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arXiv 2024年

作者： de la Rosa, Ezequiel Reyes, Mauricio Liew, Sook-Lei Hutton, Alexandre Wiest, Roland Kaesmacher, Johannes Hanning, Uta Hakim, Arsany Zubal, Richard Valenzuela, Waldo Robben, David Sima, Diana M. Anania, Vincenzo Brys, Arne Meakin, James A. Mickan, Anne Broocks, Gabriel Heitkamp, Christian Gao, Shengbo Liang, Kongming Zhang, Ziji Siddiquee, Md Mahfuzur Rahman Myronenko, Andriy Ashtari, Pooya Van Huffel, Sabine Jeong, Hyun-Su Yoon, Chi-Ho Kim, Chulhong Huo, Jiayu Ourselin, Sebastien Sparks, Rachel Clèrigues, Albert Oliver, Arnau Lladó, Xavier Chalcroft, Liam Pappas, Ioannis Bertels, Jeroen Heylen, Ewout Moreau, Juliette Hatami, Nima Frindel, Carole Qayyum, Abdul Mazher, Moona Puig, Domenec Lin, Shao-Chieh Juan, Chun-Jung Hu, Tianxi Boone, Lyndon Goubran, Maged Liu, Yi-Jui Wegener, Susanne Kofler, Florian Ezhov, Ivan Shit, Suprosanna Hernandez Petzsche, Moritz R. Menze, Bjoern Kirschke, Jan S. Wiestler, Benedikt Department of Quantitative Biomedicine University of Zurich Zurich Switzerland Department of Informatics Technical University Munich Germany Icometrix Leuven Belgium ARTORG Center for Biomedical Research University of Bern Bern Switzerland Department of Radiation Oncology University Hospital Bern University of Bern Switzerland University of Bern Bern Switzerland Chan Division of Occupational Science and Occupational Therapy University of Southern California Los AngelesCA United States Stevens Neuroimaging and Informatics Institute Department of Neurology Keck School of Medicine University of Southern California United States University Institute of Diagnostic and Interventional Neuroradiology Inselspital Bern Switzerland University Institute of Diagnostic and Interventional Neuroradiology University Hospital Bern Inselspital University of Bern Bern Switzerland Department of Diagnostic and Interventional neuroradiology University Medical Center Hamburg-Eppendorf Hamburg Germany Department of Medical Imaging Radboud University Medical Center Institute for Health Sciences Nijmegen Netherlands Deepwise AI Lab Beijing China Beijing University of Posts and Telecommunications Bejing China School of Computing and Augmented Intelligence Arizona State University TempeAZ United States NVIDIA Santa ClaraCA United States STADIUS Center for Dynamical Systems Signal Processing and Data Analytics KU Leuven Leuven Belgium Pohang Korea Republic of School of Biomedical Engineering & Imaging Sciences King’s College London United Kingdom Institute of Computer Vision and Robotics University of Girona Spain Wellcome Centre for Human Neuroimaging University College London London United Kingdom Laboratory of Neuro Imaging Stevens Institute for Neuroimaging and Informatics Keck School of Medicine University of Southern California Los Angeles United States KU Leuven Leuven Belgium CREATIS Université Lyon1 CNRS UMR5220 INSERM U1206 INSA-Lyon Villeurbanne696

Diffusion-weighted MRI (DWI) is essential for stroke diagnosis, treatment decisions, and prognosis. However, image and disease variability hinder the development of generalizable AI algorithms with clinical value. We address this gap by presenting a novel ensemble algorithm derived from the 2022 Ischemic Stroke Lesion Segmentation (ISLES) challenge. ISLES’22 provided 400 patient scans with ischemic stroke from various medical centers, facilitating the development of a wide range of cutting-edge segmentation algorithms by the research community. By assessing them against a hidden test set, we identified strengths, weaknesses, and potential biases. Through collaboration with leading teams, we combined top-performing algorithms into an ensemble model that overcomes the limitations of individual solutions. Our ensemble model combines the individual algorithms’ strengths and achieved superior ischemic lesion detection and segmentation accuracy (median Dice score: 0.82, median lesion-wise F1 score: 0.86) on our internal test set compared to individual algorithms. This accuracy generalized well across diverse image and disease variables. Furthermore, the model excelled in extracting clinical biomarkers like lesion types and affected vascular territories. Notably, in a Turing-like test, neuroradiologists consistently preferred the algorithm’s segmentations over manual expert efforts, highlighting increased comprehensiveness and precision. Validation using a real-world external dataset (N=1686) confirmed the model’s generalizability (median Dice score: 0.82, median lesion-wise F1 score: 0.86). The algorithm’s outputs also demonstrated strong correlations with clinical scores (admission NIHSS and 90-day mRS) on par with or exceeding expert-derived results, underlining its clinical relevance. This study offers two key findings. First, we present an ensemble algorithm that detects and segments ischemic stroke lesions on DWI across diverse scenarios on par with expert (neuro)rad

关键词： Diagnosis

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Modeling state-transition dynamics in resting-state brain signals by the hidden Markov and Gaussian mixture models

arXiv

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arXiv 2020年

作者： Ezaki, Takahiro Himeno, Yu Watanabe, Takamitsu Masuda, Naoki Research Center for Advanced Science and Technology The University of Tokyo 4-6-1 Komaba Meguro-ku Tokyo153-8904 Japan PRESTO JST 4-1-8 Honcho Kawaguchi Saitama332-0012 Japan Department of Aeronautics and Astronautics The University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo113-8656 Japan Laboratory for Cognition Circuit Dynamics RIKEN Centre for Brain Science Saitama351-0198 Japan International Research Center for Neurointelligence The University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo113-0033 Japan Department of Mathematics State University of New York at Buffalo BuffaloNY14260-2900 United States Computational and Data-Enabled Science and Engineering Program State University of New York at Buffalo BuffaloNY14260-5030 United States

Recent studies have proposed that one can summarize brain activity into dynamics among a relatively small number of hidden states and that such an approach is a promising tool for revealing brain function. Hidden Markov models (HMMs) are a prevalent approach to inferring such neural dynamics among discrete brain states. However, the impact of assuming Markovian structure in neural time series data has not been sufficiently examined. Here, to address this situation and examine the performance of the HMM, we compare the model with the Gaussian mixture model (GMM), which is with no temporal regularization and thus a statistically simpler model than the HMM, by applying both models to synthetic time series generated from empirical resting-state functional magnetic resonance imaging (fMRI) data. We compared the GMM and HMM for various sampling frequencies, lengths of recording per participant, numbers of participants, and numbers of independent component signals. We find that the HMM attains a better accuracy of estimating the hidden state than the GMM in a majority of cases. However, we also find that the accuracy of the GMM is comparable to that of the HMM under the condition that the sampling frequency is reasonably low (e.g., TR = 2.88 or 3.60 s) or the data is relatively short. These results suggest that the GMM can be a viable alternative to the HMM for investigating hidden-state dynamics under this condition. Copyright © 2020, The Authors. All rights reserved.

关键词： Hidden Markov models

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Prior COVID-19 vaccination and reduced risk of cerebrovascular diseases among COVID-19 survivors

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Journal of Medical Virology 2024年第5期96卷 e29648页

