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

• Published in: Neurobiology of aging Vol. 35; no. 4; pp. 808 - 818
• Main Authors: Yu, Peng, Sun, Jia, Wolz, Robin, Stephenson, Diane, Brewer, James, Fox, Nick C., Cole, Patricia E., Jack, Clifford R., Hill, Derek L.G., Schwarz, Adam J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2014
• Subjects: Aged; Aged, 80 and over; Algorithms; Alzheimer Disease; Biomarker; Biomarkers; Clinical trials; Clinical Trials as Topic; Cognitive Dysfunction - diagnosis; Cognitive Dysfunction - pathology; Enrichment; Female; Hepatitis C virus; Hippocampal volume; Hippocampus; Hippocampus - pathology; Humans; Inclusion criterion; Internal Medicine; Male; Middle Aged; MRI; Neuroimaging; Neurology; Neuropsychological Tests; Patient Selection; Sample Size; Structural MRI; Enrichment; Biomarker; MRI; Clinical trials; Structural MRI; Hippocampal volume; Hippocampus; Inclusion criterion
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2013.09.039

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.