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CellLENS enables cross-domain information fusion for enhanced cell population delineation in single-cell spatial omics data

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Nature immunology 2025年第6期26卷 2025 May 22页

作者： Bokai Zhu Sheng Gao Shuxiao Chen Yuchen Wang Jason Yeung Yunhao Bai Amy Y Huang Yao Yu Yeo Guanrui Liao Shulin Mao Zhenghui G Jiang Scott J Rodig Ka-Chun Wong Alex K Shalek Garry P Nolan Sizun Jiang Zongming Ma Ragon Institute of MGH MIT and Harvard Cambridge MA USA. Broad Institute of MIT and Harvard Cambridge MA USA. Massachusetts Institute of Technology Cambridge MA USA. Department of Statistics and Data Science The Wharton School University of Pennsylvania Philadelphia PA USA. Center for Virology and Vaccine Research Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA. Department of Computer Science City University of Hong Kong Hong Kong People's Republic of China. Dana-Farber Cancer Institute Boston MA USA. Center of Hepato-Pancreato-Biliary Surgery The First Affiliated Hospital of Sun Yat-sen University Guangzhou People's Republic of China. Division of Genetics and Genomics Boston Children's Hospital Harvard Medical School Boston MA USA. Program in Biological and Biomedical Sciences Harvard Medical School Boston MA USA. Division of Gastroenterology/Liver Center Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA. Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston MA USA. Institute for Medical Engineering and Science Massachusetts Institute of Technology Cambridge MA USA. Department of Chemistry Massachusetts Institute of Technology Cambridge MA USA. Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge MA USA. Department of Pathology Stanford University Stanford CA USA. gnolan@stanford.edu. Broad Institute of MIT and Harvard Cambridge MA USA. sjiang3@bidmc.harvard.edu. Center for Virology and Vaccine Research Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA. sjiang3@bidmc.harvard.edu. Dana-Farber Cancer Institute Boston MA USA. sjiang3@bidmc.harvard.edu. Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston MA USA. sjiang3@bidmc.harvard.edu. Department of Statistics and Data Science Yale University New Haven CT USA. zongming.ma@yale.edu.

Delineating cell populations is crucial for understanding immune function in health and disease. Spatial omics technologies offer insights by capturing three complementary domains: single-cell molecular biomarker expression, cellular spatial relationships and tissue architecture. However, current computational methods often fail to fully integrate these multidimensional data, particularly for immune cell populations and intrinsic functional states. We introduce Cell Local Environment and Neighborhood Scan (CellLENS), a self-supervised computational method that learns cellular representations by fusing information across three spatial omics domains (expression, neighborhood and image). CellLENS markedly enhances de novo discovery of biologically relevant immune cell populations at fine granularity by integrating individual cells' molecular profiles with their neighborhood context and tissue localization. By applying CellLENS to diverse spatial proteomic and transcriptomic datasets across multiple tissue types and disease settings, we uncover unique immune cell populations functionally stratified according to their spatial contexts. Our work demonstrates the power of multi-domain data integration in spatial omics to reveal insights into immune cell heterogeneity and tissue-specific functions.

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The repertoire of mutational signatures in human cancer (vol 578, pg 94, 2020)

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NATURE 2023年第7948期614卷 E41-E41页

作者： Alexandrov, Ludmil B. Kim, Jaegil Haradhvala, Nicholas J. Huang, Mi Ni Ng, Alvin Wei Tian Wu, Yang Boot, Arnoud Covington, Kyle R. Gordenin, Dmitry A. Bergstrom, Erik N. Islam, S. M. Ashiqul Lopez-Bigas, Nuria Klimczak, Leszek J. McPherson, John R. Morganella, Sandro Sabarinathan, Radhakrishnan Wheeler, David A. Mustonen, Ville Getz, Gad Rozen, Steven G. Stratton, Michael R. Department of Cellular and Molecular Medicine Department of Bioengineering Moores Cancer Center University of California San Diego CA USA Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK Department of Cellular and Molecular Medicine and Department of Bioengineering University of California San Diego La Jolla CA USA UC San Diego Moores Cancer Center San Diego CA USA University of California San Diego San Diego CA USA Broad Institute of MIT and Harvard Cambridge MA USA Center for Cancer Research Massachusetts General Hospital Boston MA USA Massachusetts General Hospital Boston MA USA Department of Pathology Massachusetts General Hospital Boston MA USA Harvard Medical School Boston MA USA Laboratory for Medical Science Mathematics RIKEN Center for Integrative Medical Sciences Yokohama Japan Computational Biology Program Ontario Institute for Cancer Research Toronto ON Canada Programme in Cancer & Stem Cell Biology Duke-NUS Medical School Singapore Singapore Centre for Computational Biology Duke-NUS Medical School Singapore Singapore Programme in Cancer and Stem Cell Biology Duke-NUS Medical School Singapore Singapore Programme in Cancer and Stem Cell Biology Centre for Computational Biology Duke-NUS Medical School Singapore Singapore SingHealth Duke-NUS Institute of Precision Medicine National Heart Centre Singapore Singapore Singapore Cancer Science Institute of Singapore National University of Singapore Singapore Singapore Institute of Molecular and Cell Biology Singapore Singapore Laboratory of Cancer Epigenome Division of Medical Science National Cancer Centre Singapore Singapore Singapore Duke-NUS Medical School Singapore Singapore Human Genome Sequencing Center Baylor College of Medicine Houston TX USA Dan L. Duncan Cancer Center Baylor College of Medicine Houston TX USA Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA Genome Integrity and Structural Biology Laboratory National Ins

