title: 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.
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.
authors.affiliation: Informatics, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.affiliation: Informatics, Eli Lilly and Company, Indianapolis, IN, USA; Biostatistics Division, School of Public Health, University of Texas, Houston, TX, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Sun
authors.affiliation: IXICO Ltd, London, UK; Department of Computing, Imperial College, London, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Wolz
authors.affiliation: Critical Path Institute, Tucson, AZ, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Stephenson
authors.affiliation: Departments of Radiology and Neurosciences, University of San Diego, San Diego, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Brewer
authors.affiliation: Dementia Research Centre, University College Institute of Neurology, London, UK.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: Tailored Therapeutics, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Cole
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.affiliation: IXICO Ltd, London, UK; Dementia Research Centre, University College Institute of Neurology, London, UK.
authors.forename: Derek L G
authors.initials: DL
authors.lastname: Hill
authors.affiliation: Tailored Therapeutics, Eli Lilly and Company, Indianapolis, IN, USA. Electronic address: a.schwarz@lilly.com.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Schwarz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000544:Alzheimer Disease; D015415:Biomarkers; D002986:Clinical Trials as Topic; D060825:Cognitive Dysfunction / Q000175:diagnosis* / Q000473:pathology*; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D009483:Neuropsychological Tests; D018579:Patient Selection; D018401:Sample Size
chemical_list: D015415:Biomarkers
keywords: Biomarker; Clinical trials; Enrichment; Hippocampal volume; Hippocampus; Inclusion criterion; MRI; Structural MRI