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

The 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.