The evolutionary history of 2,658 cancers (vol 578, pg 122, 2020)

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NATURE 2023年第7948期614卷 E42-E42页

作者： Gerstung, Moritz Jolly, Clemency Leshchiner, Ignaty Dentro, Stefan C. Gonzalez, Santiago Rosebrock, Daniel Mitchell, Thomas J. Rubanova, Yulia Anur, Pavana Yu, Kaixian Tarabichi, Maxime Deshwar, Amit Wintersinger, Jeff Kleinheinz, Kortine Vazquez-Garcia, Ignacio Haase, Kerstin Jerman, Lara Sengupta, Subhajit Macintyre, Geoff Malikic, Salem Donmez, Nilgun Livitz, Dimitri G. Cmero, Marek Demeulemeester, Jonas Schumacher, Steven Fan, Yu Yao, Xiaotong Lee, Juhee Schlesner, Matthias Boutros, Paul C. Bowtell, David D. Zhu, Hongtu Getz, Gad Imielinski, Marcin Beroukhim, Rameen Sahinalp, S. Cenk Ji, Yuan Peifer, Martin Markowetz, Florian Mustonen, Ville Yuan, Ke Wang, Wenyi Morris, Quaid D. Spellman, Paul T. Wedge, David C. Van Loo, Peter European Molecular Biology Laboratory European Bioinformatics Institute (EMBL-EBI) Cambridge UK European Molecular Biology Laboratory Genome Biology Unit Heidelberg Germany Wellcome Sanger Institute Cambridge UK Genome Biology Unit European Molecular Biology Laboratory (EMBL) Heidelberg Germany University of Ljubljana Ljubljana Slovenia The Francis Crick Institute London UK Big Data Institute University of Oxford Oxford UK Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK Big Data Institute Li Ka Shing Centre University of Oxford Oxford UK University of Cambridge Cambridge UK Cambridge University Hospitals NHS Foundation Trust Cambridge UK Department of Applied Mathematics and Theoretical Physics Centre for Mathematical Sciences University of Cambridge Cambridge UK Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA Department of Statistics Columbia University New York NY USA Department of Haematology University of Cambridge Cambridge UK University of Leuven Leuven Belgium Broad Institute of MIT and Harvard Cambridge MA USA Center for Cancer Research Massachusetts General Hospital Charlestown MA USA Department of Pathology Massachusetts General Hospital Boston MA USA Harvard Medical School Boston MA USA Center for Cancer Research Massachusetts General Hospital Boston MA USA Dana-Farber Cancer Institute Boston MA USA Department of Medical Oncology Dana-Farber Cancer Institute Boston MA USA Department of Cancer Biology Dana-Farber Cancer Institute Boston MA USA Oxford NIHR Biomedical Research Centre Oxford UK Oxford NIHR Biomedical Research Centre University of Oxford Oxford UK University of Toronto Toronto Ontario Canada Vector Institute Toronto Ontario Canada Vector Institute Toronto ON Canada Department of Computer Science University of Toronto Toronto ON Canada Ontario Institute for Cancer Research Toronto Ontario Canada University of California Los Angeles

