Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

• DOI: 10.1038/s41467-018-05892-0
• Publication Date: 2018-10-09T14:18:41Z
• Authors: Alexandra L Young; Razvan V Marinescu; Neil P Oxtoby; Martina Bocchetta; Keir Yong; Nicholas C Firth; David M Cash; David L Thomas; Katrina M Dick; Jorge Cardoso; John van Swieten; Barbara Borroni; Daniela Galimberti; Mario Masellis; Maria Carmela Tar...; James B Rowe; Caroline Graff; Fabrizio Tagliavini; Giovanni B Frisoni; Robert Laforce; Elizabeth Finger; Alexandre de Mend...; Sandro Sorbi; Jason D Warren; Sebastian Crutch; Nick C Fox; Sebastien Ourselin; Jonathan M Schott; Jonathan D Rohrer; Daniel C Alexander; ; Christin Andersson; Silvana Archetti; Andrea Arighi; Luisa Benussi; Giuliano Binetti; Sandra Black; Maura Cosseddu; Marie Fallström; Carlos Ferreira; Chiara Fenoglio; Morris Freedman; Giorgio G Fumagalli; Stefano Gazzina; Roberta Ghidoni; Marina Grisoli; Vesna Jelic; Lize Jiskoot; Ron Keren; Gemma Lombardi; Carolina Maruta; Lieke Meeter; Simon Mead; Rick van Minkelen; Benedetta Nacmias; Linn Öijerstedt; Alessandro Padovani; Jessica Panman; Michela Pievani; Cristina Polito; Enrico Premi; Sara Prioni; Rosa Rademakers; Veronica Redaelli; Ekaterina Rogaeva; Giacomina Rossi; Martin Rossor; Elio Scarpini; David Tang-Wai; Hakan Thonberg; Pietro Tiraboschi; Ana Verdelho; ; Michael W Weiner; Paul Aisen; Ronald Petersen; Clifford R Jack; William Jagust; John Q Trojanowki; Arthur W Toga; Laurel Beckett; Robert C Green; Andrew J Saykin; John Morris; Leslie M Shaw; Zaven Khachaturian; Greg Sorensen; Lew Kuller; Marc Raichle; Steven Paul; Peter Davies; Howard Fillit; Franz Hefti; Davie Holtzman; M Marcel Mesulam; William Potter; Peter Snyder; Adam Schwartz; Tom Montine; Ronald G Thomas; Michael Donohue; Sarah Walter; Devon Gessert; Tamie Sather; Gus Jiminez; Danielle Harvey; Matthew Bernstein; Paul Thompson; Norbert Schuff; Bret Borowski; Jeff Gunter; Matt Senjem; Prashanthi Vemuri; David Jones; Kejal Kantarci; Chad Ward; Robert A Koeppe; Norm Foster; Eric M Reiman; Kewei Chen; Chet Mathis; Susan Landau; Nigel J Cairns; Erin Householder; Lisa Taylor-Reinwald; Virginia Lee; Magdalena Korecka; Michal Figurski; Karen Crawford; Scott Neu; Tatiana M Foroud; Steven Potkin; Li Shen; Kelley Faber; Sungeun Kim; Kwangsik Nho; Leon Thal; Neil Buckholtz; Marylyn Albert; Richard Frank; John Hsiao; Jeffrey Kaye; Joseph Quinn; Betty Lind; Raina Carter; Sara Dolen; Lon S Schneider; Sonia Pawluczyk; Mauricio Beccera; Liberty Teodoro; Bryan M Spann; James Brewer; Helen Vanderswag; Adam Fleisher; Judith L Heidebrink; Joanne L Lord; Sara S Mason; Colleen S Albers; David Knopman; Kris Johnson; Rachelle S Doody; Javier Villanueva...; Munir Chowdhury; Susan Rountree; Mimi Dang; Yaakov Stern; Lawrence S Honig; Karen L Bell; Beau Ances; Maria Carroll; Sue Leon; Mark A Mintun; Stacy Schneider; Angela Oliver; Daniel Marson; Randall Griffith; David Clark; David Geldmacher; John Brockington; Erik Roberson; Hillel Grossman; Effie Mitsis; Leyla de Toledo-M...; Raj C Shah; Ranjan Duara; Daniel Varon; Maria T Greig; Peggy Roberts; Marilyn Albert; Chiadi Onyike; Daniel D’Agostino; Stephanie Kielb; James E Galvin; Brittany Cerbone; Christina A Michel; Henry Rusinek; Mony J de Leon; Lidia Glodzik; Susan De Santi; P Murali Doraiswamy; Jeffrey R Petrella; Terence Z Wong; Steven E Arnold; Jason H Karlawish; David Wolk; Charles D Smith; Greg Jicha; Peter Hardy; Partha Sinha; Elizabeth Oates; Gary Conrad; Oscar L Lopez; MaryAnn Oakley; Donna M Simpson; Anton P Porsteinsson; Bonnie S Goldstein; Kim Martin; Kelly M Makino; M Saleem Ismail; Connie Brand; Ruth A Mulnard; Gaby Thai; Catherine Mc-Adam...; Kyle Womack; Dana Mathews; Mary Quiceno; Ramon Diaz-Arrastia; Richard King; Myron Weiner; Kristen Martin-Cook; Michael DeVous; Allan I Levey; James J Lah; Janet S Cellar; Jeffrey M Burns; Heather S Anderson; Russell H Swerdlow; Liana Apostolova; Kathleen Tingus; Ellen Woo; Daniel Hs Silverman; Po H Lu; George Bartzokis; Neill R