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

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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.; Aisen, Paul S.

I: Alzheimer's and Dementia: Translational Research and Clinical Interventions, Vol. 3, Nr. 1, 01.01.2017, s. 123-129.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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TY - JOUR

T1 - Cross-validation of optimized composites for preclinical Alzheimer's disease

AU - Donohue, Michael C.

AU - Sun, Chung Kai

AU - Raman, Rema

AU - Insel, Philip S.

AU - Aisen, Paul S.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - Cognitive composites

KW - End-point validation

KW - Preclinical Alzheimer's disease

UR - http://www.scopus.com/inward/record.url?scp=85013449855&partnerID=8YFLogxK

U2 - 10.1016/j.trci.2016.12.001

DO - 10.1016/j.trci.2016.12.001

M3 - Article

VL - 3

SP - 123

EP - 129

JO - Alzheimer's and Dementia: Translational Research and Clinical Interventions

T2 - Alzheimer's and Dementia: Translational Research and Clinical Interventions

JF - Alzheimer's and Dementia: Translational Research and Clinical Interventions

SN - 2352-8737

IS - 1

ER -