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.

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.

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.

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.

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.

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.

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 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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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/.

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.

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

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

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.

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.

In domains with high stakes such as law, recruitment, and healthcare, learning models frequently rely on sensitive user data for inference, necessitating the complete set of features. This not only poses significant privacy risks for individuals but also demands substantial human effort from organizations to verify information accuracy. This paper asks whether it is necessary to use all input features for accurate predictions at inference time. The paper demonstrates that, in a personalized setting, individuals may only need to disclose a small subset of their features without compromising decision-making accuracy. The paper also provides an efficient sequential algorithm to determine the appropriate attributes for each individual to provide. Evaluations across various learning tasks show that individuals can potentially report as little as 10\% of their information while maintaining the same accuracy level as a model that employs the full set of user information.

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.

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.

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.

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.

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 domains ranging from computer vision to natural language processing, machine learning models have been shown to exhibit stark disparities, often performing worse for members of traditionally underserved groups. One factor contributing to these performance gaps is a lack of representation in the data the models are trained on. It is often unclear, however, how to operationalize representativeness in specific applications. Here we formalize the problem of creating equitable training datasets, and propose a statistical framework for addressing this problem. We consider a setting where a model builder must decide how to allocate a fixed data collection budget to gather training data from different subgroups. We then frame dataset creation as a constrained optimization problem, in which one maximizes a function of group-specific performance metrics based on (estimated) group-specific learning rates and costs per sample. This flexible approach incorporates preferences of model-builders and other stakeholders, as well as the statistical properties of the learning task. When data collection decisions are made sequentially, we show that under certain conditions this optimization problem can be efficiently solved even without prior knowledge of the learning rates. To illustrate our approach, we conduct a simulation study of polygenic risk scores on synthetic genomic data -- an application domain that often suffers from non-representative data collection. We find that our adaptive sampling strategy outperforms several common data collection heuristics, including equal and proportional sampling, demonstrating the value of strategic dataset design for building equitable models.

Genomic language models (gLMs) have shown mostly modest success in identifying evolutionarily constrained elements in mammalian genomes. To address this issue, we introduce a novel framework for training gLMs that explicitly models nucleotide evolution on phylogenetic trees using multispecies whole-genome alignments. Our approach integrates an alignment into the loss function during training but does not require it for making predictions, thereby enhancing the model's applicability. We applied this framework to train PhyloGPN, a model that excels at predicting functionally disruptive variants from a single sequence alone and demonstrates strong transfer learning capabilities.

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.

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.

Pre-trained language models like ChatGPT have significantly improved code generation. As these models scale up, there is an increasing need for the output to handle more intricate tasks. Moreover, in bioinformatics, generating functional programs poses additional notable challenges due to the amount of domain knowledge, the need for complicated data operations, and intricate functional dependencies between the operations. Here, we present BioCoder, a benchmark developed to evaluate existing pre-trained models in generating bioinformatics code. In relation to function-code generation, BioCoder covers potential package dependencies, class declarations, and global variables. It incorporates 1026 functions and 1243 methods in Python and Java from GitHub and 253 examples from the Rosalind Project. BioCoder incorporates a fuzz-testing framework for evaluation, and we have applied it to evaluate many models including InCoder, CodeGen, CodeGen2, SantaCoder, StarCoder, StarCoder+, InstructCodeT5+, and ChatGPT. Our detailed analysis of these models emphasizes the importance of domain knowledge, pragmatic code generation, and contextual understanding. Our dataset, benchmark, Docker images, and scripts required for testing are all available at https://github.com/gersteinlab/biocoder.

Data of sequential nature arise in many application domains in forms of, e.g. textual data, DNA sequences, and software execution traces. Different research disciplines have developed methods to learn sequence models from such datasets: (i) in the machine learning field methods such as (hidden) Markov models and recurrent neural networks have been developed and successfully applied to a wide-range of tasks, (ii) in process mining process discovery techniques aim to generate human-interpretable descriptive models, and (iii) in the grammar inference field the focus is on finding descriptive models in the form of formal grammars. Despite their different focuses, these fields share a common goal - learning a model that accurately describes the behavior in the underlying data. Those sequence models are generative, i.e, they can predict what elements are likely to occur after a given unfinished sequence. So far, these fields have developed mainly in isolation from each other and no comparison exists. This paper presents an interdisciplinary experimental evaluation that compares sequence modeling techniques on the task of next-element prediction on four real-life sequence datasets. The results indicate that machine learning techniques that generally have no aim at interpretability in terms of accuracy outperform techniques from the process mining and grammar inference fields that aim to yield interpretable models.

Understanding how deep learning models predict oncology patient risk can provide critical insights into disease progression, support clinical decision-making, and pave the way for trustworthy and data-driven precision medicine. Building on recent advances in the spatial modeling of the tumor microenvironment using graph neural networks, we present an explainable cell graph (xCG) approach for survival prediction. We validate our model on a public cohort of imaging mass cytometry (IMC) data for 416 cases of lung adenocarcinoma. We explain survival predictions in terms of known phenotypes on the cell level by computing risk attributions over cell graphs, for which we propose an efficient grid-based layer-wise relevance propagation (LRP) method. Our ablation studies highlight the importance of incorporating the cancer stage and model ensembling to improve the quality of risk estimates. Our xCG method, together with the IMC data, is made publicly available to support further research.

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.

Background: Electronic Health Records hold detailed longitudinal information about each patient's health status and general clinical history, a large portion of which is stored within the unstructured text. Existing approaches focus mostly on structured data and a subset of single-domain outcomes. We explore how temporal modelling of patients from free text and structured data, using deep generative transformers can be used to forecast a wide range of future disorders, substances, procedures or findings. Methods: We present Foresight, a novel transformer-based pipeline that uses named entity recognition and linking tools to convert document text into structured, coded concepts, followed by providing probabilistic forecasts for future medical events such as disorders, substances, procedures and findings. We processed the entire free-text portion from three different hospital datasets totalling 811336 patients covering both physical and mental health. Findings: On tests in two UK hospitals (King's College Hospital, South London and Maudsley) and the US MIMIC-III dataset precision@10 0.68, 0.76 and 0.88 was achieved for forecasting the next disorder in a patient timeline, while precision@10 of 0.80, 0.81 and 0.91 was achieved for forecasting the next biomedical concept. Foresight was also validated on 34 synthetic patient timelines by five clinicians and achieved relevancy of 97% for the top forecasted candidate disorder. As a generative model, it can forecast follow-on biomedical concepts for as many steps as required. Interpretation: Foresight is a general-purpose model for biomedical concept modelling that can be used for real-world risk forecasting, virtual trials and clinical research to study the progression of disorders, simulate interventions and counterfactuals, and educational purposes.

We consider the problem of predicting gene expressions from DNA sequences. A key challenge of this task is to find the regulatory elements that control gene expressions. Here, we introduce Seq2Exp, a Sequence to Expression network explicitly designed to discover and extract regulatory elements that drive target gene expression, enhancing the accuracy of the gene expression prediction. Our approach captures the causal relationship between epigenomic signals, DNA sequences and their associated regulatory elements. Specifically, we propose to decompose the epigenomic signals and the DNA sequence conditioned on the causal active regulatory elements, and apply an information bottleneck with the Beta distribution to combine their effects while filtering out non-causal components. Our experiments demonstrate that Seq2Exp outperforms existing baselines in gene expression prediction tasks and discovers influential regions compared to commonly used statistical methods for peak detection such as MACS3. The source code is released as part of the AIRS library (https://github.com/divelab/AIRS/).

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).

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.

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.

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.

Offline model-based optimization aims to maximize a black-box objective function with a static dataset of designs and their scores. In this paper, we focus on biological sequence design to maximize some sequence score. A recent approach employs bidirectional learning, combining a forward mapping for exploitation and a backward mapping for constraint, and it relies on the neural tangent kernel (NTK) of an infinitely wide network to build a proxy model. Though effective, the NTK cannot learn features because of its parametrization, and its use prevents the incorporation of powerful pre-trained Language Models (LMs) that can capture the rich biophysical information in millions of biological sequences. We adopt an alternative proxy model, adding a linear head to a pre-trained LM, and propose a linearization scheme. This yields a closed-form loss and also takes into account the biophysical information in the pre-trained LM. In addition, the forward mapping and the backward mapping play different roles and thus deserve different weights during sequence optimization. To achieve this, we train an auxiliary model and leverage its weak supervision signal via a bi-level optimization framework to effectively learn how to balance the two mappings. Further, by extending the framework, we develop the first learning rate adaptation module Adaptive-eta, which is compatible with all gradient-based algorithms for offline model-based optimization. Experimental results on DNA/protein sequence design tasks verify the effectiveness of our algorithm. Our code is available~https://anonymous.4open.science/r/BIB-ICLR2023-Submission/README.md{here.}

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.

