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SSRN 2025年

作者： Liu, Tianyu Zhang, Xiangyu Ying, Rex Zhao, Hongyu Interdepartmental Program in Computational Biology & Bioinformatics Yale University New HavenCT06511 United States Department of Biostatistics Yale University New HavenCT06511 United States Department of Computer Science Yale University New HavenCT06511 United States

Sequence-to-function models can predict gene expression from sequence data and be used to link genetic information with transcriptomics data to understand regulatory processes and their effects on complex phenotypes. The genomic language models are pre-trained with large-scale DNA sequences and can generate robust representations of these sequences by learning the genomic context. However, few studies can estimate the predictability of gene expression levels and bridge these two classes of models together to explore individualized gene expression prediction. In this manuscript, we propose UKBioBERT as a DNA language model pre-trained with genetic variants from UK BioBank. We demonstrate that UKBioBERT generates informative embeddings capable of identifying gene functions, and improving gene expression prediction in cell lines, thereby enhancing our understanding of gene expression predictability. Building upon these embeddings, we combine UKBioBERT with state-of-the-art sequence-to-function architectures, Enformer and Borzoi, to create UKBioFormer and UKBioZoi. These models exhibit better performance in predicting highly predictable gene expression levels and can be generalized across different cohorts. Furthermore, UKBioFormer effectively captures the relationship between genetic variants and expression variations, enabling in-silico mutation analyses. Collectively, our findings underscore the value of integrating genomic language models and sequence-to-function approaches for advancing functional genomics research. © 2025, The Authors. All rights reserved.

关键词： Genome

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Engineering Mice to Study Human Immunity

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Annual Review of Immunology 2025年第1期43卷 451-487页

作者： Sefik, Esen Xiao, Tianli Chiorazzi, Michael Odell, Ian Zhang, Fengrui Agrawal, Kriti Micevic, Goran Flavell, Richard A. Department of Immunobiology Yale School of Medicine New Haven CT United States Howard Hughes Medical Institute Yale School of Medicine New Haven CT United States Department of Internal Medicine Section of Medical Oncology Yale School of Medicine New Haven CT United States Department of Dermatology Yale School of Medicine New Haven CT United States Computational Biology and Bioinformatics Program Yale University New Haven CT United States Department of Pathology Yale School of Medicine New Haven CT United States

Humanized mice, which carry a human hematopoietic and immune system, have greatly advanced our understanding of human immune responses and immunological diseases. These mice are created via the transplantation of human hematopoietic stem and progenitor cells into immunocompromised murine hosts further engineered to support human hematopoiesis and immune cell growth. This article explores genetic modifications in mice that enhance xeno-tolerance, promote human hematopoiesis and immunity, and enable xenotransplantation of human tissues with resident immune cells. We also discuss genetic editing of the human immune system, provide examples of how humanized mice with humanized organs model diseases for mechanistic studies, and highlight the roles of these models in advancing knowledge of organ biology, immune responses to pathogens, and preclinical drugs tested for cancer treatment. The integration of multi-omics and state-of-the art approaches with humanized mouse models is crucial for bridging existing human data with causality and promises to significantly advance mechanistic studies. Copyright © 2025 by the author(s).

关键词： cancer human hematopoietic stem and progenitor cells human immunity human organ modeling humanized mice immunological diseases infectious diseases xenotransplantation

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Quantum variational autoencoder utilizing regularized mixed-state latent representations

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Physical Review A 2025年第4期111卷 042416-042416页

作者： Gaoyuan Wang Jonathan Warrell Prashant S. Emani Mark Gerstein Program in Computational Biology and Bioinformatics Yale University New Haven Connecticut 06520 USA Department of Molecular Biophysics and Biochemistry Yale University New Haven Connecticut 06520 USA NEC Laboratories America Princeton New Jersey 08540 USA Department of Computer Science Yale University New Haven Connecticut 06520 USA Department of Statistics & Data Science Yale University New Haven Connecticut 06520 USA Department of Biomedical Informatics & Data Science Yale University New Haven Connecticut 06520 USA