作者： Chen, Sheng-Yin Hsieh, Tina Yi Jin Hung, Yao-Min Oh, Jae Won Chen, Shen-Kai Wang, Shiow-Ing Chang, Renin Wei, James Cheng-Chung Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston Morocco Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston Morocco Department of Epidemiology Harvard T. H. Chan School of Public Health Boston Morocco Department of Obstetrics & Gynecology Beth Israel Deaconess Medical Center Boston Morocco Department of Bioinformatics Harvard Medical School Boston Morocco Division of Nephrology Department of Internal Medicine Taipei Veterans General Hospital Taitung Branch Taiwan Master Program in Biomedicine College of Science and Engineering National Taitung University Taitung Taiwan College of Health and Nursing Meiho University Pingtung Taiwan Department of Neurology Brigham and Women's Hospital Boston Morocco Department of Neurology Harvard Medical School Boston MA United States Department of Education Kaohsiung Chang Gung Memorial Hospital Boston MA United States Center for Health Data Science Department of Medical Research Chung Shan Medical University Hospital Taichung Taiwan Institute of Medicine College of Medicine Chung Shan Medical University Taichung Taiwan Department of Nursing Jen-Teh Junior College of Medicine Nursing and Management Miaoli County Taiwan Department of Medical Education and Research Kaohsiung Veterans General Hospital Kaohsiung Taiwan Department of Emergency Medicine Kaohsiung Veterans General Hospital Kaohsiung Taiwan School of Medicine Chung Shan Medical University Taichung Taiwan Department of Recreation and Sports Management Tajen University Pintung Taiwan Department of Allergy Immunology & Rheumatology Chung Shan Medical University Hospital Taichung Taiwan Department of Nursing Chung Shan Medical University Taichung Taiwan Graduate Institute of Integrated Medicine China Medical University Taichung Taiwan Office of Research and Development Asia University Taichung Taiwan

The effects of COVID-19 vaccination on short-term and long-term cerebrovascular risks among COVID-19 survivors remained unknown. We conducted a national multi-center retrospective cohort study with 151 597 vaccinated and 151 597 unvaccinated COVID-19 patients using the TriNetX database, from January 1, 2020 to December 31, 2023. Patients baseline characteristics were balanced with propensity score matching (PSM). The outcomes were incident cerebrovascular diseases occurred between 1st and 30th days (short-term) after COVID-19 diagnosis. Nine subgroup analyses were conducted to explore potential effect modifications. We performed six sensitivity analyses, including evaluation of outcomes between 1st to 180th days, accounting for competing risk, and incorporating different variant timeline to test the robustness of our results. Kaplan-Meier curves and Log-Rank tests were performed to evaluate survival difference. Cox proportional hazards regressions were adopted to estimate the PSM-adjusted hazard ratios (HR). The overall short-term cerebrovascular risks were lower in the vaccinated group compared to the unvaccinated group (HR: 0.66, 95% CI: 0.56–0.77), specifically cerebral infarction (HR: 0.62, 95% CI: 0.48–0.79), occlusion and stenosis of precerebral arteries (HR: 0.74, 95% CI: 0.53–0.98), other cerebrovascular diseases (HR: 0.57, 95% CI: 0.42–0.77), and sequelae of cerebrovascular disease (HR: 0.39, 95% CI:0.23–0.68). Similarly, the overall cerebrovascular risks were lower in those vaccinated among most subgroups. The long-term outcomes, though slightly attenuated, were consistent (HR: 0.80, 95% CI: 0.73–0.87). Full 2-dose vaccination was associated with a further reduced risk of cerebrovascular diseases (HR: 0.63, 95% CI: 0.50–0.80) compared to unvaccinated patients. Unvaccinated COVID-19 survivors have significantly higher cerebrovascular risks than their vaccinated counterparts. Thus, clinicians are recommended to monitor this population closely for stroke even

关键词： cohort study COVID-19 vaccination strokes

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scTenifoldXct: A semi-supervised method for predicting cell-cell interactions and mapping cellular communication graphs

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Cell systems 2023年第4期14卷 302-311.e4页