Data profiling is an essential process in modern data-driven industries. One of its critical components is the discovery and validation of complex statistics, including functional dependencies, data constraints, association rules, and others. However, most existing data profiling systems that focus on complex statistics do not provide proper integration with the tools used by contemporary data scientists. This creates a significant barrier to the adoption of these tools in the industry. Moreover, existing systems were not created with industrial-grade workloads in mind. Finally, they do not aim to provide descriptive explanations, i.e. why a given pattern is not found. It is a significant issue as it is essential to understand the underlying reasons for a specific pattern's absence to make informed decisions based on the data. Because of that, these patterns are effectively rest in thin air: their application scope is rather limited, they are rarely used by the broader public. At the same time, as we are going to demonstrate in this presentation, complex statistics can be efficiently used to solve many classic data quality problems. Desbordante is an open-source data profiler that aims to close this gap. It is built with emphasis on industrial application: it is efficient, scalable, resilient to crashes, and provides explanations. Furthermore, it provides seamless Python integration by offloading various costly operations to the C++ core, not only mining. In this demonstration, we show several scenarios that allow end users to solve different data quality problems. Namely, we showcase typo detection, data deduplication, and data anomaly detection scenarios.

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.

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.

Discrete diffusion or flow models could enable faster and more controllable sequence generation than autoregressive models. We show that na\"ive linear flow matching on the simplex is insufficient toward this goal since it suffers from discontinuities in the training target and further pathologies. To overcome this, we develop Dirichlet flow matching on the simplex based on mixtures of Dirichlet distributions as probability paths. In this framework, we derive a connection between the mixtures' scores and the flow's vector field that allows for classifier and classifier-free guidance. Further, we provide distilled Dirichlet flow matching, which enables one-step sequence generation with minimal performance hits, resulting in O(L) speedups compared to autoregressive models. On complex DNA sequence generation tasks, we demonstrate superior performance compared to all baselines in distributional metrics and in achieving desired design targets for generated sequences. Finally, we show that our classifier-free guidance approach improves unconditional generation and is effective for generating DNA that satisfies design targets. Code is available at https://github.com/HannesStark/dirichlet-flow-matching.

In drug-discovery-related tasks such as virtual screening, machine learning is emerging as a promising way to predict molecular properties. Conventionally, molecular fingerprints (numerical representations of molecules) are calculated through rule-based algorithms that map molecules to a sparse discrete space. However, these algorithms perform poorly for shallow prediction models or small datasets. To address this issue, we present SMILES Transformer. Inspired by Transformer and pre-trained language models from natural language processing, SMILES Transformer learns molecular fingerprints through unsupervised pre-training of the sequence-to-sequence language model using a huge corpus of SMILES, a text representation system for molecules. We performed benchmarks on 10 datasets against existing fingerprints and graph-based methods and demonstrated the superiority of the proposed algorithms in small-data settings where pre-training facilitated good generalization. Moreover, we define a novel metric to concurrently measure model accuracy and data efficiency.

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.

Survival prediction is a complicated ordinal regression task that aims to predict the ranking risk of death, which generally benefits from the integration of histology and genomic data. Despite the progress in joint learning from pathology and genomics, existing methods still suffer from challenging issues: 1) Due to the large size of pathological images, it is difficult to effectively represent the gigapixel whole slide images (WSIs). 2) Interactions within tumor microenvironment (TME) in histology are essential for survival analysis. Although current approaches attempt to model these interactions via co-attention between histology and genomic data, they focus on only dense local similarity across modalities, which fails to capture global consistency between potential structures, i.e. TME-related interactions of histology and co-expression of genomic data. To address these challenges, we propose a Multimodal Optimal Transport-based Co-Attention Transformer framework with global structure consistency, in which optimal transport (OT) is applied to match patches of a WSI and genes embeddings for selecting informative patches to represent the gigapixel WSI. More importantly, OT-based co-attention provides a global awareness to effectively capture structural interactions within TME for survival prediction. To overcome high computational complexity of OT, we propose a robust and efficient implementation over micro-batch of WSI patches by approximating the original OT with unbalanced mini-batch OT. Extensive experiments show the superiority of our method on five benchmark datasets compared to the state-of-the-art methods. The code is released.

Accurate career path prediction can support many stakeholders, like job seekers, recruiters, HR, and project managers. However, publicly available data and tools for career path prediction are scarce. In this work, we introduce KARRIEREWEGE, a comprehensive, publicly available dataset containing over 500k career paths, significantly surpassing the size of previously available datasets. We link the dataset to the ESCO taxonomy to offer a valuable resource for predicting career trajectories. To tackle the problem of free-text inputs typically found in resumes, we enhance it by synthesizing job titles and descriptions resulting in KARRIEREWEGE+. This allows for accurate predictions from unstructured data, closely aligning with real-world application challenges. We benchmark existing state-of-the-art (SOTA) models on our dataset and a prior benchmark and observe improved performance and robustness, particularly for free-text use cases, due to the synthesized data.

A reliable resume-job matching system helps a company recommend suitable candidates from a pool of resumes and helps a job seeker find relevant jobs from a list of job posts. However, since job seekers apply only to a few jobs, interaction labels in resume-job datasets are sparse. We introduce ConFit v2, an improvement over ConFit to tackle this sparsity problem. We propose two techniques to enhance the encoder's contrastive training process: augmenting job data with hypothetical reference resume generated by a large language model; and creating high-quality hard negatives from unlabeled resume/job pairs using a novel hard-negative mining strategy. We evaluate ConFit v2 on two real-world datasets and demonstrate that it outperforms ConFit and prior methods (including BM25 and OpenAI text-embedding-003), achieving an average absolute improvement of 13.8% in recall and 17.5% in nDCG across job-ranking and resume-ranking tasks.

The advancement of transformer neural networks has significantly elevated the capabilities of sentence similarity models, particularly in creating effective vector representations of natural language inputs. However, these models face notable challenges in domain-specific contexts, especially in highly specialized scientific sub-fields. Traditional methods often struggle in this regime, either overgeneralizing similarities within a niche or being overly sensitive to minor differences, resulting in inaccurate text classification and subpar vector representation. In an era where retrieval augmentation and search are increasingly crucial, precise and concise numerical representations are essential. In this paper, we target this issue by assembling niche datasets using co-citations as a similarity metric, focusing on biomedical domains. We employ two key strategies for fine-tuning state-of-the-art models: 1. Domain-specific Fine-Tuning, which tailors pretrained models to a single domain, and 2. Universal Applicability with Mixture of Experts (MoE), adapting pretrained models with enforced routing for multiple domains simultaneously. Our training approach emphasizes the use of abstracts for faster training, incorporating Multiple Negative Rankings loss for efficient contrastive learning. Notably, our MoE variants, equipped with N experts, achieve the efficacy of N individual models, heralding a new era of versatile, One-Size-Fits-All transformer networks for various tasks. This methodology marks significant advancements in scientific text classification metrics and holds promise for enhancing vector database search and compilation.

Pre-trained language models have attracted increasing attention in the biomedical domain, inspired by their great success in the general natural language domain. Among the two main branches of pre-trained language models in the general language domain, i.e., BERT (and its variants) and GPT (and its variants), the first one has been extensively studied in the biomedical domain, such as BioBERT and PubMedBERT. While they have achieved great success on a variety of discriminative downstream biomedical tasks, the lack of generation ability constrains their application scope. In this paper, we propose BioGPT, a domain-specific generative Transformer language model pre-trained on large scale biomedical literature. We evaluate BioGPT on six biomedical NLP tasks and demonstrate that our model outperforms previous models on most tasks. Especially, we get 44.98%, 38.42% and 40.76% F1 score on BC5CDR, KD-DTI and DDI end-to-end relation extraction tasks respectively, and 78.2% accuracy on PubMedQA, creating a new record. Our larger model BioGPT-Large achieves 81.0% on PubMedQA. Our case study on text generation further demonstrates the advantage of BioGPT on biomedical literature to generate fluent descriptions for biomedical terms. Code is available at https://github.com/microsoft/BioGPT.

Machine learning models are often personalized with categorical attributes that are protected, sensitive, self-reported, or costly to acquire. In this work, we show models that are personalized with group attributes can reduce performance at a group level. We propose formal conditions to ensure the "fair use" of group attributes in prediction tasks by training one additional model -- i.e., collective preference guarantees to ensure that each group who provides personal data will receive a tailored gain in performance in return. We present sufficient conditions to ensure fair use in empirical risk minimization and characterize failure modes that lead to fair use violations due to standard practices in model development and deployment. We present a comprehensive empirical study of fair use in clinical prediction tasks. Our results demonstrate the prevalence of fair use violations in practice and illustrate simple interventions to mitigate their harm.

