@article{6389f5060d4b40e7913bbf3d08623a57,
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.",
keywords = "Biomarker, Clinical trials, Enrichment, Hippocampal volume, Hippocampus, Inclusion criterion, MRI, Structural MRI",
author = "Peng Yu and Jia Sun and Robin Wolz and Diane Stephenson and James Brewer and Fox, {Nick C.} and Cole, {Patricia E.} and Jack, {Clifford R.} and Hill, {Derek L.G.} and Schwarz, {Adam J.}",
note = "Funding Information: This work was performed in collaboration with the Coalition Against Major Diseases (CAMD), part of the Critical Path Institute. The Critical Path Institute's CAMD is supported by the U.S. Food and Drug Administration (grant no. U01FD003865 ) and Science Foundation Arizona (grant no. SRG 0335-08 ). Data collection and sharing for this project was funded by ADNI ( National Institutes of Health grant U01 AG024904 ). ADNI is funded by the National Institute on Aging , the National Institute of Biomedical Imaging and Bioengineering , and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc; Biogen Idec Inc; Bristol-Myers Squibb Company; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc; GE Healthcare; Innogenetics, N.V.; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Medpace, Inc; Merck & Co, Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; Servier; Synarc Inc; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private-sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org/ ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer{\textquoteright}s Disease Cooperative Study at the University of California, Rev October 16, 2012, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by National Institutes of Healy grants P30 AG010129 and K01 AG030514. Funding Information: A.J. Schwarz, P. Yu, and P. E. Cole are employees and shareholders of Eli Lilly and Company. J. Sun is a paid contractor for Eli Lilly and Company. R. Wolz is an employee of Philips Healthcare and consultant for IXICO Ltd, D. Stephenson is an employee of the Critical Path Institute and was previously employed by Pfizer. J. Brewer's research is supported by National Institute of Neurological and Communicative Disorders and Stroke K02 NS067427, NIA U01 AG10483, NIA P50 AG005131 , NIA R01AG034062, and General Electric Medical Foundation . He was an investigator for, and received research funds from, Janssen Alzheimer Immunotherapy . He has served on advisory boards for Elan, Bristol-Myers Squibb, Avanir, and Eli Lilly, and holds stock options in CorTechs Labs, Inc. N. C. Fox's research group has received payment for consultancy or for conducting studies from AVID, Bristol-Myers Squibb, Elan Pharmaceuticals, Eisai, Lilly Research Laboratories, GE Healthcare, IXICO, Janssen Alzheimer Immunotherapy, Johnson & Johnson, Janssen-Cilig, Lundbeck, Neurochem Inc, Novartis Pharma AG, Pfizer Inc, Sanofi-Aventis, and Wyeth Pharmaceuticals. N. C. Fox has a National Institute for Health Research Senior Investigator award and receives support from the Wolfson Foundation ; NIHR Biomedical Research Unit (Dementia) at University College, London, the Engineering and Physical Sciences Research Council; Alzheimer's Research UK ; and the NIA. N. C. Fox receives no personal compensation for the activities mentioned. C. R. Jack provides consulting services for Siemens Healthcare. He receives research funding from the National Institutes of Health ( R01-AG011378 , RO1-AG041851 , RO1-AG037551 , U01-HL096917 , U01-AG032438 , U01-AG024904 ) and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Foundation . D. L. G. Hill is an employee and shareholder of IXICO Ltd. ",
year = "2014",
month = apr,
doi = "10.1016/j.neurobiolaging.2013.09.039",
language = "English (US)",
volume = "35",
pages = "808--818",
journal = "Neurobiology of aging",
issn = "0197-4580",
publisher = "Elsevier Inc.",
number = "4",
}