作者： Yongjian Yang Guanxun Li Yan Zhong Qian Xu Yu-Te Lin Cristhian Roman-Vicharra Robert S Chapkin James J Cai Department of Electrical and Computer Engineering Texas A&M University College Station TX 77843 USA. Department of Statistics Texas A&M University College Station TX 77843 USA. Key Laboratory of Advanced Theory and Application in Statistics and Data Science-MOE School of Statistics East China Normal University 3663 North Zhongshan Road Shanghai 200062 China. Department of Veterinary Integrative Biosciences Texas A&M University College Station TX 77843 USA. Graduate Institute of Biomedical Electronics and Bioinformatics National Taiwan University Taipei Taiwan. Department of Nutrition and the Program in Integrative Nutrition & Complex Diseases Texas A&M University College Station TX 77843 USA. Electronic address: r-chapkin@tamu.edu. Department of Electrical and Computer Engineering Texas A&M University College Station TX 77843 USA Department of Veterinary Integrative Biosciences Texas A&M University College Station TX 77843 USA Interdisciplinary Program of Genetics Texas A&M University College Station TX 77843 USA. Electronic address: jcai@tamu.edu.

We present scTenifoldXct, a semi-supervised computational tool for detecting ligand-receptor (LR)-mediated cell-cell interactions and mapping cellular communication graphs. Our method is based on manifold alignment, using LR pairs as inter-data correspondences to embed ligand and receptor genes expressed in interacting cells into a unified latent space. Neural networks are employed to minimize the distance between corresponding genes while preserving the structure of gene regression networks. We apply scTenifoldXct to real datasets for testing and demonstrate that our method detects interactions with high consistency compared with other methods. More importantly, scTenifoldXct uncovers weak but biologically relevant interactions overlooked by other methods. We also demonstrate how scTenifoldXct can be used to compare different samples, such as healthy vs. diseased and wild type vs. knockout, to identify differential interactions, thereby revealing functional implications associated with changes in cellular communication status.

关键词： cell-cell interaction cellular communication gene regression network machine learning manifold alignment neural networks scRNA-seq single-cell RNA sequencing

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Small inter-event times govern epidemic spreading on temporal networks

arXiv

引用

arXiv 2019年

作者： Masuda, Naoki Holme, Petter Department of Mathematics University at Buffalo State University of New York BuffaloNY14260-2900 United States Computational and Data-Enabled Science and Engineering Program University at Buffalo State University of New York BuffaloNY14260-5030 United States Institute of Innovative Research Tokyo Institute of Technology Yokohama226-8503 Japan

Just like the degrees of human and animal interaction networks, the distribution of the times between interactions is known to often be right-skewed and fat-tailed. Both these distributions affect epidemic dynamics strongly, but, as we show in this Letter, for very different reasons. Whereas the high degrees of the tail are critical for facilitating epidemics, it is the small interevent times that control the dynamics of epidemics. We investigate this effect both analytically and numerically for different versions of the Susceptible-Infected-Recovered model on different types of networks. Copyright © 2019, The Authors. All rights reserved.

关键词： Epidemiology

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Comparative analyses for plant virus-based cancer immunotherapy drug development

Cell Biomaterials

引用

Cell Biomaterials 2025年

作者： Anthony O. Omole Hannah S. Newton Edward Cedrone Kimia Nematpour Shaojun Xie Yongmei Zhao Bao Tran Marina A. Dobrovolskaia Nicole F. Steinmetz Aiiso Yufeng Li Family Department of Chemical and Nano Engineering University of California San Diego La Jolla San Diego CA 92093 USA Shu and K.C. Chien and Peter Farrell Collaboratory University of California San Diego La Jolla San Diego CA 92093 USA Center for Nano-ImmunoEngineering University of California San Diego La Jolla San Diego CA 92093 USA Moores Cancer Center University of California San Diego La Jolla San Diego CA 92093 USA Nanotechnology Characterization Lab Cancer Research Technology Program Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute Frederick MD 21702 USA Sequencing Facility Bioinformatics Group Biomedical Informatics and Data Science Directorate Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute Frederick MD 21702 USA CCR Sequencing Facility Cancer Research Technology Program Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute Frederick MD 21702 USA Department of Bioengineering University of California San Diego La Jolla San Diego CA 92093 USA Department of Radiology University of California San Diego La Jolla San Diego CA USA Institute for Materials Discovery and Design University of California San Diego La Jolla San Diego CA 92093 USA Center for Engineering in Cancer Institute of Engineering Medicine University of California San Diego La Jolla San Diego CA 92093 USA

Cowpea mosaic virus (CPMV) is a plant virus with potent anti-tumor efficacy. Intratumoral CPMV, but not cowpea chlorotic mottle virus (CCMV), reprograms the tumor microenvironment priming durable, systemic anti-tumor immunity. Here, we performed a side-by-side mechanism of action comparison between CPMV and CCMV. Through immune-multiplexing and trafficking studies we observed that CPMV and CCMV are taken up by innate immune cells at similar rates but are processed differently. While CCMV induces proinflammatory interleukins 22, 23, and 27, CPMV is a strong inducer of type I, II, and III interferons, which contribute to the activation and enhancement of immune cell function. We observed that CPMV RNAs activate Toll-like receptor (TLR) 7 upon delivery—and not CCMV RNAs; CPMV RNAs persist longer within cells compared with CCMV. Taken together, this work identifies determinants for CPMV’s unique mechanism for intratumoral immunotherapy. It also broadens our understanding of the utility of plant viruses for biomedical applications.

关键词： plant viruses intratumoral immunotherapy cowpea mosaic virus cowpea chlorotic mottle virus cancer nanotechnology

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A Causal Roadmap for Generating High-Quality Real-World Evidence

arXiv

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arXiv 2023年

作者： Dang, Lauren E. Gruber, Susan Lee, Hana Dahabreh, Issa Stuart, Elizabeth A. Williamson, Brian D. Wyss, Richard Díaz, Iván Ghosh, Debashis Kıcıman, Emre Alemayehu, Demissie Hoffman, Katherine L. Vossen, Carla Y. Huml, Raymond A. Ravn, Henrik Kvist, Kajsa Pratley, Richard Shih, Mei-Chiung Pennello, Gene Martin, David Waddy, Salina P. Barr, Charles E. Akacha, Mouna Buse, John B. van der Laan, Mark Petersen, Maya Department of Biostatistics University of California BerkeleyCA United States TL Revolution CambridgeMA United States Office of Biostatistics Office of Translational Sciences Center for Drug Evaluation and Research U.S. Food and Drug Administration Silver SpringMD United States Department of Epidemiology Harvard T.H. Chan School of Public Health BostonMA United States Department of Mental Health Johns Hopkins Bloomberg School of Public Health BaltimoreMD United States Biostatistics Division Kaiser Permanente Washington Health Research Institute SeattleWA United States Division of Pharmacoepidemiology and Pharmacoeconomics Brigham and Women’s Hospital Harvard Medical School BostonMA United States Division of Biostatistics Department of Population Health New York University Grossman School of Medicine New YorkNY United States Department of Biostatistics and Informatics Colorado School of Public Health University of Colorado Anschutz Medical Campus AuroraCO United States Microsoft Research RedmondWA United States Global Biometrics and Data Management Pfizer Inc. New YorkNY United States Department of Epidemiology Mailman School of Public Health Columbia University New YorkNY United States Syneos Health Clinical Solutions Amsterdam Netherlands Syneos Health Clinical Solutions MorrisvilleNC United States Novo Nordisk Søborg Denmark AdventHealth Translational Research Institute OrlandoFL United States Cooperative Studies Program Coordinating Center VA Palo Alto Health Care System Palo AltoCA United States Department of Biomedical Data Science Stanford University StanfordCA United States Division of Imaging Diagnostics and Software Reliability Office of Science and Engineering Laboratories Center for Devices and Radiological Health U.S. Food and Drug Administration Silver SpringMD United States Global Real World Evidence Group Moderna CambridgeMA United States National Center for Advancing Translational Sciences BethesdaMD United States G

Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized controlled trials with outcomes assessed using RWD to fully observational studies. Yet many RWE study proposals lack sufficient detail to evaluate adequacy, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to pre-specify analytic study designs;it addresses a wide range of guidance within a single framework. By requiring transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on pre-specified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers, with companion papers demonstrating application of the Causal Roadmap for specific use cases. Copyright © 2023, The Authors. All rights reserved.

关键词： Decision making

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Development of Moving Equipment for Fishermen's Catches using the Portable Conveyor System 1

Development of Moving Equipment for Fishermen's Catches usin...

引用

1st International Conference on Renewable Energy Research and Challenge, ICoRER 2019

作者： Susanto, Herry Hendroko Setyobudi, Roy Muhammad Nur, Syukri Yandri, Erkata Saepul Uyun, Aep Yaro, Abubakar Abdullah, Kamaruddin Krido Wahono, Satriyo Burlakovs, Juris Adhi Nugroho, Yogo Department of Mechanical Engineering Darma Persada University Jl. Taman Malaka Selatan No.22 Jakarta Timur13450 Indonesia School of Renewable Energy Darma Persada University Jl. Taman Malaka Selatan No.22 Jakarta Timur13450 Indonesia Department of Agriculture Science Postgraduate Program University of Muhammadiyah Malang Jl. Raya Tlogomas No.246 Malang65145 Indonesia Institute of Health Sciences and Research Ahro Scientific Publishing 272 Bath Street GlasgowG2 4JR United Kingdom Research Division for Natural Product Technology - Indonesian Institute of Sciences Jl. Jogja Wonosari km 31.5 Gunung Kidul Yogyakarta55861 Indonesia Department of Water Management Estonian University of Life Sciences Friedrich Reinhold Kreutzwaldi la Tartu51014 Estonia Individual Researcher Alumni School of Ipb University Bogor Indonesia Data Processing Rumah Paper - Editage Services Jl. Tokala No.1 East Java65146 Indonesia

Indonesia is an archipelago that has a wealth of marine fish resources, and the country with the second-longest coastline in the world. The improvement witnessed in the economy of Indonesia in recent years, is as a result of the growth experienced in various sectors, among which is the fisheries and marine. To overcome this problem, a portable conveyor system of moving equipment for fishermen's catches was designed. It can be placed at the dock or port where the fishermen are anchored and unloading the fishermen's catches from the sea. It designed to have the ability to move up and down in the moving frame, making this conveyor system can be used both in high tides and low tides of seawater level conditions. The advantage of this portable conveyor system is could be done continuously with a little human power. Other than that, from the results of the calculations, known that with increasing motor rotation, the required traveling time will only become shorter. The resulting conveyor capacity shows an increase. Also, it can use drive motors that are available on the market with a power capacity of 0.37 kW. Therefore, the process of this portable conveyor system can be more efficient. © The Authors, published by EDP sciences, 2020.

关键词： Fish

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Critical mass effect in evolutionary games triggered by zealots

arXiv

引用

arXiv 2019年

作者： Cardillo, Alessio Masuda, Naoki Department of Engineering Mathematics University of Bristol BristolBS8 1UB United Kingdom Department of Computer Science and Mathematics University Rovira i Virgili TarragonaE-43007 Spain University of Zaragoza ZaragozaE-50018 Spain Department of Mathematics University at Buffalo BuffaloNY14260-2900 United States Computational and Data-Enabled Science and Engineering Program University at Buffalo State University of New York BuffaloNY14260-5030 United States

Tiny perturbations may trigger large responses in systems near criticality, shifting them across equilibria. Committed minorities are suggested to be responsible for the emergence of collective behaviors in many physical, social, and biological systems. Using evolutionary game theory, we address the question whether a finite fraction of zealots can drive the system to large-scale coordination. We find that a tipping point exists in coordination games, whereas the same phenomenon depends on the selection pressure, update rule, and network structure in other types of games. Our study paves the way to understand social systems driven by the individuals’ benefit in presence of zealots, such as human vaccination behavior or cooperative transports in animal groups. Copyright © 2019, The Authors. All rights reserved.

