Abstract
INTRODUCTION: As currently used, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) has low sensitivity for measuring Alzheimer's disease progression in clinical trials. A major reason behind the low sensitivity is its sub-optimal scoring methodology, which can be improved to obtain better sensitivity.
METHODS: Using item response theory, we developed a new scoring methodology (ADAS-CogIRT) for the ADAS-Cog, which addresses several major limitations of the current scoring methodology. The sensitivity of the ADAS-CogIRT methodology was evaluated using clinical trial simulations as well as a negative clinical trial, which had shown an evidence of a treatment effect.
RESULTS: The ADAS-Cog was found to measure impairment in three cognitive domains of memory, language, and praxis. The ADAS-CogIRT methodology required significantly fewer patients and shorter trial durations as compared to the current scoring methodology when both were evaluated in simulated clinical trials. When validated on data from a real clinical trial, the ADAS-CogIRT methodology had higher sensitivity than the current scoring methodology in detecting the treatment effect.
CONCLUSIONS: The proposed scoring methodology significantly improves the sensitivity of the ADAS-Cog in measuring progression of cognitive impairment in clinical trials focused in the mild-to-moderate Alzheimer's disease stage. This provides a boost to the efficiency of clinical trials requiring fewer patients and shorter durations for investigating disease-modifying treatments.
| Original language | English (US) |
|---|---|
| Article number | 64 |
| Pages (from-to) | 64 |
| Journal | Alzheimer's Research and Therapy |
| Volume | 7 |
| Issue number | 1 |
| DOIs | |
| State | Published - Nov 12 2015 |
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
- Cognitive Neuroscience
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In: Alzheimer's Research and Therapy, Vol. 7, No. 1, 64, 12.11.2015, p. 64.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - New scoring methodology improves the sensitivity of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) in clinical trials
AU - Verma, Nishant
AU - Beretvas, S Natasha
AU - Pascual, Belen
AU - Masdeu, Joseph C
AU - Markey, Mia K
AU - Alzheimer's Disease Neuroimaging Initiative
N1 - Funding Information: The authors would like to sincerely thank the reviewers for their insightful comments on the paper, which significantly improved the presentation and the quality of this research work. The authors also acknowledge the Texas Advanced Computing Center (https://www.tacc.utexas.edu/) at The University of Texas at Austin for providing high performance computing resources that were used for conducting the trial simulation experiments reported in this paper. The collection of a subset of the data used in this study was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). 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; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; 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; Neurotrack Technologies; 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 (http://fnih.org/fnih/). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Ethics approval was obtained from the institutional review boards of each institution involved: Oregon Health and Science University; University of Southern California; University of California San Diego; University of Michigan; Mayo Clinic, Rochester; Baylor College of Medicine; Columbia University Medical Center; Washington University, St. Louis; University of Alabama Birmingham; Mount Sinai School of Medicine; Rush University Medical Center; Wien Center; Johns Hopkins University; New York University; Duke University Medical Center; University of Pennsylvania; University of Kentucky; University of Pittsburgh; University of Rochester Medical Center; University of California, Irvine; University of Texas Southwestern Medical School; Emory University; University of Kansas, Medical Center; University of California, Los Angeles; Mayo Clinic, Jacksonville; Indiana University; Yale University School of Medicine; McGill University, Montreal-Jewish General Hospital; Sunnybrook Health Sciences, Ontario; U.B.C. Clinic for AD & Related Disorders; Cognitive Neurology - St. Joseph’s, Ontario; Cleveland Clinic Lou Ruvo Center for Brain Health; Northwestern University; Premiere Research Institution (Palm Beach Neurology); Georgetown University Medical Center; Brigham and Women’s Hospital; Stanford University; Banner Sun Health Research Institute; Boston University; Howard University; Case Western Reserve University; University of California, Davis – Sacramento; Neurological Care of CNY; Parkwood Hospital; University of Wisconsin; University of California, Irvine; Banner Alzheimer’s Institute; Dent Neurologic Institute; Ohio State University; Albany Medical College; Hartford Hospital, Olin Neuropsychiatry Research Center; Dartmouth-Hitchcock Medical Center; Wake Forest University Health Sciences; Rhode Island Hospital; Butler Hospital; University of California San Francisco; Medical University South Carolina; St. Joseph’s Health Care Nathan Kline Institute; University of Iowa College of Medicine; Cornell University and University of South Florida: USF Health Byrd Alzheimer’s Institute. Funding Information: The authors also acknowledge the Texas Advanced Computing Center (https://www.tacc.utexas.edu/) at The University of Texas at Austin for providing high performance computing resources that were used for conducting the trial simulation experiments reported in this paper. The collection of a subset of the data used in this study was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). 