Daily Papers

Inspired by the success of unsupervised pre-training paradigms, researchers have applied these approaches to DNA pre-training. However, we argue that these approaches alone yield suboptimal results because pure DNA sequences lack sufficient information, since their functions are regulated by genomic profiles like chromatin accessibility. Here, we demonstrate that supervised training for genomic profile prediction serves as a more effective alternative to pure sequence pre-training. Furthermore, considering the multi-species and multi-profile nature of genomic profile prediction, we introduce our Species-Profile Adaptive Collaborative Experts (SPACE) that leverages Mixture of Experts (MoE) to better capture the relationships between DNA sequences across different species and genomic profiles, thereby learning more effective DNA representations. Through extensive experiments across various tasks, our model achieves state-of-the-art performance, establishing that DNA models trained with supervised genomic profiles serve as powerful DNA representation learners. The code is available at https://github.com/ZhuJiwei111/SPACE.

Predicting clinical outcomes from preclinical data is essential for identifying safe and effective drug combinations. Current models rely on structural or target-based features to identify high-efficacy, low-toxicity drug combinations. However, these approaches fail to incorporate the multimodal data necessary for accurate, clinically-relevant predictions. Here, we introduce MADRIGAL, a multimodal AI model that learns from structural, pathway, cell viability, and transcriptomic data to predict drug combination effects across 953 clinical outcomes and 21842 compounds, including combinations of approved drugs and novel compounds in development. MADRIGAL uses a transformer bottleneck module to unify preclinical drug data modalities while handling missing data during training and inference--a major challenge in multimodal learning. It outperforms single-modality methods and state-of-the-art models in predicting adverse drug interactions. MADRIGAL performs virtual screening of anticancer drug combinations and supports polypharmacy management for type II diabetes and metabolic dysfunction-associated steatohepatitis (MASH). It identifies transporter-mediated drug interactions. MADRIGAL predicts resmetirom, the first and only FDA-approved drug for MASH, among therapies with the most favorable safety profile. It supports personalized cancer therapy by integrating genomic profiles from cancer patients. Using primary acute myeloid leukemia samples and patient-derived xenograft models, it predicts the efficacy of personalized drug combinations. Integrating MADRIGAL with a large language model allows users to describe clinical outcomes in natural language, improving safety assessment by identifying potential adverse interactions and toxicity risks. MADRIGAL provides a multimodal approach for designing combination therapies with improved predictive accuracy and clinical relevance.

With the rapid advances in high-throughput sequencing technologies, the focus of survival analysis has shifted from examining clinical indicators to incorporating genomic profiles with pathological images. However, existing methods either directly adopt a straightforward fusion of pathological features and genomic profiles for survival prediction, or take genomic profiles as guidance to integrate the features of pathological images. The former would overlook intrinsic cross-modal correlations. The latter would discard pathological information irrelevant to gene expression. To address these issues, we present a Cross-Modal Translation and Alignment (CMTA) framework to explore the intrinsic cross-modal correlations and transfer potential complementary information. Specifically, we construct two parallel encoder-decoder structures for multi-modal data to integrate intra-modal information and generate cross-modal representation. Taking the generated cross-modal representation to enhance and recalibrate intra-modal representation can significantly improve its discrimination for comprehensive survival analysis. To explore the intrinsic crossmodal correlations, we further design a cross-modal attention module as the information bridge between different modalities to perform cross-modal interactions and transfer complementary information. Our extensive experiments on five public TCGA datasets demonstrate that our proposed framework outperforms the state-of-the-art methods.

Healthcare data now span EHRs, medical imaging, genomics, and wearable sensors, but most diagnostic models still process these modalities in isolation. This limits their ability to capture early, cross-modal disease signatures. This paper introduces a multimodal foundation model built on a transformer architecture that integrates heterogeneous clinical data through modality-specific encoders and cross-modal attention. Each modality is mapped into a shared latent space and fused using multi-head attention with residual normalization. We implement the framework using a multimodal dataset that simulates early-stage disease patterns across EHR sequences, imaging patches, genomic profiles, and wearable signals, including missing-modality scenarios and label noise. The model is trained using supervised classification together with self-supervised reconstruction and contrastive alignment to improve robustness. Experimental evaluation demonstrates strong performance in early-detection settings, with stable classification metrics, reliable uncertainty estimates, and interpretable attention patterns. The approach moves toward a flexible, pretrain-and-fine-tune foundation model that supports precision diagnostics, handles incomplete inputs, and improves early disease detection across oncology, cardiology, and neurology applications.

Foundation models are reshaping computational pathology by enabling transfer learning, where models pre-trained on vast datasets can be adapted for downstream diagnostic, prognostic, and therapeutic response tasks. Despite these advances, foundation models are still limited in their ability to encode the entire gigapixel whole-slide images without additional training and often lack complementary multimodal data. Here, we introduce Threads, a slide-level foundation model capable of generating universal representations of whole-slide images of any size. Threads was pre-trained using a multimodal learning approach on a diverse cohort of 47,171 hematoxylin and eosin (H&E)-stained tissue sections, paired with corresponding genomic and transcriptomic profiles - the largest such paired dataset to be used for foundation model development to date. This unique training paradigm enables Threads to capture the tissue's underlying molecular composition, yielding powerful representations applicable to a wide array of downstream tasks. In extensive benchmarking across 54 oncology tasks, including clinical subtyping, grading, mutation prediction, immunohistochemistry status determination, treatment response prediction, and survival prediction, Threads outperformed all baselines while demonstrating remarkable generalizability and label efficiency. It is particularly well suited for predicting rare events, further emphasizing its clinical utility. We intend to make the model publicly available for the broader community.

Advancements in DNA sequencing technologies have significantly improved our ability to decode genomic sequences. However, the prediction and interpretation of these sequences remain challenging due to the intricate nature of genetic material. Large language models (LLMs) have introduced new opportunities for biological sequence analysis. Recent developments in genomic language models have underscored the potential of LLMs in deciphering DNA sequences. Nonetheless, existing models often face limitations in robustness and application scope, primarily due to constraints in model structure and training data scale. To address these limitations, we present GENERator, a generative genomic foundation model featuring a context length of 98k base pairs (bp) and 1.2B parameters. Trained on an expansive dataset comprising 386B bp of eukaryotic DNA, the GENERator demonstrates state-of-the-art performance across both established and newly proposed benchmarks. The model adheres to the central dogma of molecular biology, accurately generating protein-coding sequences that translate into proteins structurally analogous to known families. It also shows significant promise in sequence optimization, particularly through the prompt-responsive generation of promoter sequences with specific activity profiles. These capabilities position the GENERator as a pivotal tool for genomic research and biotechnological advancement, enhancing our ability to interpret and predict complex biological systems and enabling precise genomic interventions.

Diagnosis and risk stratification of cancer and many other diseases require the detection of genomic breakpoints as a prerequisite of calling copy number alterations (CNA). This, however, is still challenging and requires time-consuming manual curation. As deep-learning methods outperformed classical state-of-the-art algorithms in various domains and have also been successfully applied to life science problems including medicine and biology, we here propose Deep SNP, a novel Deep Neural Network to learn from genomic data. Specifically, we used a manually curated dataset from 12 genomic single nucleotide polymorphism array (SNPa) profiles as truth-set and aimed at predicting the presence or absence of genomic breakpoints, an indicator of structural chromosomal variations, in windows of 40,000 probes. We compare our results with well-known neural network models as well as Rawcopy though this tool is designed to predict breakpoints and in addition genomic segments with high sensitivity. We show, that Deep SNP is capable of successfully predicting the presence or absence of a breakpoint in large genomic windows and outperforms state-of-the-art neural network models. Qualitative examples suggest that integration of a localization unit may enable breakpoint detection and prediction of genomic segments, even if the breakpoint coordinates were not provided for network training. These results warrant further evaluation of DeepSNP for breakpoint localization and subsequent calling of genomic segments.

Interrogating the evolution of biological changes at early stages of life requires longitudinal profiling of molecules, such as DNA methylation, which can be challenging with children. We introduce a probabilistic and longitudinal machine learning framework based on multi-mean Gaussian processes (GPs), accounting for individual and gene correlations across time. This method provides future predictions of DNA methylation status at different individual ages while accounting for uncertainty. Our model is trained on a birth cohort of children with methylation profiled at ages 0-4, and we demonstrated that the status of methylation sites for each child can be accurately predicted at ages 5-7. We show that methylation profiles predicted by multi-mean GPs can be used to estimate other phenotypes, such as epigenetic age, and enable comparison to other health measures of interest. This approach encourages epigenetic studies to move towards longitudinal design for investigating epigenetic changes during development, ageing and disease progression.

Protein family design emerges as a promising alternative by combining the advantages of de novo protein design and mutation-based directed evolution.In this paper, we propose ProfileBFN, the Profile Bayesian Flow Networks, for specifically generative modeling of protein families. ProfileBFN extends the discrete Bayesian Flow Network from an MSA profile perspective, which can be trained on single protein sequences by regarding it as a degenerate profile, thereby achieving efficient protein family design by avoiding large-scale MSA data construction and training. Empirical results show that ProfileBFN has a profound understanding of proteins. When generating diverse and novel family proteins, it can accurately capture the structural characteristics of the family. The enzyme produced by this method is more likely than the previous approach to have the corresponding function, offering better odds of generating diverse proteins with the desired functionality.

Advancements in genomic research such as high-throughput sequencing techniques have driven modern genomic studies into "big data" disciplines. This data explosion is constantly challenging conventional methods used in genomics. In parallel with the urgent demand for robust algorithms, deep learning has succeeded in a variety of fields such as vision, speech, and text processing. Yet genomics entails unique challenges to deep learning since we are expecting from deep learning a superhuman intelligence that explores beyond our knowledge to interpret the genome. A powerful deep learning model should rely on insightful utilization of task-specific knowledge. In this paper, we briefly discuss the strengths of different deep learning models from a genomic perspective so as to fit each particular task with a proper deep architecture, and remark on practical considerations of developing modern deep learning architectures for genomics. We also provide a concise review of deep learning applications in various aspects of genomic research, as well as pointing out potential opportunities and obstacles for future genomics applications.

Recent advances in large language model (LLM) embeddings have enabled powerful representations for biological data, but most applications to date focus only on gene-level information. We present one of the first systematic frameworks to generate variant-level embeddings across the entire human genome. Using curated annotations from FAVOR, ClinVar, and the GWAS Catalog, we constructed semantic text descriptions for 8.9 billion possible variants and generated embeddings at three scales: 1.5 million HapMap3+MEGA variants, ~90 million imputed UK Biobank variants, and ~9 billion all possible variants. Embeddings were produced with both OpenAI's text-embedding-3-large and the open-source Qwen3-Embedding-0.6B models. Baseline experiments demonstrate high predictive accuracy for variant properties, validating the embeddings as structured representations of genomic variation. We outline two downstream applications: embedding-informed hypothesis testing by extending the Frequentist And Bayesian framework to genome-wide association studies, and embedding-augmented genetic risk prediction that enhances standard polygenic risk scores. These resources, publicly available on Hugging Face, provide a foundation for advancing large-scale genomic discovery and precision medicine.

Large language models (LLMs) trained on text demonstrated remarkable results on natural language processing (NLP) tasks. These models have been adapted to decipher the language of DNA, where sequences of nucleotides act as "words" that encode genomic functions. However, the genome differs fundamentally from natural language, as it lacks clearly defined words or a consistent grammar. Although DNA language models (DNALMs) such as DNABERT, GENA-LM have achieved high level of performance on genome-related biological tasks, these models do not encode biological functions in the presence of sequence variations. To address this problem, we pre-train foundation models that effectively integrate sequence variations, in particular Single Nucleotide Polymorphisms (SNPs), as they underlie important biological functions. Specifically, we use ModernBERT to pre-train two different Biomedical Foundation Models (BMFM), namely, BMFM-DNA-REF in which the model is trained with sequences of varying lengths along with their reverse complements derived from the reference genome and BMFM-DNA-SNP in which the model is trained with sequences created using a novel representation scheme that encodes sequence variations. Our findings indicate that integrating sequence variations into DNALMs helps capture the biological functions as seen in improvements on all fine-tuning tasks. To explore the model's practical utility, we experimented with various strategies for SNP imputation on promoter detection task introduced in DNABERT-2. However, we acknowledge that the current benchmarks are limited in their ability to fully evaluate these models. To enable more comprehensive assessment in the future and encourage community contributions, we release our models through HuggingFace and the code to reproduce the results at https://github.com/BiomedSciAI/biomed-multi-omic

Pre-trained large language models(LLMs) have attracted increasing attention in biomedical domains due to their success in natural language processing. However, the complex traits and heterogeneity of multi-sources genomics data pose significant challenges when adapting these models to the bioinformatics and biomedical field. To address these challenges, we present GP-GPT, the first specialized large language model for genetic-phenotype knowledge representation and genomics relation analysis. Our model is fine-tuned in two stages on a comprehensive corpus composed of over 3,000,000 terms in genomics, proteomics, and medical genetics, derived from multiple large-scale validated datasets and scientific publications. GP-GPT demonstrates proficiency in accurately retrieving medical genetics information and performing common genomics analysis tasks, such as genomics information retrieval and relationship determination. Comparative experiments across domain-specific tasks reveal that GP-GPT outperforms state-of-the-art LLMs, including Llama2, Llama3 and GPT-4. These results highlight GP-GPT's potential to enhance genetic disease relation research and facilitate accurate and efficient analysis in the fields of genomics and medical genetics. Our investigation demonstrated the subtle changes of bio-factor entities' representations in the GP-GPT, which suggested the opportunities for the application of LLMs to advancing gene-phenotype research.

Evaluating personalized recommendations remains a central challenge, especially in long-form audio domains like podcasts, where traditional offline metrics suffer from exposure bias and online methods such as A/B testing are costly and operationally constrained. In this paper, we propose a novel framework that leverages Large Language Models (LLMs) as offline judges to assess the quality of podcast recommendations in a scalable and interpretable manner. Our two-stage profile-aware approach first constructs natural-language user profiles distilled from 90 days of listening history. These profiles summarize both topical interests and behavioral patterns, serving as compact, interpretable representations of user preferences. Rather than prompting the LLM with raw data, we use these profiles to provide high-level, semantically rich context-enabling the LLM to reason more effectively about alignment between a user's interests and recommended episodes. This reduces input complexity and improves interpretability. The LLM is then prompted to deliver fine-grained pointwise and pairwise judgments based on the profile-episode match. In a controlled study with 47 participants, our profile-aware judge matched human judgments with high fidelity and outperformed or matched a variant using raw listening histories. The framework enables efficient, profile-aware evaluation for iterative testing and model selection in recommender systems.

Recent advances in self-supervised models for natural language, vision, and protein sequences have inspired the development of large genomic DNA language models (DNALMs). These models aim to learn generalizable representations of diverse DNA elements, potentially enabling various genomic prediction, interpretation and design tasks. Despite their potential, existing benchmarks do not adequately assess the capabilities of DNALMs on key downstream applications involving an important class of non-coding DNA elements critical for regulating gene activity. In this study, we introduce DART-Eval, a suite of representative benchmarks specifically focused on regulatory DNA to evaluate model performance across zero-shot, probed, and fine-tuned scenarios against contemporary ab initio models as baselines. Our benchmarks target biologically meaningful downstream tasks such as functional sequence feature discovery, predicting cell-type specific regulatory activity, and counterfactual prediction of the impacts of genetic variants. We find that current DNALMs exhibit inconsistent performance and do not offer compelling gains over alternative baseline models for most tasks, while requiring significantly more computational resources. We discuss potentially promising modeling, data curation, and evaluation strategies for the next generation of DNALMs. Our code is available at https://github.com/kundajelab/DART-Eval.

