Multi-Omic Framework

Multi-omics sequences contain complex biological patterns, yet deciphering their mechanisms for automated scientific discovery remains challenging. As large language models (LLMs) interpret these sequences, evaluating both predictions and scientific reasoning is critical. However, existing benchmarks for multi-omics sequence tasks rely on classification and regression metrics, neglecting whether models grasp the underlying biological evidence. We introduce OmicsBench, the first reasoning benchmark for multi-omics sequences, comprising 1,160 expert-validated questions across six tasks spanning DNA regulation, RNA processing, and protein function. OmicsBench requires traceable evidence chains, evaluated using instance-specific rubrics developed with domain experts. Evaluating 17 LLMs reveals an inverse relationship: while scientific LLMs outperform general-purpose LLMs in sequence classification accuracy, they fail to provide valid evidence to support their predictions. One plausible interpretation is shortcut learning: specialized models may rely on statistical patterns rather than the biological mechanisms needed for scientific discovery. Motivated by this finding, we introduce tool-augmented on-policy distillation (TA-OPD), a post-training method to align sequence prediction with evidence-grounded biological reasoning. Across five Qwen3.5 models spanning 0.8B to 27B parameters, TA-OPD consistently strengthens biological evidence grounding while improving predictive performance on most tasks. These gains persist across model scales, indicating that stronger sequence reasoning does not arise solely from increased model capacity, but can be improved through evidence-aware training. Together, OmicsBench and TA-OPD provide a framework for diagnosing reasoning failures in multi-omics LLMs and a path toward models whose predictions are better grounded in biologically meaningful evidence.

Federated learning enables collaborative training without sharing patient-level data, but most studies remain simulations. Based on five requirements derived from the literature, we analyzed 14 FL frameworks and found that none fully satisfied these requirements. We present FL-Net, a novel federated clinical research framework to fulfill all requirements. It integrates modular data harmonization, data discovery, disclosure control, securely built versioned FL-Net-Tools and containerized federated workflow execution into a persistent network. It enables the re-use of harmonized data and workflows across studies. FL-Net's end-to-end capabilities were evaluated through harmonization, cross-study patient discovery across MIMIC and US-130, and reproducible, audited federated workflows with up to 50 concurrent clients. FL-Net is being developed within the dAIbetes and Microb-AI-ome EU projects and will cover over 800,000 patients across 10 hospitals in 9 countries covering longitudinal and single point in time data, FL-Net provides a practical foundation for interoperable, reproducible, and privacy-preserving multicenter clinical research.

Drug response prediction (DRP) models are an active area of research in pharmacogenomics, with growing potential to accelerate the identification of effective anticancer drugs. However, their predictive performance is often constrained by limited dataset scale and insufficient coverages of cancer and chemical spaces. In addition, inconsistent benchmarking practices hinder reliable comparison across models. Standardized frameworks, such as the Innovative Methodologies and New Data for Predictive Oncology Model Evaluation (IMPROVE) project, provide unified data schemas and evaluation protocols for consistent benchmarking, but improving model generalizability requires larger and more diverse training data. In this work, we substantially expand the IMPROVE benchmark through large-scale integration of pharmacogenomic data, primarily from PharmacoDB, together with additional smaller data sources. The expanded resource includes millions of drug response measurements, broader multi-omics coverage, and a major increase in chemical diversity, adding more than 50,000 compounds. To evaluate the impact of the new dataset compared to the original IMPROVE benchmark dataset, we trained DRP models using the two datasets and assess their prediction performance using a common test set and several evaluation strategies, including drug-blind, cancer-blind, and disjoint data splits. While cancer-blind performance remained comparable to the original benchmark, models trained on the expanded dataset showed consistent improvements in drug-blind and disjoint settings, indicating enhanced generalization to previously unseen compounds. These results position the expanded dataset as a community resource that provides a richer foundation for developing DRP models intended to aid in the discovery of novel anticancer drugs.