A major challenge in near-term quantum computing is its application to large real-world datasets due to scarce quantum hardware resources. One approach to enabling tractable quantum models for such datasets involves finding low-dimensional representations that preserve essential information for downstream analysis. In classical machine learning, variational autoencoders (VAEs) facilitate efficient data compression, representation learning for subsequent tasks, and novel data generation. However, no quantum model has been proposed that exactly captures all of these features for direct application to quantum data on quantum computers. Some existing quantum models for data compression lack regularization of latent representations, thus preventing direct use for generation and control of generalization. Others are hybrid models with only some internal quantum components, impeding direct training on quantum data. To address this, we present a fully quantum framework, ζ-QVAE, which encompasses all the capabilities of classical VAEs and can be directly applied to map both classical and quantum data to a lower-dimensional space, while effectively reconstructing much of the original state from it. Our model utilizes regularized mixed states to attain optimal latent representations. It accommodates various divergences for reconstruction and regularization. Furthermore, by accommodating mixed states at every stage, it can utilize the full data density matrix and allow for a training objective defined on probabilistic mixtures of input data. Doing so, in turn, makes efficient optimization possible and has potential implications for private and federated learning. In addition to exploring the theoretical properties of ζ-QVAE, we demonstrate its performance on representative genomics and synthetic data. Our results indicate that ζ-QVAE consistently learns representations that better utilize the capacity of the latent space and exhibits similar or better performance compared with

关键词： Quantum computers

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Learning Multi-cellular Representations of Single-Cell Transcriptomics Data Enables Characterization of Patient-Level Disease States

Learning Multi-cellular Representations of Single-Cell Tran...

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29th International Conference on Research in computational Molecular biology, RECOMB 2025

作者： Liu, Tianyu De Brouwer, Edward Kuo, Tony Diamant, Nathaniel Missarova, Alsu Wang, Hanchen Hao, Minsheng Bravo, Hector Corrada Scalia, Gabriele Regev, Aviv Heimberg, Graham Research and Early Development Genentech South San FranciscoCA94080 United States Interdepartmental Program in Computational Biology and Bioinformatics Yale University New HavenCT06511 United States Roche Informatics F. Hoffmann-La Roche Ltd. Mississauga Canada Department of Computer Science Stanford University Palo AltoCA94035 United States

ISBN: (纸本)9783031902512

Single-cell RNA-seq (scRNA-seq) has become a prominent tool for studying human biology and disease. The availability of massive scRNA-seq datasets and advanced machine learning techniques has recently driven the development of single-cell foundation models that provide informative and versatile cell representations based on expression profiles. However, to understand disease states, we need to consider entire tissue ecosystems, simultaneously considering many different interacting cells. Here, we tackle this challenge by generating patient-level representations derived from multi-cellular expression context measured with scRNA-seq of tissues. We develop PaSCient, a novel model that employs a multi-level representation learning paradigm and provides importance scores at the individual cell and gene levels for fine-grained analysis across multiple cell types and gene programs characteristic of a given disease. We apply PaSCient to learn a disease model across a large-scale scRNA-seq atlas of 12.5 million cells from over 2,700 patients. Comprehensive and rigorous benchmarking demonstrates the superiority of PaSCient in disease classification and its multiple downstream applications, including dimensionality reduction, gene/cell type prioritization, and patient subgroup discovery. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2025.

关键词： Biomolecules

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HiPoNet: A Topology-Preserving Multi-View Neural Network For High Dimensional Point Cloud and Single-Cell Data

arXiv

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arXiv 2025年

作者： Viswanath, Siddharth Madhu, Hiren Bhaskar, Dhananjay Kovalic, Jake Johnson, Dave Ying, Rex Tape, Christopher Adelstein, Ian Perlmutter, Michael Krishnaswamy, Smita Department of Computer Science Yale University New Haven United States Department of Genetics Yale University New Haven United States Department of Applied Physics Yale University New Haven United States Program in Computing Boise State University Idaho United States Cell Communication Lab Department of Oncology University College London Cancer Institute London United Kingdom Department of Mathematics Yale University New Haven United States Department of Mathematics Boise State University Idaho United States Computational Biology and Bioinformatics Program Yale University New Haven United States Wu-Tsai Institute Yale University New Haven United States Program for Applied Math Yale University New Haven United States