In modern commercial systems, including Recommendation, Ranking, and E-Commerce platforms, there is a trend towards improving customer experiences by incorporating Personalization context as input into Large Language Models (LLMs). However, LLMs often struggle to effectively parse and utilize sparse and complex personal context without additional processing or contextual enrichment, underscoring the need for more sophisticated context understanding mechanisms. In this work, we propose Guided Profile Generation (GPG), a general method designed to generate personal profiles in natural language. As is observed, intermediate guided profile generation enables LLMs to summarize, and extract the important, distinctive features from the personal context into concise, descriptive sentences, precisely tailoring their generation more closely to an individual's unique habits and preferences. Our experimental results show that GPG improves LLM's personalization ability across different tasks, for example, it increases 37% accuracy in predicting personal preference compared to directly feeding the LLMs with raw personal context.

Recent studies in DNA sequence classification have leveraged sophisticated machine learning techniques, achieving notable accuracy in categorizing complex genomic data. Among these, methods such as k-mer counting have proven effective in distinguishing sequences from varied species like chimpanzees, dogs, and humans, becoming a staple in contemporary genomic research. However, these approaches often demand extensive computational resources, posing a challenge in terms of scalability and efficiency. Addressing this issue, our study introduces a novel adaptation of Jiang et al.'s compressor-based, parameter-free classification method, specifically tailored for DNA sequence analysis. This innovative approach utilizes a variety of compression algorithms, such as Gzip, Brotli, and LZMA, to efficiently process and classify genomic sequences. Not only does this method align with the current state-of-the-art in terms of accuracy, but it also offers a more resource-efficient alternative to traditional machine learning methods. Our comprehensive evaluation demonstrates the proposed method's effectiveness in accurately classifying DNA sequences from multiple species. We present a detailed analysis of the performance of each algorithm used, highlighting the strengths and limitations of our approach in various genomic contexts. Furthermore, we discuss the broader implications of our findings for bioinformatics, particularly in genomic data processing and analysis. The results of our study pave the way for more efficient and scalable DNA sequence classification methods, offering significant potential for advancements in genomic research and applications.

Pre-trained large language models demonstrate potential in extracting information from DNA sequences, yet adapting to a variety of tasks and data modalities remains a challenge. To address this, we propose DNAGPT, a generalized DNA pre-training model trained on over 200 billion base pairs from all mammals. By enhancing the classic GPT model with a binary classification task (DNA sequence order), a numerical regression task (guanine-cytosine content prediction), and a comprehensive token language, DNAGPT can handle versatile DNA analysis tasks while processing both sequence and numerical data. Our evaluation of genomic signal and region recognition, mRNA abundance regression, and artificial genomes generation tasks demonstrates DNAGPT's superior performance compared to existing models designed for specific downstream tasks, benefiting from pre-training using the newly designed model structure.

DNA sequence alignment involves assigning short DNA reads to the most probable locations on an extensive reference genome. This process is crucial for various genomic analyses, including variant calling, transcriptomics, and epigenomics. Conventional methods, refined over decades, tackle this challenge in 2 steps: genome indexing followed by efficient search to locate likely positions for given reads. Building on the success of Large Language Models in encoding text into embeddings, where the distance metric captures semantic similarity, recent efforts have explored whether the same Transformer architecture can produce embeddings for DNA sequences. Such models have shown early promise in classifying short DNA sequences, such as detecting coding/non-coding regions, and enhancer, promoter sequences. However, performance at sequence classification tasks does not translate to sequence alignment, where it is necessary to search across the genome to align each read, a significantly longer-range task. We bridge this gap by framing the Sequence Alignment task for Transformer models as an "Embed-Search-Align" task. In this framework, a novel Reference-Free DNA Embedding model generates embeddings of reads and reference fragments, which are projected into a shared vector space where the read-fragment distance is used as a surrogate for alignment. Technical contributions include: (1) Contrastive loss for self-supervised training of DNA sequence representations, facilitating rich reference-free, sequence-level embeddings, and (2) a DNA vector store to enable search across fragments on a global scale. DNA-ESA is 99% accurate when aligning 250-length reads onto a human genome (3gb), rivaling conventional methods such as Bowtie and BWA-Mem. DNA-ESA exceeds the performance of 6 Transformer model baselines such as Nucleotide Transformer, Hyena-DNA, and shows task transfer across chromosomes and species.

Immunotherapy is an effective precision medicine treatment for several cancers. Imaging signatures of the underlying genome (radiogenomics) in glioblastoma patients may serve as preoperative biomarkers of the tumor-host immune apparatus. Validated biomarkers would have the potential to stratify patients during immunotherapy clinical trials, and if trials are beneficial, facilitate personalized neo-adjuvant treatment. The increased use of whole genome sequencing data, and the advances in bioinformatics and machine learning make such developments plausible. We performed a systematic review to determine the extent of development and validation of immune-related radiogenomic biomarkers for glioblastoma. A systematic review was performed following PRISMA guidelines using the PubMed, Medline, and Embase databases. Qualitative analysis was performed by incorporating the QUADAS 2 tool and CLAIM checklist. PROSPERO registered CRD42022340968. Extracted data were insufficiently homogenous to perform a meta-analysis. Results Nine studies, all retrospective, were included. Biomarkers extracted from magnetic resonance imaging volumes of interest included apparent diffusion coefficient values, relative cerebral blood volume values, and image-derived features. These biomarkers correlated with genomic markers from tumor cells or immune cells or with patient survival. The majority of studies had a high risk of bias and applicability concerns regarding the index test performed. Radiogenomic immune biomarkers have the potential to provide early treatment options to patients with glioblastoma. Targeted immunotherapy, stratified by these biomarkers, has the potential to allow individualized neo-adjuvant precision treatment options in clinical trials. However, there are no prospective studies validating these biomarkers, and interpretation is limited due to study bias with little evidence of generalizability.

Wheat varieties show a large diversity of traits and phenotypes. Linking them to genetic variability is essential for shorter and more efficient wheat breeding programs. Newly desirable wheat variety traits include disease resistance to reduce pesticide use, adaptation to climate change, resistance to heat and drought stresses, or low gluten content of grains. Wheat breeding experiments are documented by a large body of scientific literature and observational data obtained in-field and under controlled conditions. The cross-referencing of complementary information from the literature and observational data is essential to the study of the genotype-phenotype relationship and to the improvement of wheat selection. The scientific literature on genetic marker-assisted selection describes much information about the genotype-phenotype relationship. However, the variety of expressions used to refer to traits and phenotype values in scientific articles is a hinder to finding information and cross-referencing it. When trained adequately by annotated examples, recent text mining methods perform highly in named entity recognition and linking in the scientific domain. While several corpora contain annotations of human and animal phenotypes, currently, no corpus is available for training and evaluating named entity recognition and entity-linking methods in plant phenotype literature. The Triticum aestivum trait Corpus is a new gold standard for traits and phenotypes of wheat. It consists of 540 PubMed references fully annotated for trait, phenotype, and species named entities using the Wheat Trait and Phenotype Ontology and the species taxonomy of the National Center for Biotechnology Information. A study of the performance of tools trained on the Triticum aestivum trait Corpus shows that the corpus is suitable for the training and evaluation of named entity recognition and linking.

Genomic (DNA) sequences encode an enormous amount of information for gene regulation and protein synthesis. Similar to natural language models, researchers have proposed foundation models in genomics to learn generalizable features from unlabeled genome data that can then be fine-tuned for downstream tasks such as identifying regulatory elements. Due to the quadratic scaling of attention, previous Transformer-based genomic models have used 512 to 4k tokens as context (<0.001% of the human genome), significantly limiting the modeling of long-range interactions in DNA. In addition, these methods rely on tokenizers to aggregate meaningful DNA units, losing single nucleotide resolution where subtle genetic variations can completely alter protein function via single nucleotide polymorphisms (SNPs). Recently, Hyena, a large language model based on implicit convolutions was shown to match attention in quality while allowing longer context lengths and lower time complexity. Leveraging Hyenas new long-range capabilities, we present HyenaDNA, a genomic foundation model pretrained on the human reference genome with context lengths of up to 1 million tokens at the single nucleotide-level, an up to 500x increase over previous dense attention-based models. HyenaDNA scales sub-quadratically in sequence length (training up to 160x faster than Transformer), uses single nucleotide tokens, and has full global context at each layer. We explore what longer context enables - including the first use of in-context learning in genomics for simple adaptation to novel tasks without updating pretrained model weights. On fine-tuned benchmarks from the Nucleotide Transformer, HyenaDNA reaches state-of-the-art (SotA) on 12 of 17 datasets using a model with orders of magnitude less parameters and pretraining data. On the GenomicBenchmarks, HyenaDNA surpasses SotA on all 8 datasets on average by +9 accuracy points.

The application of deep learning methods, particularly foundation models, in biological research has surged in recent years. These models can be text-based or trained on underlying biological data, especially omics data of various types. However, comparing the performance of these models consistently has proven to be a challenge due to differences in training data and downstream tasks. To tackle this problem, we developed an architecture-agnostic benchmarking approach that, instead of evaluating the models directly, leverages entity representation vectors from each model and trains simple predictive models for each benchmarking task. This ensures that all types of models are evaluated using the same input and output types. Here we focus on gene properties collected from professionally curated bioinformatics databases. These gene properties are categorized into five major groups: genomic properties, regulatory functions, localization, biological processes, and protein properties. Overall, we define hundreds of tasks based on these databases, which include binary, multi-label, and multi-class classification tasks. We apply these benchmark tasks to evaluate expression-based models, large language models, protein language models, DNA-based models, and traditional baselines. Our findings suggest that text-based models and protein language models generally outperform expression-based models in genomic properties and regulatory functions tasks, whereas expression-based models demonstrate superior performance in localization tasks. These results should aid in the development of more informed artificial intelligence strategies for biological understanding and therapeutic discovery. To ensure the reproducibility and transparency of our findings, we have made the source code and benchmark data publicly accessible for further investigation and expansion at github.com/BiomedSciAI/gene-benchmark.

The genome sequence contains the blueprint for governing cellular processes. While the availability of genomes has vastly increased over the last decades, experimental annotation of the various functional, non-coding and regulatory elements encoded in the DNA sequence remains both expensive and challenging. This has sparked interest in unsupervised language modeling of genomic DNA, a paradigm that has seen great success for protein sequence data. Although various DNA language models have been proposed, evaluation tasks often differ between individual works, and might not fully recapitulate the fundamental challenges of genome annotation, including the length, scale and sparsity of the data. In this study, we introduce BEND, a Benchmark for DNA language models, featuring a collection of realistic and biologically meaningful downstream tasks defined on the human genome. We find that embeddings from current DNA LMs can approach performance of expert methods on some tasks, but only capture limited information about long-range features. BEND is available at https://github.com/frederikkemarin/BEND.

Human medical data can be challenging to obtain due to data privacy concerns, difficulties conducting certain types of experiments, or prohibitive associated costs. In many settings, data from animal models or in-vitro cell lines are available to help augment our understanding of human data. However, this data is known for having low etiological validity in comparison to human data. In this work, we augment small human medical datasets with in-vitro data and animal models. We use Invariant Risk Minimisation (IRM) to elucidate invariant features by considering cross-organism data as belonging to different data-generating environments. Our models identify genes of relevance to human cancer development. We observe a degree of consistency between varying the amounts of human and mouse data used, however, further work is required to obtain conclusive insights. As a secondary contribution, we enhance existing open source datasets and provide two uniformly processed, cross-organism, homologue gene-matched datasets to the community.

User profiling is pivotal for recommendation systems, as it transforms raw user interaction data into concise and structured representations that drive personalized recommendations. While traditional embedding-based profiles lack interpretability and adaptability, recent advances with large language models (LLMs) enable text-based profiles that are semantically richer and more transparent. However, existing methods often adhere to fixed formats that limit their ability to capture the full diversity of user behaviors. In this paper, we introduce LettinGo, a novel framework for generating diverse and adaptive user profiles. By leveraging the expressive power of LLMs and incorporating direct feedback from downstream recommendation tasks, our approach avoids the rigid constraints imposed by supervised fine-tuning (SFT). Instead, we employ Direct Preference Optimization (DPO) to align the profile generator with task-specific performance, ensuring that the profiles remain adaptive and effective. LettinGo operates in three stages: (1) exploring diverse user profiles via multiple LLMs, (2) evaluating profile quality based on their impact in recommendation systems, and (3) aligning the profile generation through pairwise preference data derived from task performance. Experimental results demonstrate that our framework significantly enhances recommendation accuracy, flexibility, and contextual awareness. This work enhances profile generation as a key innovation for next-generation recommendation systems.

The way in which data are shared can affect their utility and reusability. Here, we demonstrate how data that we had previously shared in bulk can be mobilized further through a knowledge graph that allows for much more granular exploration and interrogation. The original dataset is about the computational reproducibility of GitHub-hosted Jupyter notebooks associated with biomedical publications. It contains rich metadata about the publications, associated GitHub repositories and Jupyter notebooks, and the notebooks' reproducibility. We took this dataset, converted it into semantic triples and loaded these into a triple store to create a knowledge graph, FAIR Jupyter, that we made accessible via a web service. This enables granular data exploration and analysis through queries that can be tailored to specific use cases. Such queries may provide details about any of the variables from the original dataset, highlight relationships between them or combine some of the graph's content with materials from corresponding external resources. We provide a collection of example queries addressing a range of use cases in research and education. We also outline how sets of such queries can be used to profile specific content types, either individually or by class. We conclude by discussing how such a semantically enhanced sharing of complex datasets can both enhance their FAIRness, i.e., their findability, accessibility, interoperability, and reusability, and help identify and communicate best practices, particularly with regards to data quality, standardization, automation and reproducibility.

Large language models (LLMs) are having transformative impacts across a wide range of scientific fields, particularly in the biomedical sciences. Just as the goal of Natural Language Processing is to understand sequences of words, a major objective in biology is to understand biological sequences. Genomic Language Models (gLMs), which are LLMs trained on DNA sequences, have the potential to significantly advance our understanding of genomes and how DNA elements at various scales interact to give rise to complex functions. To showcase this potential, we highlight key applications of gLMs, including functional constraint prediction, sequence design, and transfer learning. Despite notable recent progress, however, developing effective and efficient gLMs presents numerous challenges, especially for species with large, complex genomes. Here, we discuss major considerations for developing and evaluating gLMs.

Motivation: The Genomic Data Commons (GDC) provides access to high quality, harmonized cancer genomics data through a unified curation and analysis platform centered around patient cohorts. While GDC users can interactively create complex cohorts through the graphical Cohort Builder, users (especially new ones) may struggle to find specific cohort descriptors across hundreds of possible fields and properties. However, users may be better able to describe their desired cohort in free-text natural language. Results: We introduce GDC Cohort Copilot, an open-source copilot tool for curating cohorts from the GDC. GDC Cohort Copilot automatically generates the GDC cohort filter corresponding to a user-input natural language description of their desired cohort, before exporting the cohort back to the GDC for further analysis. An interactive user interface allows users to further refine the generated cohort. We develop and evaluate multiple large language models (LLMs) for GDC Cohort Copilot and demonstrate that our locally-served, open-source GDC Cohort LLM achieves better results than GPT-4o prompting in generating GDC cohorts. Availability and implementation: The standalone docker image for GDC Cohort Copilot is available at https://quay.io/repository/cdis/gdc-cohort-copilot. Source code is available at https://github.com/uc-cdis/gdc-cohort-copilot. GDC Cohort LLM weights are available at https://huggingface.co/uc-ctds.