High temperature structure detection in ferromagnets

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arXiv 2018年

作者： Cao, Yuan Neykov, Matey Liu, Han Program in Applied and Computational Mathematics Princeton University PrincetonNJ United States Department of Statistics & Data Science Carnegie Mellon University PittsburghPA United States Department of Electrical Engineering and Computer Science Northwestern University EvanstonIL United States

This paper studies structure detection problems in high temperature ferromagnetic (positive interaction only) Ising models. The goal is to distinguish whether the underlying graph is empty, i.e., the model consists of independent Rademacher variables, versus the alternative that the underlying graph contains a subgraph of a certain structure. We give matching upper and lower minimax bounds under which testing this problem is possible/impossible respectively. Our results reveal that a key quantity called graph arboricity drives the testability of the problem. On the computational front, under a conjecture of the computational hardness of sparse principal component analysis, we prove that, unless the signal is strong enough, there are no polynomial time linear tests on the sample covariance matrix which are capable of testing this problem. Copyright © 2018, The Authors. All rights reserved.

关键词： Ferromagnetism

JS08.6.A A connectivity signature for glioblastoma

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Neuro-Oncology 2022年第SUPPLEMENT_2期24卷 ii8-ii9页

作者： Hoffmann, D C Hai, L Wagener, R Mandelbaum, H Xie, R Hausmann, D Dominguez Azorín, D Weil, S Sievers, P Cebulla, G Ito, J Warnken, U Venkataramani, V Ernst, K Reibold, D Will, R Suvà, M L Herold-Mende, C Sahm, F Winkler, F Schlesner, M Wick, W Kessler, T Clinical Cooperation Unit Neurooncology German Cancer Consortium (DKTK) German Cancer Research Center (DKFZ) Heidelberg Germany Department of Neurology and Neurooncology Program National Center for Tumor Diseases Heidelberg University Hospital Heidelberg Germany Faculty of Biosciences Heidelberg University Heidelberg Germany Bioinformatics and Omics Data Analytics DKFZ Heidelberg Germany Department of Neuropathology Institute of Pathology University Hospital Heidelberg Heidelberg Germany Clinical Cooperation Unit Neuropathology DKTK DKFZ Heidelberg Germany Department of Neuroanatomy Institute for Anatomy and Cell Biology Heidelberg University Heidelberg Germany Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ) Heidelberg Germany Division of Pediatric Neurooncology DKTK DKFZ Heidelberg Germany Genomics and Proteomics Core Facility DKTK DKFZ Heidelberg Germany Broad Institute of Harvard and MIT Cambridge MA United States Department of Pathology and Center for Cancer Research Massachusetts General Hospital and Harvard Medical School Boston MA United States Department of Neurosurgery Heidelberg University Hospital Heidelberg Germany Biomedical Informatics Data Mining and Data Analytics Faculty of Applied Computer Science and Medical Faculty University of Augsburg Augsburg Germany

Modeling temporal networks with bursty activity patterns of nodes and links

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arXiv 2019年

作者： Hiraoka, Takayuki Masuda, Naoki Li, Aming Jo, Hang-Hyun Asia Pacific Center for Theoretical Physics Pohang37673 Korea Republic of 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 Department of Zoology University of Oxford OxfordOX1 3PS United Kingdom Department of Biochemistry University of Oxford OxfordOX1 3QU United Kingdom Department of Physics Pohang University of Science and Technology Pohang37673 Korea Republic of Department of Computer Science Aalto University EspooFI-00076 Finland

The concept of temporal networks provides a framework to understand how the interaction between system components changes over time. In empirical communication data, we often detect non-Poissonian, so-called bursty behavior in the activity of nodes as well as in the interaction between nodes. However, such reconciliation between node burstiness and link burstiness cannot be explained if the interaction processes on different links are independent of each other. This is because the activity of a node is the superposition of the interaction processes on the links incident to the node and the superposition of independent bursty point processes is not bursty in general. Here we introduce a temporal network model based on bursty node activation and show that it leads to heavy-tailed inter-event time distributions for both node dynamics and link dynamics. Our analysis indicates that activation processes intrinsic to nodes give rise to dynamical correlations across links. Our framework offers a way to model competition and correlation between links, which is key to understanding dynamical processes in various systems. Copyright © 2019, The Authors. All rights reserved.