Despite the remarkable progress in the development of predictive models for healthcare, applying these algorithms on a large scale has been challenging. Algorithms trained on a particular task, based on specific data formats available in a set of medical records, tend to not generalize well to other tasks or databases in which the data fields may differ. To address this challenge, we propose General Healthcare Predictive Framework (GenHPF), which is applicable to any EHR with minimal preprocessing for multiple prediction tasks. GenHPF resolves heterogeneity in medical codes and schemas by converting EHRs into a hierarchical textual representation while incorporating as many features as possible. To evaluate the efficacy of GenHPF, we conduct multi-task learning experiments with single-source and multi-source settings, on three publicly available EHR datasets with different schemas for 12 clinically meaningful prediction tasks. Our framework significantly outperforms baseline models that utilize domain knowledge in multi-source learning, improving average AUROC by 1.2%P in pooled learning and 2.6%P in transfer learning while also showing comparable results when trained on a single EHR dataset. Furthermore, we demonstrate that self-supervised pretraining using multi-source datasets is effective when combined with GenHPF, resulting in a 0.6%P AUROC improvement compared to models without pretraining. By eliminating the need for preprocessing and feature engineering, we believe that this work offers a solid framework for multi-task and multi-source learning that can be leveraged to speed up the scaling and usage of predictive algorithms in healthcare.

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.

Building a general-purpose task model similar to ChatGPT has been an important research direction for gene large language models. Instruction fine-tuning is a key component in building ChatGPT, but existing instructions are primarily based on natural language. Natural language and gene sequences have significant differences in tokenization and encoding. Therefore, constructing a multilingual model that can handle both natural language and gene sequences is crucial for solving this problem.In this paper, we expand the capabilities of the LLaMA large language model to include gene language. This involves expanding the vocabulary using the Byte Pair Encoding (BPE) method, specifically tailored for DNA and protein sequences, and conducting further pre-training on these sequences. We then convert various downstream gene task data into a unified format for instruction fine-tuning and further fine-tune the model on this data.Our study demonstrates that a mixed model of gene and natural language, fine-tuned with instructions, achieves results comparable to the current state-of-the-art (SOTA) in tasks such as gene classification and gene sequence interaction. This provides a promising direction for building a unified large language model for gene tasks.

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.

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.

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

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.

AI-driven discovery can greatly reduce design time and enhance new therapeutics' effectiveness. Models using simulators explore broad design spaces but risk violating implicit constraints due to a lack of experimental priors. For example, in a new analysis we performed on a diverse set of models on the GuacaMol benchmark using supervised classifiers, over 60\% of molecules proposed had high probability of being mutagenic. In this work, we introduce \ourdataset, a dataset of priors for design problems extracted from literature describing compounds used in lab settings. It is constructed with LLM pipelines for discovering therapeutic entities in relevant paragraphs and summarizing information in concise fair-use facts. \ourdataset~ consists of 32.3 million pairs of natural language facts, and appropriate entity representations (i.e. SMILES or refseq IDs). To demonstrate the potential of the data, we train LLM, CLIP, and LLava architectures to reason jointly about text and design targets and evaluate on tasks from the Therapeutic Data Commons (TDC). \ourdataset~is highly effective for creating models with strong priors: in supervised prediction problems that use our data as pretraining, our best models with 15M learnable parameters outperform larger 2B TxGemma on both regression and classification TDC tasks, and perform comparably to 9B models on average. Models built with \ourdataset~can be used as constraints while optimizing for novel molecules in GuacaMol, resulting in proposals that are safer and nearly as effective. We release our dataset at https://huggingface.co/datasets/medexanon/Medex{huggingface.co/datasets/medexanon/Medex}, and will provide expanded versions as available literature grows.

Complex prediction models such as deep learning are the output from fitting machine learning, neural networks, or AI models to a set of training data. These are now standard tools in science. A key challenge with the current generation of models is that they are highly parameterized, which makes describing and interpreting the prediction strategies difficult. We use topological data analysis to transform these complex prediction models into pictures representing a topological view. The result is a map of the predictions that enables inspection. The methods scale up to large datasets across different domains and enable us to detect labeling errors in training data, understand generalization in image classification, and inspect predictions of likely pathogenic mutations in the BRCA1 gene.

Machine learning models are often trained to predict the outcome resulting from a human decision. For example, if a doctor decides to test a patient for disease, will the patient test positive? A challenge is that historical decision-making determines whether the outcome is observed: we only observe test outcomes for patients doctors historically tested. Untested patients, for whom outcomes are unobserved, may differ from tested patients along observed and unobserved dimensions. We propose a Bayesian model class which captures this setting. The purpose of the model is to accurately estimate risk for both tested and untested patients. Estimating this model is challenging due to the wide range of possibilities for untested patients. To address this, we propose two domain constraints which are plausible in health settings: a prevalence constraint, where the overall disease prevalence is known, and an expertise constraint, where the human decision-maker deviates from purely risk-based decision-making only along a constrained feature set. We show theoretically and on synthetic data that domain constraints improve parameter inference. We apply our model to a case study of cancer risk prediction, showing that the model's inferred risk predicts cancer diagnoses, its inferred testing policy captures known public health policies, and it can identify suboptimalities in test allocation. Though our case study is in healthcare, our analysis reveals a general class of domain constraints which can improve model estimation in many settings.

Link prediction, a fundamental task on graphs, has proven indispensable in various applications, e.g., friend recommendation, protein analysis, and drug interaction prediction. However, since datasets span a multitude of domains, they could have distinct underlying mechanisms of link formation. Evidence in existing literature underscores the absence of a universally best algorithm suitable for all datasets. In this paper, we endeavor to explore principles of link prediction across diverse datasets from a data-centric perspective. We recognize three fundamental factors critical to link prediction: local structural proximity, global structural proximity, and feature proximity. We then unearth relationships among those factors where (i) global structural proximity only shows effectiveness when local structural proximity is deficient. (ii) The incompatibility can be found between feature and structural proximity. Such incompatibility leads to GNNs for Link Prediction (GNN4LP) consistently underperforming on edges where the feature proximity factor dominates. Inspired by these new insights from a data perspective, we offer practical instruction for GNN4LP model design and guidelines for selecting appropriate benchmark datasets for more comprehensive evaluations.

We study the problem of optimizing biological sequences, e.g., proteins, DNA, and RNA, to maximize a black-box score function that is only evaluated in an offline dataset. We propose a novel solution, bootstrapped training of score-conditioned generator (BootGen) algorithm. Our algorithm repeats a two-stage process. In the first stage, our algorithm trains the biological sequence generator with rank-based weights to enhance the accuracy of sequence generation based on high scores. The subsequent stage involves bootstrapping, which augments the training dataset with self-generated data labeled by a proxy score function. Our key idea is to align the score-based generation with a proxy score function, which distills the knowledge of the proxy score function to the generator. After training, we aggregate samples from multiple bootstrapped generators and proxies to produce a diverse design. Extensive experiments show that our method outperforms competitive baselines on biological sequential design tasks. We provide reproducible source code: https://github.com/kaist-silab/bootgen{https://github.com/kaist-silab/bootgen}.

Financial risk prediction plays a crucial role in the financial sector. Machine learning methods have been widely applied for automatically detecting potential risks and thus saving the cost of labor. However, the development in this field is lagging behind in recent years by the following two facts: 1) the algorithms used are somewhat outdated, especially in the context of the fast advance of generative AI and large language models (LLMs); 2) the lack of a unified and open-sourced financial benchmark has impeded the related research for years. To tackle these issues, we propose FinPT and FinBench: the former is a novel approach for financial risk prediction that conduct Profile Tuning on large pretrained foundation models, and the latter is a set of high-quality datasets on financial risks such as default, fraud, and churn. In FinPT, we fill the financial tabular data into the pre-defined instruction template, obtain natural-language customer profiles by prompting LLMs, and fine-tune large foundation models with the profile text to make predictions. We demonstrate the effectiveness of the proposed FinPT by experimenting with a range of representative strong baselines on FinBench. The analytical studies further deepen the understanding of LLMs for financial risk prediction.

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).

Summarization models often generate text that is poorly calibrated to quality metrics because they are trained to maximize the likelihood of a single reference (MLE). To address this, recent work has added a calibration step, which exposes a model to its own ranked outputs to improve relevance or, in a separate line of work, contrasts positive and negative sets to improve faithfulness. While effective, much of this work has focused on how to generate and optimize these sets. Less is known about why one setup is more effective than another. In this work, we uncover the underlying characteristics of effective sets. For each training instance, we form a large, diverse pool of candidates and systematically vary the subsets used for calibration fine-tuning. Each selection strategy targets distinct aspects of the sets, such as lexical diversity or the size of the gap between positive and negatives. On three diverse scientific long-form summarization datasets (spanning biomedical, clinical, and chemical domains), we find, among others, that faithfulness calibration is optimal when the negative sets are extractive and more likely to be generated, whereas for relevance calibration, the metric margin between candidates should be maximized and surprise--the disagreement between model and metric defined candidate rankings--minimized. Code to create, select, and optimize calibration sets is available at https://github.com/griff4692/calibrating-summaries

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.

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.