In this paper, we propose HiPoNet, an end-to-end differentiable neural network for regression, classification, and representation learning on high-dimensional point clouds. Single-cell data can have high dimensionality exceeding the capabilities of existing methods for point clouds which are tailored for 3D data. Moreover, modern single-cell and spatial experiments now yield entire cohorts of datasets (i.e. one on every patient), necessitating models that can process large, high-dimensional point clouds at scale. Most current approaches build a single nearest-neighbor graph, discarding important geometric information. In contrast, HiPoNet forms higher-order simplicial complexes through learnable feature reweighting, generating multiple data views that disentangle distinct biological processes. It then employs simplicial wavelet transforms to extract multiscale features—capturing both local and global topology. We empirically show that these components preserve topological information in the learned representations, and that HiPoNet significantly outperforms state-of-the-art point-cloud and graph-based models on single cell. We also show an application of HiPoNet on spatial transcriptomics datasets using spatial co-ordinates as one of the views. Overall, HiPoNet offers a robust and scalable solution for high-dimensional data analysis. © 2025, CC BY.

关键词： Network topology

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Characterizing Emergency Department Care for Patients With Histories of Incarceration

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JACEP Open 2025年第1期6卷 100022-100022页

作者： Huang, Thomas Socrates, Vimig Ovchinnikova, Polina Faustino, Isaac Kumar, Anusha Safranek, Conrad Chi, Ling Wang, Emily A. Puglisi, Lisa Wong, Ambrose H. Wang, Karen H. Taylor, R. Andrew Department of Emergency Medicine Yale School of Medicine New Haven CT United States Department for Biomedical Informatics and Data Science Yale University School of Medicine New Haven CT United States Program of Computational Biology and Bioinformatics Yale University New Haven CT United States SEICHE Center for Health and Justice Yale School of Medicine New Haven CT United States Equity Research and Innovation Center Yale School of Medicine Yale University New Haven CT United States

Objectives: Patients with a history of incarceration experience bias from health care team members, barriers to privacy, and a multitude of health care disparities. We aimed to assess care processes delivered in emergency departments (EDs) for people with histories of incarceration. Methods: We utilized a fine-tuned large language model to identify patient incarceration status from 480,374 notes from the ED setting. We compared socio-demographic characteristics, comorbidities, and care processes, including disposition, restraint use, and sedation, between individuals with and without a history of incarceration. We then conducted multivariable logistic regression to assess the independent correlation of incarceration history and management in the ED while adjusting for demographic characteristics, health behaviors, presentation, and past medical history. Results: We found 1734 unique patient encounters with a history of incarceration from a total of 177,987 encounters. Patients with history of incarceration were more likely to be male, Black, Hispanic, or other race/ethnicity, currently unemployed or disabled, and had smoking and substance use histories, compared with those without. This cohort demonstrated higher odds of elopement (OR: 3.59 [95% CI: 2.41–5.12]), leaving against medical advice (OR: 2.39 [95% CI: 1.46–3.67]), and being subjected to sedation (OR: 3.89 [95% CI: 3.19–4.70]) and restraint use (OR: 3.76 [95% CI: 3.06–4.57]). After adjusting for covariates, the association between incarceration and elopement remained significant (adjusted odds ratio: 1.65 [95% CI: 1.08–2.43]), while associations with other dispositions, restraint use, and sedation did not persist. Conclusion: This study identified differences in patient characteristics and care processes in the ED for patients with histories of incarceration and demonstrated the potential of using natural language processing in measuring care processes in populations that are largely hidden, but highly prev

关键词： artificial intelligence emergency medicine incarceration large language models quality of health care

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KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection

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Science (New York, N.Y.) 2025年第6735期387卷 eadn2337页

作者： Fagerberg, Eric Attanasio, John Dien, Christine Singh, Jaiveer Kessler, Emily A. Abdullah, Leena Shen, Jian Hunt, Brian G. Connolly, Kelli A. De Brouwer, Edward He, Jiaming Iyer, Nivedita R. Buck, Jessica Borr, Emily R. Damo, Martina Foster, Gena G. Giles, Josephine R. Huang, Yina H. Tsang, John S. Krishnaswamy, Smita Cui, Weiguo Joshi, Nikhil S. Department of Immunobiology Yale University School of Medicine New Haven CT United States Program in Computational Biology & Bioinformatics Yale University New Haven CT United States Department of Microbiology and Immunology Geisel School of Medicine at Dartmouth NH United States Department of Pathology Feinberg School of Medicine at Northwestern University Chicago IL United States Department of Genetics and Computer Science Yale University School of Medicine New Haven CT United States Department of Medicine University of Chicago Chicago IL United States Section of Hematology Department of Internal Medicine Yale University School of Medicine New Haven CT United States Department of Systems Pharmacology and Translational Therapeutics University of Pennsylvania Philadelphia PA United States Institute for Immunology Perelman School of Medicine University of Pennsylvania Philadelphia PA United States Parker Institute for Cancer Immunotherapy Perelman School of Medicine University of Pennsylvania Philadelphia PA United States Yale Center for Systems and Engineering Immunology Yale University School of Medicine New Haven CT United States New Haven CT United States Department of Biomedical Engineering Yale University New Haven CT United States Computational Biology and Bioinformatics Program Yale University CT USA New Haven United States Applied Math Program Yale University New Haven CT United States

Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9-based perturbation sequencing to assess the role of ~40 transcription factors (TFs) and epigenetic modulators in T cell fate decisions. Unexpectedly, we found that knockout of the TF Klf2 resulted in aberrant differentiation to exhausted-like CD8 T cells during acute infection. KLF2 was required to suppress the exhaustion-promoting TF TOX and to enable the TF TBET to drive effector differentiation. KLF2 was also necessary to maintain a polyfunctional tumor-specific progenitor state. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.

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Mapping Emergency Medicine Data to the Observational Medical Outcomes Partnership Common Data Model: A Gap Analysis of the American College of Emergency Physicians Clinical Emergency Data Registry

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JACEP Open 2025年第1期6卷 100016-100016页

作者： Cohen, Inessa Diao, Zihan Goyal, Pawan Gupta, Aarti Hawk, Kathryn Malcom, Bill Malicki, Caitlin Sharma, Dhruv Sweeney, Brian Weiner, Scott G. Venkatesh, Arjun Taylor, R. Andrew Department of Emergency Medicine Yale School of Medicine New Haven CT United States Section for Biomedical Informatics and Data Science Yale University School of Medicine New Haven CT United States Program of Computational Biology and Bioinformatics Yale University New Haven CT United States American College of Emergency Physicians Washington DC United States Department of Emergency Medicine Brigham and Women's Hospital Boston MA United States Center for Outcomes Research and Evaluation (CORE) Section of Cardiovascular Medicine Yale School of Medicine New Haven CT United States

Objectives: This study aims to conduct a gap analysis to determine the feasibility of mapping electronic health record data from the Clinical Emergency Data Registry (CEDR) to the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM). Methods: We employed a structured approach using a custom-built comparison matrix. This matrix facilitated the alignment of CEDR data fields with the corresponding elements in the OMOP-CDM schema. Each field was evaluated for compatibility, with categorization into 3 distinct types: direct matches, fields requiring transformation, and fields with no OMOP-CDM equivalent. The mapping process was informed by consultations with the Observational Health Data Sciences and Informatics community forums and was guided by existing documentation and best practices in data harmonization. We performed descriptive analyses, quantifying the extent of direct matches and identifying the specific transformations needed for each CEDR-CDM field to ensure compliance with the OMOP-CDM model. Results: Our analysis indicates a high degree of compatibility between CEDR and OMOP, with over 90% (244/269) of CEDR fields being successfully mapped. Specifically, 173 fields had direct matches, whereas 71 required transformations. Challenges identified include addressing fields unique to CEDR with no OMOP-CDM equivalent and managing the transformations required for proper alignment. Conclusion: The OMOP-CDM presents a promising framework for standardizing emergency medicine data, thereby enhancing future query automation, analytics, and cross-institutional collaboration. Despite the potential challenges in capturing unique CEDR fields and addressing necessary transformations, most emergency department data can be standardized within the OMOP-CDM, fostering broader insights and applications in research and public health. © 2024 The Author(s)

关键词： databases electronic health records emergency service informatics opioid/adverse effects quality of health care registries

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ChromActivity: integrative epigenomic and functional characterization assay based annotation of regulatory activity across diverse human cell types

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Genome biology 2025年第1期26卷 123页

