Abstract
Introduction: Conventional Z-scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z-scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z-scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency. Methods: In this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance). Results: Corrected Z-scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted-R2. Discussion: Nonlinearly corrected Z-scores with respect to age, sex, and education with age-varying residual standard deviation allow for improved detection of non-normative extreme cognitive scores.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 797-808 |
| Number of pages | 12 |
| Journal | Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring |
| Volume | 11 |
| DOIs | |
| State | Published - Dec 2019 |
Keywords
- Generalized additive models
- Heterogenous variance modeling
- Neuropsychological testing scores
- Nonlinear Z-score correction
- Shape constrained additive models
ASJC Scopus subject areas
- Clinical Neurology
- Psychiatry and Mental health
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In: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring, Vol. 11, 12.2019, p. 797-808.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Nonlinear Z-score modeling for improved detection of cognitive abnormality
AU - ARTFL/LEFFTDS Consortium
AU - Kornak, John
AU - Fields, Julie
AU - Kremers, Walter
AU - Farmer, Sara
AU - Heuer, Hilary W.
AU - Forsberg, Leah
AU - Brushaber, Danielle
AU - Rindels, Amy
AU - Dodge, Hiroko
AU - Weintraub, Sandra
AU - Besser, Lilah
AU - Appleby, Brian
AU - Bordelon, Yvette
AU - Bove, Jessica
AU - Brannelly, Patrick
AU - Caso, Christina
AU - Coppola, Giovanni
AU - Dever, Reilly
AU - Dheel, Christina
AU - Dickerson, Bradford
AU - Dickinson, Susan
AU - Dominguez, Sophia
AU - Domoto-Reilly, Kimiko
AU - Faber, Kelley
AU - Ferrall, Jessica
AU - Fishman, Ann
AU - Fong, Jamie
AU - Foroud, Tatiana
AU - Gavrilova, Ralitza
AU - Gearhart, Deb
AU - Ghazanfari, Behnaz
AU - Ghoshal, Nupur
AU - Goldman, Jill
AU - Graff-Radford, Jonathan
AU - Graff-Radford, Neill
AU - Grant, Ian M.
AU - Grossman, Murray
AU - Haley, Dana
AU - Hsiao, John
AU - Hsiung, Robin
AU - Huey, Edward D.
AU - Irwin, David
AU - Jones, David
AU - Jones, Lynne
AU - Kantarci, Kejal
AU - Karydas, Anna
AU - Kaufer, Daniel
AU - Kerwin, Diana
AU - Knopman, David
AU - Kraft, Ruth
N1 - Funding Information: Kornak J. has provided expert witness testimony for Teva Pharmaceuticals in Forest Laboratories Inc. et al. v. Teva Pharmaceuticals USA, Inc., Case Nos. 1:14-cv-00121 and 1:14-cv-00686 (D. Del. filed Jan. 31, 2014 and May 30, 2014) regarding the drug memantine; for Apotex/HEC/Ezra in Novartis AG et al. v. Apotex Inc., No. 1:15-cv-975 (D. Del. filed Oct. 26, 2015, regarding the drug Fingolimod; and for Puma Biotechnology in Hsingching Hsu et al. vs. Puma Biotechnology, INC., et al. 2018 regarding the drug Neratinib, Case No. 8:15-cv-00865. He has also provided testimony on behalf of Hikma Pharmaceuticals, USA, INC., et al. in Amarin Pharma, Inc. and Amarin Pharmaceuticals Ireland Limited vs. Hikma Pharmaceuticals USA Inc., et al. 2019 regarding the drug Vascepa. Case No. 2:16-cv-02562-MMD-NJK (Consolidated with 2:16-cv-02562-MMD-NJK). He receives research support from the NIH (R01EB022055, U01AG045390, U54NS092089 R01CA132870). Fields J receives research support from NIH. Kremers W receives research funding from AstraZeneca, Biogen, Roche, DOD, and NIH. Heuer H.W. receives research support from NIH. Forsberg L receives research support from NIH. Weintraub S. receives research support from the NIH. Appleby B. receives research funding from CDC (NU38CK000480). Brannelly P. employed by the Rainwater Charitable Foundation. Coppola G. receives research support from NIH. Dickerson B. receives research support from NIH. Dickinson S. is an staff at the Association for Frontotemporal Degeneration and a member of the National Institute for Neurological Disorders and Stroke Advisory Council. Faber K. receives research support from NIH. Foroud T. receives research support from NIH. Gavrilova R. receives research support from NIH. Ghoshal N. has participated or is currently participating in clinical trials of antidementia drugs sponsored by the following companies: Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) study, and A4 (The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. She receives research support from Tau Consortium and Association for Frontotemporal Dementia and is funded by the NIH. Goldman J. is serving as a consultant to the Novartis Alzheimer's Prevention Advisory Board. She receives research support from NIH, HDSA, and New York State Department of Health (RFA # 1510130358). Graff-Radford N.R. receives royalties from UpToDate and has participated in multicenter therapy studies sponsored by Biogen, TauRx, AbbVie, Novartis, and Lilly. He receives research support from NIH. Grossman M. receives