title: Estimating long-term multivariate progression from short-term data.
abstract: BACKGROUND
  Diseases that progress slowly are often studied by observing cohorts at different stages of disease for short periods of time. The Alzheimer's Disease Neuroimaging Initiative (ADNI) follows elders with various degrees of cognitive impairment, from normal to impaired. The study includes a rich panel of novel cognitive tests, biomarkers, and brain images collected every 6 months for as long as 6 years. The relative timing of the observations with respect to disease pathology is unknown. We propose a general semiparametric model and iterative estimation procedure to estimate simultaneously the pathological timing and long-term growth curves. The resulting estimates of long-term progression are fine-tuned using cognitive trajectories derived from the long-term "Personnes Agées Quid" study.
  
  
  RESULTS
  We demonstrate with simulations that the method can recover long-term disease trends from short-term observations. The method also estimates temporal ordering of individuals with respect to disease pathology, providing subject-specific prognostic estimates of the time until onset of symptoms. When the method is applied to ADNI data, the estimated growth curves are in general agreement with prevailing theories of the Alzheimer's disease cascade. Other data sets with common outcome measures can be combined using the proposed algorithm.
  
  
  BACKGROUND
  Software to fit the model and reproduce results with the statistical software R is available as the grace package. ADNI data can be downloaded from the Laboratory of NeuroImaging.
authors.affiliation: Department of Family and Preventive Medicine, Division of Biostatistics and Bioinformatics, University of California San Diego, La Jolla, CA, USA. Electronic address: mdonohue@ucsd.edu.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Donohue
authors.affiliation: INSERM, U897, Biostatistics Department, Bordeaux, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Jacqmin-Gadda
authors.affiliation: INSERM, U897, Biostatistics Department, Bordeaux, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Le Goff
authors.affiliation: Department of Neuroscience, University of California San Diego, La Jolla, CA, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Thomas
authors.affiliation: Department of Family and Preventive Medicine, Division of Biostatistics and Bioinformatics, University of California San Diego, La Jolla, CA, USA; Department of Neuroscience, University of California San Diego, La Jolla, CA, USA.
authors.forename: Rema
authors.initials: R
authors.lastname: Raman
authors.affiliation: Department of Family and Preventive Medicine, Division of Biostatistics and Bioinformatics, University of California San Diego, La Jolla, CA, USA; Department of Neuroscience, University of California San Diego, La Jolla, CA, USA.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Gamst
authors.affiliation: Department of Public Health Sciences, Biostatistics Unit, University of California Davis, Davis, CA, USA.
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Beckett
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.affiliation: Center for Imaging of Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.affiliation: INSERM, U897, Aging Department, Bordeaux, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dartigues
authors.affiliation: Department of Neuroscience, University of California San Diego, La Jolla, CA, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
mesh_terms: D000465:Algorithms; D000544:Alzheimer Disease / Q000503:physiopathology; D003198:Computer Simulation; D016208:Databases, Factual; D018450:Disease Progression; D006801:Humans; D008954:Models, Biological; D015999:Multivariate Analysis; D011379:Prognosis; D012984:Software
keywords: Growth curves; Multiple outcomes; Progression curves; Self-modeling regression; Semiparametric regression