We present a novel approach for the prediction of anticancer compound sensitivity by means of multi-modal attention-based neural networks (PaccMann). In our approach, we integrate three key pillars of drug sensitivity, namely, the molecular structure of compounds, transcriptomic profiles of cancer cells as well as prior knowledge about interactions among proteins within cells. Our models ingest a drug-cell pair consisting of SMILES encoding of a compound and the gene expression profile of a cancer cell and predicts an IC50 sensitivity value. Gene expression profiles are encoded using an attention-based encoding mechanism that assigns high weights to the most informative genes. We present and study three encoders for SMILES string of compounds: 1) bidirectional recurrent 2) convolutional 3) attention-based encoders. We compare our devised models against a baseline model that ingests engineered fingerprints to represent the molecular structure. We demonstrate that using our attention-based encoders, we can surpass the baseline model. The use of attention-based encoders enhance interpretability and enable us to identify genes, bonds and atoms that were used by the network to make a prediction.

In recent years, cancer genome sequencing and other high-throughput studies of cancer genomes have generated many notable discoveries. In this review, Novel genomic alteration mechanisms, such as chromothripsis (chromosomal crisis) and kataegis (mutation storms), and their implications for cancer are discussed. Genomic alterations spur cancer genome evolution. Thus, the relationship between cancer clonal evolution and cancer stems cells is commented. The key question in cancer biology concerns how these genomic alterations support cancer development and metastasis in the context of biological functioning. Thus far, efforts such as pathway analysis have improved the understanding of the functional contributions of genetic mutations and DNA copy number variations to cancer development, progression and metastasis. However, the known pathways correspond to a small fraction, plausibly 5-10%, of somatic mutations and genes with an altered copy number. To develop a comprehensive understanding of the function of these genomic alterations in cancer, an integrative network framework is proposed and discussed. Finally, the challenges and the directions of studying cancer omic data using an integrative network approach are commented.

Gene expression analysis holds the key to many biomedical discoveries, yet extracting insights from raw transcriptomic data remains formidable due to the complexity of multiple large, semi-structured files and the need for extensive domain expertise. Current automation approaches are often limited by either inflexible workflows that break down in edge cases or by fully autonomous agents that lack the necessary precision for rigorous scientific inquiry. GenoMAS charts a different course by presenting a team of LLM-based scientists that integrates the reliability of structured workflows with the adaptability of autonomous agents. GenoMAS orchestrates six specialized LLM agents through typed message-passing protocols, each contributing complementary strengths to a shared analytic canvas. At the heart of GenoMAS lies a guided-planning framework: programming agents unfold high-level task guidelines into Action Units and, at each juncture, elect to advance, revise, bypass, or backtrack, thereby maintaining logical coherence while bending gracefully to the idiosyncrasies of genomic data. On the GenoTEX benchmark, GenoMAS reaches a Composite Similarity Correlation of 89.13% for data preprocessing and an F_1 of 60.48% for gene identification, surpassing the best prior art by 10.61% and 16.85% respectively. Beyond metrics, GenoMAS surfaces biologically plausible gene-phenotype associations corroborated by the literature, all while adjusting for latent confounders. Code is available at https://github.com/Liu-Hy/GenoMAS.

In this white paper we introduce Helix, an AI based solution for missense pathogenicity prediction. With recent advances in the sequencing of human genomes, massive amounts of genetic data have become available. This has shifted the burden of labor for genetic diagnostics and research from the gathering of data to its interpretation. Helix presents a state of the art platform for the prediction of pathogenicity in human missense variants. In addition to offering best-in-class predictive performance, Helix offers a platform that allows researchers to analyze and interpret variants in depth that can be accessed at helixlabs.ai.

A principal component analysis of the TCGA data for 15 cancer localizations unveils the following qualitative facts about tumors: 1) The state of a tissue in gene expression space may be described by a few variables. In particular, there is a single variable describing the progression from a normal tissue to a tumor. 2) Each cancer localization is characterized by a gene expression profile, in which genes have specific weights in the definition of the cancer state. There are no less than 2500 differentially-expressed genes, which lead to power-like tails in the expression distribution functions. 3) Tumors in different localizations share hundreds or even thousands of differentially expressed genes. There are 6 genes common to the 15 studied tumor localizations. 4) The tumor region is a kind of attractor. Tumors in advanced stages converge to this region independently of patient age or genetic variability. 5) There is a landscape of cancer in gene expression space with an approximate border separating normal tissues from tumors.

User profile modeling plays a key role in personalized systems, as it requires building accurate profiles and updating them with new information. In this paper, we present two high-quality open-source user profile datasets: one for profile construction and another for profile updating. These datasets offer a strong basis for evaluating user profile modeling techniques in dynamic settings. We also show a methodology that uses large language models (LLMs) to tackle both profile construction and updating. Our method uses a probabilistic framework to predict user profiles from input text, allowing for precise and context-aware profile generation. Our experiments demonstrate that models like Mistral-7b and Llama2-7b perform strongly in both tasks. LLMs improve the precision and recall of the generated profiles, and high evaluation scores confirm the effectiveness of our approach.

Cancer is known as a disease mainly caused by gene alterations. Discovery of mutated driver pathways or gene sets is becoming an important step to understand molecular mechanisms of carcinogenesis. However, systematically investigating commonalities and specificities of driver gene sets among multiple cancer types is still a great challenge, but this investigation will undoubtedly benefit deciphering cancers and will be helpful for personalized therapy and precision medicine in cancer treatment. In this study, we propose two optimization models to de novo discover common driver gene sets among multiple cancer types (ComMDP) and specific driver gene sets of one certain or multiple cancer types to other cancers (SpeMDP), respectively. We first apply ComMDP and SpeMDP to simulated data to validate their efficiency. Then, we further apply these methods to 12 cancer types from The Cancer Genome Atlas (TCGA) and obtain several biologically meaningful driver pathways. As examples, we construct a common cancer pathway model for BRCA and OV, infer a complex driver pathway model for BRCA carcinogenesis based on common driver gene sets of BRCA with eight cancer types, and investigate specific driver pathways of the liquid cancer lymphoblastic acute myeloid leukemia (LAML) versus other solid cancer types. In these processes more candidate cancer genes are also found.

We pretrain METAGENE-1, a 7-billion-parameter autoregressive transformer model, which we refer to as a metagenomic foundation model, on a novel corpus of diverse metagenomic DNA and RNA sequences comprising over 1.5 trillion base pairs. This dataset is sourced from a large collection of human wastewater samples, processed and sequenced using deep metagenomic (next-generation) sequencing methods. Unlike genomic models that focus on individual genomes or curated sets of specific species, the aim of METAGENE-1 is to capture the full distribution of genomic information present within this wastewater, to aid in tasks relevant to pandemic monitoring and pathogen detection. We carry out byte-pair encoding (BPE) tokenization on our dataset, tailored for metagenomic sequences, and then pretrain our model. In this paper, we first detail the pretraining dataset, tokenization strategy, and model architecture, highlighting the considerations and design choices that enable the effective modeling of metagenomic data. We then show results of pretraining this model on our metagenomic dataset, providing details about our losses, system metrics, and training stability over the course of pretraining. Finally, we demonstrate the performance of METAGENE-1, which achieves state-of-the-art results on a set of genomic benchmarks and new evaluations focused on human-pathogen detection and genomic sequence embedding, showcasing its potential for public health applications in pandemic monitoring, biosurveillance, and early detection of emerging health threats.

Classifying genome sequences based on metadata has been an active area of research in comparative genomics for decades with many important applications across the life sciences. Established methods for classifying genomes can be broadly grouped into sequence alignment-based and alignment-free models. Conventional alignment-based models rely on genome similarity measures calculated based on local sequence alignments or consistent ordering among sequences. However, such methods are computationally expensive when dealing with large ensembles of even moderately sized genomes. In contrast, alignment-free (AF) approaches measure genome similarity based on summary statistics in an unsupervised setting and are efficient enough to analyze large datasets. However, both alignment-based and AF methods typically assume fixed scoring rubrics that lack the flexibility to assign varying importance to different parts of the sequences based on prior knowledge. In this study, we integrate AI and network science approaches to develop a comparative genomic analysis framework that addresses these limitations. Our approach, termed the Genome Misclassification Network Analysis (GMNA), simultaneously leverages misclassified instances, a learned scoring rubric, and label information to classify genomes based on associated metadata and better understand potential drivers of misclassification. We evaluate the utility of the GMNA using Naive Bayes and convolutional neural network models, supplemented by additional experiments with transformer-based models, to construct SARS-CoV-2 sampling location classifiers using over 500,000 viral genome sequences and study the resulting network of misclassifications. We demonstrate the global health potential of the GMNA by leveraging the SARS-CoV-2 genome misclassification networks to investigate the role human mobility played in structuring geographic clustering of SARS-CoV-2.

Although DNA foundation models have advanced the understanding of genomes, they still face significant challenges in the limited scale and diversity of genomic data. This limitation starkly contrasts with the success of natural language foundation models, which thrive on substantially larger scales. Furthermore, genome understanding involves numerous downstream genome annotation tasks with inherent data heterogeneity, thereby necessitating more efficient and robust fine-tuning methods tailored for genomics. Here, we present Lingo: Language prefix fIne-tuning for GenOmes. Unlike DNA foundation models, Lingo strategically leverages natural language foundation models' contextual cues, recalibrating their linguistic knowledge to genomic sequences. Lingo further accommodates numerous, heterogeneous downstream fine-tune tasks by an adaptive rank sampling method that prunes and stochastically reintroduces pruned singular vectors within small computational budgets. Adaptive rank sampling outperformed existing fine-tuning methods on all benchmarked 14 genome understanding tasks, while requiring fewer than 2\% of trainable parameters as genomic-specific adapters. Impressively, applying these adapters on natural language foundation models matched or even exceeded the performance of DNA foundation models. Lingo presents a new paradigm of efficient and scalable genome understanding via genomic-specific adapters on language models.

Long-range dependencies are critical for understanding genomic structure and function, yet most conventional methods struggle with them. Widely adopted transformer-based models, while excelling at short-context tasks, are limited by the attention module's quadratic computational complexity and inability to extrapolate to sequences longer than those seen in training. In this work, we explore State Space Models (SSMs) as a promising alternative by benchmarking two SSM-inspired architectures, Caduceus and Hawk, on long-range genomics modeling tasks under conditions parallel to a 50M parameter transformer baseline. We discover that SSMs match transformer performance and exhibit impressive zero-shot extrapolation across multiple tasks, handling contexts 10 to 100 times longer than those seen during training, indicating more generalizable representations better suited for modeling the long and complex human genome. Moreover, we demonstrate that these models can efficiently process sequences of 1M tokens on a single GPU, allowing for modeling entire genomic regions at once, even in labs with limited compute. Our findings establish SSMs as efficient and scalable for long-context genomic analysis.

Recent advancements in machine learning have significantly improved the identification of disease-associated genes from gene expression datasets. However, these processes often require extensive expertise and manual effort, limiting their scalability. Large Language Model (LLM)-based agents have shown promise in automating these tasks due to their increasing problem-solving abilities. To support the evaluation and development of such methods, we introduce GenoTEX, a benchmark dataset for the automated analysis of gene expression data. GenoTEX provides annotated code and results for solving a wide range of gene identification problems, encompassing dataset selection, preprocessing, and statistical analysis, in a pipeline that follows computational genomics standards. The benchmark includes expert-curated annotations from bioinformaticians to ensure accuracy and reliability. To provide baselines for these tasks, we present GenoAgent, a team of LLM-based agents that adopt a multi-step programming workflow with flexible self-correction, to collaboratively analyze gene expression datasets. Our experiments demonstrate the potential of LLM-based methods in analyzing genomic data, while error analysis highlights the challenges and areas for future improvement. We propose GenoTEX as a promising resource for benchmarking and enhancing automated methods for gene expression data analysis. The benchmark is available at https://github.com/Liu-Hy/GenoTex.

Biomedical research increasingly relies on integrating diverse data modalities, including gene expression profiles, medical images, and clinical metadata. While medical images and clinical metadata are routinely collected in clinical practice, gene expression data presents unique challenges for widespread research use, mainly due to stringent privacy regulations and costly laboratory experiments. To address these limitations, we present GeMM-GAN, a novel Generative Adversarial Network conditioned on histopathology tissue slides and clinical metadata, designed to synthesize realistic gene expression profiles. GeMM-GAN combines a Transformer Encoder for image patches with a final Cross Attention mechanism between patches and text tokens, producing a conditioning vector to guide a generative model in generating biologically coherent gene expression profiles. We evaluate our approach on the TCGA dataset and demonstrate that our framework outperforms standard generative models and generates more realistic and functionally meaningful gene expression profiles, improving by more than 11\% the accuracy on downstream disease type prediction compared to current state-of-the-art generative models. Code will be available at: https://github.com/francescapia/GeMM-GAN

Motivation The genotype assignment problem consists of predicting, from the genotype of an individual, which of a known set of populations it originated from. The problem arises in a variety of contexts, including wildlife forensics, invasive species detection and biodiversity monitoring. Existing approaches perform well under ideal conditions but are sensitive to a variety of common violations of the assumptions they rely on. Results In this article, we introduce Mycorrhiza, a machine learning approach for the genotype assignment problem. Our algorithm makes use of phylogenetic networks to engineer features that encode the evolutionary relationships among samples. Those features are then used as input to a Random Forests classifier. The classification accuracy was assessed on multiple published empirical SNP, microsatellite or consensus sequence datasets with wide ranges of size, geographical distribution and population structure and on simulated datasets. It compared favorably against widely used assessment tests or mixture analysis methods such as STRUCTURE and Admixture, and against another machine-learning based approach using principal component analysis for dimensionality reduction. Mycorrhiza yields particularly significant gains on datasets with a large average fixation index (FST) or deviation from the Hardy-Weinberg equilibrium. Moreover, the phylogenetic network approach estimates mixture proportions with good accuracy.

Machine learning has emerged as a powerful tool for scientific discovery, enabling researchers to extract meaningful insights from complex datasets. For instance, it has facilitated the identification of disease-predictive genes from gene expression data, significantly advancing healthcare. However, the traditional process for analyzing such datasets demands substantial human effort and expertise for the data selection, processing, and analysis. To address this challenge, we introduce a novel framework, a Team of AI-made Scientists (TAIS), designed to streamline the scientific discovery pipeline. TAIS comprises simulated roles, including a project manager, data engineer, and domain expert, each represented by a Large Language Model (LLM). These roles collaborate to replicate the tasks typically performed by data scientists, with a specific focus on identifying disease-predictive genes. Furthermore, we have curated a benchmark dataset to assess TAIS's effectiveness in gene identification, demonstrating our system's potential to significantly enhance the efficiency and scope of scientific exploration. Our findings represent a solid step towards automating scientific discovery through large language models.

Providing dialogue agents with a profile representation can improve their consistency and coherence, leading to better conversations. However, current profile-based dialogue datasets for training such agents contain either explicit profile representations that are simple and dialogue-specific, or implicit representations that are difficult to collect. In this work, we propose a unified framework in which we bring together both standard and more sophisticated profile representations by creating a new resource where each dialogue is aligned with all possible speaker representations such as communication style, biographies, and personality. This framework allows to test several baselines built using generative language models with several profile configurations. The automatic evaluation shows that profile-based models have better generalisation capabilities than models trained on dialogues only, both in-domain and cross-domain settings. These results are consistent for fine-tuned models and instruction-based LLMs. Additionally, human evaluation demonstrates a clear preference for generations consistent with both profile and context. Finally, to account for possible privacy concerns, all experiments are done under two configurations: inter-character and intra-character. In the former, the LM stores the information about the character in its internal representation, while in the latter, the LM does not retain any personal information but uses it only at inference time.

Current genomic foundation models (GFMs) rely on extensive neural computation to implicitly approximate conserved biological motifs from single-nucleotide inputs. We propose Gengram, a conditional memory module that introduces an explicit and highly efficient lookup primitive for multi-base motifs via a genomic-specific hashing scheme, establishing genomic "syntax". Integrated into the backbone of state-of-the-art GFMs, Gengram achieves substantial gains (up to 14%) across several functional genomics tasks. The module demonstrates robust architectural generalization, while further inspection of Gengram's latent space reveals the emergence of meaningful representations that align closely with fundamental biological knowledge. By establishing structured motif memory as a modeling primitive, Gengram simultaneously boosts empirical performance and mechanistic interpretability, providing a scalable and biology-aligned pathway for the next generation of GFMs. The code is available at https://github.com/zhejianglab/Genos, and the model checkpoint is available at https://huggingface.co/ZhejiangLab/Gengram.

Genotype-by-Environment (GxE) interactions influence the performance of genotypes across diverse environments, reducing the predictability of phenotypes in target environments. In-depth analysis of GxE interactions facilitates the identification of how genetic advantages or defects are expressed or suppressed under specific environmental conditions, thereby enabling genetic selection and enhancing breeding practices. This paper introduces two key models for GxE interaction research. Specifically, it includes significance analysis based on the mixed effect model to determine whether genes or GxE interactions significantly affect phenotypic traits; stability analysis, which further investigates the interactive relationships between genes and environments, as well as the relative superiority or inferiority of genotypes across environments. Additionally, this paper presents RGxEStat, a lightweight interactive tool, which is developed by the authors and integrates the construction, solution, and visualization of the aforementioned models. Designed to eliminate the need for breeders and agronomists to learn complex SAS or R programming, RGxEStat provides a user-friendly interface for streamlined breeding data analysis, significantly accelerating research cycles. Codes and datasets are available at https://github.com/mason-ching/RGxEStat.

The approval success rate of drug candidates is very low with the majority of failure due to safety and efficacy. Increasingly available high dimensional information on targets, drug molecules and indications provides an opportunity for ML methods to integrate multiple data modalities and better predict clinically promising drug targets. Notably, drug targets with human genetics evidence are shown to have better odds to succeed. However, a recent tensor factorization-based approach found that additional information on targets and indications might not necessarily improve the predictive accuracy. Here we revisit this approach by integrating different types of human genetics evidence collated from publicly available sources to support each target-indication pair. We use Bayesian tensor factorization to show that models incorporating all available human genetics evidence (rare disease, gene burden, common disease) modestly improves the clinical outcome prediction over models using single line of genetics evidence. We provide additional insight into the relative predictive power of different types of human genetics evidence for predicting the success of clinical outcomes.

A longstanding goal of biology is to identify the key genes and species that critically impact evolution, ecology, and health. Network analysis has revealed keystone species that regulate ecosystems and master regulators that regulate cellular genetic networks. Yet these studies have focused on pairwise biological interactions, which can be affected by the context of genetic background and other species present generating higher-order interactions. The important regulators of higher-order interactions are unstudied. To address this, we applied a new high-dimensional geometry approach that quantifies epistasis in a fitness landscape to ask how individual genes and species influence the interactions in the rest of the biological network. We then generated and also reanalyzed 5-dimensional datasets (two genetic, two microbiome). We identified key genes (e.g. the rbs locus and pykF) and species (e.g. Lactobacilli) that control the interactions of many other genes and species. These higher-order master regulators can induce or suppress evolutionary and ecological diversification by controlling the topography of the fitness landscape. Thus, we provide mathematical intuition and justification for exploration of biological networks in higher dimensions.

Over the past decade, machine learning has revolutionized computers' ability to analyze text through flexible computational models. Due to their structural similarity to written language, transformer-based architectures have also shown promise as tools to make sense of a range of multi-variate sequences from protein-structures, music, electronic health records to weather-forecasts. We can also represent human lives in a way that shares this structural similarity to language. From one perspective, lives are simply sequences of events: People are born, visit the pediatrician, start school, move to a new location, get married, and so on. Here, we exploit this similarity to adapt innovations from natural language processing to examine the evolution and predictability of human lives based on detailed event sequences. We do this by drawing on arguably the most comprehensive registry data in existence, available for an entire nation of more than six million individuals across decades. Our data include information about life-events related to health, education, occupation, income, address, and working hours, recorded with day-to-day resolution. We create embeddings of life-events in a single vector space showing that this embedding space is robust and highly structured. Our models allow us to predict diverse outcomes ranging from early mortality to personality nuances, outperforming state-of-the-art models by a wide margin. Using methods for interpreting deep learning models, we probe the algorithm to understand the factors that enable our predictions. Our framework allows researchers to identify new potential mechanisms that impact life outcomes and associated possibilities for personalized interventions.

The code of nature, embedded in DNA and RNA genomes since the origin of life, holds immense potential to impact both humans and ecosystems through genome modeling. Genomic Foundation Models (GFMs) have emerged as a transformative approach to decoding the genome. As GFMs scale up and reshape the landscape of AI-driven genomics, the field faces an urgent need for rigorous and reproducible evaluation. We present OmniGenBench, a modular benchmarking platform designed to unify the data, model, benchmarking, and interpretability layers across GFMs. OmniGenBench enables standardized, one-command evaluation of any GFM across five benchmark suites, with seamless integration of over 31 open-source models. Through automated pipelines and community-extensible features, the platform addresses critical reproducibility challenges, including data transparency, model interoperability, benchmark fragmentation, and black-box interpretability. OmniGenBench aims to serve as foundational infrastructure for reproducible genomic AI research, accelerating trustworthy discovery and collaborative innovation in the era of genome-scale modeling.

The ability to accurately model the fitness landscape of protein sequences is critical to a wide range of applications, from quantifying the effects of human variants on disease likelihood, to predicting immune-escape mutations in viruses and designing novel biotherapeutic proteins. Deep generative models of protein sequences trained on multiple sequence alignments have been the most successful approaches so far to address these tasks. The performance of these methods is however contingent on the availability of sufficiently deep and diverse alignments for reliable training. Their potential scope is thus limited by the fact many protein families are hard, if not impossible, to align. Large language models trained on massive quantities of non-aligned protein sequences from diverse families address these problems and show potential to eventually bridge the performance gap. We introduce Tranception, a novel transformer architecture leveraging autoregressive predictions and retrieval of homologous sequences at inference to achieve state-of-the-art fitness prediction performance. Given its markedly higher performance on multiple mutants, robustness to shallow alignments and ability to score indels, our approach offers significant gain of scope over existing approaches. To enable more rigorous model testing across a broader range of protein families, we develop ProteinGym -- an extensive set of multiplexed assays of variant effects, substantially increasing both the number and diversity of assays compared to existing benchmarks.

Background: Cancer remains one of the leading causes of morbidity and mortality worldwide. Comprehensive datasets that combine histopathological images with genetic and survival data across various tumour sites are essential for advancing computational pathology and personalised medicine. Results: We present SurGen, a dataset comprising 1,020 H&E-stained whole slide images (WSIs) from 843 colorectal cancer cases. The dataset includes detailed annotations for key genetic mutations (KRAS, NRAS, BRAF) and mismatch repair status, as well as survival data for 426 cases. To demonstrate SurGen's practical utility, we conducted a proof-of-concept machine learning experiment predicting mismatch repair status from the WSIs, achieving a test AUROC of 0.8316. These preliminary results underscore the dataset's potential to facilitate research in biomarker discovery, prognostic modelling, and advanced machine learning applications in colorectal cancer. Conclusions: SurGen offers a valuable resource for the scientific community, enabling studies that require high-quality WSIs linked with comprehensive clinical and genetic information on colorectal cancer. Our initial findings affirm the dataset's capacity to advance diagnostic precision and foster the development of personalised treatment strategies in colorectal oncology. Data available online at https://doi.org/10.6019/S-BIAD1285.

Image-based or morphological profiling is a rapidly expanding field wherein cells are "profiled" by extracting hundreds to thousands of unbiased, quantitative features from images of cells that have been perturbed by genetic or chemical perturbations. The Cell Painting assay is the most popular imaged-based profiling assay wherein six small-molecule dyes label eight cellular compartments and thousands of measurements are made, describing quantitative traits such as size, shape, intensity, and texture within the nucleus, cytoplasm, and whole cell (Cimini et al., 2023). We have created the Cell Painting Gallery, a publicly available collection of Cell Painting datasets, with granular dataset descriptions and access instructions. It is hosted by AWS on the Registry of Open Data (RODA). As of January 2024, the Cell Painting Gallery holds 656 terabytes (TB) of image and associated numerical data. It includes the largest publicly available Cell Painting dataset, in terms of perturbations tested (Joint Undertaking for Morphological Profiling or JUMP (Chandrasekaran et al., 2023)), along with many other canonical datasets using Cell Painting, close derivatives of Cell Painting (such as LipocyteProfiler (Laber et al., 2023) and Pooled Cell Painting (Ramezani et al., 2023)).

Large Language Models (LLMs) demonstrate remarkable generalizability across diverse tasks, yet genomic foundation models (GFMs) still require separate finetuning for each downstream application, creating significant overhead as model sizes grow. Moreover, existing GFMs are constrained by rigid output formats, limiting their applicability to various genomic tasks. In this work, we revisit the transformer-based auto-regressive models and introduce Omni-DNA, a family of cross-modal multi-task models ranging from 20 million to 1 billion parameters. Our approach consists of two stages: (i) pretraining on DNA sequences with next token prediction objective, and (ii) expanding the multi-modal task-specific tokens and finetuning for multiple downstream tasks simultaneously. When evaluated on the Nucleotide Transformer and GB benchmarks, Omni-DNA achieves state-of-the-art performance on 18 out of 26 tasks. Through multi-task finetuning, Omni-DNA addresses 10 acetylation and methylation tasks at once, surpassing models trained on each task individually. Finally, we design two complex genomic tasks, DNA2Function and Needle-in-DNA, which map DNA sequences to textual functional descriptions and images, respectively, indicating Omni-DNA's cross-modal capabilities to broaden the scope of genomic applications. All the models are available through https://huggingface.co/collections/zehui127

DNA foundation models have become transformative tools in bioinformatics and healthcare applications. Trained on vast genomic datasets, these models can be used to generate sequence embeddings, dense vector representations that capture complex genomic information. These embeddings are increasingly being shared via Embeddings-as-a-Service (EaaS) frameworks to facilitate downstream tasks, while supposedly protecting the privacy of the underlying raw sequences. However, as this practice becomes more prevalent, the security of these representations is being called into question. This study evaluates the resilience of DNA foundation models to model inversion attacks, whereby adversaries attempt to reconstruct sensitive training data from model outputs. In our study, the model's output for reconstructing the DNA sequence is a zero-shot embedding, which is then fed to a decoder. We evaluated the privacy of three DNA foundation models: DNABERT-2, Evo 2, and Nucleotide Transformer v2 (NTv2). Our results show that per-token embeddings allow near-perfect sequence reconstruction across all models. For mean-pooled embeddings, reconstruction quality degrades as sequence length increases, though it remains substantially above random baselines. Evo 2 and NTv2 prove to be most vulnerable, especially for shorter sequences with reconstruction similarities > 90%, while DNABERT-2's BPE tokenization provides the greatest resilience. We found that the correlation between embedding similarity and sequence similarity was a key predictor of reconstruction success. Our findings emphasize the urgent need for privacy-aware design in genomic foundation models prior to their widespread deployment in EaaS settings. Training code, model weights and evaluation pipeline are released on: https://github.com/not-a-feature/DNA-Embedding-Inversion.

Large-scale cell microscopy screens are used in drug discovery and molecular biology research to study the effects of millions of chemical and genetic perturbations on cells. To use these images in downstream analysis, we need models that can map each image into a feature space that represents diverse biological phenotypes consistently, in the sense that perturbations with similar biological effects have similar representations. In this work, we present the largest foundation model for cell microscopy data to date, a new 1.9 billion-parameter ViT-G/8 MAE trained on over 8 billion microscopy image crops. Compared to a previous published ViT-L/8 MAE, our new model achieves a 60% improvement in linear separability of genetic perturbations and obtains the best overall performance on whole-genome biological relationship recall and replicate consistency benchmarks. Beyond scaling, we developed two key methods that improve performance: (1) training on a curated and diverse dataset; and, (2) using biologically motivated linear probing tasks to search across each transformer block for the best candidate representation of whole-genome screens. We find that many self-supervised vision transformers, pretrained on either natural or microscopy images, yield significantly more biologically meaningful representations of microscopy images in their intermediate blocks than in their typically used final blocks. More broadly, our approach and results provide insights toward a general strategy for successfully building foundation models for large-scale biological data.

Nucleotide sequences constitute the fundamental genetic basis of biological systems, rendering viral genomic analysis critical for biomedical advancement. Despite progress in biological foundation models, specifically nucleotide foundation models (NFMs), the field lacks a unified standard for viral genomics to facilitate community development and enforce biosecurity constraints. To address this, we introduce ViroBench, the first comprehensive and large-scale benchmark specifically designed for NFMs in viral settings. ViroBench evaluates models across two critical dimensions: biological understanding and latent biosecurity risk, covering 18 diverse scenarios within 4 task types. Extensive evaluation of 66 NFMs across diverse architectures yields three critical conclusions. Firstly, NFMs exhibit a performance degradation in biological understanding under phylogenetic and temporal shifts, indicating weak extrapolation capabilities. Secondly, generation tasks reveal a decoupling between statistical likelihood and biological functional validity, posing latent biosecurity risks. Thirdly, controlled ablation studies reveal that taxonomic diversity in pretraining data outweighs parameter scale. Specifically, a lightweight baseline trained on diverse data achieves a 67.5% performance gain over its original model. Overall, ViroBench provides interpretable, diagnostic evaluations and a reproducible measurement framework for future research on viral nucleotide foundation models. The datasets and code are publicly available at https://github.com/QIANJINYDX/ViroBench.

Many online platforms maintain user profiles for personalization. Unfortunately, these profiles are typically not interpretable or easily modifiable by the user. To remedy this shortcoming, we explore natural language-based user profiles, as they promise enhanced transparency and scrutability of recommender systems. While existing work has shown that language-based profiles from standard LLMs can be effective, such generalist LLMs are unlikely to be optimal for this task. In this paper, we introduce LangPTune, the first end-to-end learning method for training LLMs to produce language-based user profiles that optimize recommendation effectiveness. Through comprehensive evaluations of LangPTune across various training configurations and benchmarks, we demonstrate that our approach significantly outperforms existing profile-based methods. In addition, it approaches performance levels comparable to state-of-the-art, less transparent recommender systems, providing a robust and interpretable alternative to conventional systems. Finally, we validate the relative interpretability of these language-based user profiles through user studies involving crowdworkers and GPT-4-based evaluations. Implementation of LangPTune can be found at https://github.com/ZhaolinGao/LangPTune.

