title: The Effect of Age Correction on Multivariate Classification in Alzheimer's Disease, with a Focus on the Characteristics of Incorrectly and Correctly Classified Subjects.
abstract: The similarity of atrophy patterns in Alzheimer's disease (AD) and in normal aging suggests age as a confounding factor in multivariate models that use structural magnetic resonance imaging (MRI) data. To study the effect and compare different age correction approaches on AD diagnosis and prediction of mild cognitive impairment (MCI) progression as well as investigate the characteristics of correctly and incorrectly classified subjects. Data from two multi-center cohorts were included in the study [AD = 297, MCI = 445, controls (CTL) = 340]. 34 cortical thickness and 21 subcortical volumetric measures were extracted from MRI. The age correction approaches involved: using age as a covariate to MRI-derived measures and linear detrending of age-related changes based on CTL measures. Orthogonal projections to latent structures was used to discriminate between AD and CTL subjects, and to predict MCI progression to AD, up to 36-months follow-up. Both age correction approaches improved models' quality in terms of goodness of fit and goodness of prediction, as well as classification and prediction accuracies. The observed age associations in classification and prediction results were effectively eliminated after age correction. A detailed analysis of correctly and incorrectly classified subjects highlighted age associations in other factors: ApoE genotype, global cognitive impairment and gender. The two methods for age correction gave similar results and show that age can partially masks the influence of other aspects such as cognitive impairment, ApoE-e4 genotype and gender. Age-related brain atrophy may have a more important association with these factors than previously believed.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum, Plan 5, 141 57, Stockholm, Sweden. farshad.falahati@ki.se.
authors.forename: Farshad
authors.identifier: http://orcid.org/0000-0003-0851-4615
authors.initials: F
authors.lastname: Falahati
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum, Plan 5, 141 57, Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ferreira
authors.affiliation: Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mecocci
authors.affiliation: INSERM U 558, University of Toulouse, Toulouse, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vellas
authors.affiliation: 3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Magda
authors.initials: M
authors.lastname: Tsolaki
authors.affiliation: Medical University of Lodz, Lodz, Poland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Kłoszewska
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.|NIHR Biomedical Research Centre for Mental Health, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum, Plan 5, 141 57, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksdotter
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum, Plan 5, 141 57, Stockholm, Sweden.
authors.forename: Lars-Olof
authors.initials: LO
authors.lastname: Wahlund
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.|NIHR Biomedical Research Centre for Mental Health, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Simmons
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum, Plan 5, 141 57, Stockholm, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Westman
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000145:classification* / Q000473:pathology*; D000704:Analysis of Variance; D001284:Atrophy; D001921:Brain / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000473:pathology; D015331:Cohort Studies; D003951:Diagnostic Errors; D018450:Disease Progression; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D013997:Time Factors
keywords: Age correction; Alzheimer’s disease; Diagnostic misclassification; Early diagnosis; MRI; Mild cognitive impairment; OPLS