grant support from NIH, Avid, and Piramal; participates in clinical trials sponsored by Biogen, TauRx, and Alector; serves as a consultant to Bracco and UCB; and serves on the Editorial Board of Neurology. Hsiung R. has served as an investigator for clinical trials sponsored by AstraZeneca, Eli Lilly, and Roche/Genentech. He receives research support from Canadian Institutes of Health Research and the Alzheimer Society of British Columbia. Huey E. receives research support from NIH. Irwin D. receives support from NIH, BrightFocus Foundation, and Penn Institute on Aging. Jones D. receives research support from NIH and the Minnesota Partnership for Biotechnology and Medical Genomics. Kantarci K. served on the Data Safety Monitoring Board for Takeda Global Research & Development Center, Inc.; data monitoring boards of Pfizer and Janssen Alzheimer Immunotherapy; and research support from the Avid Radiopharmaceuticals, Eli Lilly, the Alzheimer's Drug Discovery Foundation, and NIH. Knopman D. serves on the DSMB of the DIAN-TU study, is a site PI for clinical trials sponsored by Biogen, Lilly and the University of Southern California, and is funded by NIH. Kramer J. receives research support from NIH. Kukull W. receives research support from NIH. Litvan I. was a member of the AbbVie advisory board, consultant for Toyama Pharmaceuticals, and member of the Biotie/Parkinson Study Group Medical Advisory Board. Her research is supported by the National Institutes of Health grants: 5P50 AG005131-31, 5T35HL007491, 1U01NS086659, and 1U54NS092089-01; Parkinson Study Group; Michael J Fox Foundation; International Parkinson and Movement Disorder Society; Parkinson Foundation; AVID Pharmaceuticals; C2N Diagnostics/AbbVie; and Bristol-Myers Squibb/Biogen. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. Lucente D. receives research support from NIH. Lungu C. receives honoraria for editorial work from Elsevier, Inc. Mackenzie I. receives research funding from Canadian Institutes of Health Research. McGinnis S. has served as an investigator for clinical trials sponsored by AbbVie, Allon Therapeutics, Biogen, Bristol-Myers Squibb, C2N Diagnostics, Eisai Inc., Eli Lilly and Co., Genentech, Janssen Pharmaceuticals, Medivation, Merck, Navidea Biopharmaceuticals, Novartis, Pfizer, and TauRx Therapeutics. He receives research support from NIH. Miller B. receives research support from NIH. Onyike C. receives research support from the NIH, CIHR, the Jane Tanger Back Fund for Young-Onset Dementias, the Nancy H. Hall Memorial Fund for Geriatric Psychiatry Research, and the Joseph Trovato Fund. He is a site PI for a study funded by Biogen, Inc. Pearlman R. employed as President by the Bluefield Project to cure FTD, a nonprofit medical research foundation. Petrucelli L. receives research support from NIH. Potter M. receives research support from NIH. Rademakers R. receives research funding from NIH and the Bluefield Project to Cure Frontotemporal Dementia. Rankin K. receives research support from NIH.Rascovsky K. receives research support from NIH. Shaw L. receives research support from NIH.Staffaroni A.M. receives research funding from the Larry H. Hillblom Foundation (2018-A-025-FEL). Tatton N. was employed by the Association for Frontotemporal Degeneration. Toga A. receives research support from the NIH and the Alzheimer's Association. Trojanowski J. may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is a coinventor and received revenue from the sale of Avid to Eli Lily as coinventor on Aβ amyloid imaging–related patents submitted by the University of Pennsylvania. He receives research support from the NIH and several nonprofits. Wong B. receives research support from the NIH.Wszolek Z. supported by the NIH, Mayo Clinic Center for Regenerative Medicine, the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, The Sol Goldman Charitable Trust, and Donald G. and Jodi P. Heeringa. He has also received grant funding support from Allergan, Inc. (educational grant) and AbbVie (medication trials). Boeve B. has served as an investigator for clinical trials sponsored by GE Healthcare and Axovant. He receives royalties from the publication of a book entitled Behavioral Neurology of Dementia (Cambridge Medicine, 2009, 2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from the NIH (U01 AG045390, U54 NS092089, R01 AG041797, P50 AG016574, U01 AG006786), the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program and the Little Family Foundation. Boxer A. receives research support from NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer's Drug Discovery Foundation and the Alzheimer's Association. He has served as a consultant for Aeton, AbbVie, Alector, Amgen, Arkuda, Ionis, Iperian, Janssen, Merck, Novartis, Samumed, Toyama, and UCB and received research support from Avid, Biogen, BMS, C2N, Cortice, Eli Lilly, Forum, Genentech, Janssen, Novartis, Pfizer, Roche, and TauRx. Rosen