Understanding the underlying linguistic rules of plant genomes remains a fundamental challenge in computational biology. Recent advances including AgroNT and PDLLMs have made notable progress although, they suffer from excessive parameter size and limited ability to model the bidirectional nature of DNA strands respectively. To address these limitations, we propose PlantBiMoE, a lightweight and expressive plant genome language model that integrates bidirectional Mamba and a Sparse Mixture-of-Experts (SparseMoE) framework. The bidirectional Mamba enables the model to effectively capture structural dependencies across both the forward and reverse DNA strands, while SparseMoE significantly reduces the number of active parameters, improving computational efficiency without sacrificing modeling capacity. We evaluated and tested our model on the Modified Plants Genome Benchmark (MPGB), an enhanced genomic benchmark, which consolidates 31 datasets across 11 representative tasks, with input sequence lengths ranging from 50 to 6,000 bp. Experimental results demonstrate that PlantBiMoE achieves the best performance on 20 out of 31 datasets and the average best when comparing with existing models. In summary, all above results demonstrate that our model can effectively represent plant genomic sequences, serving as a robust computational tool for diverse genomic tasks, while making substantive contributions to plant genomics, gene editing, and synthetic biology. The code is available at: https://github.com/HUST-Keep-Lin/PlantBiMoE

While large language models (LLMs) have been successfully applied to various tasks, they still face challenges with hallucinations. Augmenting LLMs with domain-specific tools such as database utilities can facilitate easier and more precise access to specialized knowledge. In this paper, we present GeneGPT, a novel method for teaching LLMs to use the Web APIs of the National Center for Biotechnology Information (NCBI) for answering genomics questions. Specifically, we prompt Codex to solve the GeneTuring tests with NCBI Web APIs by in-context learning and an augmented decoding algorithm that can detect and execute API calls. Experimental results show that GeneGPT achieves state-of-the-art performance on eight tasks in the GeneTuring benchmark with an average score of 0.83, largely surpassing retrieval-augmented LLMs such as the new Bing (0.44), biomedical LLMs such as BioMedLM (0.08) and BioGPT (0.04), as well as GPT-3 (0.16) and ChatGPT (0.12). Our further analyses suggest that: (1) API demonstrations have good cross-task generalizability and are more useful than documentations for in-context learning; (2) GeneGPT can generalize to longer chains of API calls and answer multi-hop questions in GeneHop, a novel dataset introduced in this work; (3) Different types of errors are enriched in different tasks, providing valuable insights for future improvements.

Decoding the linguistic intricacies of the genome is a crucial problem in biology, and pre-trained foundational models such as DNABERT and Nucleotide Transformer have made significant strides in this area. Existing works have largely hinged on k-mer, fixed-length permutations of A, T, C, and G, as the token of the genome language due to its simplicity. However, we argue that the computation and sample inefficiencies introduced by k-mer tokenization are primary obstacles in developing large genome foundational models. We provide conceptual and empirical insights into genome tokenization, building on which we propose to replace k-mer tokenization with Byte Pair Encoding (BPE), a statistics-based data compression algorithm that constructs tokens by iteratively merging the most frequent co-occurring genome segment in the corpus. We demonstrate that BPE not only overcomes the limitations of k-mer tokenization but also benefits from the computational efficiency of non-overlapping tokenization. Based on these insights, we introduce DNABERT-2, a refined genome foundation model that adapts an efficient tokenizer and employs multiple strategies to overcome input length constraints, reduce time and memory expenditure, and enhance model capability. Furthermore, we identify the absence of a comprehensive and standardized benchmark for genome understanding as another significant impediment to fair comparative analysis. In response, we propose the Genome Understanding Evaluation (GUE), a comprehensive multi-species genome classification dataset that amalgamates 28 distinct datasets across 7 tasks, with input lengths ranging from 70 to 1000. Through comprehensive experiments on the GUE benchmark, we demonstrate that DNABERT-2 achieves comparable performance to the state-of-the-art model with 21 times fewer parameters and approximately 56 times less GPU time in pre-training.

Genome-wide association studies are pivotal in understanding the genetic underpinnings of complex traits and diseases. Collaborative, multi-site GWAS aim to enhance statistical power but face obstacles due to the sensitive nature of genomic data sharing. Current state-of-the-art methods provide a privacy-focused approach utilizing computationally expensive methods such as Secure Multi-Party Computation and Homomorphic Encryption. In this context, we present a novel algorithm PP-GWAS designed to improve upon existing standards in terms of computational efficiency and scalability without sacrificing data privacy. This algorithm employs randomized encoding within a distributed architecture to perform stacked ridge regression on a Linear Mixed Model to ensure rigorous analysis. Experimental evaluation with real world and synthetic data indicates that PP-GWAS can achieve computational speeds twice as fast as similar state-of-the-art algorithms while using lesser computational resources, all while adhering to a robust security model that caters to an all-but-one semi-honest adversary setting. We have assessed its performance using various datasets, emphasizing its potential in facilitating more efficient and private genomic analyses.

With the advent of deep generative models in computational chemistry, in silico anticancer drug design has undergone an unprecedented transformation. While state-of-the-art deep learning approaches have shown potential in generating compounds with desired chemical properties, they disregard the genetic profile and properties of the target disease. Here, we introduce the first generative model capable of tailoring anticancer compounds for a specific biomolecular profile. Using a RL framework, the transcriptomic profiles of cancer cells are used as a context for the generation of candidate molecules. Our molecule generator combines two separately pretrained variational autoencoders (VAEs) - the first VAE encodes transcriptomic profiles into a smooth, latent space which in turn is used to condition a second VAE to generate novel molecular structures on the given transcriptomic profile. The generative process is optimized through PaccMann, a previously developed drug sensitivity prediction model to obtain effective anticancer compounds for the given context (i.e., transcriptomic profile). We demonstrate how the molecule generation can be biased towards compounds with high predicted inhibitory effect against individual cell lines or specific cancer sites. We verify our approach by investigating candidate drugs generated against specific cancer types and find the highest structural similarity to existing compounds with known efficacy against these cancer types. We envision our approach to transform in silico anticancer drug design by leveraging the biomolecular characteristics of the disease in order to increase success rates in lead compound discovery.

In-context learning (ICL) -- the capacity of a model to infer and apply abstract patterns from examples provided within its input -- has been extensively studied in large language models trained for next-token prediction on human text. In fact, prior work often attributes this emergent behavior to distinctive statistical properties in human language. This raises a fundamental question: can ICL arise organically in other sequence domains purely through large-scale predictive training? To explore this, we turn to genomic sequences, an alternative symbolic domain rich in statistical structure. Specifically, we study the Evo2 genomic model, trained predominantly on next-nucleotide (A/T/C/G) prediction, at a scale comparable to mid-sized LLMs. We develop a controlled experimental framework comprising symbolic reasoning tasks instantiated in both linguistic and genomic forms, enabling direct comparison of ICL across genomic and linguistic models. Our results show that genomic models, like their linguistic counterparts, exhibit log-linear gains in pattern induction as the number of in-context demonstrations increases. To the best of our knowledge, this is the first evidence of organically emergent ICL in genomic sequences, supporting the hypothesis that ICL arises as a consequence of large-scale predictive modeling over rich data. These findings extend emergent meta-learning beyond language, pointing toward a unified, modality-agnostic view of in-context learning.

Large language models (LLMs) and emerging agentic frameworks are beginning to transform single-cell biology by enabling natural-language reasoning, generative annotation, and multimodal data integration. However, progress remains fragmented across data modalities, architectures, and evaluation standards. LLM4Cell presents the first unified survey of 58 foundation and agentic models developed for single-cell research, spanning RNA, ATAC, multi-omic, and spatial modalities. We categorize these methods into five families-foundation, text-bridge, spatial, multimodal, epigenomic, and agentic-and map them to eight key analytical tasks including annotation, trajectory and perturbation modeling, and drug-response prediction. Drawing on over 40 public datasets, we analyze benchmark suitability, data diversity, and ethical or scalability constraints, and evaluate models across 10 domain dimensions covering biological grounding, multi-omics alignment, fairness, privacy, and explainability. By linking datasets, models, and evaluation domains, LLM4Cell provides the first integrated view of language-driven single-cell intelligence and outlines open challenges in interpretability, standardization, and trustworthy model development.

The impact of person-job fit on job satisfaction and performance is widely acknowledged, which highlights the importance of providing workers with next steps at the right time in their career. This task of predicting the next step in a career is known as career path prediction, and has diverse applications such as turnover prevention and internal job mobility. Existing methods to career path prediction rely on large amounts of private career history data to model the interactions between job titles and companies. We propose leveraging the unexplored textual descriptions that are part of work experience sections in resumes. We introduce a structured dataset of 2,164 anonymized career histories, annotated with ESCO occupation labels. Based on this dataset, we present a novel representation learning approach, CareerBERT, specifically designed for work history data. We develop a skill-based model and a text-based model for career path prediction, which achieve 35.24% and 39.61% recall@10 respectively on our dataset. Finally, we show that both approaches are complementary as a hybrid approach achieves the strongest result with 43.01% recall@10.

Despite being self-supervised, protein language models have shown remarkable performance in fundamental biological tasks such as predicting impact of genetic variation on protein structure and function. The effectiveness of these models on diverse set of tasks suggests that they learn meaningful representations of fitness landscape that can be useful for downstream clinical applications. Here, we interrogate the use of these language models in characterizing known pathogenic mutations in curated, medically actionable genes through an exhaustive search of putative compensatory mutations on each variant's genetic background. Systematic analysis of the predicted effects of these compensatory mutations reveal unappreciated structural features of proteins that are missed by other structure predictors like AlphaFold. While deep mutational scan experiments provide an unbiased estimate of the mutational landscape, we encourage the community to generate and curate rescue mutation experiments to inform the design of more sophisticated co-masking strategies and leverage large language models more effectively for downstream clinical prediction tasks.

Despite advancements in Large Language Model (LLM) alignment, understanding the reasons behind LLM preferences remains crucial for bridging the gap between desired and actual behavior. LLMs often exhibit biases or tendencies that diverge from human preferences, such as favoring certain writing styles or producing overly verbose outputs. However, current methods for evaluating preference alignment often lack explainability, relying on coarse-grained comparisons. To address this, we introduce PROFILE (PRObing Factors of InfLuence for Explainability), a novel framework that uncovers and quantifies the influence of specific factors driving preferences. PROFILE's factor level analysis explains the 'why' behind human-model alignment and misalignment, offering insights into the direction of model improvement. We apply PROFILE to analyze human and LLM preferences across three tasks: summarization, helpful response generation, and document-based question-answering. Our factor level analysis reveals a substantial discrepancy between human and LLM preferences in generation tasks, whereas LLMs show strong alignment with human preferences in evaluation tasks. We demonstrate how leveraging factor level insights, including addressing misaligned factors or exploiting the generation-evaluation gap, can improve alignment with human preferences. This work underscores the importance of explainable preference analysis and highlights PROFILE's potential to provide valuable training signals, driving further improvements in human-model alignment.

The molecular characterization of tumor samples by multiple omics data sets of different types or modalities (e.g. gene expression, mutation, CpG methylation) has become an invaluable source of information for assessing the expected performance of individual drugs and their combinations. Merging the relevant information from the omics data modalities provides the statistical basis for determining suitable therapies for specific cancer patients. Different data modalities may each have their specific structures that need to be taken into account during inference. In this paper, we assume that each omics data modality has a low-rank structure with only few relevant features that affect the prediction and we propose to use a composite local nuclear norm penalization for learning drug sensitivity. Numerical results show that the composite low-rank structure can improve the prediction performance compared to using a global low-rank approach or elastic net regression.

Cancer progression arises from interactions across multiple biological layers, especially beyond morphological and across molecular layers that remain invisible to image-only models. To capture this broader biological landscape, we present EXAONE Path 2.5, a pathology foundation model that jointly models histologic, genomic, epigenetic and transcriptomic modalities, producing an integrated patient representation that reflects tumor biology more comprehensively. Our approach incorporates three key components: (1) multimodal SigLIP loss enabling all-pairwise contrastive learning across heterogeneous modalities, (2) a fragment-aware rotary positional encoding (F-RoPE) module that preserves spatial structure and tissue-fragment topology in WSI, and (3) domain-specialized internal foundation models for both WSI and RNA-seq to provide biologically grounded embeddings for robust multimodal alignment. We evaluate EXAONE Path 2.5 against six leading pathology foundation models across two complementary benchmarks: an internal real-world clinical dataset and the Patho-Bench benchmark covering 80 tasks. Our framework demonstrates high data and parameter efficiency, achieving on-par performance with state-of-the-art foundation models on Patho-Bench while exhibiting the highest adaptability in the internal clinical setting. These results highlight the value of biologically informed multimodal design and underscore the potential of integrated genotype-to-phenotype modeling for next-generation precision oncology.

Nucleotide sequence variation can induce significant shifts in functional fitness. Recent nucleotide foundation models promise to predict such fitness effects directly from sequence, yet heterogeneous datasets and inconsistent preprocessing make it difficult to compare methods fairly across DNA and RNA families. Here we introduce NABench, a large-scale, systematic benchmark for nucleic acid fitness prediction. NABench aggregates 162 high-throughput assays and curates 2.6 million mutated sequences spanning diverse DNA and RNA families, with standardized splits and rich metadata. We show that NABench surpasses prior nucleotide fitness benchmarks in scale, diversity, and data quality. Under a unified evaluation suite, we rigorously assess 29 representative foundation models across zero-shot, few-shot prediction, transfer learning, and supervised settings. The results quantify performance heterogeneity across tasks and nucleic-acid types, demonstrating clear strengths and failure modes for different modeling choices and establishing strong, reproducible baselines. We release NABench to advance nucleic acid modeling, supporting downstream applications in RNA/DNA design, synthetic biology, and biochemistry. Our code is available at https://github.com/mrzzmrzz/NABench.

Whole-genome sequencing (WGS) has revealed numerous non-coding short variants whose functional impacts remain poorly understood. Despite recent advances in deep-learning genomic approaches, accurately predicting and prioritizing clinically relevant mutations in gene regulatory regions remains a major challenge. Here we introduce Deep VRegulome, a deep-learning method for prediction and interpretation of functionally disruptive variants in the human regulome, which combines 700 DNABERT fine-tuned models, trained on vast amounts of ENCODE gene regulatory regions, with variant scoring, motif analysis, attention-based visualization, and survival analysis. We showcase its application on TCGA glioblastoma WGS dataset in prioritizing survival-associated mutations and regulatory regions. The analysis identified 572 splice-disrupting and 9,837 transcription-factor binding site altering mutations occurring in greater than 10% of glioblastoma samples. Survival analysis linked 1352 mutations and 563 disrupted regulatory regions to patient outcomes, enabling stratification via non-coding mutation signatures. All the code, fine-tuned models, and an interactive data portal are publicly available.

Chromosome analysis is vital for diagnosing genetic disorders and guiding cancer therapy decisions through the identification of somatic clonal aberrations. However, developing an AI model are hindered by the overwhelming complexity and diversity of chromosomal abnormalities, requiring extensive annotation efforts, while automated methods remain task-specific and lack generalizability due to the scarcity of comprehensive datasets spanning diverse resource conditions. Here, we introduce CHROMA, a foundation model for cytogenomics, designed to overcome these challenges by learning generalizable representations of chromosomal abnormalities. Pre-trained on over 84,000 specimens (~4 million chromosomal images) via self-supervised learning, CHROMA outperforms other methods across all types of abnormalities, even when trained on fewer labelled data and more imbalanced datasets. By facilitating comprehensive mapping of instability and clonal leisons across various aberration types, CHROMA offers a scalable and generalizable solution for reliable and automated clinical analysis, reducing the annotation workload for experts and advancing precision oncology through the early detection of rare genomic abnormalities, enabling broad clinical AI applications and making advanced genomic analysis more accessible.

Multi-omics research has enhanced our understanding of cancer heterogeneity and progression. Investigating molecular data through multi-omics approaches is crucial for unraveling the complex biological mechanisms underlying cancer, thereby enabling effective diagnosis, treatment, and prevention strategies. However, predicting patient outcomes through integration of all available multi-omics data is an under-study research direction. Here, we present SeNMo (Self-normalizing Network for Multi-omics), a deep neural network trained on multi-omics data across 33 cancer types. SeNMo is efficient in handling multi-omics data characterized by high-width (many features) and low-length (fewer samples) attributes. We trained SeNMo for the task of overall survival using pan-cancer data involving 33 cancer sites from Genomics Data Commons (GDC). The training data includes gene expression, DNA methylation, miRNA expression, DNA mutations, protein expression modalities, and clinical data. We evaluated the model's performance in predicting overall survival using concordance index (C-Index). SeNMo performed consistently well in training regime, with the validation C-Index of 0.76 on GDC's public data. In the testing regime, SeNMo performed with a C-Index of 0.758 on a held-out test set. The model showed an average accuracy of 99.8% on the task of classifying the primary cancer type on the pan-cancer test cohort. SeNMo proved to be a mini-foundation model for multi-omics oncology data because it demonstrated robust performance, and adaptability not only across molecular data types but also on the classification task of predicting the primary cancer type of patients. SeNMo can be further scaled to any cancer site and molecular data type. We believe SeNMo and similar models are poised to transform the oncology landscape, offering hope for more effective, efficient, and patient-centric cancer care.

Previous studies have shown that automated text-mining tools are becoming increasingly important for successfully unlocking variant information in scientific literature at large scale. Despite multiple attempts in the past, existing tools are still of limited recognition scope and precision. We propose tmVar 3.0: an improved variant recognition and normalization tool. Compared to its predecessors, tmVar 3.0 is able to recognize a wide spectrum of variant related entities (e.g., allele and copy number variants), and to group different variant mentions belonging to the same concept in an article for improved accuracy. Moreover, tmVar3 provides additional variant normalization options such as allele-specific identifiers from the ClinGen Allele Registry. tmVar3 exhibits a state-of-the-art performance with over 90% accuracy in F-measure in variant recognition and normalization, when evaluated on three independent benchmarking datasets. tmVar3 is freely available for download. We have also processed the entire PubMed and PMC with tmVar3 and released its annotations on our FTP. Availability: ftp://ftp.ncbi.nlm.nih.gov/pub/lu/tmVar3

The cycle of scientific discovery is frequently bottlenecked by the slow, manual creation of software to support computational experiments. To address this, we present an AI system that creates expert-level scientific software whose goal is to maximize a quality metric. The system uses a Large Language Model (LLM) and Tree Search (TS) to systematically improve the quality metric and intelligently navigate the large space of possible solutions. The system achieves expert-level results when it explores and integrates complex research ideas from external sources. The effectiveness of tree search is demonstrated across a wide range of benchmarks. In bioinformatics, it discovered 40 novel methods for single-cell data analysis that outperformed the top human-developed methods on a public leaderboard. In epidemiology, it generated 14 models that outperformed the CDC ensemble and all other individual models for forecasting COVID-19 hospitalizations. Our method also produced state-of-the-art software for geospatial analysis, neural activity prediction in zebrafish, time series forecasting and numerical solution of integrals. By devising and implementing novel solutions to diverse tasks, the system represents a significant step towards accelerating scientific progress.

Metadata are general characteristics of the data in a well-curated and condensed format, and have been proven to be useful for decision making, knowledge discovery, and also heterogeneous data organization of biobank. Among all data types in the biobank, pathology is the key component of the biobank and also serves as the gold standard of diagnosis. To maximize the utility of biobank and allow the rapid progress of biomedical science, it is essential to organize the data with well-populated pathology metadata. However, manual annotation of such information is tedious and time-consuming. In the study, we develop a multimodal multitask learning framework to predict four major slide-level metadata of pathology images. The framework learns generalizable representations across tissue slides, pathology reports, and case-level structured data. We demonstrate improved performance across all four tasks with the proposed method compared to a single modal single task baseline on two test sets, one external test set from a distinct data source (TCGA) and one internal held-out test set (TTH). In the test sets, the performance improvements on the averaged area under receiver operating characteristic curve across the four tasks are 16.48% and 9.05% on TCGA and TTH, respectively. Such pathology metadata prediction system may be adopted to mitigate the effort of expert annotation and ultimately accelerate the data-driven research by better utilization of the pathology biobank.

Genetic pathways usually encode molecular mechanisms that can inform targeted interventions. It is often challenging for existing machine learning approaches to jointly model genetic pathways (higher-order features) and variants (atomic features), and present to clinicians interpretable models. In order to build more accurate and better interpretable machine learning models for genetic medicine, we introduce Pathway Augmented Nonnegative Tensor factorization for HighER-order feature learning (PANTHER). PANTHER selects informative genetic pathways that directly encode molecular mechanisms. We apply genetically motivated constrained tensor factorization to group pathways in a way that reflects molecular mechanism interactions. We then train a softmax classifier for disease types using the identified pathway groups. We evaluated PANTHER against multiple state-of-the-art constrained tensor/matrix factorization models, as well as group guided and Bayesian hierarchical models. PANTHER outperforms all state-of-the-art comparison models significantly (p<0.05). Our experiments on large scale Next Generation Sequencing (NGS) and whole-genome genotyping datasets also demonstrated wide applicability of PANTHER. We performed feature analysis in predicting disease types, which suggested insights and benefits of the identified pathway groups.

Effective DNA embedding remains crucial in genomic analysis, particularly in scenarios lacking labeled data for model fine-tuning, despite the significant advancements in genome foundation models. A prime example is metagenomics binning, a critical process in microbiome research that aims to group DNA sequences by their species from a complex mixture of DNA sequences derived from potentially thousands of distinct, often uncharacterized species. To fill the lack of effective DNA embedding models, we introduce DNABERT-S, a genome foundation model that specializes in creating species-aware DNA embeddings. To encourage effective embeddings to error-prone long-read DNA sequences, we introduce Manifold Instance Mixup (MI-Mix), a contrastive objective that mixes the hidden representations of DNA sequences at randomly selected layers and trains the model to recognize and differentiate these mixed proportions at the output layer. We further enhance it with the proposed Curriculum Contrastive Learning (C^2LR) strategy. Empirical results on 18 diverse datasets showed DNABERT-S's remarkable performance. It outperforms the top baseline's performance in 10-shot species classification with just a 2-shot training while doubling the Adjusted Rand Index (ARI) in species clustering and substantially increasing the number of correctly identified species in metagenomics binning. The code, data, and pre-trained model are publicly available at https://github.com/Zhihan1996/DNABERT_S.

Predicting gene function from its DNA sequence is a fundamental challenge in biology. Many deep learning models have been proposed to embed DNA sequences and predict their enzymatic function, leveraging information in public databases linking DNA sequences to an enzymatic function label. However, much of the scientific community's knowledge of biological function is not represented in these categorical labels, and is instead captured in unstructured text descriptions of mechanisms, reactions, and enzyme behavior. These descriptions are often captured alongside DNA sequences in biological databases, albeit in an unstructured manner. Deep learning of models predicting enzymatic function are likely to benefit from incorporating this multi-modal data encoding scientific knowledge of biological function. There is, however, no dataset designed for machine learning algorithms to leverage this multi-modal information. Here we propose a novel dataset and benchmark suite that enables the exploration and development of large multi-modal neural network models on gene DNA sequences and natural language descriptions of gene function. We present baseline performance on benchmarks for both unsupervised and supervised tasks that demonstrate the difficulty of this modeling objective, while demonstrating the potential benefit of incorporating multi-modal data types in function prediction compared to DNA sequences alone. Our dataset is at: https://hoarfrost-lab.github.io/BioTalk/.

The advancement in generative AI could be boosted with more accessible mathematics. Beyond human-AI chat, large language models (LLMs) are emerging in programming, algorithm discovery, and theorem proving, yet their genomics application is limited. This project introduces Math Agents and mathematical embedding as fresh entries to the "Moore's Law of Mathematics", using a GPT-based workflow to convert equations from literature into LaTeX and Python formats. While many digital equation representations exist, there's a lack of automated large-scale evaluation tools. LLMs are pivotal as linguistic user interfaces, providing natural language access for human-AI chat and formal languages for large-scale AI-assisted computational infrastructure. Given the infinite formal possibility spaces, Math Agents, which interact with math, could potentially shift us from "big data" to "big math". Math, unlike the more flexible natural language, has properties subject to proof, enabling its use beyond traditional applications like high-validation math-certified icons for AI alignment aims. This project aims to use Math Agents and mathematical embeddings to address the ageing issue in information systems biology by applying multiscalar physics mathematics to disease models and genomic data. Generative AI with episodic memory could help analyse causal relations in longitudinal health records, using SIR Precision Health models. Genomic data is suggested for addressing the unsolved Alzheimer's disease problem.

Predicting spatial gene expression from H&E histology offers a scalable and clinically accessible alternative to sequencing, but realizing clinical impact requires models that generalize across cancer types and capture biologically coherent signals. Prior work is often limited to per-cancer settings and variance-based evaluation, leaving functional relevance underexplored. We introduce HistoPrism, an efficient transformer-based architecture for pan-cancer prediction of gene expression from histology. To evaluate biological meaning, we introduce a pathway-level benchmark, shifting assessment from isolated gene-level variance to coherent functional pathways. HistoPrism not only surpasses prior state-of-the-art models on highly variable genes , but also more importantly, achieves substantial gains on pathway-level prediction, demonstrating its ability to recover biologically coherent transcriptomic patterns. With strong pan-cancer generalization and improved efficiency, HistoPrism establishes a new standard for clinically relevant transcriptomic modeling from routinely available histology.

Genomic alterations lead to cancer complexity and form a major hurdle for a comprehensive understanding of the molecular mechanisms underlying oncogenesis. In this review, we describe the recent advances in studying cancer-associated genes from a systems biological point of view. The integration of known cancer genes onto protein and signaling networks reveals the characteristics of cancer genes within networks. This approach shows that cancer genes often function as network hub proteins which are involved in many cellular processes and form focal nodes in the information exchange between many signaling pathways. Literature mining allows constructing gene-gene networks, in which new cancer genes can be identified. The gene expression profiles of cancer cells are used for reconstructing gene regulatory networks. By doing so, the genes, which are involved in the regulation of cancer progression, can be picked up from these networks after which their functions can be further confirmed in the laboratory.

Recent genomic foundation models largely adopt large language model architectures that treat DNA as a one-dimensional token sequence. However, exhaustive sequential reading is structurally misaligned with sparse and discontinuous genomic semantics, leading to wasted computation on low-information background and preventing understanding-driven compression for long contexts. Here, we present OpticalDNA, a vision-based framework that reframes genomic modeling as Optical Character Recognition (OCR)-style document understanding. OpticalDNA renders DNA into structured visual layouts and trains an OCR-capable vision--language model with a visual DNA encoder and a document decoder, where the encoder produces compact, reconstructible visual tokens for high-fidelity compression. Building on this representation, OpticalDNA defines prompt-conditioned objectives over core genomic primitives-reading, region grounding, subsequence retrieval, and masked span completion-thereby learning layout-aware DNA representations that retain fine-grained genomic information under a reduced effective token budget. Across diverse genomic benchmarks, OpticalDNA consistently outperforms recent baselines; on sequences up to 450k bases, it achieves the best overall performance with nearly 20times fewer effective tokens, and surpasses models with up to 985times more activated parameters while tuning only 256k trainable parameters.

In recent years, large language models (LLMs) have achieved state-of-the-art results in various biological sequence analysis tasks, such as sequence classification, structure prediction, and function prediction. Similar to advancements in AI for other scientific fields, deeper research into biological LLMs has begun to focus on using these models to rediscover important existing biological laws or uncover entirely new patterns in biological sequences.This study leverages GPT-like LLMs to utilize language transfer capabilities to rediscover the genetic code rules of the central dogma. In our experimental design, we transformed the central dogma into a binary classification problem of aligning DNA sequences with protein sequences, where positive examples are matching DNA and protein sequences, and negative examples are non-matching pairs.We first trained a GPT-2 model from scratch using a dataset comprising protein sequences, DNA sequences, and sequences from languages such as English and Chinese. Subsequently, we fine-tuned the model using the English similarity judgment dataset from PAWS-X. When tested on a dataset for DNA and protein sequence alignment judgment, the fine-tuned model achieved a classification accuracy of 76%. The study also analyzed factors contributing to this zero-shot capability, including model training stability and types of training data.This research demonstrates that LLMs can, through the transfer of natural language capabilities and solely relying on the analysis of sequences themselves, rediscover the central dogma without prior knowledge of it. This study opens a new door for AI-driven biological research.

Content generation modeling has emerged as a promising direction in computational pathology, offering capabilities such as data-efficient learning, synthetic data augmentation, and task-oriented generation across diverse diagnostic tasks. This review provides a comprehensive synthesis of recent progress in the field, organized into four key domains: image generation, text generation, molecular profile-morphology generation, and other specialized generation applications. By analyzing over 150 representative studies, we trace the evolution of content generation architectures -- from early generative adversarial networks to recent advances in diffusion models and generative vision-language models. We further examine the datasets and evaluation protocols commonly used in this domain and highlight ongoing limitations, including challenges in generating high-fidelity whole slide images, clinical interpretability, and concerns related to the ethical and legal implications of synthetic data. The review concludes with a discussion of open challenges and prospective research directions, with an emphasis on developing integrated and clinically deployable generation systems. This work aims to provide a foundational reference for researchers and practitioners developing content generation models in computational pathology.

Motivation: Phenotype concept recognition (CR) is a fundamental task in biomedical text mining. However, existing methods either require ontology-specific training, making them struggle to generalize across diverse text styles and evolving biomedical terminology, or depend on general-purpose large language models (LLMs) that lack necessary domain knowledge. Results: To address these limitations, we propose AutoPCR, a prompt-based phenotype CR method designed to automatically generalize to new ontologies and unseen data without ontology-specific training. To further boost performance, we also introduce an optional self-supervised training strategy. Experiments show that AutoPCR achieves the best average and most robust performance across datasets. Further ablation and transfer studies demonstrate its inductive capability and generalizability to new ontologies. Availability and Implementation: Our code is available at https://github.com/yctao7/AutoPCR. Contact: drjieliu@umich.edu

The objective of personalized medicine is to tailor interventions to an individual patient's unique characteristics. A key technology for this purpose involves medical digital twins, computational models of human biology that can be personalized and dynamically updated to incorporate patient-specific data collected over time. Certain aspects of human biology, such as the immune system, are not easily captured with physics-based models, such as differential equations. Instead, they are often multi-scale, stochastic, and hybrid. This poses a challenge to existing model-based control and optimization approaches that cannot be readily applied to such models. Recent advances in automatic differentiation and neural-network control methods hold promise in addressing complex control problems. However, the application of these approaches to biomedical systems is still in its early stages. This work introduces dynamics-informed neural-network controllers as an alternative approach to control of medical digital twins. As a first use case for this method, the focus is on agent-based models, a versatile and increasingly common modeling platform in biomedicine. The effectiveness of the proposed neural-network control method is illustrated and benchmarked against other methods with two widely-used agent-based model types. The relevance of the method introduced here extends beyond medical digital twins to other complex dynamical systems.

Gene expression can be used to subtype breast cancer with improved prediction of risk of recurrence and treatment responsiveness over that obtained using routine immunohistochemistry (IHC). However, in the clinic, molecular profiling is primarily used for ER+ breast cancer, which is costly, tissue destructive, requires specialized platforms and takes several weeks to obtain a result. Deep learning algorithms can effectively extract morphological patterns in digital histopathology images to predict molecular phenotypes quickly and cost-effectively. We propose a new, computationally efficient approach called hist2RNA inspired by bulk RNA-sequencing techniques to predict the expression of 138 genes (incorporated from six commercially available molecular profiling tests), including luminal PAM50 subtype, from hematoxylin and eosin (H&E) stained whole slide images (WSIs). The training phase involves the aggregation of extracted features for each patient from a pretrained model to predict gene expression at the patient level using annotated H&E images from The Cancer Genome Atlas (TCGA, n=335). We demonstrate successful gene prediction on a held-out test set (n = 160, corr = 0.82 across patients, corr = 0.29 across genes) and perform exploratory analysis on an external tissue microarray (TMA) dataset (n = 498) with known IHC and survival information. Our model is able to predict gene expression and luminal PAM50 subtype (Luminal A versus Luminal B) on the TMA dataset with prognostic significance for overall survival in univariate analysis (c-index = 0.56, hazard ratio = 2.16 (95% CI 1.12-3.06), p < 5 x 10-3), and independent significance in multivariate analysis incorporating standard clinicopathological variables (c-index = 0.65, hazard ratio = 1.85 (95% CI 1.30-2.68), p < 5 x 10-3).

