sequences and rely on rigid model assumptions. We propose \textsc{Tempo}, a Transformer architecture that learns both ordinal and continuous event sequences through simulation-based supervised learning. \textsc{Tempo} uses two Transformer modules: one treats biomarkers as tokens to infer event sequencing; the other treats patients as tokens, representing each by their per-biomarker abnormality profile, to infer patients' disease stages. On synthetic benchmarks, \textsc{Tempo} reduces normalized Kendall's Tau distance by 52.89% and staging MAE by 25.33% compared to state-of-the-art SA-EBM, with larger reductions in high-dimensional settings (58.88% and 61.10%). Applied to ADNI, \textsc{Tempo} recovers a biologically plausible Alzheimer's progression: early medial temporal atrophy, followed by amyloid accumulation and cognitive decline, and late-stage tau pathology with terminal acceleration of global neurodegeneration -- broadly consistent with established disease models. \textsc{Tempo} also eliminates the need to derive custom inference algorithms and enables rapid empirical comparison of generative hypotheses.

Feature selection in high-dimensional genomic data ($d \gg n$) demands methods that are simultaneously accurate, sparse, and stable. Existing approaches either require manual threshold specification (mRMR, stability selection), produce unstable selections under data perturbation (Lasso, Boruta), or ignore biological structure entirely. We introduce StackFeat-RL, a meta-learning framework that optimises the hyperparameters of an iterative dual-criterion feature selection algorithm via REINFORCE policy gradients. The dual criterion, requiring both coefficient consistency and selection frequency, guards against two failure modes missed by single-criterion methods, while iterative accumulation provides convergence guarantees via the law of large numbers. On COVID-19 miRNA data (GSE240888, 332 features) and three Alzheimer's disease classification tasks (GSE84422, 13237 genes; Normal vs.\ Possible, Probable, and Definite AD), StackFeat-RL achieves the highest predictive accuracy among all evaluated methods, including ElasticNet, Boruta, mRMR, and stability selection, while requiring 3--4$\times$ fewer features. Keywords: feature selection, reinforcement learning, REINFORCE, elastic net, biomarker discovery, Alzheimer's disease, dual-criterion selection, protein interaction networks

Several brain foundation models (FM) have recently been proposed to predict brain disorders by modelling dynamic functional connectivity (FC). While they demonstrate remarkable model performance and zero- or few-shot generalization, the salient features identified as potential biomarkers are yet to be thoroughly evaluated. We propose RE-CONFIRM, a framework for evaluating the robustness of potential biomarker candidates elucidated by deep learning (DL) models including FMs. From experiments on five large datasets of Autism Spectrum Disorder (ASD), Attention-deficit Hyperactivity Disorder (ADHD), and Alzheimer's Disease (AD), we found that although commonly used performance metrics provide an intuitive assessment of model predictions, they are insufficient for evaluating the robustness of biomarkers identified by these models. RE-CONFIRM metrics revealed that simply finetuning FMs leads to models that fail to capture regional hubs effectively, even in disorders where hubs are known to be implicated, such as ASD and ADHD. In view of this, we propose Hub-LoRA (Low-Rank Adaptation) as a fine-tuning technique that enables FMs to not only outperform customised DL models but also produce neurobiologically faithful biomarkers supported by meta-analyses. RE-CONFIRM is generalizable and can be easily applied to ascertain the robustness of DL models trained on functional MRI datasets. Code is available at: https://github.com/SCSE-Biomedical-Computing-Group/RE-CONFIRM.

Linear models are widely used in computational neuroimaging to identify biomarkers associated with brain pathologies. However, interpreting the learned weights remains challenging, as they do not always yield clinically meaningful insights. This difficulty arises in part from the inherent correlation between brain regions, which causes linear weights to reflect shared rather than region-specific contributions. In particular, some groups of regions, including homologous structures in the left and right hemispheres, are known to exhibit strong anatomical correlations. In this work, we leverage this prior neuroanatomical knowledge to introduce a whitening approach applied to groups of regions with known shared variance, designed to disentangle overlapping information across correlated brain measures. We additionally propose a regularized variant that allows controlled tuning of the degree of decorrelation. We evaluate this method using region-of-interest features in two psychiatric classification tasks, distinguishing individuals with bipolar disorder or schizophrenia from healthy controls. Importantly, unlike PCA or ICA which use whitening as a dimensionality reduction step, our approach decorrelates anatomically informed pairs of neuroanatomical regions while retaining the full input signal, making it specifically suited for feature interpretation rather than feature selection. Our findings demonstrate that whitening improves the interpretability of model weights while preserving predictive performance, providing a robust framework for linking linear model outputs to neurobiological mechanisms.

The integration of single-cell proteomic data is often hindered by the fragmented nature of targeted antibody panels. To address this limitation, we introduce scpFormer, a transformer-based foundation model designed for single-cell proteomics. Pre-trained on over 390 million cells, scpFormer replaces standard index-based tokenization with a continuous, sequence-anchored approach. By combining Evolutionary Scale Modeling (ESM) with value-aware expression embeddings, it dynamically maps variable panels into a shared semantic space without artificial discretization. We demonstrate that scpFormer generates global cell representations that perform competitively in large-scale batch integration and unsupervised clustering. Moreover, its open-vocabulary architecture facilitates in silico panel expansion, assisting in the reconstruction of biological manifolds in sparse clinical datasets. Finally, this learned protein co-expression logic is transferable to bulk-omics tasks, supporting applications like cancer drug response prediction. scpFormer provides a versatile, panel-agnostic framework to facilitate scalable biomarker discovery and precision oncology.

Modern medicine generates vast multimodal data across siloed systems, yet no existing model integrates the full breadth and temporal depth of the clinical record into a unified patient representation. We introduce Apollo, a multimodal temporal foundation model trained and evaluated on over three decades of longitudinal hospital records from a major US hospital system, composed of 25 billion records from 7.2 million patients, representing 28 distinct medical modalities and 12 major medical specialties. Apollo learns a unified representation space integrating over 100 thousand unique medical events in our clinical vocabulary as well as images and clinical text. This "atlas of medical concepts" forms a computational substrate for modeling entire patient care journeys comprised of sequences of structured and unstructured events, which are compressed by Apollo into virtual patient representations. To assess the potential of these whole-patient representations, we created 322 prognosis and retrieval tasks from a held-out test set of 1.4 million patients. We demonstrate the generalized clinical forecasting potential of Apollo embeddings, including predicting new disease onset risk up to five years in advance (95 tasks), disease progression (78 tasks), treatment response (59 tasks), risk of treatment-related adverse events (17 tasks), and hospital operations endpoints (12 tasks). Using feature attribution techniques, we show that model predictions align with clinically-interpretable multimodal biomarkers. We evaluate semantic similarity search on 61 retrieval tasks, and moreover demonstrate the potential of Apollo as a multimodal medical search engine using text and image queries. Together, these modeling capabilities establish the foundation for computable medicine, where the full context of patient care becomes accessible to computational reasoning.

Quantum machine learning offers a promising new paradigm for computational biology by leveraging quantum mechanical principles to enhance cancer classification, biomarker discovery, and bioinformatics diagnostics. In this study, we apply QML to identify subtype specific biomarkers for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), the two predominant forms of non-small cell lung cancer. Our methodology involves a two-phase process: in Phase 1, differential expression analysis and methylation analysis between tumor and normal samples allows us to identify LUAD-specific and LUSC-specific genes, revealing potential prognostic biomarkers for cancer subtypes. Phase 2 focuses on developing a quantum classifier capable of distinguishing between LUAD and LUSC tumors, as well as between tumor and normal samples. This classifier not only enhances diagnostic precision but also demonstrates the quantum advantage in processing large-scale multiomic datasets. Our results consistently demonstrated that Sample3, representing the combined gene set, achieved the highest overall predictive performance in all metrics. These results demonstrate that QML provides an effective and scalable approach for biomarker discovery and subtype specific cancer classification. GO enrichment analysis highlighted the significant involvement of genes in synaptic signaling, ion channel regulation, and neuronal development. In the quantum phase, KEGG analysis further identified enrichment in cancer-associated pathways, including neurotrophin, MAPK, Ras, and PI3KAkt signaling, with key genes such as NGFR, NTRK2, and NTF3 suggesting a central role in neurotrophinmediated oncogenic processes. Our findings highlight the growing potential of quantum computing to advance precision oncology and next-generation biomedical analytics.

Wearable devices generate continuous physiological and behavioral data, but converting these signals into clinically reviewable biomarker hypotheses remains labor-intensive. We introduce CoDaS, an AI co-data-scientist that integrates multi-agent hypothesis generation, deterministic statistical analysis, adversarial validation and literature-grounded interpretation under human oversight. Across three wearable cohorts comprising 9,279 participant-observations, CoDaS prioritized candidate associations for mental-health and metabolic endpoints after internal checks for replication, stability, robustness and leakage. The system identified related circadian-instability signals associated with depression, including sleep-duration variability in DWB ($ρ$ = 0.252, $p$ < 0.001) and sleep-onset variability in GLOBEM ($ρ$ = 0.126, $p$ < 0.001), and derived a wearable cardiovascular-fitness index associated with insulin resistance (steps/resting heart rate; $ρ$ = -0.374, $p$ < 0.001). Adding these features to demographic models produced modest gains ($ΔR^2$ = 0.040 for depression, 0.021 for insulin resistance). In a 12-clinician review totaling approximately 25 active hours, clinician validity judgments aligned with CoDaS confidence tiers ($ρ$ = 0.67, $p$ = 0.005), whereas added clinical value and confidence to act were rated lower. CoDaS supports traceable, hypothesis-generating prioritization of wearable candidate biomarkers.

Purpose. Athlete monitoring is constrained by small cohorts, heterogeneous biomarker scales, limited feasibility of repeated sampling, and the lack of reliable injury ground truth. These limitations reduce the interpretability and utility of traditional univariate and binary risk models. This study addresses these challenges by proposing an unsupervised multivariate framework to identify latent physiological states in athletes using real data. Methods. We propose a modular computational framework that operates in the joint biomarker space, integrating preprocessing, clinical safety screening, unsupervised clustering, and centroid-based physiological interpretation. Profiles are learned exclusively from amateur soccer players during a competitive microcycle. Synthetic data augmentation evaluates robustness and scalability. Ward hierarchical clustering supports monitoring and etiological differentiation, while Gaussian Mixture Models (GMM) enable structural stability analysis in high-dimensional settings. Results. The framework identifies coherent profiles that distinguish mechanical damage from metabolic stress while preserving homeostatic states. Synthetic data augmentation demonstrates feasibility and detection of latent silent risk phenotypes typically missed by univariate monitoring. Structural analyses indicate robustness under augmentation and higher-dimensional settings. Conclusion. The framework enables interpretable identification of latent physiological states from multivariate biomarker data without injury labels. By distinguishing mechanisms and revealing silent risk patterns not captured by conventional monitoring, it provides actionable insights for individualized athlete monitoring and decision making.

Alzheimer's disease is a progressive neurodegenerative disorder in which mild cognitive impairment (MCI) precedes dementia. Structural MRI provides biomarkers but requires costly infrastructure, limiting population-scale deployment. Speech offers a non-invasive alternative, yet speech-only classifiers are developed independently of neuroimaging and lack biological grounding for CN-versus-MCI classification. We propose MINT (Multimodal Imaging-to-Speech Knowledge Transfer), a three-stage framework that transfers MRI-derived biomarker structure to speech during training. An MRI teacher defines a compact embedding space for CN-versus-MCI classification, while a residual projection head aligns speech representations to this space using a combined geometric loss. The frozen MRI classifier enables imaging-free inference. On ADNI-4, aligned speech achieves performance comparable to speech baselines, while multimodal fusion improves over MRI alone. Ablations identify dropout regularization and self-supervised pretraining as important design choices. To our knowledge, MINT is the first demonstration of MRI-to-speech knowledge transfer for early Alzheimer's screening without imaging at inference.

Automatic extraction of retinal vascular biomarkers from color fundus images (CFI) is crucial for large-scale studies of the retinal vasculature. We present VascX, an open-source Python toolbox that extracts biomarkers from CFI artery-vein segmentations. VascX starts from vessel segmentation masks, extracts their skeletons, builds undirected and directed vessel graphs, and resolves vessel segments into longer vessels. A comprehensive set of biomarkers is derived, including vascular density, central retinal equivalents (CREs), and tortuosity. Spatially localized biomarkers may be calculated over grids placed relative to the fovea and optic disc. VascX is released via GitHub and PyPI with comprehensive documentation and examples. Our test-retest reproducibility analysis on repeat imaging of the same eye by different devices shows that most VascX biomarkers have moderate to excellent agreement (ICC > 0.5), with important differences in the level of robustness of different biomarkers. Our analyses of biomarker sensitivity to image perturbations and heuristic parameter values support these differences and further characterize VascX biomarkers. Ultimately, VascX provides an explainable and easily modifiable feature-extraction toolbox that complements segmentation to produce reliable retinal vascular biomarkers. Our graph-based biomarker computation stages support reproducible, region-aware measurements suited for large-scale clinical and epidemiological research. By enabling easy extraction of existing biomarkers and rapid experimentation with new ones, VascX supports oculomics research. Its robustness and computational efficiency facilitate scalable deployment in large databases, while open-source distribution lowers barriers to adoption for ophthalmic researchers and clinicians.

Feature selection (FS) is essential for biomarker discovery and clinical predictive modeling. Over the past decades, methodological literature on FS has become rich and mature, offering a wide spectrum of algorithmic approaches. However, much of this methodological progress has not fully translated into applied biomedical research. Moreover, challenges inherent in biomedical data, such as high-dimensional feature space, low sample size, multicollinearity, and missing values, make FS non-trivial. To help bridge this gap between methodological development and practical application, we propose ROOFS (RObust biOmarker Feature Selection), a Python package available at https://gitlab.inria.fr/compo/roofs, designed to help researchers in the choice of FS method adapted to their problem. ROOFS benchmarks multiple FS methods on the user's data and generates reports summarizing a comprehensive set of evaluation metrics, including downstream predictive performance estimated using optimism correction, stability, robustness of individual features, and true positive and false positive rates assessed on semi-synthetic data with a simulated outcome. We demonstrate the utility of ROOFS on data from the PIONeeR clinical trial, aimed at identifying predictors of resistance to anti-PD-(L)1 immunotherapy in lung cancer. Of the 34 FS methods gathered in ROOFS, we evaluated 23 in combination with 11 classifiers (253 models) and identified a filter based on the union of Benjamini-Hochberg false discovery rate-adjusted p-values from t-test and logistic regression as the optimal approach, outperforming other methods including widely used LASSO. We conclude that comprehensive benchmarking with ROOFS has the potential to improve the reproducibility of FS discoveries and increase the translational value of clinical models.

Sleep is essential for health, yet studying its dynamics requires manual sleep staging, a labor-intensive step in research and clinical care. Across centers, polysomnography (PSG) recordings are traditionally scored in 30-s epochs for pragmatic, not physiological, reasons and vary in electrode count, montage, and subject characteristics. These constraints challenge harmonized multi-center studies and the discovery of robust biomarkers on shorter timescales. We present AnySleep, a deep neural network that scores sleep from any electroencephalography (EEG) or electrooculography (EOG) data at adjustable temporal resolutions. We trained and validated the model on over 20,000 overnight recordings (> 200,000 hours of EEG and EOG) from 28 datasets across multiple clinics to promote robust generalization across sites. The model attains state-of-the-art performance and surpasses or equals established baselines at 30-s epochs. Performance improves with more channels, yet remains strong when EOG is absent or only EOG or single EEG derivations (frontal, central, or occipital) are available. On sub-30-s timescales, the model captures short wake intrusions consistent with arousals and improves prediction of pathophysiological conditions (obstructive sleep apnea, narcolepsy type 1, insomnia) over 30-s scoring. We make the model publicly available to facilitate large-scale studies with heterogeneous electrode setups and accelerate biomarker discovery in sleep.

Molecular biomarker testing in pathology is often costly and tissue-consuming, limiting scalable clinical deployment. Artificial intelligence applied to hematoxylin and eosin (HE)-stained histology could enable rapid biomarker screening, but clinical translation requires models that are both accurate and interpretable. Here we introduce Hireca, a biomarker-focused pathology foundation model pretrained on more than 80,000 whole-slide images spanning 38 organ types from three medical centers, together with CytoMap, an interpretability module that localizes cellular-scale evidence underlying predictions. Across 10 biomarker tasks encompassing morphological, molecular, genetic, and spatial-transcriptomic-proxy readouts, Hireca ranked first in five tasks and outperformed comparable models overall. In evaluation by eight pathologists from two countries, CytoMap was consistently preferred over alternative visualization approaches and revealed error patterns in difficult cases. These results position Hireca and CytoMap as a transparent framework for clinically reviewable biomarker assessment directly from routine HE histology.

Dementia affects over 55 million people worldwide, projected to reach 139 million by 2050, with Alzheimer's disease (AD) accounting for 60-70% of cases. AD is associated with disruptions in metabolic brain connectivity. Detecting these disruptions early is crucial for AD management. FDG-PET is a useful tool for identifying such impairments. However, most studies rely on group-level analyses or thresholding, potentially masking individual differences and overlooking weaker yet biologically critical brain connections. Moreover, AD prediction largely focuses on univariate rather than multivariate outcomes. To address this, we introduce explainable graph-theoretical machine learning (XGML), a framework for constructing individual metabolic brain graphs and identifying subgraphs most predictive of multivariate disease-related outcomes. Using Alzheimer's Disease Neuroimaging Initiative (ADNI) FDG-PET data, we compared six graph representations against three non-graph baselines, each with six machine learning models using repeated stratified 3-fold cross-validation (10 repeats). The best configuration combined kernel density estimation with Hellinger distance and random forest. Across eight cognitive scores, it reached an overall Fisher-z-averaged Pearson correlation of r=0.595, with strongest performance for ADAS13 (r=0.67), ADAS11 (r=0.65), and ADASQ4 (r=0.62). We identified key edges that were jointly but differentially predictive across outcomes, suggesting their potential as network biomarkers of cognitive decline. Preliminary external feasibility validation on an OASIS3 cohort yielded weak predictive performance for CDRSB (r=0.26) and MMSE (r=0.18), likely reflecting cohort, protocol, and diagnostic differences. Overall, our results suggest the promise of graph-theoretical machine learning for biomarker discovery, disease prediction, and understanding the neural mechanisms underlying AD.

Interpretability is crucial for utilizing machine learning models as clinical decision support tools for medical diagnostics. However, most state-of-the-art image classifiers based on neural networks are not interpretable. As a result, clinicians often resort to known biomarkers to guide diagnosis, although biomarker-based classification often suffers from drastic information loss compared to raw medical images. This work proposes a method that preserves the rich imaging information while simultaneously enhancing the interpretability of predictions for diabetic retinopathy staging from optical coherence tomography angiography (OCTA) images. The core contribution of our method is a novel biology-informed heterogeneous graph representation that models retinal vessel segments, intercapillary areas, and the foveal avascular zone (FAZ) in a human-interpretable way. This graph representation allows us to frame diabetic retinopathy staging as a graph-level classification task, which we solve using an established, efficient graph neural network architecture. We compare our method against established methods, including classical biomarker-based classifiers, convolutional neural networks (CNNs), and vision transformers in predicting the clinically assigned DR stage based on color fundus photography images. We find stage agreement rates of our method and alternative vision model based classifiers saturating at AUC-ROC values of 84%. Crucially, we use our biology-informed graph to provide explanations of great detail. Our approach surpasses existing methods in precisely localizing and identifying abnormal vessels and non-perfusion areas. Our approach sets the stage for the interpretable identification of patients who require special attention due to their traceable microvascular changes, only observable using the details of OCTA images.