关键词： Chemical activation

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries (vol 55, pg 89, 2023)

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NATURE GENETICS 2023年第3期55卷 519-520页

作者： Fernandez-Rozadilla, Ceres Timofeeva, Maria Chen, Zhishan Law, Philip Thomas, Minta Schmit, Stephanie Diez-Obrero, Virginia Hsu, Li Fernandez-Tajes, Juan Palles, Claire Sherwood, Kitty Briggs, Sarah Svinti, Victoria Donnelly, Kevin Farrington, Susan Blackmur, James Vaughan-Shaw, Peter Shu, Xiao-ou Long, Jirong Cai, Qiuyin Guo, Xingyi Lu, Yingchang Broderick, Peter Studd, James Huyghe, Jeroen Harrison, Tabitha Conti, David Dampier, Christopher Devall, Mathew Schumacher, Fredrick Melas, Marilena Rennert, Gad Obon-Santacana, Mireia Martin-Sanchez, Vicente Moratalla-Navarro, Ferran Oh, Jae Hwan Kim, Jeongseon Jee, Sun Ha Jung, Keum Ji Kweon, Sun-Seog Shin, Min-Ho Shin, Aesun Ahn, Yoon-Ok Kim, Dong-Hyun Oze, Isao Wen, Wanqing Matsuo, Keitaro Matsuda, Koichi Tanikawa, Chizu Ren, Zefang Gao, Yu-Tang Jia, Wei-Hua Hopper, John Jenkins, Mark Win, Aung Ko Pai, Rish Figueiredo, Jane Haile, Robert Gallinger, Steven Woods, Michael Newcomb, Polly Duggan, David Cheadle, Jeremy Kaplan, Richard Maughan, Timothy Kerr, Rachel Kerr, David Kirac, Iva Bohm, Jan Mecklin, Lukka-Pekka Jousilahti, Pekka Knekt, Paul Aaltonen, Lauri Rissanen, Harri Pukkala, Eero Eriksson, Johan Cajuso, Tatiana Hanninen, Ulrika Kondelin, Johanna Palin, Kimmo Tanskanen, Tomas Renkonen-Sinisalo, Laura Zanke, Brent Mannisto, Satu Albanes, Demetrius Weinstein, Stephanie Ruiz-Narvaez, Edward Palmer, Julie Buchanan, Daniel Platz, Elizabeth Visvanathan, Kala Ulrich, Cornelia Siegel, Erin Brezina, Stefanie Gsur, Andrea Campbell, Peter Chang-Claude, Jenny Hoffmeister, Michael Brenner, Hermann Slattery, Martha Potter, John Tsilidis, Konstantinos Schulze, Matthias Gunter, Marc Murphy, Neil Castells, Antoni Castellvi-Bel, Sergi Moreira, Leticia Arndt, Volker Shcherbina, Anna Stern, Mariana Pardamean, Bens Bishop, Timothy Giles, Graham Southey, Melissa Idos, Gregory McDonnell, Kevin Abu-Ful, Zomoroda Greenson, Joel Shulman, Katerina Lejbkowicz, Flavio Offit, Kenneth Su, Yu-Ru Steinfelder, Robert Keku, Temitope van Guelpen, Bethany Hudson, Thomas Hampel, Heather Pearlman, Edinburgh Cancer Research Centre Institute of Genomics and Cancer University of Edinburgh Edinburgh UK Genomic Medicine Group Instituto de Investigacion Sanitaria de Santiago Santiago de Compostela Spain Colon Cancer Genetics Group Medical Research Council Human Genetics Unit Institute of Genetics and Cancer University of Edinburgh Edinburgh UK Danish Institute for Advanced Study Department of Public Health University of Southern Denmark Odense Denmark Division of Epidemiology Department of Medicine Vanderbilt-Ingram Cancer Center Vanderbilt Epidemiology Center Vanderbilt University Medical Center Nashville TN USA Division of Genetics and Epidemiology Institute of Cancer Research London UK Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA USA Genomic Medicine Institute Cleveland Clinic Cleveland OH USA Population and Cancer Prevention Program Case Comprehensive Cancer Center Cleveland OH USA Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute Barcelona Spain Oncology Data Analytics Program Catalan Institute of Oncology Barcelona Spain Consortium for Biomedical Research in Epidemiology and Public Health Madrid Madrid Spain Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain Department of Biostatistics School of Public Health University of Washington Seattle WA USA Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham UK Department of Public Health Richard Doll Building University of Oxford Oxford UK Department of Biomedical Informatics Vanderbilt University School of Medicine Nashville TN USA Department of Preventive Medicine USC Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles CA USA Center for Public Health Genomics Department of Public Health Sciences University of Virginia Charlottesville VA USA Department of Populat