Spatial transcriptomics can resolve gene expression at single-cell resolution, but it is costly, limited to targeted panels of a few hundred to a few thousand genes, and applicable to only a small number of samples. H&E imaging, by contrast, is cheap and collected routinely at scale. This makes predicting single-cell expression directly from morphology a practical way to bring molecular analysis to large tissue archives. We therefore present VOICE, a multimodal foundation model that predicts single-cell gene expression from H&E images using paired Xenium data. VOICE first aligns cell centered H&E morphology from a pathology foundation model with single-cell expression embeddings from a transcriptome foundation model, trained using contrastive learning over 23 million cells. Next it predicts expression through two branches. One branch directly regresses expression from morphology. The other branch retrieves measured expression from similar reference cells, recovering genes that do not have morphological signal. Because genes vary in morphological predictability, VOICE fuses the two branches with a per-gene weight. After training, VOICE generalizes to heldout patients, slides, and partially overlapping gene panels from Xenium, and it consistently outperforms prior single-cell expression prediction methods on seven metrics.

Attention mechanisms have been widely utilized in modern deep learning, and many existing multi-omics models inherit their conventional use to allow unrestricted bidirectional interactions. However, the fundamental logic of life is directional. Existing designs often overlook the directionality suggested by the central dogma, potentially limiting transfer across heterogeneous cancers, downstream tasks, and incomplete modality settings. In this work, we present DoGMA, a central-dogma-guided foundation model for pan-cancer multi-omics analysis, arguing that robust transfer requires representations with domain-specific inductive bias. Concretely, we build it on a Transformer-MoE architecture where directed attention biases inter-omics communication toward central-dogma information flow. We further pretrain our model with masked hierarchical omics reconstruction to guide it toward learning central-dogma-consistent interactions. Across diverse downstream tasks, including cancer representation learning, survival prediction, and metastasis prediction, DoGMA consistently demonstrates strong predictive performance. Ablations and analyses further suggest that the performance gains arise from the synergy between central-dogma-guided directed attention and reconstruction-based pretraining, which together promote more biologically consistent cross-omics information exchange. Overall, DoGMA demonstrates that domain-specific inductive biases can improve the robustness and transferability of multi-omics foundation models, offering new insights into the design of attention mechanisms for multi-omics representation learning.

Transformer models for high-dimensional omics analysis process thousands of genes or pathways, although only a subset requires deep computation. Mixture-of-Recursions (MoR) improves efficiency through adaptive token-choice or expert-choice routing. We propose bioMoR, which, to the best of our knowledge, is the first framework to apply MoR to gene-level and pathway-level learning. Our contributions include identifying three locations for integrating structured biological knowledge within an MoR backbone: graph-based information sharing refines token embeddings, a structural bias guides self-attention toward biologically related tokens, and a graph-aware router uses neighborhood information to determine each token's recursion depth. These techniques are centered on our insight that additional knowledge of token interaction can effectively help models construct embeddings and select which tokens should be learned more deeply. Across eight benchmarks spanning diverse omics data types and evaluated under a unified five-fold cross-validation protocol, bioMoR improves average macro-F1 by 8.2 percentage points and balanced accuracy by 7.1 percentage points over the strongest biology-agnostic MoR baseline while using 75 percent fewer parameters and up to 58 percent fewer FLOPs than a non-recursive Transformer. The selected marker genes or pathways provide biological interpretability, while their token-specific recursion depths reveal how computation is allocated.

Multimodal learning is a robust approach to improve predictive performance in applications such as medical prognosis. However, the clinical applicability of models that use multimodal learning is hampered by their poor performance under noisy or uninformative data streams. Present fusion approaches often lack robust mechanisms for the dynamic assessment of data quality and for the provision of a trustable confidence score on the final prediction. This dissuades their deployment in safety-critical settings. To address these limitations, we introduce Adaptive Confidence-weighted Expansion (ACE), a novel framework to enhance the trustworthiness of multimodal fusion models. ACE first enhances the multimodal space by generating new, complementary modalities from intra-modality correlations. It then employs a dual-level confidence mechanism that (1) adaptively reweighs all modalities by their reliability before fusion and (2) estimates a global trust score over the fused, final decision. To evaluate ACE, we used four challenging multi-omics datasets (BRCA, KIPAN, LGG, and ROSMAP). ACE significantly outperforms existing state-of-the-art algorithms in both classification performance and confidence calibration. Our framework provides a more stable and robust data fusion method that facilitates the use of multimodal learning in addressing high-stakes problems.