Graff-Rad...; Francine Parfitt; Tracy Kendall; Heather Johnson; Martin R Farlow; Ann Marie Hake; Brandy R Matthews; Scott Herring; Cynthia Hunt; Christopher H van...; Richard E Carson; Martha G MacAvoy; Howard Chertkow; Howard Bergman; Chris Hosein; Bojana Stefanovic; Curtis Caldwell; Ging-Yuek Robin H...; Howard Feldman; Benita Mudge; Michele Assaly; Andrew Kertesz; John Rogers; Charles Bernick; Donna Munic; Diana Kerwin; Marek-Marsel Mesulam; Kristine Lipowski; Chuang-Kuo Wu; Nancy Johnson; Carl Sadowsky; Walter Martinez; Teresa Villena; Raymond Scott Turner; Kathleen Johnson; Brigid Reynolds; Reisa A Sperling; Keith A Johnson; Gad Marshall; Meghan Frey; Barton Lane; Allyson Rosen; Jared Tinklenberg; Marwan N Sabbagh; Christine M Belden; Sandra A Jacobson; Sherye A Sirrel; Neil Kowall; Ronald Killiany; Andrew E Budson; Alexander Norbash; Patricia Lynn Joh...; Joanne Allard; Alan Lerner; Paula Ogrocki; Leon Hudson; Evan Fletcher; Owen Carmichael; John Olichney; Charles DeCarli; Smita Kittur; Michael Borrie; T-Y Lee; Rob Bartha; Sterling Johnson; Sanjay Asthana; Cynthia M Carlsson; Steven G Potkin; Adrian Preda; Dana Nguyen; Pierre Tariot; Stephanie Reeder; Vernice Bates; Horacio Capote; Michelle Rainka; Douglas W Scharre; Maria Kataki; Anahita Adeli; Earl A Zimmerman; Dzintra Celmins; Alice D Brown; Godfrey D Pearlson; Karen Blank; Karen Anderson; Robert B Santulli; Tamar J Kitzmiller; Eben S Schwartz; Kaycee M Sink; Jeff D Williamson; Pradeep Garg; Franklin Watkins; Brian R Ott; Henry Querfurth; Geoffrey Tremont; Stephen Salloway; Paul Malloy; Stephen Correia; Howard J Rosen; Bruce L Miller; Jacobo Mintzer; Kenneth Spicer; David Bachman; Stephen Pasternak; Irina Rachinsky; Dick Drost; Nunzio Pomara; Raymundo Hernando; Antero Sarrael; Susan K Schultz; Laura L Boles Ponto; Hyungsub Shim; Karen Elizabeth S...; Norman Relkin; Gloria Chaing; Lisa Raudin; Amanda Smith; Kristin Fargher; Balebail Ashok Raj; Thomas Neylan; Jordan Grafman; Melissa Davis; Rosemary Morrison; Jacqueline Hayes; Shannon Finley; Karl Friedl; Debra Fleischman; Konstantinos Arfa...; Olga James; Dino Massoglia; J Jay Fruehling; Sandra Harding; Elaine R Peskind; Eric C Petrie; Gail Li; Jerome A Yesavage; Joy L Taylor; Ansgar J Furst
• Keywords: Alzheimer Disease; Frontotemporal Dementia; Genotype; Humans; Models, Neurological; Neurodegenerative Diseases; Phenotype; Reproducibility of Results; Time Factors; Aging; Time Factors; Genotype; Science; Neurodegenerative Diseases/classification/pathology; EMC OR-01; Models, Neurological; 610; Neurodegenerative; Alzheimer's Disease; Frontotemporal Dementia/genetics/pathology; Article; 12. Responsible consumption; 03 medical and health sciences; 0302 clinical medicine; Models; Alzheimer Disease; Health Sciences; Acquired Cognitive Impairment; Genetics; Machine Learning and Artificial Intelligence; 2.1 Biological and endogenous factors; Humans; Alzheimer Disease; Frontotemporal Dementia; Genotype; Humans; Models, Neurological; Neurodegenerative Diseases; Phenotype; Reproducibility of Results; Time Factors; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all); Precision Medicine; Q; Neurosciences; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Reproducibility of Results; Genetic FTD Initiative; Alzheimer Disease/genetics/pathology; Neurodegenerative Diseases; Alzheimer’s Disease Neuroimaging Initiative; Biological Sciences; info:eu-repo/classification/ddc/618.97; Brain Disorders; 4.1 Discovery and preclinical testing of markers and technologies; 3. Good health; Good Health and Well Being; Phenotype; Frontotemporal Dementia; Neurological; ddc:618.97; Dementia; Biochemistry and Cell Biology

AbstractThe heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique—Subtype and Stage Inference (SuStaIn)—able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer’s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 × 10−4) or temporal stage (p = 3.96 × 10−5). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine.