Image-based multivariate profiling of drug responses from single cells

Nature Methods
Lit-Hsin LooSteven J Altschuler

Abstract

Quantitative analytical approaches for discovering new compound mechanisms are required for summarizing high-throughput, image-based drug screening data. Here we present a multivariate method for classifying untreated and treated human cancer cells based on approximately 300 single-cell phenotypic measurements. This classification provides a score, measuring the magnitude of the drug effect, and a vector, indicating the simultaneous phenotypic changes induced by the drug. These two quantities were used to characterize compound activities and identify dose-dependent multiphasic responses. A systematic survey of profiles extracted from a 100-compound compendium of image data revealed that only 10-15% of the original features were required to detect a compound effect. We report the most informative image features for each compound and fluorescence marker set using a method that will be useful for determining minimal collections of readouts for drug screens. Our approach provides human-interpretable profiles and automatic determination of on- and off-target effects.

References

Sep 3, 1999·Nature Biotechnology·A Dove
Sep 24, 1999·Biochemical and Biophysical Research Communications·T K YeungZ Wang
Sep 25, 1999·IEEE Engineering in Medicine and Biology Magazine : the Quarterly Magazine of the Engineering in Medicine & Biology Society·M V Boland, R F Murphy
Oct 22, 2003·Journal of Biomolecular Screening·Betina Kerstin LundholtLen Pagliaro
Jun 3, 2004·Genome Research·Christian ConradRoland Eils
Jun 9, 2004·Current Opinion in Chemical Biology·Paul A Clemons
Nov 13, 2004·Science·Zachary E PerlmanSteven J Altschuler
Nov 30, 2004·Chembiochem : a European Journal of Chemical Biology·Zachary E PerlmanThomas U Mayer
Apr 1, 2005·PLoS Biology·Masahiro TanakaCynthia L Adams
Jun 30, 2005·Proceedings of the National Academy of Sciences of the United States of America·Dulal PandaLeslie Wilson
Nov 25, 2005·Assay and Drug Development Technologies·Kenneth A GiulianoD Lansing Taylor
Dec 21, 2005·Proceedings of the National Academy of Sciences of the United States of America·Yoshikazu OhyaShinichi Morishita
Feb 9, 2006·Nature Biotechnology·Nathalie MaloRobert Nadon
Feb 18, 2006·Nature Reviews. Drug Discovery·Christine B Yoo, Peter A Jones
Apr 4, 2006·Nature Reviews. Drug Discovery·Paul LangAlexander Scheer
Apr 22, 2006·Nature Methods·Beate NeumannJan Ellenberg
Jun 2, 2006·Molecular Systems Biology·Karolina MaciagLani F Wu

Citations

Sep 22, 2009·Nature Methods·Lit-Hsin LooSteven J Altschuler
Apr 26, 2011·Nature Methods·Bjorn L MillardPeter K Sorger
Jun 30, 2012·Nature Methods·Kevin W EliceiriAnne E Carpenter
Dec 5, 2008·Proceedings of the National Academy of Sciences of the United States of America·Michael D SlackSteven J Altschuler
Mar 27, 2010·Bioinformatics·Gregoire PauWolfgang Huber
Dec 4, 2008·Journal of the Royal Society, Interface·Hyuk-Sang KwonPeter T C So
May 6, 2009·Annual Review of Biomedical Engineering·Martin L Yarmush, Kevin R King
Sep 16, 2010·Cancer Research·Xiaofeng XiaStephen T C Wong
Jan 9, 2010·BMC Bioinformatics·Merlin VeronikaJagath C Rajapakse
Jan 16, 2010·BMC Bioinformatics·Benjamin MisselwitzWolf-Dietrich Hardt
May 3, 2011·BMC Bioinformatics·Bailing Zhang, Tuan D Pham
Oct 18, 2013·BMC Bioinformatics·Gregoire PauWolfgang Huber
Feb 26, 2014·BMC Bioinformatics·Danai LaksameethanasanLit-Hsin Loo
Dec 3, 2010·PLoS Computational Biology·L ShamirIlya G Goldberg
May 2, 2013·PLoS Computational Biology·Fuhai LiStephen T C Wong
Dec 7, 2013·PloS One·Sigrun M GustafsdottirAlykhan F Shamji
Sep 27, 2012·Viruses·Gianluca PegoraroRekha G Panchal
Jun 18, 2010·Cellular and Molecular Life Sciences : CMLS·Sylvia E Le DévédecBob van de Water
Feb 15, 2013·Nature Methods·Assen RoguevNevan J Krogan
Jun 5, 2013·International Journal of Computer Vision·Wei WangGustavo K Rohde
Feb 24, 2010·The Journal of Cell Biology·Christian Conrad, Daniel W Gerlich
Jan 12, 2016·Biomolecules·Tsz-Lun YeungSamuel C Mok
Apr 23, 2015·Proceedings of the National Academy of Sciences of the United States of America·Sahand HormozBoris I Shraiman
Nov 14, 2012·Drug Discovery Today·Paola Lecca, Corrado Priami
Dec 8, 2015·Cell·Michael BoutrosChristina Laufer
Apr 1, 2010·Drug Discovery Today. Technologies
Mar 30, 2010·Trends in Biotechnology·Fabian ZanellaWolfgang Link
Sep 11, 2007·Biochimie·Klaudia BrixSilvia Jordans
Aug 7, 2009·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·M Zeder, J Pernthaler
Jul 8, 2008·Current Opinion in Cell Biology·Raphael SacherLucas Pelkmans
Jun 2, 2012·Biotechnology Journal·Gerrit ErdmannMichael Boutros
Mar 7, 2013·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Laura FuriaMario Faretta
Apr 20, 2011·Genesis : the Journal of Genetics and Development·Thai V Truong, Willy Supatto
Jan 28, 2010·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Kerby Shedden, Gus R Rosania
Oct 13, 2009·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·W H De VosP Van Oostveldt
Feb 13, 2010·IEEE/ACM Transactions on Computational Biology and Bioinformatics·Ju HanBahram Parvin
Aug 1, 2009·IEEE Transactions on Medical Imaging·Fuhai LiStephen T C Wong
Feb 4, 2009·Proceedings of the National Academy of Sciences of the United States of America·Thouis R JonesDavid M Sabatini
Oct 7, 2015·Frontiers in Genetics·Alexander Agrotis, Robin Ketteler
Nov 27, 2014·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Robert J SteiningerSteven J Altschuler
Dec 18, 2014·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Man Ching CheungDaniel J Ehrlich
Feb 5, 2014·Biochemical and Biophysical Research Communications·Chiara PastrelloIgor Jurisica
Jun 6, 2015·Cell·Stuart L SchreiberNIH Molecular Libraries Project Team
Oct 19, 2011·Current Opinion in Genetics & Development·Alexander Loewer, Galit Lahav
Apr 19, 2016·Current Opinion in Biotechnology·Juan C CaicedoAnne E Carpenter
Nov 6, 2009·Current Opinion in Neurobiology·Aaron DaubSteven Finkbeiner
Dec 24, 2013·Biophysical Journal·Peter T C SoChristopher Rowlands
Apr 28, 2016·Trends in Cell Biology·Mojca Mattiazzi UsajBrenda J Andrews
Jun 17, 2016·Bioinformatics·Yue DengLani F Wu
Jul 20, 2016·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Nicola Bougen-ZhukovLit-Hsin Loo
Jun 24, 2017·IEEE Transactions on Nanobioscience·Michael F LohrerGang-Yu Liu
Oct 7, 2016·Scientific Reports·Katherin PatschDaniel Ruderman
Jul 20, 2007·Nature Chemical Biology·Anne E Carpenter
Jun 1, 2009·Expert Opinion on Drug Discovery·Fabio Gasparri
Jul 2, 2009·Nature Reviews. Drug Discovery·Yan FengJohn A Tallarico
Jun 10, 2010·Integrative Biology : Quantitative Biosciences From Nano to Macro·Dirk R AlbrechtJagesh V Shah
May 13, 2010·Molecular Systems Biology·Dinesh Kumar SinghSteven J Altschuler
Jun 10, 2010·Molecular Systems Biology·Florian FuchsMichael Boutros
Jun 8, 2010·Journal of Biomolecular Screening·Alvin Y J NgJames G Evans
Jun 26, 2010·Analytical and Bioanalytical Chemistry·Marc Bickle
Jul 20, 2010·Journal of Biomolecular Screening·D Lansing Taylor
May 14, 2011·The Journal of Biological Chemistry·Hon Nian Chua, Frederick P Roth
Mar 8, 2012·Journal of Biomolecular Screening·Anne KümmelDaniela Gabriel
May 29, 2012·Nature Methods·Qing ZhongDaniel W Gerlich
Jun 20, 2012·Expert Opinion on Drug Discovery·J Paul RobinsonVincent Jo Davisson
Sep 1, 2017·Nature Methods·Juan C CaicedoAnne E Carpenter
Sep 24, 2013·Molecular BioSystems·Marcos H WoehrmannR Scott Lokey
Sep 21, 2013·Journal of Biomolecular Screening·Hind AzegrouzMaría C Montoya
Sep 21, 2013·Journal of Biomolecular Screening·Vebjorn LjosaAnne E Carpenter
Oct 5, 2013·Scientific Reports·Debby D WangVictor Lee
Nov 1, 2012·Asia-Pacific Journal of Ophthalmology·Liyun ZhangYuk Fai Leung
Nov 22, 2013·BMC Bioinformatics·Xian Zhang, Michael Boutros
Mar 7, 2014·Journal of Biomolecular Screening·Yann AbrahamChristian N Parker
Apr 9, 2014·Journal of Biomolecular Screening·Shantanu SinghAuguste Genovesio
Dec 3, 2014·Nature Reviews. Genetics·Prisca LiberaliLucas Pelkmans
Apr 29, 2015·Journal of Biomolecular Screening·Jonathan RamesederMichael B Yaffe
Jan 26, 2016·Critical Reviews in Biochemistry and Molecular Biology·Oren Z Kraus, Brendan J Frey
Jan 19, 2018·GigaScience·Dijun ChenChristian Klukas
Oct 2, 2014·Current Protocols in Cytometry·Laura FuriaMario Faretta
Jan 11, 2013·BMC Bioinformatics·Sungin ParkKyu-Baek Hwang
Feb 24, 2017·SLAS Discovery·Albert GoughD Lansing Taylor
Feb 11, 2020·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Mohammad Shifat-E-RabbiGustavo K Rohde
Mar 22, 2019·Scientific Reports·Jin Yeop KimKyeong Sook Choi
Aug 8, 2007·Biotechnology Journal·Urban Liebel, Wolfgang Link
Aug 25, 2007·Pharmacogenomics·Steven A Haney
Nov 22, 2007·Expert Opinion on Therapeutic Targets·Steven A Haney
Dec 15, 2007·Nature Reviews. Drug Discovery·Andrew Bullen
Nov 28, 2008·Electrophoresis·Ken-ichi OhnoAndreas Manz
Dec 17, 2009·Journal of Biomolecular Screening·Nick Thomas
Feb 22, 2011·Journal of Biomolecular Screening·Anne KümmelDaniela Gabriel
Jun 22, 2013·Journal of Biomolecular Screening·Yangzhong TangTimothy J Mitchison
Jan 12, 2013·Journal of Biomolecular Screening·Raquel Torres-GuzmánMaría José Lallena
Aug 11, 2015·Assay and Drug Development Technologies·Felix ReisenPaul Selzer
Feb 20, 2008·Proteomics·Anke PrinzCarsten Schultz
Sep 22, 2015·Acta Pharmacologica Sinica·Xiao-xiao Sun, Qiang Yu
Feb 12, 2017·BMC Bioinformatics·Beatriz Serrano-SolanoJuan A G Ranea
Nov 8, 2017·Alternatives to Laboratory Animals : ATLA·Lit-Hsin Loo, Daniele Zink
Dec 13, 2016·The Journal of Cell Biology·Ben T GrysBrenda J Andrews
Jul 17, 2018·Nucleic Acids Research·Isar Nassiri, Matthew N McCall
Aug 10, 2010·Nature Methods·Michael HeldDaniel W Gerlich
Jun 1, 2012·Expert Opinion on Drug Discovery·Martin Oheim
Dec 15, 2015·Integrative Biology : Quantitative Biosciences From Nano to Macro·Simon GordonovMark Bathe
Nov 24, 2016·Nature Communications·Adriana San-MiguelHang Lu
Mar 7, 2015·Médecine sciences : M/S·Priscille BrodinEmmanuelle Soleilhac
Jul 17, 2010·Journal of Computational Biology : a Journal of Computational Molecular Cell Biology·Shuguang Huang
Jul 28, 2010·Biochemical Society Transactions·Ivana BarbaricPeter W Andrews
Jul 28, 2016·Scientific Reports·Colleen M GarveyShannon M Mumenthaler
Sep 5, 2017·Nature Methods·Satwik RajaramSteven J Altschuler
Jan 19, 2016·Natural Product Reports·V FetzF Sasse
Oct 1, 2015·Assay and Drug Development Technologies·Tony J CollinsDavid W Andrews
Mar 1, 2017·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Gregory R JohnsonRobert F Murphy
Jan 4, 2020·Toxicology and Applied Pharmacology·Johanna NyffelerJoshua A Harrill
Dec 1, 2020·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Andre WoloshukSeth Winfree
Dec 24, 2020·Nature Reviews. Drug Discovery·Srinivas Niranj ChandrasekaranAnne E Carpenter
Jan 24, 2021·Drug Discovery Today·Sophia Malandraki-Miller, Paul R Riley
Sep 19, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Katie Paul FriedmanRussell S Thomas
Nov 15, 2020·Communications Biology·Samuel BerrymanHongshen Ma
Jun 3, 2008·Analytical Chemistry·Pravin K NaoghareJoon Myong Song
Nov 12, 2017·Trends in Biotechnology·Ross A MarkleinSteven R Bauer
Feb 13, 2018·Computer Methods and Programs in Biomedicine·Mohammad R HasanSamir M Iqbal

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