Social determinants of health (SDoH) have an important impact on patient outcomes but are incompletely collected from the electronic health records (EHR). This study researched the ability of large language models to extract SDoH from free text in EHRs, where they are most commonly documented, and explored the role of synthetic clinical text for improving the extraction of these scarcely documented, yet extremely valuable, clinical data. 800 patient notes were annotated for SDoH categories, and several transformer-based models were evaluated. The study also experimented with synthetic data generation and assessed for algorithmic bias. Our best-performing models were fine-tuned Flan-T5 XL (macro-F1 0.71) for any SDoH, and Flan-T5 XXL (macro-F1 0.70). The benefit of augmenting fine-tuning with synthetic data varied across model architecture and size, with smaller Flan-T5 models (base and large) showing the greatest improvements in performance (delta F1 +0.12 to +0.23). Model performance was similar on the in-hospital system dataset but worse on the MIMIC-III dataset. Our best-performing fine-tuned models outperformed zero- and few-shot performance of ChatGPT-family models for both tasks. These fine-tuned models were less likely than ChatGPT to change their prediction when race/ethnicity and gender descriptors were added to the text, suggesting less algorithmic bias (p<0.05). At the patient-level, our models identified 93.8% of patients with adverse SDoH, while ICD-10 codes captured 2.0%. Our method can effectively extracted SDoH information from clinic notes, performing better compare to GPT zero- and few-shot settings. These models could enhance real-world evidence on SDoH and aid in identifying patients needing social support.

This paper presents a Patherea, a framework for point-based cell detection and classification that provides a complete solution for developing and evaluating state-of-the-art approaches. We introduce a large-scale dataset collected to directly replicate a clinical workflow for Ki-67 proliferation index estimation and use it to develop an efficient point-based approach that directly predicts point-based predictions, without the need for intermediate representations. The proposed approach effectively utilizes point proposal candidates with the hybrid Hungarian matching strategy and a flexible architecture that enables the usage of various backbones and (pre)training strategies. We report state-of-the-art results on existing public datasets - Lizard, BRCA-M2C, BCData, and the newly proposed Patherea dataset. We show that the performance on existing public datasets is saturated and that the newly proposed Patherea dataset represents a significantly harder challenge for the recently proposed approaches. We also demonstrate the effectiveness of recently proposed pathology foundational models that our proposed approach can natively utilize and benefit from. We also revisit the evaluation protocol that is used in the broader field of cell detection and classification and identify the erroneous calculation of performance metrics. Patherea provides a benchmarking utility that addresses the identified issues and enables a fair comparison of different approaches. The dataset and the code will be publicly released upon acceptance.

The memorization of sensitive and personally identifiable information (PII) by large language models (LLMs) poses growing privacy risks as models scale and are increasingly deployed in real-world applications. Existing efforts to study sensitive and PII data memorization and develop mitigation strategies are hampered by the absence of comprehensive, realistic, and ethically sourced datasets reflecting the diversity of sensitive information found on the web. We introduce PANORAMA - Profile-based Assemblage for Naturalistic Online Representation and Attribute Memorization Analysis, a large-scale synthetic corpus of 384,789 samples derived from 9,674 synthetic profiles designed to closely emulate the distribution, variety, and context of PII and sensitive data as it naturally occurs in online environments. Our data generation pipeline begins with the construction of internally consistent, multi-attribute human profiles using constrained selection to reflect real-world demographics such as education, health attributes, financial status, etc. Using a combination of zero-shot prompting and OpenAI o3-mini, we generate diverse content types - including wiki-style articles, social media posts, forum discussions, online reviews, comments, and marketplace listings - each embedding realistic, contextually appropriate PII and other sensitive information. We validate the utility of PANORAMA by fine-tuning the Mistral-7B model on 1x, 5x, 10x, and 25x data replication rates with a subset of data and measure PII memorization rates - revealing not only consistent increases with repetition but also variation across content types, highlighting PANORAMA's ability to model how memorization risks differ by context. Our dataset and code are publicly available, providing a much-needed resource for privacy risk assessment, model auditing, and the development of privacy-preserving LLMs.

Based on the BioBricks standard, restriction synthesis is a novel catabolic iterative DNA synthesis method that utilizes endonucleases to synthesize a query sequence from a reference sequence. In this work, the reference sequence is built from shorter subsequences by classifying them as applicable or inapplicable for the synthesis method using three different machine learning methods: Support Vector Machines (SVMs), random forest, and Convolution Neural Networks (CNNs). Before applying these methods to the data, a series of feature selection, curation, and reduction steps are applied to create an accurate and representative feature space. Following these preprocessing steps, three different pipelines are proposed to classify subsequences based on their nucleotide sequence and other relevant features corresponding to the restriction sites of over 200 endonucleases. The sensitivity using SVMs, random forest, and CNNs are 94.9%, 92.7%, 91.4%, respectively. Moreover, each method scores lower in specificity with SVMs, random forest, and CNNs resulting in 77.4%, 85.7%, and 82.4%, respectively. In addition to analyzing these results, the misclassifications in SVMs and CNNs are investigated. Across these two models, different features with a derived nucleotide specificity visually contribute more to classification compared to other features. This observation is an important factor when considering new nucleotide sensitivity features for future studies.

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.

Recommender systems typically retrieve items from an item corpus for personalized recommendations. However, such a retrieval-based recommender paradigm faces two limitations: 1) the human-generated items in the corpus might fail to satisfy the users' diverse information needs, and 2) users usually adjust the recommendations via inefficient passive feedback, e.g., clicks. Nowadays, AI-Generated Content (AIGC) has revealed significant success, offering the potential to overcome these limitations: 1) generative AI can produce personalized items to satisfy users' information needs, and 2) the newly emerged large language models significantly reduce the efforts of users to precisely express information needs via natural language instructions. In this light, the boom of AIGC points the way towards the next-generation recommender paradigm with two new objectives: 1) generating personalized content through generative AI, and 2) integrating user instructions to guide content generation. To this end, we propose a novel Generative Recommender paradigm named GeneRec, which adopts an AI generator to personalize content generation and leverages user instructions. Specifically, we pre-process users' instructions and traditional feedback via an instructor to output the generation guidance. Given the guidance, we instantiate the AI generator through an AI editor and an AI creator to repurpose existing items and create new items. Eventually, GeneRec can perform content retrieval, repurposing, and creation to satisfy users' information needs. Besides, to ensure the trustworthiness of the generated items, we emphasize various fidelity checks. Moreover, we provide a roadmap to envision future developments of GeneRec and several domain-specific applications of GeneRec with potential research tasks. Lastly, we study the feasibility of implementing AI editor and AI creator on micro-video generation.

The ability to engineer novel proteins with higher fitness for a desired property would be revolutionary for biotechnology and medicine. Modeling the combinatorially large space of sequences is infeasible; prior methods often constrain optimization to a small mutational radius, but this drastically limits the design space. Instead of heuristics, we propose smoothing the fitness landscape to facilitate protein optimization. First, we formulate protein fitness as a graph signal then use Tikunov regularization to smooth the fitness landscape. We find optimizing in this smoothed landscape leads to improved performance across multiple methods in the GFP and AAV benchmarks. Second, we achieve state-of-the-art results utilizing discrete energy-based models and MCMC in the smoothed landscape. Our method, called Gibbs sampling with Graph-based Smoothing (GGS), demonstrates a unique ability to achieve 2.5 fold fitness improvement (with in-silico evaluation) over its training set. GGS demonstrates potential to optimize proteins in the limited data regime. Code: https://github.com/kirjner/GGS

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

We present the findings of "The Alzheimer's Disease Prediction Of Longitudinal Evolution" (TADPOLE) Challenge, which compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease. Challenge participants were required to make a prediction, for each month of a 5-year future time period, of three key outcomes: clinical diagnosis, Alzheimer's Disease Assessment Scale Cognitive Subdomain (ADAS-Cog13), and total volume of the ventricles. The methods used by challenge participants included multivariate linear regression, machine learning methods such as support vector machines and deep neural networks, as well as disease progression models. No single submission was best at predicting all three outcomes. For clinical diagnosis and ventricle volume prediction, the best algorithms strongly outperform simple baselines in predictive ability. However, for ADAS-Cog13 no single submitted prediction method was significantly better than random guesswork. Two ensemble methods based on taking the mean and median over all predictions, obtained top scores on almost all tasks. Better than average performance at diagnosis prediction was generally associated with the additional inclusion of features from cerebrospinal fluid (CSF) samples and diffusion tensor imaging (DTI). On the other hand, better performance at ventricle volume prediction was associated with inclusion of summary statistics, such as the slope or maxima/minima of biomarkers. TADPOLE's unique results suggest that current prediction algorithms provide sufficient accuracy to exploit biomarkers related to clinical diagnosis and ventricle volume, for cohort refinement in clinical trials for Alzheimer's disease. However, results call into question the usage of cognitive test scores for patient selection and as a primary endpoint in clinical trials.