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; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; 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; Neurotrack Technologies; 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 (http://fnih.org/fnih/). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Ethics approval was obtained from the institutional review boards of each institution involved: Oregon Health and Science University; University of Southern California; University of California San Diego; University of Michigan; Mayo Clinic, Rochester; Baylor College of Medicine; Columbia University Medical Center; Washington University, St. Louis; University of Alabama Birmingham; Mount Sinai School of Medicine; Rush University Medical Center; Wien Center; Johns Hopkins University; New York University; Duke University Medical Center; University of Pennsylvania; University of Kentucky; University of Pittsburgh; University of Rochester Medical Center; University of California, Irvine; University of Texas Southwestern Medical School; Emory University; University of Kansas, Medical Center; University of California, Los Angeles; Mayo Clinic, Jacksonville; Indiana University; Yale University School of Medicine; McGill University, Montreal-Jewish General Hospital; Sunnybrook Health Sciences, Ontario; U.B.C. Clinic for AD & Related Disorders; Cognitive Neurology - St. Joseph's, Ontario; Cleveland Clinic Lou Ruvo Center for Brain Health; Northwestern University; Premiere Research Institution (Palm Beach Neurology); Georgetown University Medical Center; Brigham and Women's Hospital; Stanford University; Banner Sun Health Research Institute; Boston University; Howard University; Case Western Reserve University; University of California, Davis - Sacramento; Neurological Care of CNY; Parkwood Hospital; University of Wisconsin; University of California, Irvine; Banner Alzheimer's Institute; Dent Neurologic Institute; Ohio State University; Albany Medical College; Hartford Hospital, Olin Neuropsychiatry Research Center; Dartmouth-Hitchcock Medical Center; Wake Forest University Health Sciences; Rhode Island Hospital; Butler Hospital; University of California San Francisco; Medical University South Carolina; St. Joseph's Health Care Nathan Kline Institute; University of Iowa College of Medicine; Cornell University and University of South Florida: USF Health Byrd Alzheimer's Institute. Publisher Copyright: © 2015 Verma et al.
PY - 2015/11/12
Y1 - 2015/11/12
N2 - INTRODUCTION: As currently used, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) has low sensitivity for measuring Alzheimer's disease progression in clinical trials. A major reason behind the low sensitivity is its sub-optimal scoring methodology, which can be improved to obtain better sensitivity.METHODS: Using item response theory, we developed a new scoring methodology (ADAS-CogIRT) for the ADAS-Cog, which addresses several major limitations of the current scoring methodology. The sensitivity of the ADAS-CogIRT methodology was evaluated using clinical trial simulations as well as a negative clinical trial, which had shown an evidence of a treatment effect.RESULTS: The ADAS-Cog was found to measure impairment in three cognitive domains of memory, language, and praxis. The ADAS-CogIRT methodology required significantly fewer patients and shorter trial durations as compared to the current scoring methodology when both were evaluated in simulated clinical trials. When validated on data from a real clinical trial, the ADAS-CogIRT methodology had higher sensitivity than the current scoring methodology in detecting the treatment effect.CONCLUSIONS: The proposed scoring methodology significantly improves the sensitivity of the ADAS-Cog in measuring progression of cognitive impairment in clinical trials focused in the mild-to-moderate Alzheimer's disease stage. This provides a boost to the efficiency of clinical trials requiring fewer patients and shorter durations for investigating disease-modifying treatments.
AB - INTRODUCTION: As currently used, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) has low sensitivity for measuring Alzheimer's disease progression in clinical trials. A major reason behind the low sensitivity is its sub-optimal scoring methodology, which can be improved to obtain better sensitivity.METHODS: Using item response theory, we developed a new scoring methodology (ADAS-CogIRT) for the ADAS-Cog, which addresses several major limitations of the current scoring methodology. The sensitivity of the ADAS-CogIRT methodology was evaluated using clinical trial simulations as well as a negative clinical trial, which had shown an evidence of a treatment effect.RESULTS: The ADAS-Cog was found to measure impairment in three cognitive domains of memory, language, and praxis. The ADAS-CogIRT methodology required significantly fewer patients and shorter trial durations as compared to the current scoring methodology when both were evaluated in simulated clinical trials. When validated on data from a real clinical trial, the ADAS-CogIRT methodology had higher sensitivity than the current scoring methodology in detecting the treatment effect.CONCLUSIONS: The proposed scoring methodology significantly improves the sensitivity of the ADAS-Cog in measuring progression of cognitive impairment in clinical trials focused in the mild-to-moderate Alzheimer's disease stage. This provides a boost to the efficiency of clinical trials requiring fewer patients and shorter durations for investigating disease-modifying treatments.
UR - http://www.scopus.com/inward/record.url?scp=84946762305&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84946762305&partnerID=8YFLogxK
U2 - 10.1186/s13195-015-0151-0
DO - 10.1186/s13195-015-0151-0
M3 - Article
C2 - 26560146
AN - SCOPUS:84946762305
SN - 1758-9193
VL - 7
SP - 64
JO - Alzheimer's Research and Therapy
JF - Alzheimer's Research and Therapy
IS - 1
M1 - 64
ER -