Spatially resolved omics studies increasingly combine transcriptomic and epigenomic assays, yet downstream analysis is often still performed using single-modality pipelines. We present LATTICE (Latent Alignment of Tissue-level and Transcriptomic Information for Cross-modal Embedding), a graph-based self-supervised framework that learns spot-level representations from harmonized multimodal features. LATTICE integrates five aligned modality blocks per Visium spot: Visium RNA, scMultiome RNA, scMultiome ATAC, spatial ATAC, and spatial CUT&Tag. These modalities capture spatial transcriptomic measurements, single-cell inferred regulatory activity, and in situ chromatin and histone states within a unified lattice representation. LATTICE constructs a spatial neighborhood graph and trains a TransformerConv encoder using masked reconstruction, cross-modal alignment, and spatial smoothness objectives. On a private 11-sample melanoma cohort from an anonymized clinical collaborator comprising 54{,}912 total spots, LATTICE demonstrated stable optimization behavior, reproducible embeddings across analysis seeds, and complete multimodal integration across all samples. Adding scMultiome RNA to Visium RNA alone substantially improved concordance with Space Ranger clusters across 11 runs (adjusted Rand index [ARI] +0.157, normalized mutual information [NMI] +0.143, and spatial contiguity +0.174). Additional modalities further improved spatial contiguity and multimodal utility score (MUS), although they sometimes reduced agreement with RNA-derived reference labels, likely because the learned embeddings captured chromatin and regulatory structure beyond transcriptomic similarity alone. These results position LATTICE as a practical and empirically grounded framework for multimodal spatial omics integration, while also highlighting the need for stronger supervision and broader external benchmarking.

Integrating complex, multi-omics data presents significant challenges. Existing approaches often face a trade-off between model interpretability and representational capacity, with most either relying on post-hoc interpretation or use linear models that may overlook complex interactions. We report Pathway Activity Autoencoders for the multi-omics setting, which embed prior knowledge via pathway-informed architectural constraints, fostering interpretability, while preserving representational power. Our multi-omic framework is applied in the context of breast cancer and is evaluated in survival prediction and subtype classification with results indicating a positive effect of integration. We conduct analysis of individual omics layer impact on end-task performance, revealing that gene, protein, and microRNA expression layers provide the strongest contribution. Repeatability studies indicate that, while dropout improves model robustness and consistency, excessive regularisation can reduce predictive performance. Finally, visualizations of the learned feature space illustrate the framework's intrinsic transparency and clinical relevance. The results underscore the value of multi-omic integration and delineate the impact of individual omics layers, establishing practical guidelines for integration within our framework. Overall, our pathway activity autoencoder frameworks yield superior latent representations that are biologically meaningful and are directly translatable into clinically relevant insights.

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.

Matched multi-omics can improve WSI-based biomarker and prognosis prediction, but most existing pipelines use omics as a paral lel feature stream or textual context rather than as an explicit retrieval constraint. HERO asks whether observed omics can be a testable mor phology hypothesis: a sparse pathway-to-morphology prior maps DNA methylation and miRNA into a K-dimensional intent vector m (K=16), TF-IDF retrieval over structured 10 captions selects endpoint-relevant regions, and a cosine gate c=cos(m,v) triggers deterministic deficit driven repair when c<τc. This closed-loop design bounds VLM calls, reduces reliance on embedding-based semantic matching, and makes every retrieval and verification step lexically auditable. On TCGA-BRCA (930WSIs, patient-level 5-fold CV), HERO sets new state-of-the-art across ER, PR, HER2, subtype, and risk prediction, outperforming both multimodal fusion and VLM-based baselines.

