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Neurobiol Aging. 2014 Apr;35(4):808-18. doi: 10.1016/j.neurobiolaging.2013.09.039. Epub 2013 Oct 3.

Operationalizing hippocampal volume as an enrichment biomarker for amnestic mild cognitive impairment trials: effect of algorithm, test-retest variability, and cut point on trial cost, duration, and sample size.

Author information

1
Informatics, Eli Lilly and Company, Indianapolis, IN, USA.
2
Informatics, Eli Lilly and Company, Indianapolis, IN, USA; Biostatistics Division, School of Public Health, University of Texas, Houston, TX, USA.
3
IXICO Ltd, London, UK; Department of Computing, Imperial College, London, UK.
4
Critical Path Institute, Tucson, AZ, USA.
5
Departments of Radiology and Neurosciences, University of San Diego, San Diego, CA, USA.
6
Dementia Research Centre, University College Institute of Neurology, London, UK.
7
Tailored Therapeutics, Eli Lilly and Company, Indianapolis, IN, USA.
8
Department of Radiology, Mayo Clinic, Rochester, MN, USA.
9
IXICO Ltd, London, UK; Dementia Research Centre, University College Institute of Neurology, London, UK.
10
Tailored Therapeutics, Eli Lilly and Company, Indianapolis, IN, USA. Electronic address: a.schwarz@lilly.com.

Abstract

The objective of this study was to evaluate the effect of computational algorithm, measurement variability, and cut point on hippocampal volume (HCV)-based patient selection for clinical trials in mild cognitive impairment (MCI). We used normal control and amnestic MCI subjects from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) as normative reference and screening cohorts. We evaluated the enrichment performance of 4 widely used hippocampal segmentation algorithms (FreeSurfer, Hippocampus Multi-Atlas Propagation and Segmentation (HMAPS), Learning Embeddings Atlas Propagation (LEAP), and NeuroQuant) in terms of 2-year changes in Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Clinical Dementia Rating Sum of Boxes (CDR-SB). We modeled the implications for sample size, screen fail rates, and trial cost and duration. HCV based patient selection yielded reduced sample sizes (by ∼40%-60%) and lower trial costs (by ∼30%-40%) across a wide range of cut points. These results provide a guide to the choice of HCV cut point for amnestic MCI clinical trials, allowing an informed tradeoff between statistical and practical considerations.

KEYWORDS:

Biomarker; Clinical trials; Enrichment; Hippocampal volume; Hippocampus; Inclusion criterion; MRI; Structural MRI

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