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Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

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NATURE COMMUNICATIONS 2024年第1期15卷 396页

作者： Hamel, Andrew R. Yan, Wenjun Rouhana, John M. Monovarfeshani, Aboozar Jiang, Xinyi Mehta, Puja A. Advani, Jayshree Luo, Yuyang Liang, Qingnan Rajasundaram, Skanda Shrivastava, Arushi Duchinski, Katherine Mantena, Sreekar Wang, Jiali van Zyl, Tave Pasquale, Louis R. Swaroop, Anand Gharahkhani, Puya Khawaja, Anthony P. MacGregor, Stuart Chen, Rui Vitart, Veronique Sanes, Joshua R. Wiggs, Janey L. Segre, Ayellet V. Massachusetts Eye & Ear Dept Ophthalmol Ocular Genom Inst Boston MA 02114 USA Harvard Med Sch Dept Ophthalmol Boston MA 02115 USA Broad Inst Harvard & MIT Cambridge MA 02142 USA Harvard Univ Dept Mol & Cellular Biol Cambridge MA 02138 USA Harvard Univ Ctr Brain Sci Cambridge MA 02138 USA Univ Edinburgh Inst Genet & Canc MRC Human Genet Unit Edinburgh Midlothian Scotland Univ Edinburgh Inst Genet & Mol Med Ctr Genom & Expt Med Edinburgh Midlothian Scotland NEI Neurobiol Neurodegenerat & Repair Lab NIH Bethesda MD 20892 USA Baylor Coll Med Dept Mol & Human Genet Houston TX 77030 USA Univ Oxford Ctr Evidence Based Med Oxford England Imperial Coll London Fac Med London England Harvard Med Sch Bioinformat & Integrat Genom BIG PhD Program Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Yale Sch Med Dept Ophthalmol & Visual Sci New Haven CT USA Icahn Sch Med Mt Sinai Dept Ophthalmol New York NY USA QIMR Berghofer Med Res Inst Brisbane Qld 4029 Australia Moorfields Eye Hosp NHS Fdn Trust NIHR Biomed Res Ctr London England UCL Inst Ophthalmol London England

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.

关键词： Functional genomics Optic nerve diseases Statistical methods

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mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient

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CELL 2017年第3期171卷 642-+页

作者： Wyant, Gregory A. Abu-Remaileh, Monther Wolfson, Rachel L. Chen, Walter W. Freinkman, Elizaveta Danai, Laura V. Heiden, Matthew G. Vander Sabatini, David M. Whitehead Inst Biomed Res Cambridge MA 02142 USA MIT Dept Biol 9 Cambridge Ctr Cambridge MA 02142 USA Howard Hughes Med Inst Cambridge MA 02139 USA Koch Inst Integrat Canc Res 77 Massachusetts Ave Cambridge MA 02139 USA Broad Inst MIT & Harvard 7 Cambridge Ctr Cambridge MA 02142 USA Harvard Med Sch MD PhD Program Daniel C Tosteson Med Educ Ctr 260 Longwood Ave Boston MA 02115 USA Dana Farber Canc Inst Boston MA 02115 USA Metabolon Inc Res Triangle Pk NC 27709 USA

The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. SLC38A9 mediates the transport, in an arginine- regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins. SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1. Pancreatic cancer cells, which use macropinocytosed protein as a nutrient source, require SLC38A9 to form tumors. Thus, through SLC38A9, arginine serves as a lysosomal messenger that couples mTORC1 activation to the release from lysosomes of the essential amino acids needed to drive cell growth.