Foundation models (FMs) have emerged as powerful representation extractors for medical data, yet their generalizability to datasets under distribution shift remains underexplored. This work systematically evaluates FM-based representations on a suite of computational pathology tasks across two real-world commercial cohorts, IH-BC and IH-NSCLC, drawn from the licensed in-house (IH) oncology dataset. The analysis focuses on two modalities, whole-slide images and transcriptomic profiles, drawn from the IH multimodal data. We first benchmark unimodal probing performance across five FMs on eight downstream classification tasks, and find that image and omics representations carry complementary predictive signals. Then we investigate whether multimodal fusion can yield additional gains over unimodal baselines by comparing three image-omics fusion strategies built on paired representations. The trustworthiness of selected unimodal and multimodal pipelines is further assessed through conformal prediction. Our results show that FM representations achieve competitive performance on out-of-distribution data and that multimodal fusion helps mainly when no single modality dominates the signal. Conformal prediction reveals that in the majority of cases where a point prediction fails, the true diagnosis remains recoverable within the prediction set, reinforcing the value of uncertainty-aware inference for clinical support.

Health digital twins (HDTs) promise patient-specific modeling and decision support but current approaches remain structurally fragmented: monolithic models that address a single organ or task lack cross-scale fidelity, while system-level twins lack generalizable architectural frameworks. We propose OmniBioTwin, a System-of-Twinned-Systems (SoTS) framework that organizes HDTs as modular computational entities coupled through explicit interaction operators within a multi-layer network architecture. The framework comprises seven coordinated layers - spanning data integration, autonomous twin modeling, cross-scale coupling, temporal synchronization, and human-in-the-loop decision support. We demonstrate OmniBioTwin by instantiating a multiscale twin for glucagon-like peptide-1 (GLP-1) signaling pathways in Alzheimer's disease, illustrating how molecular, cellular, and organ-level twins can be composed and coupled within a unified system.

The rapid advancement of high-throughput sequencing has led to large, high-dimensional omics datasets. Deep unsupervised learning architectures, particularly Autoencoders (AEs), are increasingly used for dimensionality reduction and representation learning in this domain. However, AEs are highly sensitive to architectural choices and hyperparameters, and unsupervised optimization typically relies on reconstruction loss, which may be a poor proxy for downstream utility. Exhaustive hyperparameter optimization (HPO) is computationally expensive, leading researchers to frequently rely on suboptimal default configurations. To democratize access to large-scale unsupervised HPO research, we introduce $\textbf{BBOmix}$, the first open-source tabular benchmark for unsupervised representation learning on real-world biological data. Our benchmark includes 105,000 evaluations across four AE architectures and seven multi-omics modalities from the TCGA and SCHC datasets. We quantify the correlation between reconstruction loss and downstream task performance and provide an extensive evaluation of state-of-the-art single-fidelity, multi-fidelity, and transfer learning HPO methods, establishing a rigorous baseline for future research in unsupervised biological representation learning.

Multi-omics data provide complementary molecular characterizations of disease phenotypes and play an important role in disease diagnosis and subtype classification in precision medicine. However, acquiring complete multi-omics profiles is expensive and time-consuming, while most existing deep learning methods assume full modality availability during inference, resulting in substantial redundancy and limited practicality in clinical settings. To address this issue, we propose SDM-Q, a reinforcement learning framework for adaptive and cost-aware multi-omics classification. Specifically, multi-omics diagnosis is reformulated as a finite-horizon sequential decision problem, where the currently acquired omics modalities define the diagnostic state at each stage. An action--value function determines whether to acquire an additional modality or terminate the decision process and output the final prediction. To balance diagnostic utility and acquisition cost, the reward is defined only at the terminal stage and jointly determined by classification correctness and cumulative modality acquisition cost. A backward stage-wise optimization strategy is introduced to improve policy consistency and training stability. Experiments on four public multi-omics datasets, including ROSMAP, LGG, BRCA, and KIPAN, demonstrate that SDM-Q effectively reduces redundant modality acquisition while maintaining competitive classification performance compared with methods using complete multi-omics inputs. In the BRCA and KIPAN datasets, more than 99% and 95% of subjects, respectively, achieve accurate classification using only a single omics modality, while the average number of acquired modalities remains below two for ROSMAP and LGG. These results suggest that cost-aware sequential decision-making provides an effective paradigm for improving the efficiency of precision medicine workflows.

