Development and validation of the Uniform Data Set (v3.0) executive function composite score (UDS3-EF)

Adam M Staffaroni, Breton M Asken, Kaitlin B Casaletto, Corrina Fonseca, Michelle You, Howard J Rosen, Adam L Boxer, Fanny M Elahi, John Kornak, Dan Mungas, Joel H Kramer, Adam M Staffaroni, Breton M Asken, Kaitlin B Casaletto, Corrina Fonseca, Michelle You, Howard J Rosen, Adam L Boxer, Fanny M Elahi, John Kornak, Dan Mungas, Joel H Kramer

Abstract

Introduction: Cognitive composite scores offer a means of precisely measuring executive functioning (EF).

Methods: We developed the Uniform Data Set v3.0 EF composite score (UDS3-EF) in 3507 controls from the National Alzheimer's Coordinating Center dataset using item-response theory and applied nonlinear and linear demographic adjustments. The UDS3-EF was validated with other neuropsychological tests and brain magnetic resonance imaging from independent research cohorts using linear models.

Results: Final model fit was good-to-excellent: comparative fit index = 0.99; root mean squared error of approximation = 0.057. UDS3-EF scores differed across validation cohorts (controls > mild cognitive impairment > Alzheimer's disease-dementia ≈ behavioral variant frontotemporal dementia; P < 0.001). The UDS3-EF correlated most strongly with other EF tests (βs = 0.50 to 0.85, Ps < 0.001) and more with frontal, parietal, and temporal lobe gray matter volumes (βs = 0.18 to 0.33, Ps ≤ 0.004) than occipital gray matter (β = 0.12, P = 0.04). The total sample needed to detect a 40% reduction in UDS3-EF change (n = 286) was ≈40% of the next best measure (F-words; n = 714).

Conclusions: The UDS3-EF is well suited to quantify EF in research and clinical trials and offers psychometric and practical advantages over its component tests.

Keywords: Alzheimer's disease; National Alzheimer's Coordinating Center; cognition; composite score; executive function; item response theory; mild cognitive impairment; uniform data set.

Conflict of interest statement

Dr. Kornak reports providing expert witness testimony for Teva Pharmaceuticals in Forest Laboratories Inc. et al. versus 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. versus Apotex Inc., No. 1:15‐cv‐975 (D. Del. filed Oct. 26, 2015), regarding the drug fingolimod. He has also given testimony on behalf of Puma Biotechnology in Hsingching Hsu et al. versus Puma Biotechnology, INC., et al. 2018 regarding the drug neratinib. Dr. Kramer reports receiving research support from NIH, the Tau Research Consortium, and the Larry L. Hillblom Foundation, and he has provided consultation to Biogen. Dr. Rosen reports having a consulting agreement with Ionis pharmaceuticals. Sources of NIH funding support are listed above. All authors report no conflicts of interest directly related to this project.

© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Figures

FIGURE 1
FIGURE 1
Standardized factor loadings for the final confirmatory factor analysis model. Trails, Trail Making Test; UDS3, Uniform Data Set version 3.0
FIGURE 2
FIGURE 2
A–B, Scatterplots showing UDS3‐EF scores in the NACC sample as a function of age with separate fit lines for years of education (A) and as a function of education with separate fit lines for age groups (B). NACC, National Alzheimer's Coordinating Center; UDS3, Uniform Data Set version 3.0
FIGURE 3
FIGURE 3
UDS3‐EF score comparison between diagnostic groups. UDS3‐EF score differences among controls, MCI, AD‐dementia, and behavioral variant frontotemporal dementia diagnostic groups in the validation sample. The mean ± standard deviation of the UDS3‐EF score is provided. Box plots represent the median (horizontal line) and interquartile range (top and bottom whiskers) of UDS3‐EF scores. AD, Alzheimer's disease; MCI, mild cognitive impairment; UDS3, Uniform Data Set version 3.0
FIGURE 4
FIGURE 4
Association of the UDS3‐EF score with other cognitive test scores and brain volumes. A, There were 305 participants with a UDS3‐EF and a standard error P < 0.001 for all except Craft Story and Benson Figure). B, Structural neuroimaging data were available for 210 participants (age 66.6 ± 11.4 years old, 52% female, education 16.6 ± 2.5 years; AD‐dementia, N = 52; mild cognitive impairment, N = 46; behavioral variant frontotemporal dementia, N = 37; controls, N = 75). Regression coefficients describe the strength of association between the UDS3‐EF and brain gray matter volumes. Standardized beta‐weights reflect associations after covarying for age, sex, total intracranial volume, and CDR Sum of Boxes (P < 0.005 for all listed βs > .18). AD‐dementia, Alzheimer's disease dementia; ACC, anterior cingulate cortex; CDR, Clinical Dementia Rating; DLPFC, dorsolateral prefrontal cortex; OFC, orbitofrontal cortex; UDS3, Uniform Data Set version 3.0

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