关键词： amino acid sensing nutrient sensing mTOR lysosome micropinocytosis autophagy

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Morphological integration of the human brain across adolescence and adulthood

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2021年第14期118卷 2023860118-2023860118页

作者： Nadig, Ajay Seidlitz, Jakob McDermott, Cassidy L. Liu, Siyuan Bethlehem, Richard Moore, Tyler M. Mallard, Travis T. Clasen, Liv S. Blumenthal, Jonathan D. Lalonde, Francois Gur, Ruben C. Gur, Raquel E. Bullmore, Edward T. Satterthwaite, Theodore D. Raznahan, Armin Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA NIMH Sect Dev Neurogen Bethesda MD 20892 USA Childrens Hosp Philadelphia Dept Child & Adolescent Psychiat & Behav Sci Philadelphia PA 19104 USA Univ Penn Dept Psychiat Philadelphia PA 19104 USA Univ Penn Dept Psychol Philadelphia PA 19104 USA Univ Cambridge Dept Psychiat Cambridge CB2 1TN England Univ Texas Austin Dept Psychol Austin TX 78712 USA Cambridgeshire & Peterborough NHS Fdn Trust Cambridge CB2 1TN England

Brain structural covariance norms capture the coordination of neurodevelopmental programs between different brain regions. We develop and apply anatomical imbalance mapping (AIM), a method to measure and model individual deviations from these norms, to provide a lifespan map of morphological integration in the human cortex. In cross-sectional and longitudinal data, analysis of whole-brain average anatomical imbalance reveals a reproducible tightening of structural covariance by age 25 y, which loosens after the seventh decade of life. Anatomical imbalance change in development and in aging is greatest in the association cortex and least in the sensorimotor cortex. Finally, we show that interindividual variation in whole-brain average anatomical imbalance is positively correlated with a marker of human prenatal stress (birthweight disparity between monozygotic twins) and negatively correlated with general cognitive ability. This work provides methods and empirical insights to advance our understanding of coordinated anatomical organization of the human brain and its interindividual variation.

关键词： cerebral cortex development lifespan

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Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases

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NATURE GENETICS 2023年第8期55卷 1267-+页

作者： Weeks, Elle M. M. Ulirsch, Jacob C. C. Cheng, Nathan Y. Y. Trippe, Brian L. L. Fine, Rebecca S. S. Miao, Jenkai Patwardhan, Tejal A. A. Kanai, Masahiro Nasser, Joseph Fulco, Charles P. P. Tashman, Katherine C. C. Aguet, Francois Li, Taibo Ordovas-Montanes, Jose Smillie, Christopher S. S. Biton, Moshe Shalek, Alex K. K. Ananthakrishnan, Ashwin N. N. Xavier, Ramnik J. J. Regev, Aviv Gupta, Rajat M. M. Lage, Kasper Ardlie, Kristin G. G. Hirschhorn, Joel N. N. Lander, Eric S. S. Engreitz, Jesse M. M. Finucane, Hilary K. K. Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Med Sch Program Biol & Biomed Sci Boston MA USA MIT Program Computat & Syst Biol Cambridge MA USA MIT Comp Sci & Artificial Intelligence Lab Cambridge MA USA Boston Childrens Hosp Div Endocrinol Boston MA USA Boston Childrens Hosp Ctr Basic & Translat Obes Res Boston MA USA Harvard Med Sch Dept Genet Boston MA USA Harvard Univ Dept Stat Cambridge MA USA MGH Analyt & Translat Genet Unit Boston MA 02114 USA Harvard Med Sch Program Bioinformat & Integrat Genom Boston MA USA Osaka Univ Grad Sch Med Dept Stat Genet Suita Japan Johns Hopkins Univ Sch Med MD PhD Program Baltimore MD USA Boston Childrens Hosp Div Gastroenterol Hepatol & Nutr Boston MA USA Harvard Med Sch Program Immunol Boston MA USA Harvard Stem Cell Inst Cambridge MA USA MGH Dept Mol Biol Boston MA USA MIT Inst Med Engn & Sci Cambridge MA USA MIT Dept Chem Cambridge MA USA MIT Koch Inst Integrat Canc Res Cambridge MA USA MMIT Ragon Inst MGH Cambridge MA USA MGH Ctr Study Inflammatory Bowel Dis Gastrointestinal Unit Boston MA USA Harvard Med Sch Massachusetts Gen Hosp Ctr Computat & Integrat Biol Boston MA USA MIT Howard Hughes Med Inst Cambridge MA USA Brigham & Womens Hosp Dept Med Div Cardiovasc Med & Genet Boston MA USA Harvard Med Sch Boston MA USA MGH Dept Surg Boston MA USA Johns Hopkins Univ Dept Biomed Engn Baltimore MD USA Harvard Med Sch Dept Pediat Boston MA USA MIT Dept Biol Cambridge MA USA Harvard Med Sch Dept Syst Biol Boston MA USA Stanford Univ Sch Med Dept Genet Stanford CA USA Stanford Univ Lucile Packard Childrens Hosp Betty Irene Moore Childrens Heart Ctr BASE InitiatSch Med Stanford CA USA Illumina Inc Artificial Intelligence Lab San Diego CA USA Vertex Pharmaceut Inc Boston MA USA Bristol Myers Squibb Cambridge MA USA Weizmann Inst Sci Dept Biol Regulat Rehovot Israel Genentech Inc San Francisco CA USA