Non-contrast computed tomography calcium scoring (CTCS) is widely recognized as an effective tool for cardiovascular risk stratification. This study aimed to develop a novel machine learning framework for predicting myocardial ischemia from routine non-contrast CTCS scans using quantitative coronary calcium assessment. This study analyzed 1,375 patients who underwent both non-contrast CTCS and regadenoson stress cardiac positron emission tomography myocardial perfusion imaging within one year at University Hospitals Cleveland Medical Center. A total of 74 variables, including clinical variables, Agatston score, and calcium-omics features, were evaluated. Relevant features were identified using XGBoost with Shapley Additive exPlanations (SHAP). Predictive models were trained and evaluated using 5-fold cross-validation. Among 987 patients, 89 (9%) were positive for myocardial ischemia. The final model incorporated the Agatston score, eight calcium-omics features, and age. The proposed model achieved a precision of 98.9+/-3.0%, sensitivity of 79.2+/-8.4, and F1 score of 87.7+/-5.3%. The addition of calcium-omics features significantly improved predictive performance compared with models using clinical variables alone or clinical variables with the Agatston score (p<0.05). Interestingly, the number of calcified arteries, despite being the lowest-ranked feature based on SHAP analysis, showed the strongest association with myocardial ischemia in logistic regression analysis (odds ratio: 3.63, 95% confidence interval: 2.80-4.77, p<0.00001). We developed a machine learning approach for predicting myocardial ischemia using routinely acquired non-contrast CTCS scans. Calcium-omics features provided incremental predictive value beyond conventional risk factors and Agatston scoring and may support more accessible cardiovascular risk stratification.

Graph Neural Networks (GNNs) have become the dominant framework for inductive graph-level learning. Yet most benchmarks focus on the regime $n \gg p$, where the number of graphs $n$ greatly exceeds the number of nodes per graph $p$. This overlooks biological domains such as omics, which operate in the opposite $n \ll p$ regime, characterized by large graphs of genes, transcripts, or proteins across few patient samples. This raises the question: \textit{how do GNNs perform in this low-sample, high-node omics setting?} We introduce \texttt{OgBench} (Omics-Graph Bench), the first benchmarking platform for graph-level prediction in the $n \ll p$ regime characteristic of omics data. We provide a standardized, end-to-end modular infrastructure from raw omics data to families of featured graphs with varied structural properties. We benchmark classical GNNs, as well as GNNs designed for large graphs and omics applications, alongside MLPs and machine learning baselines to establish reference performances. Our results show that widely used GNNs often do not outperform simple MLPs and classical baselines. These findings challenge the prevailing assumption that graph structure inherently adds value in this domain, fostering a critical reassessment of current learning paradigms. Ultimately, by exposing these limitations, OgBench provides the open-source ecosystem necessary for the community to develop and validate novel architectures explicitly tailored for biological graphs. The code is available at https://github.com/geometric-intelligence/ogbench.

Inferring spatially resolved gene expression from histology images offers a cost-effective complement to spatial transcriptomics (ST). However, existing methods reduce this task to a simple morphology-to-expression mapping, where visual similarity does not guarantee molecular consistency. Meanwhile, single-cell data has amassed rich resources far surpassing the scale of ST data, yet it remains underexplored in vision-omics modeling. Furthermore, current approaches commit to a monolithic paradigm with bottlenecks, unable to balance expressive flexibility with biological fidelity. To bridge these gaps, we propose DUET, a novel dual-paradigm framework that synergizes parametric prediction and memory-based retrieval under cellular inductive priors. DUET implements a parallel regression-retrieval paradigm, adaptively reconciling the outputs of its complementary pathways. To mitigate aleatoric vision ambiguity, we incorporate large-scale single-cell references to impose molecular states as biological constraints for faithful learning. Building upon structural refinement, we further design a lightweight adapter to dynamically assign branch preference across spatial contexts to achieve optimal performance. Extensive experiments on three public datasets across varied gene scales demonstrate that DUET achieves SOTA performance, with consistent gains contributed by each proposed component. Code is available at https://github.com/Junchao-Zhu/DUET

Cancer is one of the leading causes of death worldwide, making the development of rapid, minimally invasive, label-free and scalable diagnostic strategies a major challenge in modern oncology. In this context, spectroscopic liquid biopsy has emerged as a promising alternative, as it enables the holistic characterization of biochemical alterations in biological fluids. In this work, we propose a multimodal spectroscopic liquid biopsy framework for multicancer detection based on the combination of Fourier Transform Infrared (FTIR) spectroscopy, Raman spectroscopy, and Excitation-Emission Matrix (EEM) fluorescence spectroscopy together with Machine Learning (ML) methodologies. Serum samples from breast cancer patients, colorectal cancer patients, and healthy controls were analyzed through the three spectroscopic modalities. After modality-specific preprocessing, low-level data fusion (LLDF) was employed to integrate the complementary biochemical information encoded within the different spectroscopic measurements, and classification was performed using XGBoost models. Seven experimental configurations were evaluated, including the three unimodal approaches, all pairwise bimodal configurations, and the full multimodal approach of FTIR, Raman, and EEM fluorescence. The results show that although several individual modalities achieved high discrimination performance, the multimodal fusion provided the most balanced overall results, reaching a ROC-AUC of 0.997 for breast cancer and 0.994 for colorectal cancer, together with highly balanced sensitivity and specificity values.

Multiple technologies that measure expression levels of protein mixtures in the human body offer a potential for detection and understanding the disease. The recent increase of these technologies prompts researchers to evaluate the individual and combined utility of data generated by the technologies. In this work, we study two data sources to measure the expression of protein mixtures in the human body: whole-sample MS profiling and multiplexed protein arrays. We investigate the individual and combined utility of these technologies by learning and testing a variety of classification models on the data from a pancreatic cancer study. We show that for the combination of these two (heterogeneous) datasets, classification models that work well on one of them individually fail on the combination of the two datasets. We study and propose a class of model fusion methods that acknowledge the differences and try to reap most of the benefits from their combination.

Interpreting transcriptomic data is one of the most common analytical tasks in modern biology. Yet most current models either consume expression profiles without producing natural-language biological explanations, or reason in language without direct access to quantitative omics measurements. We introduce OmicsLM, a multimodal LLM that connects quantitative omics profiles with natural-language biological tasks. OmicsLM represents each transcriptomic profile as a compact continuous representation within the LLM context. This interface preserves quantitative expression signal while allowing natural-language instructions, explicit gene mentions, and multiple interleaved biological samples to be processed together in one model context. We train OmicsLM on more than 5.5 million instruction-following examples spanning over 70 task types, combining continuous transcriptomic inputs, experimental data rendered through diverse language templates, and free-text biological knowledge and question-answering data. This mixture covers cell type annotation, perturbation prediction, clinical prediction, pathway reasoning, and open-ended biological question answering. Existing benchmarks evaluate either profile-level prediction or text-only biological QA, leaving language-guided, multi-sample reasoning over real expression profiles unmeasured. To close this gap, we introduce GEO-OmicsQA, a benchmark for multi-sample biological question answering built from real Gene Expression Omnibus (GEO) studies. We demonstrate that OmicsLM can use expression profiles directly and perform comparably to specialized omics models on profile-level tasks, while outperforming both omics-specialized models and general LLMs on language-guided biological reasoning over expression data.

Translational medicine turns underspecified development goals into evidence synthesis that must combine literature, trials, patents, and quantitative multi-omics analysis while preserving identifiers, uncertainty, and retrievable provenance. General-purpose foundation models and off-the-shelf tool-augmented or multi-agent systems are not built for this: they tend to produce single-shot answers or run open-endedly, and fall short on the auditable, scenario-specific workflows that heterogeneous biomedical sources demand. This paper introduces Ingenix BioResearcher, a scenario-guided multi-agent system that maps queries to versioned research playbooks, delegates to specialized subagents over 30+ tools and machine-learning endpoints, mixes structured database access with sandboxed code for genome-scale analyses, and applies claim-level multi-model reconciliation before editorial assembly. We evaluate BioResearcher across unit-level capabilities, open-ended biomedical reasoning, and end-to-end clinical discovery. It leads evaluated baselines on 109 single-step tests (83.49% pass rate; 0.892 average score), achieves strong biomedical benchmark performance (89.33% on BixBench-Verified-50 and the top 0.758 mean score on BaisBench Scientific Discovery), and leads on a 30-query clinical end-to-end benchmark with the highest positive hit rate (74.7% $\pm$ 3.3%) and negative clear rate (96.8% $\pm$ 0.2%). These results show broad, competitive performance across unit-level, open-ended, and end-to-end clinical evaluations.

In this work, we introduce CellxPert, a scalable multimodal foundation model that unifies single-cell and spatial multi-omics within a common representation space. CellxPert jointly encodes transcriptomic (scRNA-seq), chromatin-accessibility (ATAC-seq), and surface-proteomic (CITE-seq) measurements, while directly incorporating MERFISH and imaging mass-cytometry data as 2D or 3D spatial-visual layers. CellxPert facilitates four key downstream tasks out of the box: (i) cell-type annotation across a broad ontology of 154 largely overlapping identities -- the largest label space addressed to date and a stringent test of fine-grained discrimination, (ii) efficient fine-tuning using Low Rank Adaptation (LoRA), (iii) genome-wide transcriptomic response prediction to in-silico perturbations (ISP), and (iv) seamless multi-omic integration across various assays and platforms. Unlike current single-cell foundation models, which approximate gene perturbations by deleting or reordering tokenized gene expression ranks, CellxPert employs a Metropolis-Hastings sampler whose proposal kernel uses the model's masked conditional distributions to transition to new transcriptomic states conditioned on the perturbed genes. This Markov-chain procedure mitigates out-of-distribution artifacts introduced by abrupt token manipulation and produces trajectories that are biologically interpretable. Evaluations on PBMC68K, Replogle Perturb-seq, Systema, and BMMC benchmarks show that CellxPert surpasses classical and state-of-the-art baselines in cell-type annotation, perturbation response prediction, and multi-omic integration.

Motivation: Multi-omics integration can improve cancer subtyping, but modality informativeness and noise vary across cancer types and patients. Existing graph-based methods optimize modality weights jointly with the classification objective and therefore lack independent reliability estimates, so low-quality omics distort patient similarity graphs and amplify noise through message passing. Results: We propose CMGL, a two-stage framework that estimates per-sample modality reliability through evidential deep learning and uses the frozen confidence scores to guide cross-omics fusion and graph construction. On four MLOmics cancer-subtype tasks and the 32-class pan-cancer task, CMGL consistently improves over the strongest baseline, surpassing it by 4.03% in average accuracy on the four single-cancer tasks. Its representations recover the PAM50 intrinsic subtypes of breast invasive carcinoma (BRCA), and the BRCA-trained model transfers without fine-tuning to kidney renal clear cell carcinoma (KIRC), stratifying patients into prognostically distinct groups.

Liver cirrhosis is a major global health problem causing millions of deaths annually, and timely detection with aggressive treatment can significantly improve patients' quality of life. Modelling complex diseases from biomedical data is computationally challenging due to high dimensionality, strong feature correlations, noise, and limited labelled samples. Conventional Machine Learning (ML) pipelines often struggle with robustness, interpretability, and generalisation under such conditions. In this study, we propose an ML-driven multi-stage decision framework for complex disease modelling and therapeutic exploration. The framework integrates single-cell transcriptomic profiling, high-dimensional network-based feature stabilisation, multi-model learning, deep representation construction, and post-hoc decision support. Specifically, single-cell sequencing data were analysed to identify key cellular subpopulations, followed by high-dimensional weighted gene co-expression network analysis (hdWGCNA) to stabilise gene modules under sparsity and noise. To enhance non-linear feature interaction modelling, tabular molecular features were restructured into two-dimensional disease maps and analysed using a CNN. Finally, molecular docking was incorporated as a decision-support module to evaluate candidate therapeutic compounds. Using liver cirrhosis as a representative case, the framework identified a disease-associated endothelial subpopulation and extracted seven robust signature genes (HSPB1, GADD45A, CLDN5, ATP1B3, C1QBP, ENPP2, and PARL). The CNN-based representation learning module outperformed conventional pipelines in classification. The framework is disease-agnostic and readily extends to other omics-driven biomedical applications involving uncertainty, heterogeneity, and limited samples.