Multimodal pathology-genomic analysis is critical for cancer survival prediction. However, existing approaches predominantly integrate formalin-fixed paraffin-embedded (FFPE) slides with genomic data, while neglecting the availability of other preservation slides, such as Fresh Froze (FF) slides. Moreover, as the high-resolution spatial nature of pathology data tends to dominate the cross-modality fusion process, it hinders effective multimodal fusion and leads to modality imbalance challenges between pathology and genomics. These methods also typically require complete data modalities, limiting their clinical applicability with incomplete modalities, such as missing either pathology or genomic data. In this paper, we propose a multimodal survival prediction framework that leverages hypergraph learning to effectively integrate multi-WSI information and cross-modality interactions between pathology slides and genomics data while addressing modality imbalance. In addition, we introduce a memory mechanism that stores previously learned paired pathology-genomic features and dynamically compensates for incomplete modalities. Experiments on five TCGA datasets demonstrate that our model outperforms advanced methods by over 2.3% in C-Index. Under incomplete modality scenarios, our approach surpasses pathology-only (3.3%) and gene-only models (7.9%). Code: https://github.com/MCPathology/M2Surv

In this study, we investigate the potential of Large Language Models to complement biomedical knowledge graphs in the training of semantic models for the biomedical and clinical domains. Drawing on the wealth of the UMLS knowledge graph and harnessing cutting-edge Large Language Models, we propose a new state-of-the-art approach for obtaining high-fidelity representations of biomedical concepts and sentences, consisting of three steps: an improved contrastive learning phase, a novel self-distillation phase, and a weight averaging phase. Through rigorous evaluations via the extensive BioLORD testing suite and diverse downstream tasks, we demonstrate consistent and substantial performance improvements over the previous state of the art (e.g. +2pts on MedSTS, +2.5pts on MedNLI-S, +6.1pts on EHR-Rel-B). Besides our new state-of-the-art biomedical model for English, we also distill and release a multilingual model compatible with 50+ languages and finetuned on 7 European languages. Many clinical pipelines can benefit from our latest models. Our new multilingual model enables a range of languages to benefit from our advancements in biomedical semantic representation learning, opening a new avenue for bioinformatics researchers around the world. As a result, we hope to see BioLORD-2023 becoming a precious tool for future biomedical applications.

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.

Convolutional Neural Networks (CNN) have gained great success in many artificial intelligence tasks. However, finding a good set of hyperparameters for a CNN remains a challenging task. It usually takes an expert with deep knowledge, and trials and errors. Genetic algorithms have been used in hyperparameter optimizations. However, traditional genetic algorithms with fixed-length chromosomes may not be a good fit for optimizing deep learning hyperparameters, because deep learning models have variable number of hyperparameters depending on the model depth. As the depth increases, the number of hyperparameters grows exponentially, and searching becomes exponentially harder. It is important to have an efficient algorithm that can find a good model in reasonable time. In this article, we propose to use a variable length genetic algorithm (GA) to systematically and automatically tune the hyperparameters of a CNN to improve its performance. Experimental results show that our algorithm can find good CNN hyperparameters efficiently. It is clear from our experiments that if more time is spent on optimizing the hyperparameters, better results could be achieved. Theoretically, if we had unlimited time and CPU power, we could find the optimized hyperparameters and achieve the best results in the future.

The transformer architecture has revolutionized bioinformatics and driven progress in the understanding and prediction of the properties of biomolecules. Almost all research on large-scale biosequence transformers has focused on one domain at a time (single-omic), usually nucleotides or peptides. These models have seen incredible success in downstream tasks in each domain and have achieved particularly noteworthy breakthroughs in sequences of peptides and structural modeling. However, these single-omic models are naturally incapable of modeling multi-omic tasks, one of the most biologically critical being nucleotide-peptide interactions. We present our work training the first multi-omic nucleotide-peptide foundation models. We show that these multi-omic models (MOMs) can learn joint representations between various single-omic distributions that are emergently consistent with the Central Dogma of molecular biology, despite only being trained on unlabeled biosequences. We further demonstrate that MOMs can be fine-tuned to achieve state-of-the-art results on peptide-nucleotide interaction tasks, namely predicting the change in Gibbs free energy ({\Delta}G) of the binding interaction between a given oligonucleotide and peptide, as well as the effect on this binding interaction due to mutations in the oligonucleotide sequence ({\Delta}{\Delta}G). Remarkably, we show that multi-omic biosequence transformers emergently learn useful structural information without any prior structural training, allowing us to predict which peptide residues are most involved in the peptide-nucleotide binding interaction. Lastly, we provide evidence that multi-omic biosequence models are non-inferior to foundation models trained on single-omics distributions, suggesting a more generalized or foundational approach to building these models.

Large-scale sequence modeling has sparked rapid advances that now extend into biology and genomics. However, modeling genomic sequences introduces challenges such as the need to model long-range token interactions, the effects of upstream and downstream regions of the genome, and the reverse complementarity (RC) of DNA. Here, we propose an architecture motivated by these challenges that builds off the long-range Mamba block, and extends it to a BiMamba component that supports bi-directionality, and to a MambaDNA block that additionally supports RC equivariance. We use MambaDNA as the basis of Caduceus, the first family of RC equivariant bi-directional long-range DNA language models, and we introduce pre-training and fine-tuning strategies that yield Caduceus DNA foundation models. Caduceus outperforms previous long-range models on downstream benchmarks; on a challenging long-range variant effect prediction task, Caduceus exceeds the performance of 10x larger models that do not leverage bi-directionality or equivariance.

Clinical trials drive improvements in cancer treatments and outcomes. However, most adults with cancer do not participate in trials, and trials often fail to enroll enough patients to answer their scientific questions. Artificial intelligence could accelerate matching of patients to appropriate clinical trials. Here, we describe the development and evaluation of the MatchMiner-AI pipeline for clinical trial searching and ranking. MatchMiner-AI focuses on matching patients to potential trials based on core criteria describing clinical "spaces," or disease contexts, targeted by a trial. It aims to accelerate the human work of identifying potential matches, not to fully automate trial screening. The pipeline includes modules for extraction of key information from a patient's longitudinal electronic health record; rapid ranking of candidate trial-patient matches based on embeddings in vector space; and classification of whether a candidate match represents a reasonable clinical consideration. Code and synthetic data are available at https://huggingface.co/ksg-dfci/MatchMiner-AI . Model weights based on synthetic data are available at https://huggingface.co/ksg-dfci/TrialSpace and https://huggingface.co/ksg-dfci/TrialChecker . A simple cancer clinical trial search engine to demonstrate pipeline components is available at https://huggingface.co/spaces/ksg-dfci/trial_search_alpha .

Cancer is a genetic disorder whose clonal evolution can be monitored by tracking noisy genome-wide copy number variants. We introduce the Copy Number Stochastic Block Model (CN-SBM), a probabilistic framework that jointly clusters samples and genomic regions based on discrete copy number states using a bipartite categorical block model. Unlike models relying on Gaussian or Poisson assumptions, CN-SBM respects the discrete nature of CNV calls and captures subpopulation-specific patterns through block-wise structure. Using a two-stage approach, CN-SBM decomposes CNV data into primary and residual components, enabling detection of both large-scale chromosomal alterations and finer aberrations. We derive a scalable variational inference algorithm for application to large cohorts and high-resolution data. Benchmarks on simulated and real datasets show improved model fit over existing methods. Applied to TCGA low-grade glioma data, CN-SBM reveals clinically relevant subtypes and structured residual variation, aiding patient stratification in survival analysis. These results establish CN-SBM as an interpretable, scalable framework for CNV analysis with direct relevance for tumor heterogeneity and prognosis.

During times of increasing antibiotic resistance and the spread of infectious diseases like COVID-19, it is important to classify genes related to antibiotic resistance. As natural language processing has advanced with transformer-based language models, many language models that learn characteristics of nucleotide sequences have also emerged. These models show good performance in classifying various features of nucleotide sequences. When classifying nucleotide sequences, not only the sequence itself, but also various background knowledge is utilized. In this study, we use not only a nucleotide sequence-based language model but also a text language model based on PubMed articles to reflect more biological background knowledge in the model. We propose a method to fine-tune the nucleotide sequence language model and the text language model based on various databases of antibiotic resistance genes. We also propose an LLM-based augmentation technique to supplement the data and an ensemble method to effectively combine the two models. We also propose a benchmark for evaluating the model. Our method achieved better performance than the nucleotide sequence language model in the drug resistance class prediction.

In recent years supervised representation learning has provided state of the art or close to the state of the art results in semantic analysis tasks including ranking and information retrieval. The core idea is to learn how to embed items into a latent space such that they optimize a supervised objective in that latent space. The dimensions of the latent space have no clear semantics, and this reduces the interpretability of the system. For example, in personalization models, it is hard to explain why a particular item is ranked high for a given user profile. We propose a novel model of representation learning called Supervised Explicit Semantic Analysis (SESA) that is trained in a supervised fashion to embed items to a set of dimensions with explicit semantics. The model learns to compare two objects by representing them in this explicit space, where each dimension corresponds to a concept from a knowledge base. This work extends Explicit Semantic Analysis (ESA) with a supervised model for ranking problems. We apply this model to the task of Job-Profile relevance in LinkedIn in which a set of skills defines our explicit dimensions of the space. Every profile and job are encoded to this set of skills their similarity is calculated in this space. We use RNNs to embed text input into this space. In addition to interpretability, our model makes use of the web-scale collaborative skills data that is provided by users for each LinkedIn profile. Our model provides state of the art result while it remains interpretable.