Polygenic Priority Score (PoPS) prioritizes candidate effector genes at complex trait loci by integrating genome-wide association summary statistics with other data types. Combining PoPS with methods that leverage local genetic signals further improves the performance. Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.

关键词： Computational biology and bioinformatics Genetics

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Multiplexed CRISPR-based microfluidic platform for clinical testing of respiratory viruses and identification of SARS-CoV-2 variants

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NATURE MEDICINE 2022年第5期28卷 1083-+页

作者： Welch, Nicole L. Zhu, Meilin Hua, Catherine Weller, Juliane Mirhashemi, Marzieh Ezzaty Nguyen, Tien G. Mantena, Sreekar Bauer, Matthew R. Shaw, Bennett M. Ackerman, Cheri M. Thakku, Sri Gowtham Tse, Megan W. Kehe, Jared Uwera, Marie-Martine Eversley, Jacqueline S. Bielwaski, Derek A. McGrath, Graham Braidt, Joseph Johnson, Jeremy Cerrato, Felecia Moreno, Gage K. Krasilnikova, Lydia A. Petros, Brittany A. Gionet, Gabrielle L. King, Ewa Huard, Richard C. Jalbert, Samantha K. Cleary, Michael L. Fitzgerald, Nicholas A. Gabriel, Stacey B. Gallagher, Glen R. Smole, Sandra C. Madoff, Lawrence C. Brown, Catherine M. Keller, Matthew W. Wilson, Malania M. Kirby, Marie K. Barnes, John R. Park, Daniel J. Siddle, Katherine J. Happi, Christian T. Hung, Deborah T. Springer, Michael MacInnis, Bronwyn L. Lemieux, Jacob E. Rosenberg, Eric Branda, John A. Blainey, Paul C. Sabeti, Pardis C. Myhrvold, Cameron Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Med Sch Div Med Sci Harvard Program Virol Boston MA 02115 USA MIT Dept Biol Engn 77 Massachusetts Ave Cambridge MA 02139 USA Massachusetts Gen Hosp Dept Med Div Infect Dis Boston MA 02114 USA Wellcome Sanger Inst Wellcome Genome Campus Hinxton England Harvard Med Sch Harvard Program Biol & Biomed Sci Boston MA 02115 USA Harvard Med Sch Div Hlth Sci & Technol Cambridge MA USA MIT 77 Massachusetts Ave Cambridge MA 02139 USA Harvard Univ Dept Organism & Evolutionary Biol Cambridge MA 02138 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Med Sch Dept Syst Biol Boston MA 02115 USA Rhode Isl Dept Hlth State Hlth Labs Providence RI 02908 USA Massachusetts Dept Publ Hlth Boston MA USA Ctr Dis Control & Prevent Influenza Div Natl Ctr Immunizat & Resp Dis Atlanta GA USA Redeemers Univ African Ctr Excellence Genom Infect Dis Ede Nigeria Redeemers Univ Coll Nat Sci Dept Biol Sci Ede Nigeria Massachusetts Gen Hosp Mol Biol Dept Boston MA 02114 USA Massachusetts Gen Hosp Ctr Computat & Integrat Biol Boston MA 02114 USA Harvard Univ Dept Immunol & Infect Dis Harvard TH Chan Sch Publ Hlth Boston MA 02115 USA Massachusetts Gen Hosp Dept Pathol Boston MA 02114 USA Harvard Med Sch Boston MA 02115 USA MIT Koch Inst Integrat Canc Res 77 Massachusetts Ave Cambridge MA 02139 USA Howard Hughes Med Inst Chevy Chase MD 20815 USA Princeton Univ Dept Mol Biol Princeton NJ 08544 USA

