1. Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials
- Author
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Alan Percy, Cathy Wood-Siverio, Oksana Suchowersky, Claudia Testa, Yvette Bordelon, Kevin M. Biglan, Francis O. Walker, David P. Richman, Rustom Sethna, Eric Siemers, Shirley Eberly, Marie Saint-Hilaire, Alicia Brocht, Madaline B. Harrison, Richard H. Myers, Carlos Singer, Karen Blindauer, Rajeev Ananda Kumar, Jody Goldstein, Diana Rosas, Anne Young, Charles H. Adler, Kimberly Quaid, James F. Gusella, Carolyn Gray, Penelope Hogarth, James B. Caress, J. B. Penney, Kelvin L. Chou, Teresa Tempkin, Christopher Ross, Jody Corey-Bloom, Brad Racette, Victoria Hunt, William Weiner, Thomas D. Bird, J. Decolongon, Greg Suter, Eric Molho, Megan Romer, Blair Leavitt, Mary Lou Klimek, Hillary Lipe, Peter Como, Dawn Radtke, Constance Nickerson, Roger L. Albin, Karen Marder, Marcy E. MacDonald, Sandra Kostyk, Christine Weaver, David Oakes, William Mallonee, Amy Duffy, Tatiana Foroud, Marguerite Wieler, Clifford W. Shults, Sarah Furtado, Julie C. Stout, William C. Johnson, Timothy Greenamyre, Ira Shoulson, Carol Moskowitz, J.S. Paulsen, Karl Kieburtz, Lauren Seeberger, Douglas Hobson, Scott R. Bundlie, Steven M. Hersch, Leon S. Dure, Arthur Watts, Vicki L. Wheelock, Donald S. Higgins, Lorne A. Clarke, Stanley Fahn, Nestor Galvez-Jimenez, Andrew Feigin, Lynn A. Raymond, Joseph Jankovic, Sylvain Chouinard, Caroline M. Tanner, Melissa Wesson, Barbara Shannon, Marie Cox, Cynthia L. Comella, John N. Caviness, Guerry M. Peavy, Adam Rosenblatt, Robert A. Hauser, Carol Zimmerman, Christine Hunter, Christine O'Neill, Juan Sanchez-Ramos, Corrine Baic, Peter Novak, Sharon Evans, Hongwei Zhao, Stewart A. Factor, W.R. Wayne Martin, Candace Cotto, Richard Dubinsky, David D. Song, M. Aileen Shinaman, Susan B. Perlman, Joel S. Perlmutter, Ali Samii, Elise Kayson, Mark Guttman, Frederick J. Marshall, Kathleen L. Shannon, and M. Nance
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Neurogenetics ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Huntington's disease ,Internal medicine ,medicine ,Humans ,Single-Blind Method ,Functional ability ,Longitudinal Studies ,Prospective Studies ,Psychiatry ,Prospective cohort study ,Genetic Association Studies ,Randomized Controlled Trials as Topic ,Repeated measures design ,Middle Aged ,medicine.disease ,Clinical trial ,030104 developmental biology ,Huntington Disease ,Mutation ,Observational study ,Female ,Neurology (clinical) ,Psychology ,Trinucleotide Repeat Expansion ,030217 neurology & neurosurgery ,Cohort study - Abstract
Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials.To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013.Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion.Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years.Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P .001), cognitive (P .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P .001 for all); behavioral domain scores did not diverge significantly between groups.Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.
- Published
- 2015