BrainAGE is a promising imaging-derived biomarker of neurobiological ageing and disease risk, yet current approaches rely predominantly on T1-weighted structural MRI, overlooking functional vascular changes that may precede tissue damage and cognitive decline. DeepCBV maps, synthesized from non-contrast MRI, offer a scalable alternative to contrast-enhanced perfusion imaging by capturing vascular information relevant to early neurodegeneration. We developed a multimodal BrainAGE framework that combines predictions from two separate three-dimensional convolutional neural networks: one trained only on structural MRI scans and another trained only on DeepCBV maps. Each model was trained and validated on 2851 scans from 13 open-source datasets and was evaluated for concordance with MCI and AD. The combined model achieved the most accurate brain age gap for CN controls, with a mean absolute error of 3.95 years, outperforming models trained on MRI or DeepCBV alone. Saliency maps revealed complementary modality contributions: MRI emphasized white matter and cortical atrophy, while DeepCBV highlighted vascular-rich and periventricular regions implicated in hypoperfusion and early cerebrovascular dysfunction, consistent with known patterns of normal ageing. Next, we observed that BrainAGE increased stepwise across diagnostic strata (CN < MCI < AD) and correlated with cognitive impairment. DeepCBV-based BrainAGE showed a particularly strong separation between stable versus progressive MCI, suggesting sensitivity to prodromal vascular changes that precede overt atrophy. Integrating structural MRI with deep learning-derived vascular measures substantially enhances BrainAGE estimation and improves sensitivity to MCI and AD progression, supporting its potential role in risk stratification, early detection and monitoring of therapeutic response.

As global life expectancy increases, so does the burden of chronic diseases, yet individuals exhibit considerable variability in the rate at which they age. Identifying biomarkers that distinguish fast from slow ageing is crucial for understanding the biology of ageing, enabling early disease detection, and improving prevention strategies. Using contrastive deep learning, we show that skin biopsy images alone are sufficient to determine an individual's age. We then use visual features in histopathology slides of the skin biopsies to construct a novel biomarker of ageing. By linking with comprehensive health registers in Denmark, we demonstrate that visual features in histopathology slides of skin biopsies predict mortality and the prevalence of chronic age-related diseases. Our work highlights how routinely collected health data can provide additional value when used together with deep learning, by creating a new biomarker for ageing which can be actively used to determine mortality over time.

Brownian motion is a compact mathematical language for continuous-time uncertainty in biostatistics. This tutorial develops the process from construction and path properties to tools that recur in applied biomedical work: the Markov and strong Markov properties, the Karhunen-Loeve expansion, functional principal component analysis (Functional PCA), reflection principles, local time, stochastic differential equations (SDEs), Brownian bridges, and empirical-process limits. The applications emphasize longitudinal biomarkers, degradation modelling, first-passage endpoints, dynamic frailty, group-sequential monitoring, calibration diagnostics, recurrent-event processes, electronic health records, and wearable streams. A short cross-domain section uses literary and historical archives to make Brownian-bridge thinking concrete without shifting the paper away from biostatistics, and includes a reproducible chapter-level experiment on Frankenstein. The Black-Merton-Scholes model is included as a solved SDE template, not as a finance application in its own right. The aim is to connect rigorous probability with modelling decisions faced by biostatisticians when biological processes evolve between noisy observation times.

Quantitative assessment of muscle MRI is crucial for monitoring neuromuscular disorders (NMD). This study introduces an automated radiomic phenotyping framework based on original features engineered across five main architectural domains: quantitative morphometry, spatial distribution, geometric shape, interactions between progressive fat replacement stages, and graph-based topology. Utilizing 1184 MRI scans from the CoMPaSS-NMD project, we map the complex 3D architecture of heterogeneous intramuscular lipodegeneration into objective, morphologically interpretable biomarkers. We introduce a graph-based skeletonization of fat infiltrates to quantify muscle architectural changes, establishing a multi-dimensional extension of traditional, spatially-agnostic volume metrics by mapping topological networks across the entire 3D muscle volume. Statistical screening via non-parametric Kruskal-Wallis analysis confirmed the discriminative power of these novel descriptors across the genetic hierarchy. Notably, topological network metrics (e.g., SF1_Skel_Nodes, $\epsilon^2$ = 0.2656) and interface dynamics metrics (e.g., SF2_To_SF1_Dist_Min, $\epsilon^2$ = 0.2092) demonstrated substantial effect sizes, providing deeper structural insights than classical volumetric assessments. Post-hoc pairwise evaluations and UMAP projections further indicated the capability of these topological and 3D geometric invariants to capture disease-specific macroscopic infiltration patterns. These results demonstrate that global architectural features represent a highly promising class of biomarkers for differential diagnosis, offering new avenues for tracking longitudinal disease dynamics in neuromuscular diagnostics. The developed automated feature extraction pipeline is integrated and available within the MUSCAT (MUSCle fAt Topology) library.