Efficient computation or approximation of Levenshtein distance, a widely-used metric for evaluating sequence similarity, has attracted significant attention with the emergence of DNA storage and other biological applications. Sequence embedding, which maps Levenshtein distance to a conventional distance between embedding vectors, has emerged as a promising solution. In this paper, a novel neural network-based sequence embedding technique using Poisson regression is proposed. We first provide a theoretical analysis of the impact of embedding dimension on model performance and present a criterion for selecting an appropriate embedding dimension. Under this embedding dimension, the Poisson regression is introduced by assuming the Levenshtein distance between sequences of fixed length following a Poisson distribution, which naturally aligns with the definition of Levenshtein distance. Moreover, from the perspective of the distribution of embedding distances, Poisson regression approximates the negative log likelihood of the chi-squared distribution and offers advancements in removing the skewness. Through comprehensive experiments on real DNA storage data, we demonstrate the superior performance of the proposed method compared to state-of-the-art approaches.

Prediction sets have recently been shown to be a promising strategy for quantifying the uncertainty of deep neural networks in a way that provides theoretical guarantees. However, existing techniques have largely targeted settings where the space of labels is simple, so prediction sets can be arbitrary subsets of labels. For structured prediction problems where the space of labels is exponential in size, even prediction sets containing a small fraction of all labels can be exponentially large. In the context of code generation, we propose a solution that considers a restricted set of prediction sets that can compactly be represented as partial programs, which are programs with portions replaced with holes. Given a trained code generation model, our algorithm leverages a programming language's abstract syntax tree to generate a set of programs such that the correct program is in the set with high-confidence. Valuable applications of our algorithm include a Codex-style code generator with holes in uncertain parts of the generated code, which provides a partial program with theoretical guarantees. We evaluate our approach on PICARD (a T5 model for SQL semantic parsing) and Codex (a GPT model for over a dozen programming languages, including Python), demonstrating that our approach generates compact PAC prediction sets. This is the first research contribution that generates PAC prediction sets for generative code models.

Integrating heterogeneous biomedical data including imaging, omics, and clinical records supports accurate diagnosis and personalised care. Graph-based models fuse such non-Euclidean data by capturing spatial and relational structure, yet clinical uptake requires regulator-ready interpretability. We present the first technical survey of interpretable graph based models for multimodal biomedical data, covering 26 studies published between Jan 2019 and Sep 2024. Most target disease classification, notably cancer and rely on static graphs from simple similarity measures, while graph-native explainers are rare; post-hoc methods adapted from non-graph domains such as gradient saliency, and SHAP predominate. We group existing approaches into four interpretability families, outline trends such as graph-in-graph hierarchies, knowledge-graph edges, and dynamic topology learning, and perform a practical benchmark. Using an Alzheimer disease cohort, we compare Sensitivity Analysis, Gradient Saliency, SHAP and Graph Masking. SHAP and Sensitivity Analysis recover the broadest set of known AD pathways and Gene-Ontology terms, whereas Gradient Saliency and Graph Masking surface complementary metabolic and transport signatures. Permutation tests show all four beat random gene sets, but with distinct trade-offs: SHAP and Graph Masking offer deeper biology at higher compute cost, while Gradient Saliency and Sensitivity Analysis are quicker though coarser. We also provide a step-by-step flowchart covering graph construction, explainer choice and resource budgeting to help researchers balance transparency and performance. This review synthesises the state of interpretable graph learning for multimodal medicine, benchmarks leading techniques, and charts future directions, from advanced XAI tools to under-studied diseases, serving as a concise reference for method developers and translational scientists.

CPU performance prediction, which involves forecasting the performance scores of a CPU based on its hardware characteristics during its operation, is a critical technology for computational system design and resource management in the big data era. However, this research field currently faces two significant challenges. First, collecting real-world data is challenging due to the wide variety of CPU products on the market and the highly specialized nature of relevant hardware characteristics. In the research process, this field lacks a standard dataset with unified hardware characteristics, wide data coverage, and comprehensive benchmarks. Second, existing methods based on hardware simulation models or machine learning exhibit notable shortcomings, such as lengthy simulation test cycles and low prediction accuracy. To bridge these gaps, we first collect, preprocess, and standardize historical data from the 4th Generation Intel Xeon Scalable Processors across multiple benchmark suites to create a new dataset, named PerfCastDB. Subsequently, we design a deep learning based model called Nova CPU Performance Predictor (NCPP) as the baseline for this new dataset. The NCPP network is designed based on group attention mechanism. It effectively quantifies the implicit relationships between hardware characteristics within and across groups and comprehensively models the impact of various hardware characteristics on CPU performance prediction. We conduct comparative experiments using the proposed PerfCastDB dataset. Compared to existing approaches, NCPP achieves superior evaluation results, demonstrating its effectiveness. Furthermore, we have open-sourced part of the dataset and the NCPP network code to facilitate subsequent research. The resources can be accessed at https://github.com/xiaoman-liu/NCPP.

Large language models (LLMs) have emerged as powerful tools for analyzing complex datasets. Recent studies demonstrate their potential to generate useful, personalized responses when provided with patient-specific health information that encompasses lifestyle, biomarkers, and context. As LLM-driven health applications are increasingly adopted, rigorous and efficient one-sided evaluation methodologies are crucial to ensure response quality across multiple dimensions, including accuracy, personalization and safety. Current evaluation practices for open-ended text responses heavily rely on human experts. This approach introduces human factors and is often cost-prohibitive, labor-intensive, and hinders scalability, especially in complex domains like healthcare where response assessment necessitates domain expertise and considers multifaceted patient data. In this work, we introduce Adaptive Precise Boolean rubrics: an evaluation framework that streamlines human and automated evaluation of open-ended questions by identifying gaps in model responses using a minimal set of targeted rubrics questions. Our approach is based on recent work in more general evaluation settings that contrasts a smaller set of complex evaluation targets with a larger set of more precise, granular targets answerable with simple boolean responses. We validate this approach in metabolic health, a domain encompassing diabetes, cardiovascular disease, and obesity. Our results demonstrate that Adaptive Precise Boolean rubrics yield higher inter-rater agreement among expert and non-expert human evaluators, and in automated assessments, compared to traditional Likert scales, while requiring approximately half the evaluation time of Likert-based methods. This enhanced efficiency, particularly in automated evaluation and non-expert contributions, paves the way for more extensive and cost-effective evaluation of LLMs in health.

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.

Breast cancer survival prediction in computational pathology presents a remarkable challenge due to tumor heterogeneity. For instance, different regions of the same tumor in the pathology image can show distinct morphological and molecular characteristics. This makes it difficult to extract representative features from whole slide images (WSIs) that truly reflect the tumor's aggressive potential and likely survival outcomes. In this paper, we present PathoHR, a novel pipeline for accurate breast cancer survival prediction that enhances any size of pathological images to enable more effective feature learning. Our approach entails (1) the incorporation of a plug-and-play high-resolution Vision Transformer (ViT) to enhance patch-wise WSI representation, enabling more detailed and comprehensive feature extraction, (2) the systematic evaluation of multiple advanced similarity metrics for comparing WSI-extracted features, optimizing the representation learning process to better capture tumor characteristics, (3) the demonstration that smaller image patches enhanced follow the proposed pipeline can achieve equivalent or superior prediction accuracy compared to raw larger patches, while significantly reducing computational overhead. Experimental findings valid that PathoHR provides the potential way of integrating enhanced image resolution with optimized feature learning to advance computational pathology, offering a promising direction for more accurate and efficient breast cancer survival prediction. Code will be available at https://github.com/AIGeeksGroup/PathoHR.

High-throughput drug screening -- using cell imaging or gene expression measurements as readouts of drug effect -- is a critical tool in biotechnology to assess and understand the relationship between the chemical structure and biological activity of a drug. Since large-scale screens have to be divided into multiple experiments, a key difficulty is dealing with batch effects, which can introduce systematic errors and non-biological associations in the data. We propose InfoCORE, an Information maximization approach for COnfounder REmoval, to effectively deal with batch effects and obtain refined molecular representations. InfoCORE establishes a variational lower bound on the conditional mutual information of the latent representations given a batch identifier. It adaptively reweighs samples to equalize their implied batch distribution. Extensive experiments on drug screening data reveal InfoCORE's superior performance in a multitude of tasks including molecular property prediction and molecule-phenotype retrieval. Additionally, we show results for how InfoCORE offers a versatile framework and resolves general distribution shifts and issues of data fairness by minimizing correlation with spurious features or removing sensitive attributes. The code is available at https://github.com/uhlerlab/InfoCORE.

