Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05892-0
Keywords
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Categories
Funding
- EPSRC
- Biomarkers Across Neurodegenerative Diseases programme
- Michael J. Fox Foundation for Parkinson's Research
- Alzheimer's Association
- Alzheimer's Research UK
- Weston Brain Institute
- EPSRC Centre For Doctoral Training in Medical Imaging [EP/L016478/1]
- UCL Leonard Wolfson Experimental Neurology Centre [PR/ylr/18575]
- Alzheimer's Society PhD Studentship
- Wellcome Trust [103838]
- Associazione Italiana Ricerca Alzheimer ONLUS (AIRAlzh Onlus)-COOP Italia
- Alzheimer's Society
- NIHR UCLH Biomedical Research Centre
- NIHR Queen Square Dementia BRU
- ARUK [ART-SRF2010-3, ARUK-Network 2012-6-ICE, ARUK-PG2017-1946]
- ESRC/NIHR [ES/L001810/1]
- EPSRC [EP/M006093/1, EP/J020990/1, EP/J020990/01, EP/M020533/1]
- NIHR UCL/H Biomedical Research Centre
- Wolfson Foundation
- MRC [MR/L023784/1]
- Brain Research Trust [UCC14191]
- European Union's Horizon 2020 research and innovation programme [666992]
- MRC Clinician Scientist Fellowship [MR/M008525/1]
- NIHR Rare Disease Translational Research Collaboration
- Brain Research Trust
- NIHR Queen Square Dementia Biomedical Research Unit
- European Union [666992]
- MRC UK GENFI [MR/M023664/1]
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- AbbVie
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Eisai Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.
- Fujirebio
- GE Healthcare
- IXICO Ltd.
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development LLC.
- Lumosity
- Lundbeck
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC.
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Piramal Imaging
- Servier
- Takeda Pharmaceutical Company
- Transition Therapeutics
- Canadian Institutes of Health Research
- EPSRC [EP/J020990/1, EP/M020533/1, EP/M006093/1] Funding Source: UKRI
- ESRC [ES/L001810/1] Funding Source: UKRI
- MRC [MC_U105597119, G0601846, MR/M008525/1, MC_UU_00005/12, MR/J009482/1, MR/M024873/1, MR/M023664/1, G116/143, MR/M009041/1, G0801306, G0401247, UKDRI-1001, MR/M009106/1, MC_UU_00024/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/M020533/1, EP/M006093/1, EP/J020990/1] Funding Source: researchfish
- Medical Research Council [MR/L023784/1] Funding Source: researchfish
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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 x 10(-4)) or temporal stage (p = 3.96 x 10(-5)). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine.
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