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

关键词： Colorectal cancer Epigenomics Genome-wide association studies Transcriptomics

Network topology mapping from partial virtual coordinates and graph geodesics

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arXiv 2018年

作者： Jayasumana, Anura P. Paffenroth, Randy Mahindre, Gunjan Ramasamy, Sridhar Gajamannage, Kelum Department of Electrical & Computer Engineering Colorado State University Fort CollinsCO80525 United States Department of Mathematical Sciences Department of Computer Science Data Science Program Worcester Polytechnic Institute WorcesterMA01609 United States Department of Mathematical Sciences Worcester Polytechnic Institute WorcesterMA01609 United States

For many important network types (e.g., sensor networks in complex harsh environments and social networks) physical coordinate systems (e.g., Cartesian), and physical distances (e.g., Euclidean), are either difficult to discern or inapplicable. Accordingly, coordinate systems and characterizations based on hop-distance measurements, such as Topology Preserving Maps (TPMs) and Virtual-Coordinate (VC) systems are attractive alternatives to Cartesian coordinates for many network algorithms. Herein, we present an approach to recover geometric and topological properties of a network with a small set of distance measurements. In particular, our approach is a combination of shortest path (often called geodesic) recovery concepts and low-rank matrix completion, generalized to the case of hop-distances in graphs. Results for sensor networks embedded in 2-D and 3-D spaces, as well as a social networks, indicates that the method can accurately capture the network connectivity with a small set of measurements. TPM generation can now also be based on various context appropriate measurements or VC systems, as long as they characterize different nodes by distances to small sets of random nodes (instead of a set of global anchors). The proposed method is a significant generalization that allows the topology to be extracted from a random set of graph shortest paths, making it applicable in contexts such as social networks where VC generation may not be possible. Copyright © 2018, The Authors. All rights reserved.

关键词： Sensor networks

Unsupervised extraction of phenotypes from cancer clinical notes for association studies

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arXiv 2019年

作者： Stark, Stefan G. Hyland, Stephanie L. Pradier, Melanie F. Lehmann, Kjong-Van Wicki, Andreas Perez-Cruz, Fernando Vogt, Julia E. Rätsch, Gunnar Computational Biology Program Memorial Sloan Kettering Cancer Center New York United States Tri-Institutional Ph.D. Program in Computational Biology and Medicine Weill Cornell Medicine New York United States Department of Computer Science ETH Zürich Zürich Switzerland Medical Informatics Group University Hospital Zürich Zürich Switzerland Swiss Institute for Bioinformatics Zurich Switzerland Department of Biology ETH Zürich Zürich Switzerland Department of Signal Processing and Information Theory University Carlos III in Madrid Leganés Spain School of Engineering and Applied Sciences Harvard University CambridgeMA United States Department of Biomedicine University of Basel Basel Switzerland Tumorzentrum University Hospital Basel Basel Switzerland Swiss Data Science Center ETH Zürich and EPFL Lausanne Switzerland Department of Mathematics and Computer Science University of Basel Basel Switzerland

The recent adoption of Electronic Health Records (EHRs) by healthcare providers has introduced an important source of data that provides detailed and highly specific insights into patient phenotypes over large cohorts. These datasets, in combination with machine learning and statistical approaches, generate new opportunities for research and clinical care. However, many methods require the patient representations to be in structured formats, while the information in the EHR is often locked in unstructured text designed for human readability. In this work, we develop the methodology to automatically extract clinical features from clinical narratives from large EHR corpora without the need for prior knowledge. We consider medical terms and sentences appearing in clinical narratives as atomic information units. We propose an efficient clustering strategy suitable for the analysis of large text corpora and utilize the clusters to represent information about the patient compactly. Additionally, we define the sentences on ontologic and natural language vocabularies to automatically detect pertinent combinations of concepts present in the corpus, even when an ontology is not available. To demonstrate the utility of our approach, we perform an association study of clinical features with somatic mutation profiles from 4,007 cancer patients and their tumors. We apply the proposed algorithm to a dataset consisting of .65 thousand documents with a total of .3.2 million sentences. After correcting for cancer type and other confounding factors, we identify a total of 340 significant statistical associations between the presence of somatic mutations and clinical features. We annotated these associations according to their novelty and we report several known associations. We also propose 37 plausible, testable hypothesis for associations where the underlying biological mechanism does not appear to be known. These results illustrate that the automated discovery of clinical features

关键词： Diseases