Large Language Models (LLMs) and LLM-based agents show great promise in accelerating scientific research. Existing benchmarks for measuring this potential and guiding future development continue to evolve from pure recall and rote knowledge tasks, towards more practical work such as literature review and experimental planning. Bioinformatics is a domain where fully autonomous AI-driven discovery may be near, but no extensive benchmarks for measuring progress have been introduced to date. We therefore present the Bioinformatics Benchmark (BixBench), a dataset comprising over 50 real-world scenarios of practical biological data analysis with nearly 300 associated open-answer questions designed to measure the ability of LLM-based agents to explore biological datasets, perform long, multi-step analytical trajectories, and interpret the nuanced results of those analyses. We evaluate the performance of two frontier LLMs (GPT-4o and Claude 3.5 Sonnet) using a custom agent framework we open source. We find that even the latest frontier models only achieve 17% accuracy in the open-answer regime, and no better than random in a multiple-choice setting. By exposing the current limitations of frontier models, we hope BixBench can spur the development of agents capable of conducting rigorous bioinformatic analysis and accelerate scientific discovery.

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.

Protein Language Models (PLMs) have emerged as performant and scalable tools for predicting the functional impact and clinical significance of protein-coding variants, but they still lag experimental accuracy. Here, we present a novel fine-tuning approach to improve the performance of PLMs with experimental maps of variant effects from Deep Mutational Scanning (DMS) assays using a Normalised Log-odds Ratio (NLR) head. We find consistent improvements in a held-out protein test set, and on independent DMS and clinical variant annotation benchmarks from ProteinGym and ClinVar. These findings demonstrate that DMS is a promising source of sequence diversity and supervised training data for improving the performance of PLMs for variant effect prediction.

The rapid advancement of single-cell ATAC sequencing (scATAC-seq) technologies holds great promise for investigating the heterogeneity of epigenetic landscapes at the cellular level. The amplification process in scATAC-seq experiments often introduces noise due to dropout events, which results in extreme sparsity that hinders accurate analysis. Consequently, there is a significant demand for the generation of high-quality scATAC-seq data in silico. Furthermore, current methodologies are typically task-specific, lacking a versatile framework capable of handling multiple tasks within a single model. In this work, we propose ATAC-Diff, a versatile framework, which is based on a latent diffusion model conditioned on the latent auxiliary variables to adapt for various tasks. ATAC-Diff is the first diffusion model for the scATAC-seq data generation and analysis, composed of auxiliary modules encoding the latent high-level variables to enable the model to learn the semantic information to sample high-quality data. Gaussian Mixture Model (GMM) as the latent prior and auxiliary decoder, the yield variables reserve the refined genomic information beneficial for downstream analyses. Another innovation is the incorporation of mutual information between observed and hidden variables as a regularization term to prevent the model from decoupling from latent variables. Through extensive experiments, we demonstrate that ATAC-Diff achieves high performance in both generation and analysis tasks, outperforming state-of-the-art models.

Gene set knowledge discovery is essential for advancing human functional genomics. Recent studies have shown promising performance by harnessing the power of Large Language Models (LLMs) on this task. Nonetheless, their results are subject to several limitations common in LLMs such as hallucinations. In response, we present GeneAgent, a first-of-its-kind language agent featuring self-verification capability. It autonomously interacts with various biological databases and leverages relevant domain knowledge to improve accuracy and reduce hallucination occurrences. Benchmarking on 1,106 gene sets from different sources, GeneAgent consistently outperforms standard GPT-4 by a significant margin. Moreover, a detailed manual review confirms the effectiveness of the self-verification module in minimizing hallucinations and generating more reliable analytical narratives. To demonstrate its practical utility, we apply GeneAgent to seven novel gene sets derived from mouse B2905 melanoma cell lines, with expert evaluations showing that GeneAgent offers novel insights into gene functions and subsequently expedites knowledge discovery.

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

Developing clinical prediction models (e.g., mortality prediction) based on electronic health records (EHRs) typically relies on expert opinion for feature selection and adjusting observation window size. This burdens experts and creates a bottleneck in the development process. We propose Retrieval-Enhanced Medical prediction model (REMed) to address such challenges. REMed can essentially evaluate an unlimited number of clinical events, select the relevant ones, and make predictions. This approach effectively eliminates the need for manual feature selection and enables an unrestricted observation window. We verified these properties through experiments on 27 clinical tasks and two independent cohorts from publicly available EHR datasets, where REMed outperformed other contemporary architectures that aim to handle as many events as possible. Notably, we found that the preferences of REMed align closely with those of medical experts. We expect our approach to significantly expedite the development of EHR prediction models by minimizing clinicians' need for manual involvement.

Clinical diagnosis prediction models, when provided with a patient's medical history, aim to detect potential diseases early, facilitating timely intervention and improving prognostic outcomes. However, the inherent scarcity of patient data and large disease candidate space often pose challenges in developing satisfactory models for this intricate task. The exploration of leveraging Large Language Models (LLMs) for encapsulating clinical decision processes has been limited. We introduce MERA, a clinical diagnosis prediction model that bridges pertaining natural language knowledge with medical practice. We apply hierarchical contrastive learning on a disease candidate ranking list to alleviate the large decision space issue. With concept memorization through fine-tuning, we bridge the natural language clinical knowledge with medical codes. Experimental results on MIMIC-III and IV datasets show that MERA achieves the state-of-the-art diagnosis prediction performance and dramatically elevates the diagnosis prediction capabilities of generative LMs.

Synthetic data generation has become an increasingly popular way of training models without the need for large, manually labeled datasets. For tasks like text embedding, synthetic data offers diverse and scalable training examples, significantly reducing the cost of human annotation. However, most current approaches rely heavily on proprietary models like GPT-4, which are expensive and inefficient for generating large-scale embedding data. In this paper, we introduce SPEED, a framework that aligns open-source small models (8B) to efficiently generate large-scale synthetic embedding data. Through supervised fine-tuning, preference optimization, and self-improvement, SPEED enables small open-source models to produce high-quality data. Remarkably, SPEED uses only less than 1/10 of the GPT API calls, outperforming the state-of-the-art embedding model E5_mistral when both are trained solely on their synthetic data. Using this efficient generator, we conduct a comprehensive study on how various factors within the alignment pipeline impact data quality and reveal the scaling law for synthetic embedding data.

Predicting how different interventions will causally affect a specific individual is important in a variety of domains such as personalized medicine, public policy, and online marketing. There are a large number of methods to predict the effect of an existing intervention based on historical data from individuals who received it. However, in many settings it is important to predict the effects of novel interventions (e.g., a newly invented drug), which these methods do not address. Here, we consider zero-shot causal learning: predicting the personalized effects of a novel intervention. We propose CaML, a causal meta-learning framework which formulates the personalized prediction of each intervention's effect as a task. CaML trains a single meta-model across thousands of tasks, each constructed by sampling an intervention, along with its recipients and nonrecipients. By leveraging both intervention information (e.g., a drug's attributes) and individual features~(e.g., a patient's history), CaML is able to predict the personalized effects of novel interventions that do not exist at the time of training. Experimental results on real world datasets in large-scale medical claims and cell-line perturbations demonstrate the effectiveness of our approach. Most strikingly, CaML's zero-shot predictions outperform even strong baselines trained directly on data from the test interventions.

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.

Chromosome classification is critical for karyotyping in abnormality diagnosis. To expedite the diagnosis, we present a novel method named Varifocal-Net for simultaneous classification of chromosome's type and polarity using deep convolutional networks. The approach consists of one global-scale network (G-Net) and one local-scale network (L-Net). It follows three stages. The first stage is to learn both global and local features. We extract global features and detect finer local regions via the G-Net. By proposing a varifocal mechanism, we zoom into local parts and extract local features via the L-Net. Residual learning and multi-task learning strategies are utilized to promote high-level feature extraction. The detection of discriminative local parts is fulfilled by a localization subnet of the G-Net, whose training process involves both supervised and weakly-supervised learning. The second stage is to build two multi-layer perceptron classifiers that exploit features of both two scales to boost classification performance. The third stage is to introduce a dispatch strategy of assigning each chromosome to a type within each patient case, by utilizing the domain knowledge of karyotyping. Evaluation results from 1909 karyotyping cases showed that the proposed Varifocal-Net achieved the highest accuracy per patient case (%) 99.2 for both type and polarity tasks. It outperformed state-of-the-art methods, demonstrating the effectiveness of our varifocal mechanism, multi-scale feature ensemble, and dispatch strategy. The proposed method has been applied to assist practical karyotype diagnosis.