关键词： Game theory

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Polygenic enrichment distinguishes disease associations of individual cells in single-cell RNA-seq data

Research Square

引用

Research Square 2021年

作者： Zhang, Martin Jinye Hou, Kangcheng Pasaniuc, Bogdan Price, Alkes L. Dey, Kushal K. Jagadeesh, Karthik A. Weinand, Kathryn Sakaue, Saori Taychameekiatchai, Aris Rao, Poorvi Pisco, Angela Oliveira Zou, James Wang, Bruce Gandal, Michael Raychaudhuri, Soumya Harvard University United States Osaka University Japan Department of Epidemiology Harvard T.H. Chan School of Public Health BostonMA United States Program in Medical and Population Genetics Broad Institute of MIT and Harvard CambridgeMA United States Bioinformatics Interdepartmental Program University of California Los Angeles Los AngelesCA United States Department of Pathology and Laboratory Medicine David Geffen School of Medicine University of California Los Angeles Los AngelesCA United States Department of Computational Medicine David Geffen School of Medicine University of California Los Angeles Los AngelesCA United States Center for Data Sciences Brigham and Women’s Hospital BostonMA United States Division of Genetics Department of Medicine Brigham and Women’s Hospital Harvard Medical School BostonMA United States Division of Rheumatology Inflammation and Immunity Department of Medicine Brigham and Women’s Hospital Harvard Medical School BostonMA United States Department of Biomedical Informatics Harvard Medical School BostonMA United States Department of Medicine and Liver Center University of California San Francisco San FranciscoCA United States Developmental and Stem Cell Biology Graduate Program University of California San Francisco San FranciscoCA United States Chan Zuckerberg Biohub San FranciscoCA United States Department of Electrical Engineering Stanford University Palo AltoCA United States Department of Biomedical Data Science Stanford University Palo AltoCA United States Department of Psychiatry David Geffen School of Medicine University of California Los Angeles Los AngelesCA United States Department of Human Genetics David Geffen School of Medicine University of California Los Angeles Los AngelesCA United States Program in Neurobehavioral Genetics Semel Institute David Geffen School of Medicine University of California Los Angeles Los AngelesCA United States Versus Arthritis Centre for Genetics and Genomic

Gene expression at the individual cell-level resolution, as quantified by single-cell RNA-sequencing (scRNA-seq), can provide unique insights into the pathology and cellular origin of diseases and complex traits. Here, we introduce single-cell Disease Relevance Score (scDRS), an approach that links scRNA-seq with polygenic risk of disease at individual cell resolution;scDRS identifies individual cells that show excess expression levels for genes in a disease-specific gene set constructed from GWAS data. We determined via simulations that scDRS is well-calibrated and powerful in identifying individual cells associated to disease. We applied scDRS to GWAS data from 74 diseases and complex traits (average N =341K) in conjunction with 16 scRNA-seq data sets spanning 1.3 million cells from 31 tissues and organs. At the cell type level, scDRS broadly recapitulated known links between classical cell types and disease, and also produced novel biologically plausible findings. At the individual cell level, scDRS identified subpopulations of disease-associated cells that are not captured by existing cell type labels, including subpopulations of CD4+ T cells associated with inflammatory bowel disease, partially characterized by their effector-like states;subpopulations of hippocampal CA1 pyramidal neurons associated with schizophrenia, partially characterized by their spatial location at the proximal part of the hippocampal CA1 region;and subpopulations of hepatocytes associated with triglyceride levels, partially characterized by their higher ploidy levels. At the gene level, we determined that genes whose expression across individual cells was correlated with the scDRS score (thus reflecting co-expression with GWAS disease genes) were strongly enriched for gold-standard drug target and Mendelian disease genes. © 2021, CC BY.

关键词： RNA

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