A microfluidic CRISPR-based platform enables multiplexed and high-throughput identification of a wide range of respiratory viruses, including the ability to identify specific SARS-CoV-2 variants such as Delta and Omicron. The coronavirus disease 2019 (COVID-19) pandemic has demonstrated a clear need for high-throughput, multiplexed and sensitive assays for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses and their emerging variants. Here, we present a cost-effective virus and variant detection platform, called microfluidic Combinatorial Arrayed Reactions for Multiplexed Evaluation of Nucleic acids (mCARMEN), which combines CRISPR-based diagnostics and microfluidics with a streamlined workflow for clinical use. We developed the mCARMEN respiratory virus panel to test for up to 21 viruses, including SARS-CoV-2, other coronaviruses and both influenza strains, and demonstrated its diagnostic-grade performance on 525 patient specimens in an academic setting and 166 specimens in a clinical setting. We further developed an mCARMEN panel to enable the identification of 6 SARS-CoV-2 variant lineages, including Delta and Omicron, and evaluated it on 2,088 patient specimens with near-perfect concordance to sequencing-based variant classification. Lastly, we implemented a combined Cas13 and Cas12 approach that enables quantitative measurement of SARS-CoV-2 and influenza A viral copies in samples. The mCARMEN platform enables high-throughput surveillance of multiple viruses and variants simultaneously, enabling rapid detection of SARS-CoV-2 variants.

关键词： Biotechnology Infectious-disease diagnostics Biomedicine general Cancer Research Metabolic Diseases Infectious Diseases Molecular Medicine Neurosciences

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Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis

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SCIENCE ADVANCES 2024年第5期10卷 eadj9479页

作者： Maynard, Adam G. Pohl, Nancy K. Mueller, Annabel P. Petrova, Boryana Wong, Alan Y. L. Wang, Peng Culhane, Andrew J. Brook, Jeannette R. Hirsch, Leah M. Hoang, Ngoc Kirkland, Orville Braun, Tatum Ducamp, Sarah Fleming, Mark D. Li, Hojun Kanarek, Naama Boston Childrens Hosp Dept Pathol Boston MA 02115 USA Harvard Med Sch Grad Program Biol & Biomed Sci Boston MA 02115 USA Harvard Sch Publ Hlth PhD Program Boston MA 02115 USA Harvard Med Sch Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA MIT Koch Inst Integrat Canc Res Cambridge MA 02142 USA Boston Childrens Hosp Div Hematol Oncol Boston MA 02115 USA Dana Farber Canc Inst Dept Pediat Oncol Boston MA 02115 USA Univ Calif San Diego Dept Pediat San Diego CA 92093 USA Broad Inst Harvard & MIT Cambridge MA 02142 USA

Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: megaloblastic anemia. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines and primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis and accumulation of the purine synthesis intermediate and signaling molecule, 5 '-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR), followed by enhanced heme metabolism, hemoglobin synthesis, and erythroid differentiation. This is phenocopied by inhibition of folate metabolism using the inhibitor SHIN1, and by AICAR supplementation. Mechanistically, the metabolically driven differentiation is independent of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine 5 '-monophosphate-activated protein kinase (AMPK) and is instead mediated by protein kinase C. Our findings suggest that folate deprivation-induced premature differentiation of erythroid progenitor cells is a molecular etiology to folate deficiency-induced anemia.