作者： Tevfik Umut Dincer Jason Ernst Bioinformatics Interdepartmental Program University of California Los Angeles Los Angeles CA 90095 USA. Department of Biological Chemistry University of California Los Angeles Los Angeles CA 90095 USA. Bioinformatics Interdepartmental Program University of California Los Angeles Los Angeles CA 90095 USA. jason.ernst@ucla.edu. Department of Biological Chemistry University of California Los Angeles Los Angeles CA 90095 USA. jason.ernst@ucla.edu. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at University of California Los Angeles Los Angeles CA 90095 USA. jason.ernst@ucla.edu. Computer Science Department University of California Los Angeles Los Angeles CA 90095 USA. jason.ernst@ucla.edu. Jonsson Comprehensive Cancer Center University of California Los Angeles Los Angeles CA 90095 USA. jason.ernst@ucla.edu. Molecular Biology Institute University of California Los Angeles Los Angeles CA 90095 USA. jason.ernst@ucla.edu. Department of Computational Medicine University of California Los Angeles Los Angeles CA 90095 USA. jason.ernst@ucla.edu.

We introduce ChromActivity, a computational framework for predicting and annotating regulatory activity across the genome through integration of multiple epigenomic maps and various functional characterization datasets. ChromActivity generates genomewide predictions of regulatory activity associated with each functional characterization dataset across many cell types based on available epigenomic data. It then for each cell type produces ChromScoreHMM genome annotations based on the combinatorial and spatial patterns within these predictions and ChromScore tracks of overall predicted regulatory activity. ChromActivity provides a resource for analyzing and interpreting the human regulatory genome across diverse cell types.

关键词： CRISPR screens Epigenome Gene regulation Genome annotation Hidden Markov model Machine learning Massively parallel reporter assays

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Identifying Deprescribing Opportunities With Large Language Models in Older Adults: Retrospective Cohort Study

JMIR Aging

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JMIR Aging 2025年 8卷 e69504页

作者： Socrates, Vimig Wright, Donald S. Huang, Thomas Fereydooni, Soraya Dien, Christine Chi, Ling Albano, Jesse Patterson, Brian Kanaparthy, Naga Sasidhar Wright, Catherine X. Loza, Andrew Chartash, David Iscoe, Mark Taylor, Richard Andrew Department of Biomedical Informatics and Data Science School of Medicine Yale University New Haven CT United States Program of Computational Biology and Bioinformatics Yale University New Haven CT United States Department of Emergency Medicine School of Medicine Yale University New Haven CT United States VA Connecticut Healthcare System US Department of Veterans Affairs West Haven CT United States Department of Pharmacy Yale New Haven Hospital New Haven CT United States BerbeeWalsh Department of Emergency Medicine University of Wisconsin–Madison Madison WI United States Section of Cardiovascular Medicine Department of Internal Medicine Yale School of Medicine New Haven CT United States School of Medicine University College Dublin Dublin Ireland Department of Biostatistics School of Public Health Yale University New Haven CT United States

Background: Polypharmacy, the concurrent use of multiple medications, is prevalent among older adults and associated with increased risks for adverse drug events including falls. Deprescribing, the systematic process of discontinuing potentially inappropriate medications, aims to mitigate these risks. However, the practical application of deprescribing criteria in emergency settings remains limited due to time constraints and criteria complexity. Objective: This study aims to evaluate the performance of a large language model (LLM)–based pipeline in identifying deprescribing opportunities for older emergency department (ED) patients with polypharmacy, using 3 different sets of criteria: Beers, Screening Tool of Older People’s Prescriptions, and Geriatric Emergency Medication Safety Recommendations. The study further evaluates LLM confidence calibration and its ability to improve recommendation performance. Methods: We conducted a retrospective cohort study of older adults presenting to an ED in a large academic medical center in the Northeast United States from January 2022 to March 2022. A random sample of 100 patients (712 total oral medications) was selected for detailed analysis. The LLM pipeline consisted of two steps: (1) filtering high-yield deprescribing criteria based on patients’ medication lists, and (2) applying these criteria using both structured and unstructured patient data to recommend deprescribing. Model performance was assessed by comparing model recommendations to those of trained medical students, with discrepancies adjudicated by board-certified ED physicians. Selective prediction, a method that allows a model to abstain from low-confidence predictions to improve overall reliability, was applied to assess the model’s confidence and decision-making thresholds. Results: The LLM was significantly more effective in identifying deprescribing criteria (positive predictive value: 0.83;negative predictive value: 0.93;McNemar test for paired proportion

关键词： calibration deprescribing emergency medicine geriatrics large language models natural language processing potentially inappropriate medication list

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