H. has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from NIH.This study was supported by grants U01 AG045390 (PIs Bradley F. Boeve and Howard J. Rosen), U54 NS092089 (PI Adam Boxer, MD), and R01 EB022055 (PI John Kornak, PhD). The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG005131 (PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), and P50 AG047270 (PI Stephen Strittmatter, MD, PhD). Funding Information: This study was supported by grants U01 AG045390 (PIs Bradley F. Boeve and Howard J. Rosen), U54 NS092089 (PI Adam Boxer, MD), and R01 EB022055 (PI John Kornak, PhD). Funding Information: Wszolek Z. supported by the NIH , Mayo Clinic Center for Regenerative Medicine , the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, The Sol Goldman Charitable Trust, and Donald G. and Jodi P. Heeringa. He has also received grant funding support from Allergan, Inc . (educational grant) and AbbVie (medication trials). Boeve B. has served as an investigator for clinical trials sponsored by GE Healthcare and Axovant . He receives royalties from the publication of a book entitled Behavioral Neurology of Dementia (Cambridge Medicine, 2009, 2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from the NIH ( U01 AG045390 , U54 NS092089 , R01 AG041797 , P50 AG016574 , U01 AG006786 ), the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program and the Little Family Foundation. Boxer A. receives research support from NIH , the Tau Research Consortium , the Association for Frontotemporal Degeneration , Bluefield Project to Cure Frontotemporal Dementia , Corticobasal Degeneration Solutions , the Alzheimer's Drug Discovery Foundation and the Alzheimer's Association . He has served as a consultant for Aeton, AbbVie, Alector, Amgen, Arkuda, Ionis, Iperian, Janssen, Merck, Novartis, Samumed, Toyama, and UCB and received research support from Avid , Biogen , BMS , C2N , Cortice , Eli Lilly , Forum , Genentech , Janssen , Novartis , Pfizer , Roche , and TauRx . Rosen H. has received research support from Biogen Pharmaceuticals , has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from NIH . Funding Information: The NACC database is funded by NIA / NIH Grant U01 AG016976 . NACC data are contributed by the NIA -funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG005131 (PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), and P50 AG047270 (PI Stephen Strittmatter, MD, PhD). Funding Information: Rascovsky K. receives research support from NIH . Shaw L. receives research support from NIH . Funding Information: Staffaroni A.M. receives research funding from the Larry H. Hillblom Foundation ( 2018-A-025-FEL ). Tatton N. was employed by the Association for Frontotemporal Degeneration. Toga A. receives research support from the NIH and the Alzheimer's Association . Trojanowski J. may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is a coinventor and received revenue from the sale of Avid to Eli Lily as coinventor on Aβ amyloid imaging–related patents submitted by the University of Pennsylvania. He receives research support from the NIH and several nonprofits. Wong B. receives research support from the NIH . Publisher Copyright: © 2019
PY - 2019/12
Y1 - 2019/12
N2 - Introduction: Conventional Z-scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z-scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z-scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency. Methods: In this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance). Results: Corrected Z-scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted-R2. Discussion: Nonlinearly corrected Z-scores with respect to age, sex, and education with age-varying residual standard deviation allow for improved detection of non-normative extreme cognitive scores.
AB - Introduction: Conventional Z-scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z-scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z-scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency. Methods: In this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance). Results: Corrected Z-scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted-R2. Discussion: Nonlinearly corrected Z-scores with respect to age, sex, and education with age-varying residual standard deviation allow for improved detection of non-normative extreme cognitive scores.
KW - Generalized additive models
KW - Heterogenous variance modeling
KW - Neuropsychological testing scores
KW - Nonlinear Z-score correction
KW - Shape constrained additive models
UR - http://www.scopus.com/inward/record.url?scp=85075806346&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075806346&partnerID=8YFLogxK
U2 - 10.1016/j.dadm.2019.08.003
DO - 10.1016/j.dadm.2019.08.003
M3 - Article
AN - SCOPUS:85075806346
SN - 2352-8729
VL - 11
SP - 797
EP - 808
JO - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
JF - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
ER -