Knowledge of mixtures' phase equilibria is crucial in nature and technical chemistry. Phase equilibria calculations of mixtures require activity coefficients. However, experimental data on activity coefficients is often limited due to high cost of experiments. For an accurate and efficient prediction of activity coefficients, machine learning approaches have been recently developed. However, current machine learning approaches still extrapolate poorly for activity coefficients of unknown molecules. In this work, we introduce the SMILES-to-Properties-Transformer (SPT), a natural language processing network to predict binary limiting activity coefficients from SMILES codes. To overcome the limitations of available experimental data, we initially train our network on a large dataset of synthetic data sampled from COSMO-RS (10 Million data points) and then fine-tune the model on experimental data (20 870 data points). This training strategy enables SPT to accurately predict limiting activity coefficients even for unknown molecules, cutting the mean prediction error in half compared to state-of-the-art models for activity coefficient predictions such as COSMO-RS, UNIFAC, and improving on recent machine learning approaches.

Objective: We investigate whether deep learning techniques for natural language processing (NLP) can be used efficiently for patient phenotyping. Patient phenotyping is a classification task for determining whether a patient has a medical condition, and is a crucial part of secondary analysis of healthcare data. We assess the performance of deep learning algorithms and compare them with classical NLP approaches. Materials and Methods: We compare convolutional neural networks (CNNs), n-gram models, and approaches based on cTAKES that extract pre-defined medical concepts from clinical notes and use them to predict patient phenotypes. The performance is tested on 10 different phenotyping tasks using 1,610 discharge summaries extracted from the MIMIC-III database. Results: CNNs outperform other phenotyping algorithms in all 10 tasks. The average F1-score of our model is 76 (PPV of 83, and sensitivity of 71) with our model having an F1-score up to 37 points higher than alternative approaches. We additionally assess the interpretability of our model by presenting a method that extracts the most salient phrases for a particular prediction. Conclusion: We show that NLP methods based on deep learning improve the performance of patient phenotyping. Our CNN-based algorithm automatically learns the phrases associated with each patient phenotype. As such, it reduces the annotation complexity for clinical domain experts, who are normally required to develop task-specific annotation rules and identify relevant phrases. Our method performs well in terms of both performance and interpretability, which indicates that deep learning is an effective approach to patient phenotyping based on clinicians' notes.

This paper introduces a novel framework for DNA sequence generation, comprising two key components: DiscDiff, a Latent Diffusion Model (LDM) tailored for generating discrete DNA sequences, and Absorb-Escape, a post-training algorithm designed to refine these sequences. Absorb-Escape enhances the realism of the generated sequences by correcting `round errors' inherent in the conversion process between latent and input spaces. Our approach not only sets new standards in DNA sequence generation but also demonstrates superior performance over existing diffusion models, in generating both short and long DNA sequences. Additionally, we introduce EPD-GenDNA, the first comprehensive, multi-species dataset for DNA generation, encompassing 160,000 unique sequences from 15 species. We hope this study will advance the generative modelling of DNA, with potential implications for gene therapy and protein production.

In medical applications, deep learning methods are built to automate diagnostic tasks. However, a clinically relevant question that practitioners usually face, is how to predict the future trajectory of a disease (prognosis). Current methods for such a problem often require domain knowledge, and are complicated to apply. In this paper, we formulate the prognosis prediction problem as a one-to-many forecasting problem from multimodal data. Inspired by a clinical decision-making process with two agents -- a radiologist and a general practitioner, we model a prognosis prediction problem with two transformer-based components that share information between each other. The first block in this model aims to analyze the imaging data, and the second block leverages the internal representations of the first one as inputs, also fusing them with auxiliary patient data. We show the effectiveness of our method in predicting the development of structural knee osteoarthritis changes over time. Our results show that the proposed method outperforms the state-of-the-art baselines in terms of various performance metrics. In addition, we empirically show that the existence of the multi-agent transformers with depths of 2 is sufficient to achieve good performances. Our code is publicly available at https://github.com/MIPT-Oulu/CLIMAT.

This paper presents a comprehensive study on resume classification to reduce the time and labor needed to screen an overwhelming number of applications significantly, while improving the selection of suitable candidates. A total of 6,492 resumes are extracted from 24,933 job applications for 252 positions designated into four levels of experience for Clinical Research Coordinators (CRC). Each resume is manually annotated to its most appropriate CRC position by experts through several rounds of triple annotation to establish guidelines. As a result, a high Kappa score of 61% is achieved for inter-annotator agreement. Given this dataset, novel transformer-based classification models are developed for two tasks: the first task takes a resume and classifies it to a CRC level (T1), and the second task takes both a resume and a job description to apply and predicts if the application is suited to the job T2. Our best models using section encoding and multi-head attention decoding give results of 73.3% to T1 and 79.2% to T2. Our analysis shows that the prediction errors are mostly made among adjacent CRC levels, which are hard for even experts to distinguish, implying the practical value of our models in real HR platforms.

Feature selection in deep learning remains a critical challenge, particularly for high-dimensional tabular data where interpretability and computational efficiency are paramount. We present GFSNetwork, a novel neural architecture that performs differentiable feature selection through temperature-controlled Gumbel-Sigmoid sampling. Unlike traditional methods, where the user has to define the requested number of features, GFSNetwork selects it automatically during an end-to-end process. Moreover, GFSNetwork maintains constant computational overhead regardless of the number of input features. We evaluate GFSNetwork on a series of classification and regression benchmarks, where it consistently outperforms recent methods including DeepLasso, attention maps, as well as traditional feature selectors, while using significantly fewer features. Furthermore, we validate our approach on real-world metagenomic datasets, demonstrating its effectiveness in high-dimensional biological data. Concluding, our method provides a scalable solution that bridges the gap between neural network flexibility and traditional feature selection interpretability. We share our python implementation of GFSNetwork at https://github.com/wwydmanski/GFSNetwork, as well as a PyPi package (gfs_network).

Despite significant progress of generative models in the natural sciences, their controllability remains challenging. One fundamentally missing aspect of molecular or protein generative models is an inductive bias that can reflect continuous properties of interest. To that end, we propose the Regression Transformer (RT), a novel method that abstracts regression as a conditional sequence modeling problem. This introduces a new paradigm of multitask language models which seamlessly bridge sequence regression and conditional sequence generation. We thoroughly demonstrate that, despite using a nominal-scale training objective, the RT matches or surpasses the performance of conventional regression models in property prediction tasks of small molecules, proteins and chemical reactions. Critically, priming the same model with continuous properties yields a highly competitive conditional generative model that outperforms specialized approaches in a substructure-constrained, property-driven molecule generation benchmark. Our dichotomous approach is facilitated by a novel, alternating training scheme that enables the model to decorate seed sequences by desired properties, e.g., to optimize reaction yield. In sum, the RT is the first report of a multitask model that concurrently excels at predictive and generative tasks in biochemistry. This finds particular application in property-driven, local exploration of the chemical or protein space and could pave the road toward foundation models in material design. The code to reproduce all experiments of the paper is available at: https://github.com/IBM/regression-transformer

High-throughput screening techniques, such as microscopy imaging of cellular responses to genetic and chemical perturbations, play a crucial role in drug discovery and biomedical research. However, robust perturbation screening for de novo cell lines remains challenging due to the significant morphological and biological heterogeneity across cell lines. To address this, we propose a novel framework that integrates external biological knowledge into existing pretraining strategies to enhance microscopy image profiling models. Our approach explicitly disentangles perturbation-specific and cell line-specific representations using external biological information. Specifically, we construct a knowledge graph leveraging protein interaction data from STRING and Hetionet databases to guide models toward perturbation-specific features during pretraining. Additionally, we incorporate transcriptomic features from single-cell foundation models to capture cell line-specific representations. By learning these disentangled features, our method improves the generalization of imaging models to de novo cell lines. We evaluate our framework on the RxRx database through one-shot fine-tuning on an RxRx1 cell line and few-shot fine-tuning on cell lines from the RxRx19a dataset. Experimental results demonstrate that our method enhances microscopy image profiling for de novo cell lines, highlighting its effectiveness in real-world phenotype-based drug discovery 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.

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.

Biomedical researchers increasingly rely on large-scale structured databases for complex analytical tasks. However, current text-to-SQL systems often struggle to map qualitative scientific questions into executable SQL, particularly when implicit domain reasoning is required. We introduce BiomedSQL, the first benchmark explicitly designed to evaluate scientific reasoning in text-to-SQL generation over a real-world biomedical knowledge base. BiomedSQL comprises 68,000 question/SQL query/answer triples grounded in a harmonized BigQuery knowledge base that integrates gene-disease associations, causal inference from omics data, and drug approval records. Each question requires models to infer domain-specific criteria, such as genome-wide significance thresholds, effect directionality, or trial phase filtering, rather than rely on syntactic translation alone. We evaluate a range of open- and closed-source LLMs across prompting strategies and interaction paradigms. Our results reveal a substantial performance gap: GPT-o3-mini achieves 59.0% execution accuracy, while our custom multi-step agent, BMSQL, reaches 62.6%, both well below the expert baseline of 90.0%. BiomedSQL provides a new foundation for advancing text-to-SQL systems capable of supporting scientific discovery through robust reasoning over structured biomedical knowledge bases. Our dataset is publicly available at https://huggingface.co/datasets/NIH-CARD/BiomedSQL, and our code is open-source at https://github.com/NIH-CARD/biomedsql.

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.