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Cross-validation of optimized composites for preclinical Alzheimer's disease

Donohue, Michael C.; Sun, Chung Kai; Raman, Rema; Insel, Philip S. LU and Aisen, Paul S. (2017) In Alzheimer's and Dementia: Translational Research and Clinical Interventions 3(1). p.123-129
Abstract

Introduction We discuss optimization and validation of composite end points for presymptomatic Alzheimer's disease clinical trials. Optimized composites offer hope of substantial gains in statistical power or reduction in sample size. But there is tradeoff between optimization and face validity such that optimization should only be considered if there is a convincing rationale. As with statistically derived regions of interest in neuroimaging, validation on independent data sets is essential. Methods Using four data sets, we consider the optimized weighting of four components of a cognitive composite which includes measures of (1) global cognition, (2) semantic memory, (3) episodic memory, and (4) executive function. Weights are... (More)

Introduction We discuss optimization and validation of composite end points for presymptomatic Alzheimer's disease clinical trials. Optimized composites offer hope of substantial gains in statistical power or reduction in sample size. But there is tradeoff between optimization and face validity such that optimization should only be considered if there is a convincing rationale. As with statistically derived regions of interest in neuroimaging, validation on independent data sets is essential. Methods Using four data sets, we consider the optimized weighting of four components of a cognitive composite which includes measures of (1) global cognition, (2) semantic memory, (3) episodic memory, and (4) executive function. Weights are optimized to either discriminate amyloid positivity or maximize power to detect a treatment effect in an amyloid-positive population. We apply repeated 5 × 3-fold cross-validation to quantify the out-of-sample performance of optimized composite end points. Results We found the optimized weights varied greatly across the folds of the cross-validation with either optimization method. Both optimization methods tend to down-weight the measures of global cognition and executive function. However, when these optimized composites were applied to the validation sets, they did not provide consistent improvements in power. In fact, overall, the optimized composites performed worse than those without optimization. Discussion We find that component weight optimization does not yield valid improvements in sensitivity of this composite to detect treatment effects.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cognitive composites, End-point validation, Preclinical Alzheimer's disease
in
Alzheimer's and Dementia: Translational Research and Clinical Interventions
volume
3
issue
1
pages
7 pages
publisher
Elsevier Inc.
external identifiers
  • scopus:85013449855
DOI
10.1016/j.trci.2016.12.001
language
English
LU publication?
yes
id
72f4e57a-511d-4326-989a-b4a47af114fb
date added to LUP
2017-03-24 14:10:35
date last changed
2017-09-23 03:00:08
@article{72f4e57a-511d-4326-989a-b4a47af114fb,
  abstract     = {<p>Introduction We discuss optimization and validation of composite end points for presymptomatic Alzheimer's disease clinical trials. Optimized composites offer hope of substantial gains in statistical power or reduction in sample size. But there is tradeoff between optimization and face validity such that optimization should only be considered if there is a convincing rationale. As with statistically derived regions of interest in neuroimaging, validation on independent data sets is essential. Methods Using four data sets, we consider the optimized weighting of four components of a cognitive composite which includes measures of (1) global cognition, (2) semantic memory, (3) episodic memory, and (4) executive function. Weights are optimized to either discriminate amyloid positivity or maximize power to detect a treatment effect in an amyloid-positive population. We apply repeated 5 × 3-fold cross-validation to quantify the out-of-sample performance of optimized composite end points. Results We found the optimized weights varied greatly across the folds of the cross-validation with either optimization method. Both optimization methods tend to down-weight the measures of global cognition and executive function. However, when these optimized composites were applied to the validation sets, they did not provide consistent improvements in power. In fact, overall, the optimized composites performed worse than those without optimization. Discussion We find that component weight optimization does not yield valid improvements in sensitivity of this composite to detect treatment effects.</p>},
  author       = {Donohue, Michael C. and Sun, Chung Kai and Raman, Rema and Insel, Philip S. and Aisen, Paul S.},
  keyword      = {Cognitive composites,End-point validation,Preclinical Alzheimer's disease},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {123--129},
  publisher    = {Elsevier Inc.},
  series       = {Alzheimer's and Dementia: Translational Research and Clinical Interventions},
  title        = {Cross-validation of optimized composites for preclinical Alzheimer's disease},
  url          = {http://dx.doi.org/10.1016/j.trci.2016.12.001},
  volume       = {3},
  year         = {2017},
}