Accurate prediction of cancer progression remains a challenge due to the high heterogeneity of molecular omics data across patients. While biologically informed models have improved the interpretability of these predictions, a persistent limitation lies in how they encode individual genes to construct pathway representations. Existing hierarchical models typically derive gene features by directly mapping raw molecular inputs, whereas integration frameworks often rely on simple statistical aggregations of patient-level signals. These approaches often fail to explicitly learn a shared base representation for each gene, thereby limiting the expressiveness and biological accuracy of downstream pathway embeddings. To address this, we introduce PATH, a modulation-based, patient-conditioned gene embedding strategy. PATH represents a paradigm shift by starting from a shared base embedding for each gene, preserving a stable biological identity across the population, and then dynamically adapting it using patient-specific copy number variation (CNV) and mutation signals. This allows the model to capture subtle individual molecular variations while maintaining a consistent latent understanding of the gene itself. We integrate PATH into a graph transformer framework that models interactions among biologically connected pathways through pathway-guided attention. Across pancancer metastasis prediction, PATH achieves an F1 score of 0.8766, representing an 8.8 percent improvement over the current SOTA multi-omics benchmarks. Beyond superior predictive accuracy, our approach identifies biologically meaningful pathways and, crucially, reveals disease-state-specific pathway rewiring, offering new insights into the evolving pathway-pathway interactions that drive cancer progression.

Discrepancies between clinical diagnoses and omics profiles within a characterized cohort may reflect misdiagnosis, hidden subgroups or prodromal disease states. We propose MLASDO, a tool to detect and characterize such discrepancies before downstream analyses. MLASDO (1) detects outliers using two unsupervised methods, thereby flagging potential poor-quality samples; and (2) identifies and characterizes anomalous samples (ASs), i.e., individuals whose molecular profile resembles the opposite clinical class. We applied MLASDO to the Parkinson's Progression Markers Initiative (PPMI) and Parkinson's Disease Biomarkers Program (PDBP) Parkinson's disease (PD) cohorts. In PPMI, it detected 26 outliers and 12 ASs: 5 anomalous healthy controls (AHCs) and 7 anomalous PD cases (APDs). AHCs exhibited higher cerebrospinal fluid (CSF) A\b{eta}1-42 levels than controls (P < 0.0396), suggesting resistance to cognitive decline. AHC-specific genes were enriched for the MAPK pathway (P<0.0145), implicated in PD pathogenesis. One AHC later received a different neurological disorder, three months after enrollment. In PDBP, it identified 10 outliers and 8 ASs: 2 AHCs and 6 APDs. One AHC exhibited 24 clinical features consistent with a PD-like phenotype, including severe motor impairment. Results are compiled in an interactive report for inspection and querying, highlighting clinically meaningful individuals otherwise overlooked in conventional analyses.

Federated learning (FL) enables collaborative analysis of biomedical data without exchanging sensitive patient-level information, but its performance in multi-center studies may be compromised by batch effects which can obscure biological signals. Here, we systematically assess the impact of uncorrected batch effects on FL outcomes using four multi-center omics datasets, including transcriptomic, proteomic, and metabolomic data, and two representative algorithms: federated k-means clustering and federated random forest classification. Our results demonstrate that uncorrected batch effects undermine unsupervised FL and can substantially degrade supervised FL performance, indicating that privacy-aware batch-effect correction is essential for reliable FL. To enable privacy-preserving BEC in distributed bulk omics data, we introduce fedRBE ( https://featurecloud.ai/app/fedrbe ), a federated implementation of limma's removeBatchEffect() method enhanced by secure multi-party computation, suitable for datasets with missing values and non-identical feature sets across clients, including proteomics and metabolomics data.