关键词： Metabolism

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Powassan Virus Neuropathology and Genomic Diversity in Patients With Fatal Encephalitis

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OPEN FORUM INFECTIOUS DISEASES 2020年第10期7卷 1-10页

作者： Normandin, Erica Solomon, Isaac H. Zamirpour, Siavash Lemieux, Jacob Freije, Catherine A. Mukerji, Shibani S. Tomkins-Tinch, Christopher Park, Daniel Sabeti, Pardis C. Piantadosi, Anne Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Med Sch Syst Biol Boston MA 02115 USA Brigham & Womens Hosp Dept Pathol 75 Francis St Boston MA 02115 USA Harvard Univ Cambridge MA USA Massachusetts Gen Hosp Div Infect Dis Boston MA 02114 USA Harvard Univ PhD Program Virol Div Med Sci Boston MA 02115 USA Massachusetts Gen Hosp Dept Neurol Boston MA 02114 USA Harvard Univ Dept Organism & Evolutionary Biol Cambridge MA 02138 USA Harvard Sch Publ Hlth Dept Immunol & Infect Dis Boston MA USA Howard Hughes Med Inst Chevy Chase MD USA Emory Univ Sch Med 101 Woodruff CircleRoom 7207A Atlanta GA 30322 USA

Background. Powassan virus (POWV) is an emerging cause of severe encephalitis;very little is known about human pathogenicity due to challenges in diagnosis and viral RNA recovery. We present 3 patients with fatal encephalitis due to POWV lineage H (deer tick virus). Methods. We obtained 27 unique samples, including from brain biopsy and autopsy, and used metagenomic sequencing, quantitative reverse transcriptase polymerase chain reaction, and a newly developed CRISPR-based diagnostic assay to perform the first detailed characterization of POWV compartmentalization and genomics between and within human subjects. Results. In all 3 patients, imaging and histopathology findings were notable for profound cerebellar involvement. All patients were initially diagnosed with POWV by metagenomic sequencing, and 2 of the 3 had negative clinical testing by serology We detected POWV RNA in 13 clinical samples;levels were highest in the cerebellum, and there was very little involvement of peripheral tissue. We assembled complete POWV genomes from 8 samples, providing unique information about the strains of POWV lineage II (deer tick virus) that infect humans. Conclusions. We demonstrate the utility of molecular assays for detecting POWV infection, including in seronegative patients, and nominate viral genomic features that may relate to human infection and neuropathogenicity. The cerebellum was identified as a key target POWV in fatal infection, by radiological and histopathological findings as well as molecular testing.

关键词： flavivirus molecular diagnostics neuropathology viral genomics

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Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate

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NEURON 2016年第4期92卷 813-828页

作者： Jayaraman, Divya Kodani, Andrew Gonzalez, Dilenny M. Mancias, Joseph D. Mochida, Ganeshwaran H. Vagnoni, Cristiana Johnson, Jeffrey Krogan, Nevan Harper, J. Wade Reiter, Jeremy F. Yu, Timothy W. Bae, Byoung-il Walsh, Christopher A. Boston Childrens Hosp Div Genet & Genom Boston MA 02115 USA Boston Childrens Hosp Manton Ctr Orphan Dis Res Boston MA 02115 USA Howard Hughes Med Inst Chevy Chase MD 20815 USA Harvard Med Sch Program Neurosci Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Univ Calif San Francisco Cardiovasc Res Inst Dept Biochem & Biophys San Francisco CA 94158 USA Harvard Med Sch Dept Cell Biol Boston MA 02115 USA Dana Farber Canc Inst Dept Radiat Oncol Div Genom Stabil & DNA Repair Boston MA 02215 USA Harvard Med Sch Dept Pediat Boston MA 02115 USA Massachusetts Gen Hosp Dept Neurol Pediat Neurol Unit Boston MA 02114 USA Univ Oxford Dept Physiol Anat & Genet Oxford OX1 3QX England Univ Calif San Francisco Dept Cellular & Mol Pharmacol San Francisco CA 94158 USA Broad Inst MIT & Harvard Univ Program Med & Populat Genet Cambridge MA 02142 USA Harvard Med Sch Dept Neurol Boston MA 02115 USA Yale Univ Sch Med Dept Neurosurg 333 Cedar St New Haven CT 06510 USA

Mutations in several genes encoding centrosomal proteins dramatically decrease the size of the human brain. We show that Aspm (abnormal spindle-like, microcephaly-associated) and Wdr62 (WD repeat-containing protein 62) interact genetically to control brain size, with mice lacking Wdr62, Aspm, or both showing gene dose-related centriole duplication defects that parallel the severity of the microcephaly and increased ectopic basal progenitors, suggesting premature delamination from the ventricular zone. Wdr62 and Aspm localize to the proximal end of the mother centriole and interact physically, with Wdr62 required for Aspm localization, and both proteins, as well as microcephaly protein Cep63, required to localize CENPJ/CPAP/Sas-4, a final common target. Unexpectedly, Aspm and Wdr62 are required for normal apical complex localization and apical epithelial structure, providing a plausible unifying mechanism for the premature delamination and precocious differentiation of progenitors. Together, our results reveal links among centrioles, apical proteins, and cell fate, and illuminate how alterations in these interactions can dynamically regulate brain size.

关键词： Wdr62 Aspm maternal centriole apical complex

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Adversarial attacks against medical deep learning systems

arXiv

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arXiv 2018年

作者： Finlayson, Samuel G. Chung, Hyung Won Kohane, Isaac S. Beam, Andrew L. Department of Systems Biology and MD-PhD program Harvard Medical School MIT BostonMA Massachusetts Institute of Technology CambridgeMA United States Department of Biomedical Informatics Harvard Medical School BostonMA United States

The discovery of adversarial examples has raised concerns about the practical deployment of deep learning systems. In this paper, we demonstrate that adversarial examples are capable of manipulating deep learning systems across three clinical domains. For each of our representative medical deep learning classifiers, both white and black box attacks were highly successful. Our models are representative of the current state of the art in medical computer vision and, in some cases, directly reflect architectures already seeing deployment in real world clinical settings. In addition to the technical contribution of our paper, we synthesize a large body of knowledge about the healthcare system to argue that medicine may be uniquely susceptible to adversarial attacks, both in terms of monetary incentives and technical vulnerability. To this end, we outline the healthcare economy and the incentives it creates for fraud and provide concrete examples of how and why such attacks could be realistically carried out. We urge practitioners to be aware of current vulnerabilities when deploying deep learning systems in clinical settings, and encourage the machine learning community to further investigate the domain-specific characteristics of medical learning systems. Copyright © 2018, The Authors. All rights reserved.

关键词： Health care

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Defining heritability, plasticity, and transition dynamics of cellular phenotypes in somatic evolution

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NATURE GENETICS 2024年第10期56卷 2174-+页

作者： Schiffman, Joshua S. D'Avino, Andrew R. Prieto, Tamara Pang, Yakun Fan, Yilin Rajagopalan, Srinivas Potenski, Catherine Hara, Toshiro Suva, Mario L. Gawad, Charles Landau, Dan A. New York Genome Ctr New York NY USA Weill Cornell Med New York NY 10065 USA Rockefeller Univ Tri Inst MD PhD Program Mem Sloan Kettering Canc Ctr Weill Cornell Med New York NY USA Stanford Univ Stanford CA USA Massachusetts Gen Hosp Dept Pathol & Krantz Family Ctr Canc Res Boston MA USA Harvard Med Sch Boston MA USA Broad Inst Harvard Cambridge MA USA MIT Cambridge MA USA Chan Zuckerberg Biohub San Francisco CA USA

Single-cell sequencing has characterized cell state heterogeneity across diverse healthy and malignant tissues. However, the plasticity or heritability of these cell states remains largely unknown. To address this, we introduce PATH (phylogenetic analysis of trait heritability), a framework to quantify cell state heritability versus plasticity and infer cell state transition and proliferation dynamics from single-cell lineage tracing data. Applying PATH to a mouse model of pancreatic cancer, we observed heritability at the ends of the epithelial-to-mesenchymal transition spectrum, with higher plasticity at more intermediate states. In primary glioblastoma, we identified bidirectional transitions between stem- and mesenchymal-like cells, which use the astrocyte-like state as an intermediary. Finally, we reconstructed a phylogeny from single-cell whole-genome sequencing in B cell acute lymphoblastic leukemia and delineated the heritability of B cell differentiation states linked with genetic drivers. Altogether, PATH replaces qualitative conceptions of plasticity with quantitative measures, offering a framework to study somatic evolution.

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