We introduce Vox-Profile, a comprehensive benchmark to characterize rich speaker and speech traits using speech foundation models. Unlike existing works that focus on a single dimension of speaker traits, Vox-Profile provides holistic and multi-dimensional profiles that reflect both static speaker traits (e.g., age, sex, accent) and dynamic speech properties (e.g., emotion, speech flow). This benchmark is grounded in speech science and linguistics, developed with domain experts to accurately index speaker and speech characteristics. We report benchmark experiments using over 15 publicly available speech datasets and several widely used speech foundation models that target various static and dynamic speaker and speech properties. In addition to benchmark experiments, we showcase several downstream applications supported by Vox-Profile. First, we show that Vox-Profile can augment existing speech recognition datasets to analyze ASR performance variability. Vox-Profile is also used as a tool to evaluate the performance of speech generation systems. Finally, we assess the quality of our automated profiles through comparison with human evaluation and show convergent validity. Vox-Profile is publicly available at: https://github.com/tiantiaf0627/vox-profile-release.

A compartmental deterministic model that allows (1) immunity from two stages of infection and carriage, and (2) disease induced death, is used in studying the dynamics of meningitis epidemic process in a closed population. It allows for difference in the transmission rate of infection to a susceptible by a carrier and an infective. It is generalized to allow a proportion ({\phi}) of those susceptibles infected to progress directly to infectives in stage I. Both models are used in this study. The threshold conditions for the spread of carrier and infectives in stage I are derived for the two models. Sensitivity analysis is performed on the reproductive number derived from the next generation matrix. The case-carrier ratio profile for various parameters and threshold values are shown. So also are the graphs of the total number ever infected as influenced by {\epsilon} and {\phi}. The infection transmission rate (eta), the odds in favor of a carrier, over an infective, in transmitting an infection to a susceptible ({\epsilon}) and the carrier conversion rate ({\phi}) to an infective in stage I, are identified as key parameters that should be subject of attention for any control intervention strategy. The case-carrier ratio profiles provide evidence of a critical case-carrier ratio attained before the number of reported cases grows to an epidemic level. They also provide visual evidence of epidemiological context, in this case, epidemic incidence (in later part of dry season) and endemic incidence (during rainy season). Results from total proportion ever infected suggest that the model, in which {\phi}=0 obtained, can adequately represent, in essence, the generalized model for this study.

In the pharmaceutical industry, the use of artificial intelligence (AI) has seen consistent growth over the past decade. This rise is attributed to major advancements in statistical machine learning methodologies, computational capabilities and the increased availability of large datasets. AI techniques are applied throughout different stages of drug development, ranging from drug discovery to post-marketing benefit-risk assessment. Kolluri et al. provided a review of several case studies that span these stages, featuring key applications such as protein structure prediction, success probability estimation, subgroup identification, and AI-assisted clinical trial monitoring. From a regulatory standpoint, there was a notable uptick in submissions incorporating AI components in 2021. The most prevalent therapeutic areas leveraging AI were oncology (27%), psychiatry (15%), gastroenterology (12%), and neurology (11%). The paradigm of personalized or precision medicine has gained significant traction in recent research, partly due to advancements in AI techniques hamburg2010path. This shift has had a transformative impact on the pharmaceutical industry. Departing from the traditional "one-size-fits-all" model, personalized medicine incorporates various individual factors, such as environmental conditions, lifestyle choices, and health histories, to formulate customized treatment plans. By utilizing sophisticated machine learning algorithms, clinicians and researchers are better equipped to make informed decisions in areas such as disease prevention, diagnosis, and treatment selection, thereby optimizing health outcomes for each individual.

Background. In the last decades, several life science resources have structured data using the same framework and made these accessible using the same query language to facilitate interoperability. Knowledge graphs have seen increased adoption in bioinformatics due to their advantages for representing data in a generic graph format. For example, yummydata.org catalogs more than 60 knowledge graphs accessible through SPARQL, a technical query language. Although SPARQL allows powerful, expressive queries, even across physically distributed knowledge graphs, formulating such queries is a challenge for most users. Therefore, to guide users in retrieving the relevant data, many of these resources provide representative examples. These examples can also be an important source of information for machine learning, if a sufficiently large number of examples are provided and published in a common, machine-readable and standardized format across different resources. Findings. We introduce a large collection of human-written natural language questions and their corresponding SPARQL queries over federated bioinformatics knowledge graphs (KGs) collected for several years across different research groups at the SIB Swiss Institute of Bioinformatics. The collection comprises more than 1000 example questions and queries, including 65 federated queries. We propose a methodology to uniformly represent the examples with minimal metadata, based on existing standards. Furthermore, we introduce an extensive set of open-source applications, including query graph visualizations and smart query editors, easily reusable by KG maintainers who adopt the proposed methodology. Conclusions. We encourage the community to adopt and extend the proposed methodology, towards richer KG metadata and improved Semantic Web services.

User profiling has long been an important problem that investigates user interests in many real applications. Some recent works regard users and their interacted objects as entities of a graph and turn the problem into a node classification task. However, they neglect the difference of distinct interaction types, e.g. user clicks an item v.s.user purchases an item, and thus cannot incorporate such information well. To solve these issues, we propose to leverage the relation-aware heterogeneous graph method for user profiling, which also allows capturing significant meta relations. We adopt the query, key, and value mechanism in a transformer fashion for heterogeneous message passing so that entities can effectively interact with each other. Via such interactions on different relation types, our model can generate representations with rich information for the user profile prediction. We conduct experiments on two real-world e-commerce datasets and observe a significant performance boost of our approach.

Large language models (LLMs) have shown growing promise in biomedical research, particularly for knowledge-driven interpretation tasks. However, their ability to reliably reason from gene-level knowledge to functional understanding, a core requirement for knowledge-enhanced cell atlas interpretation, remains largely underexplored. To address this gap, we introduce SciHorizon-GENE, a large-scale gene-centric benchmark constructed from authoritative biological databases. The benchmark integrates curated knowledge for over 190K human genes and comprises more than 540K questions covering diverse gene-to-function reasoning scenarios relevant to cell type annotation, functional interpretation, and mechanism-oriented analysis. Motivated by behavioral patterns observed in preliminary examinations, SciHorizon-GENE evaluates LLMs along four biologically critical perspectives: research attention sensitivity, hallucination tendency, answer completeness, and literature influence, explicitly targeting failure modes that limit the safe adoption of LLMs in biological interpretation pipelines. We systematically evaluate a wide range of state-of-the-art general-purpose and biomedical LLMs, revealing substantial heterogeneity in gene-level reasoning capabilities and persistent challenges in generating faithful, complete, and literature-grounded functional interpretations. Our benchmark establishes a systematic foundation for analyzing LLM behavior at the gene scale and offers insights for model selection and development, with direct relevance to knowledge-enhanced biological interpretation.

Genome-wide association study (GWAS) tests single nucleotide polymorphism (SNP) markers across the genome to localize the underlying causal variant of a trait. Because causal variants are seldom observed directly, a surrogate model based on genotyped markers are widely considered. Although many methods estimating the parameters of the surrogate model have been proposed, the connection between the surrogate model and the true causal model is yet investigated. In this work, we establish the connection between the surrogate model and the true causal model. The connection shows that population structure is accounted in GWAS by modelling the variant of interest and not the trait. Such observation explains how environmental confounding can be partially corrected using genetic covariates and why the previously claimed connection between PC correction and linear mixed models is incorrect.

Foundation models (FMs) have exhibited remarkable performance across a wide range of downstream tasks in many domains. Nevertheless, general-purpose FMs often face challenges when confronted with domain-specific problems, due to their limited access to the proprietary training data in a particular domain. In biomedicine, there are various biological modalities, such as molecules, proteins, and cells, which are encoded by the language of life and exhibit significant modality gaps with human natural language. In this paper, we introduce BioMedGPT, an open multimodal generative pre-trained transformer (GPT) for biomedicine, to bridge the gap between the language of life and human natural language. BioMedGPT allows users to easily ``communicate'' with diverse biological modalities through free text, which is the first of its kind. BioMedGPT aligns different biological modalities with natural language via a large generative language model, namely, BioMedGPT-LM. We publish BioMedGPT-10B, which unifies the feature spaces of molecules, proteins, and natural language via encoding and alignment. Through fine-tuning, BioMedGPT-10B outperforms or is on par with human and significantly larger general-purpose foundation models on the biomedical QA task. It also demonstrates promising performance in the molecule QA and protein QA tasks, which could greatly accelerate the discovery of new drugs and therapeutic targets. In addition, BioMedGPT-LM-7B is the first large generative language model based on Llama2 in the biomedical domain, therefore is commercial friendly. Both BioMedGPT-10B and BioMedGPT-LM-7B are open-sourced to the research community. In addition, we publish the datasets that are meticulously curated for the alignment of multi-modalities, i.e., PubChemQA and UniProtQA. All the models, codes, and datasets are available at https://github.com/PharMolix/OpenBioMed.

The World Health Organization added Disease X to their shortlist of blueprint priority diseases to represent a hypothetical, unknown pathogen that could cause a future epidemic. During different virus outbreaks of the past, such as COVID-19, Influenza, Lyme Disease, and Zika virus, researchers from various disciplines utilized Google Trends to mine multimodal components of web behavior to study, investigate, and analyze the global awareness, preparedness, and response associated with these respective virus outbreaks. As the world prepares for Disease X, a dataset on web behavior related to Disease X would be crucial to contribute towards the timely advancement of research in this field. Furthermore, none of the prior works in this field have focused on the development of a dataset to compile relevant web behavior data, which would help to prepare for Disease X. To address these research challenges, this work presents a dataset of web behavior related to Disease X, which emerged from different geographic regions of the world, between February 2018 and August 2023. Specifically, this dataset presents the search interests related to Disease X from 94 geographic regions. The dataset was developed by collecting data using Google Trends. The relevant search interests for all these regions for each month in this time range are available in this dataset. This paper also discusses the compliance of this dataset with the FAIR principles of scientific data management. Finally, an analysis of this dataset is presented to uphold the applicability, relevance, and usefulness of this dataset for the investigation of different research questions in the interrelated fields of Big Data, Data Mining, Healthcare, Epidemiology, and Data Analysis with a specific focus on Disease X.

Generative modeling of discrete variables is challenging yet crucial for applications in natural language processing and biological sequence design. We introduce the Shortlisting Model (SLM), a novel simplex-based diffusion model inspired by progressive candidate pruning. SLM operates on simplex centroids, reducing generation complexity and enhancing scalability. Additionally, SLM incorporates a flexible implementation of classifier-free guidance, enhancing unconditional generation performance. Extensive experiments on DNA promoter and enhancer design, protein design, character-level and large-vocabulary language modeling demonstrate the competitive performance and strong potential of SLM. Our code can be found at https://github.com/GenSI-THUAIR/SLM

Pathogen identification is pivotal in diagnosing, treating, and preventing diseases, crucial for controlling infections and safeguarding public health. Traditional alignment-based methods, though widely used, are computationally intense and reliant on extensive reference databases, often failing to detect novel pathogens due to their low sensitivity and specificity. Similarly, conventional machine learning techniques, while promising, require large annotated datasets and extensive feature engineering and are prone to overfitting. Addressing these challenges, we introduce PathoLM, a cutting-edge pathogen language model optimized for the identification of pathogenicity in bacterial and viral sequences. Leveraging the strengths of pre-trained DNA models such as the Nucleotide Transformer, PathoLM requires minimal data for fine-tuning, thereby enhancing pathogen detection capabilities. It effectively captures a broader genomic context, significantly improving the identification of novel and divergent pathogens. We developed a comprehensive data set comprising approximately 30 species of viruses and bacteria, including ESKAPEE pathogens, seven notably virulent bacterial strains resistant to antibiotics. Additionally, we curated a species classification dataset centered specifically on the ESKAPEE group. In comparative assessments, PathoLM dramatically outperforms existing models like DciPatho, demonstrating robust zero-shot and few-shot capabilities. Furthermore, we expanded PathoLM-Sp for ESKAPEE species classification, where it showed superior performance compared to other advanced deep learning methods, despite the complexities of the task.

Text-based personality prediction by computational models is an emerging field with the potential to significantly improve on key weaknesses of survey-based personality assessment. We investigate 3848 profiles from Twitter with self-labeled Myers-Briggs personality traits (MBTI) - a framework closely related to the Five Factor Model of personality - to better understand how text-based digital traces from social engagement online can be used to predict user personality traits. We leverage BERT, a state-of-the-art NLP architecture based on deep learning, to analyze various sources of text that hold most predictive power for our task. We find that biographies, statuses, and liked tweets contain significant predictive power for all dimensions of the MBTI system. We discuss our findings and their implications for the validity of the MBTI and the lexical hypothesis, a foundational theory underlying the Five Factor Model that links language use and behavior. Our results hold optimistic implications for personality psychologists, computational linguists, and other social scientists aiming to predict personality from observational text data and explore the links between language and core behavioral traits.

A crucial step within secondary analysis of electronic health records (EHRs) is to identify the patient cohort under investigation. While EHRs contain medical billing codes that aim to represent the conditions and treatments patients may have, much of the information is only present in the patient notes. Therefore, it is critical to develop robust algorithms to infer patients' conditions and treatments from their written notes. In this paper, we introduce a dataset for patient phenotyping, a task that is defined as the identification of whether a patient has a given medical condition (also referred to as clinical indication or phenotype) based on their patient note. Nursing Progress Notes and Discharge Summaries from the Intensive Care Unit of a large tertiary care hospital were manually annotated for the presence of several high-context phenotypes relevant to treatment and risk of re-hospitalization. This dataset contains 1102 Discharge Summaries and 1000 Nursing Progress Notes. Each Discharge Summary and Progress Note has been annotated by at least two expert human annotators (one clinical researcher and one resident physician). Annotated phenotypes include treatment non-adherence, chronic pain, advanced/metastatic cancer, as well as 10 other phenotypes. This dataset can be utilized for academic and industrial research in medicine and computer science, particularly within the field of medical natural language processing.

Elucidating the functional effect of missense variants is of crucial importance, yet challenging. To understand the impact of such variants, we fine-tuned the ESM2 protein language model to classify 20 protein features at amino acid resolution. We used the resulting models to: 1) identify protein features that are enriched in either pathogenic or benign missense variants, 2) compare the characteristics of proteins with reference or alternate alleles to understand how missense variants affect protein functionality. We show that our model can be used to reclassify some variants of unknown significance. We also demonstrate the usage of our models for understanding the potential effect of variants on protein features.

We investigate how to teach large language models (LLMs) to perform scientific reasoning by leveraging expert discussions as a learning signal. Focusing on the genomics domain, we develop an automated pipeline to extract trainable data and introduce Genome-Bench, a new benchmark constructed from over a decade of scientific forum discussions on genome engineering. Our pipeline transforms raw interactions into a reinforcement learning-friendly multiple-choice questions format, supported by 3000+ high-quality question-answer pairs spanning foundational biology, experimental troubleshooting, tool usage, and beyond. We fine-tune an LLM using RL with a rule-based reward signal derived from the synthetic MCQ dataset to enhance domain-specific reasoning. Our results show that reinforcement learning from scientific discussions improves model performance by over 15% compared to the base model on Genome-Bench, narrowing the gap between open-source LLMs and expert-level reasoning. To our knowledge, this is the first end-to-end pipeline for teaching LLMs to reason from scientific discussions, with promising potential for generalization across scientific domains beyond biology.

During a virus's evolution,various regions of the genome are subjected to distinct levels of functional constraints.Combined with factors like codon bias and DNA repair efficiency,these constraints contribute to unique mutation patterns within the genome or a specific gene. In this project, we harnessed the power of Large Language Models(LLMs) to predict the evolution of SARS-CoV-2. By treating the mutation process from one generation to the next as a translation task, we trained a transformer model, called VirusT5, to capture the mutation patterns underlying SARS-CoV-2 evolution. We evaluated the VirusT5's ability to detect these mutation patterns including its ability to identify mutation hotspots and explored the potential of using VirusT5 to predict future virus variants. Our findings demonstrate the feasibility of using a large language model to model viral evolution as a translation process. This study establishes the groundbreaking concept of "mutation-as-translation," paving the way for new methodologies and tools for combating virus threats

We introduce Biomed-Enriched, a biomedical text dataset constructed from PubMed via a two-stage annotation process. In the first stage, a large language model annotates 400K paragraphs from PubMed scientific articles, assigning scores for their type (review, study, clinical case, other), domain (clinical, biomedical, other), and educational quality. The educational quality score (rated 1 to 5) estimates how useful a paragraph is for college-level learning. These annotations are then used to fine-tune a small language model, which propagates the labels across the full PMC-OA corpus. The resulting metadata allows us to extract refined subsets, including 2M clinical case paragraphs with over 450K high-quality ones from articles with commercial-use licenses, and to construct several variants via quality filtering and domain upsampling. Clinical text is typically difficult to access due to privacy constraints, as hospital records cannot be publicly shared. Hence, our dataset provides an alternative large-scale, openly available collection of clinical cases from PubMed, making it a valuable resource for biomedical and clinical NLP. Preliminary continual-pretraining experiments with OLMo2 suggest these curated subsets enable targeted improvements, with clinical upsampling boosting performance by ~5% on MMLU ProfMed and educational quality filtering improving MedQA and MedMCQA by ~1%. Combinations of these techniques led to faster convergence, reaching same performance with a third of training tokens, indicating potential for more efficient and effective biomedical pretraining strategies.

Unlocking deep, interpretable biological reasoning from complex genomic data is a major AI challenge hindering scientific discovery. Current DNA foundation models, despite strong sequence representation, struggle with multi-step reasoning and lack inherent transparent, biologically intuitive explanations. We introduce BioReason, a pioneering architecture that, for the first time, deeply integrates a DNA foundation model with a Large Language Model (LLM). This novel connection enables the LLM to directly process and reason with genomic information as a fundamental input, fostering a new form of multimodal biological understanding. BioReason's sophisticated multi-step reasoning is developed through supervised fine-tuning and targeted reinforcement learning, guiding the system to generate logical, biologically coherent deductions. On biological reasoning benchmarks including KEGG-based disease pathway prediction - where accuracy improves from 88% to 97% - and variant effect prediction, BioReason demonstrates an average 15% performance gain over strong single-modality baselines. BioReason reasons over unseen biological entities and articulates decision-making through interpretable, step-by-step biological traces, offering a transformative approach for AI in biology that enables deeper mechanistic insights and accelerates testable hypothesis generation from genomic data. Data, code, and checkpoints are publicly available at https://github.com/bowang-lab/BioReason

As AI foundation models grow in capability, a deeper question emerges: What shapes their internal cognitive identity -- beyond fluency and output? Benchmarks measure behavior, but the soul of a model resides in its latent geometry. In this work, we propose Neural DNA (nDNA) as a semantic-genotypic representation that captures this latent identity through the intrinsic geometry of belief. At its core, nDNA is synthesized from three principled and indispensable dimensions of latent geometry: spectral curvature, which reveals the curvature of conceptual flow across layers; thermodynamic length, which quantifies the semantic effort required to traverse representational transitions through layers; and belief vector field, which delineates the semantic torsion fields that guide a model's belief directional orientations. Like biological DNA, it encodes ancestry, mutation, and semantic inheritance, found in finetuning and alignment scars, cultural imprints, and architectural drift. In naming it, we open a new field: Neural Genomics, where models are not just tools, but digital semantic organisms with traceable inner cognition. Modeling statement. We read AI foundation models as semantic fluid dynamics: meaning is transported through layers like fluid in a shaped conduit; nDNA is the physics-grade readout of that flow -- a geometry-first measure of how meaning is bent, paid for, and pushed -- yielding a stable, coordinate-free neural DNA fingerprint tied to on-input behavior; with this fingerprint we cross into biology: tracing lineages across pretraining, fine-tuning, alignment, pruning, distillation, and merges; measuring inheritance between checkpoints; detecting drift as traits shift under new data or objectives; and, ultimately, studying the evolution of artificial cognition to compare models, diagnose risks, and govern change over time.

Summary: GeneFEAST, implemented in Python, is a gene-centric functional enrichment analysis summarisation and visualisation tool that can be applied to large functional enrichment analysis (FEA) results arising from upstream FEA pipelines. It produces a systematic, navigable HTML report, making it easy to identify sets of genes putatively driving multiple enrichments and to explore gene-level quantitative data first used to identify input genes. Further, GeneFEAST can compare FEA results from multiple studies, making it possible, for example, to highlight patterns of gene expression amongst genes commonly differentially expressed in two sets of conditions, and giving rise to shared enrichments under those conditions. GeneFEAST offers a novel, effective way to address the complexities of linking up many overlapping FEA results to their underlying genes and data, advancing gene-centric hypotheses, and providing pivotal information for downstream validation experiments. Availability: GeneFEAST is available at https://github.com/avigailtaylor/GeneFEAST Contact: avigail.taylor@well.ox.ac.uk

Most conventional recommendation methods (e.g., matrix factorization) represent user profiles as high-dimensional vectors. Unfortunately, these vectors lack interpretability and steerability, and often perform poorly in cold-start settings. To address these shortcomings, we explore the use of user profiles that are represented as human-readable text. We propose the Language-based Factorization Model (LFM), which is essentially an encoder/decoder model where both the encoder and the decoder are large language models (LLMs). The encoder LLM generates a compact natural-language profile of the user's interests from the user's rating history. The decoder LLM uses this summary profile to complete predictive downstream tasks. We evaluate our LFM approach on the MovieLens dataset, comparing it against matrix factorization and an LLM model that directly predicts from the user's rating history. In cold-start settings, we find that our method can have higher accuracy than matrix factorization. Furthermore, we find that generating a compact and human-readable summary often performs comparably with or better than direct LLM prediction, while enjoying better interpretability and shorter model input length. Our results motivate a number of future research directions and potential improvements.

We consider controllable DNA sequence design, where sequences are generated by conditioning on specific biological properties. While language models (LMs) such as GPT and BERT have achieved remarkable success in natural language generation, their application to DNA sequence generation remains largely underexplored. In this work, we introduce ATGC-Gen, an Automated Transformer Generator for Controllable Generation, which leverages cross-modal encoding to integrate diverse biological signals. ATGC-Gen is instantiated with both decoder-only and encoder-only transformer architectures, allowing flexible training and generation under either autoregressive or masked recovery objectives. We evaluate ATGC-Gen on representative tasks including promoter and enhancer sequence design, and further introduce a new dataset based on ChIP-Seq experiments for modeling protein binding specificity. Our experiments demonstrate that ATGC-Gen can generate fluent, diverse, and biologically relevant sequences aligned with the desired properties. Compared to prior methods, our model achieves notable improvements in controllability and functional relevance, highlighting the potential of language models in advancing programmable genomic design. The source code is released at (https://github.com/divelab/AIRS/blob/main/OpenBio/ATGC_Gen).

Many have observed that the development and deployment of generative machine learning (ML) and artificial intelligence (AI) models follow a distinctive pattern in which pre-trained models are adapted and fine-tuned for specific downstream tasks. However, there is limited empirical work that examines the structure of these interactions. This paper analyzes 1.86 million models on Hugging Face, a leading peer production platform for model development. Our study of model family trees -- networks that connect fine-tuned models to their base or parent -- reveals sprawling fine-tuning lineages that vary widely in size and structure. Using an evolutionary biology lens to study ML models, we use model metadata and model cards to measure the genetic similarity and mutation of traits over model families. We find that models tend to exhibit a family resemblance, meaning their genetic markers and traits exhibit more overlap when they belong to the same model family. However, these similarities depart in certain ways from standard models of asexual reproduction, because mutations are fast and directed, such that two `sibling' models tend to exhibit more similarity than parent/child pairs. Further analysis of the directional drifts of these mutations reveals qualitative insights about the open machine learning ecosystem: Licenses counter-intuitively drift from restrictive, commercial licenses towards permissive or copyleft licenses, often in violation of upstream license's terms; models evolve from multi-lingual compatibility towards english-only compatibility; and model cards reduce in length and standardize by turning, more often, to templates and automatically generated text. Overall, this work takes a step toward an empirically grounded understanding of model fine-tuning and suggests that ecological models and methods can yield novel scientific insights.

Inferring spatial transcriptomics (ST) from histology enables scalable histogenomic profiling, yet current methods are largely restricted to single-tissue models. This fragmentation fails to leverage biological principles shared across cancer types and hinders application to data-scarce scenarios. While pan-cancer training offers a solution, the resulting heterogeneity challenges monolithic architectures. To bridge this gap, we introduce MoLF (Mixture-of-Latent-Flow), a generative model for pan-cancer histogenomic prediction. MoLF leverages a conditional Flow Matching objective to map noise to the gene latent manifold, parameterized by a Mixture-of-Experts (MoE) velocity field. By dynamically routing inputs to specialized sub-networks, this architecture effectively decouples the optimization of diverse tissue patterns. Our experiments demonstrate that MoLF establishes a new state-of-the-art, consistently outperforming both specialized and foundation model baselines on pan-cancer benchmarks. Furthermore, MoLF exhibits zero-shot generalization to cross-species data, suggesting it captures fundamental, conserved histo-molecular mechanisms.

Traditional POI recommendation systems often lack transparency, interpretability, and scrutability due to their reliance on dense vector-based user embeddings. Furthermore, the cold-start problem -- where systems have insufficient data for new users -- limits their ability to generate accurate recommendations. Existing methods often address this by leveraging similar trajectories from other users, but this approach can be computationally expensive and increases the context length for LLM-based methods, making them difficult to scale. To address these limitations, we propose a method that generates natural language (NL) user profiles from large-scale, location-based social network (LBSN) check-ins, utilizing robust personality assessments and behavioral theories. These NL profiles capture user preferences, routines, and behaviors, improving POI prediction accuracy while offering enhanced transparency. By incorporating NL profiles as system prompts to LLMs, our approach reduces reliance on extensive historical data, while remaining flexible, easily updated, and computationally efficient. Our method is not only competitive with other LLM-based and complex agentic frameworks but is also more scalable for real-world scenarios and on-device POI recommendations. Results demonstrate that our approach consistently outperforms baseline methods, offering a more interpretable and resource-efficient solution for POI recommendation systems. Our source code is available at: https://github.com/w11wo/GenUP.

Despite the success of large language models (LLMs) on general-purpose tasks, their performance in highly specialized domains such as biomedicine remains unsatisfactory. A key limitation is the inability of LLMs to effectively leverage biomedical tools, which clinical experts and biomedical researchers rely on extensively in daily workflows. While recent general-domain tool-calling datasets have substantially improved the capabilities of LLM agents, existing efforts in the biomedical domain largely rely on in-context learning and restrict models to a small set of tools. To address this gap, we introduce BioTool, a comprehensive biomedical tool-calling dataset designed for fine-tuning LLMs. BioTool comprises 34 frequently used tools collected from the NCBI, Ensembl, and UniProt databases, along with 7,040 high-quality, human-verified query-API call pairs spanning variation, genomics, proteomics, evolution, and general biology. Fine-tuning a 4-billion-parameter LLM on BioTool yields substantial improvements in biomedical tool-calling performance, outperforming cutting-edge commercial LLMs such as GPT-5.1. Furthermore, human expert evaluations demonstrate that integrating a BioTool-fine-tuned tool caller significantly improves downstream answer quality compared to the same LLM without tool usage, highlighting the effectiveness of BioTool in enhancing the biomedical capabilities of LLMs. The full dataset and evaluation code are available at https://github.com/gxx27/BioTool

Recent research trends in computational biology have increasingly focused on integrating text and bio-entity modeling, especially in the context of molecules and proteins. However, previous efforts like BioT5 faced challenges in generalizing across diverse tasks and lacked a nuanced understanding of molecular structures, particularly in their textual representations (e.g., IUPAC). This paper introduces BioT5+, an extension of the BioT5 framework, tailored to enhance biological research and drug discovery. BioT5+ incorporates several novel features: integration of IUPAC names for molecular understanding, inclusion of extensive bio-text and molecule data from sources like bioRxiv and PubChem, the multi-task instruction tuning for generality across tasks, and a novel numerical tokenization technique for improved processing of numerical data. These enhancements allow BioT5+ to bridge the gap between molecular representations and their textual descriptions, providing a more holistic understanding of biological entities, and largely improving the grounded reasoning of bio-text and bio-sequences. The model is pre-trained and fine-tuned with a large number of experiments, including 3 types of problems (classification, regression, generation), 15 kinds of tasks, and 21 total benchmark datasets, demonstrating the remarkable performance and state-of-the-art results in most cases. BioT5+ stands out for its ability to capture intricate relationships in biological data, thereby contributing significantly to bioinformatics and computational biology. Our code is available at https://github.com/QizhiPei/BioT5.

Comprehending genomic information is essential for biomedical research, yet extracting data from complex distributed databases remains challenging. Large language models (LLMs) offer potential for genomic Question Answering (QA) but face limitations due to restricted access to domain-specific databases. GeneGPT is the current state-of-the-art system that enhances LLMs by utilizing specialized API calls, though it is constrained by rigid API dependencies and limited adaptability. We replicate GeneGPT and propose GenomAgent, a multi-agent framework that efficiently coordinates specialized agents for complex genomics queries. Evaluated on nine tasks from the GeneTuring benchmark, GenomAgent outperforms GeneGPT by 12% on average, and its flexible architecture extends beyond genomics to various scientific domains needing expert knowledge extraction.

Attention-based models trained on protein sequences have demonstrated incredible success at classification and generation tasks relevant for artificial intelligence-driven protein design. However, we lack a sufficient understanding of how very large-scale models and data play a role in effective protein model development. We introduce a suite of protein language models, named ProGen2, that are scaled up to 6.4B parameters and trained on different sequence datasets drawn from over a billion proteins from genomic, metagenomic, and immune repertoire databases. ProGen2 models show state-of-the-art performance in capturing the distribution of observed evolutionary sequences, generating novel viable sequences, and predicting protein fitness without additional finetuning. As large model sizes and raw numbers of protein sequences continue to become more widely accessible, our results suggest that a growing emphasis needs to be placed on the data distribution provided to a protein sequence model. We release the ProGen2 models and code at https://github.com/salesforce/progen.

Personalized text generation requires models not only to produce coherent text but also to align with a target user's style, tone, and topical focus. Existing retrieval-augmented approaches such as LaMP and PGraphRAG enrich profiles with user and neighbor histories, but they stop at generation and often yield outputs that drift in tone, topic, or style. We present PerFine, a unified, training-free critique-refine framework that enhances personalization through iterative, profile-grounded feedback. In each iteration, an LLM generator produces a draft conditioned on the retrieved profile, and a critic LLM - also conditioned on the same profile - provides structured feedback on tone, vocabulary, sentence structure, and topicality. The generator then revises, while a novel knockout strategy retains the stronger draft across iterations. We further study additional inference-time strategies such as Best-of-N and Topic Extraction to balance quality and efficiency. Across Yelp, Goodreads, and Amazon datasets, PerFine consistently improves personalization over PGraphRAG, with GEval gains of +7-13%, steady improvements over 3-5 refinement iterations, and scalability with increasing critic size. These results highlight that post-hoc, profile-aware feedback offers a powerful paradigm for personalized LLM generation that is both training-free and model-agnostic.