Journal article
Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials
JAMA neurology, Vol.73(1), pp.102-110
01/2016
DOI: 10.1001/jamaneurol.2015.2736
PMID: 26569098
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.
Details
- Title: Subtitle
- Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials
- Creators
- Kevin Michael Biglan - University of RochesterIra Shoulson - University of RochesterKarl Kieburtz - Georgetown UniversityDavid Oakes - University of RochesterElise Kayson - University of RochesterM Aileen Shinaman - University of RochesterHongwei Zhao - University of RochesterMegan Romer - Texas A&M UniversityAnne Young - Pennsylvania State UniversitySteven Hersch - Harvard UniversityJack Penney - Harvard UniversityKaren Marder - Harvard UniversityJane Paulsen - Columbia University Irving Medical CenterKimberly Quaid - University of IowaEric Siemers - Indiana UniversityCaroline Tanner - The Parkinson's Institute, Sunnyvale, CaliforniaWilliam Mallonee - Hereditary Neurological Disease Centre, Wichita, KansasGreg Suter - University of Kansas Medical CenterRichard Dubinsky - University of KansasCarolyn Gray - University of Kansas Medical CenterMartha Nance - University of KansasScott Bundlie - Hennepin County Medical CenterDawn Radtke - Hennepin County Medical CenterSandra Kostyk - Hennepin County Medical CenterCorrine Baic - The Ohio State UniversityJames Caress - The Ohio State UniversityFrancis Walker - Wake Forest UniversityVictoria Hunt - Wake Forest UniversityChristine O'Neill - Wake Forest UniversitySylvain Chouinard - Wake Forest UniversityStewart Factor - Hotel Dieu HospitalTimothy Greenamyre - Emory UniversityCathy Wood-Siverio - Emory UniversityJody Corey-Bloom - Emory UniversityDavid Song - University of California, San DiegoGuerry Peavy - University of California, San DiegoCarol Moskowitz - University of California, San DiegoMelissa Wesson - Indiana UniversityAli Samii - Indiana UniversityThomas Bird - University of WashingtonHillary Lipe - University of WashingtonKaren Blindauer - University of WashingtonFrederick Marshall - Medical College of WisconsinCarol Zimmerman - University of RochesterJody Goldstein - University of RochesterDiana Rosas - University of RochesterPeter Novak - Harvard UniversityJohn Caviness - Harvard UniversityCharles Adler - Mayo ClinicAmy Duffy - Mayo ClinicVicki Wheelock - Mayo Clinic in FloridaTeresa Tempkin - University of California, DavisDavid Richman - University of California, DavisLauren Seeberger - University of California, DavisRoger Albin - University of Michigan–Ann ArborKelvin L Chou - University of Michigan–Ann ArborBrad Racette - University of Michigan–Ann ArborJoel S Perlmutter - Washington University in St. LouisSusan Perlman - Washington University in St. LouisYvette Bordelon - University of California, Los AngelesWayne Martin - University of California, Los AngelesMarguerite Wieler - University of AlbertaBlair Leavitt - University of AlbertaLynn Raymond - University of British ColumbiaJoji Decolongon - University of British ColumbiaLorne Clarke - University of British ColumbiaJoseph Jankovic - University of British ColumbiaChristine Hunter - Baylor College of MedicineRobert A Hauser - Baylor College of MedicineJuan Sanchez-Ramos - University of South FloridaSarah Furtado - University of South FloridaOksana Suchowersky - University of CalgaryMary Lou Klimek - University of CalgaryMark Guttman - Baylor College of MedicineRustom Sethna - Centre for Addiction and Mental HealthAndrew Feigin - Centre for Addiction and Mental HealthMarie Cox - North Shore University HospitalBarbara Shannon - North Shore University HospitalAlan Percy - North Shore University HospitalLeon Dure - University of Alabama at BirminghamMadaline Harrison - University of Alabama at BirminghamWilliam Johnson - University of VirginiaDonald Higgins - Rutgers, The State University of New JerseyEric Molho - Albany Medical Center HospitalConstance Nickerson - Albany Medical Center HospitalSharon Evans - Albany Medical Center HospitalDouglas Hobson - Albany Medical Center HospitalCarlos Singer - University of MiamiNestor Galvez-Jimenez - University of MiamiKathleen Shannon - University of MiamiCynthia Comella - Rush UniversityChristopher Ross - Rush UniversityMarie H Saint-Hilaire - Johns Hopkins UniversityClaudia Testa - Boston UniversityAdam Rosenblatt - Virginia Commonwealth UniversityPenelope Hogarth - Virginia Commonwealth UniversityWilliam Weiner - Oregon Health & Science UniversityPeter Como - University of Maryland, BaltimoreRajeev Kumar - United States Food and Drug AdministrationCandace Cotto - Institute for Neurodegenerative DisordersJulie Stout - Monash UniversityAlicia Brocht - Monash UniversityArthur Watts - University of RochesterShirley Eberly - University of RochesterChristine Weaver - University of RochesterTatiana Foroud - University of RochesterJames Gusella - Indiana UniversityMarcy MacDonald - Harvard UniversityRichard Myers - Harvard UniversityStanley Fahn - Boston UniversityClifford Shults - Columbia University Irving Medical CenterHuntington Study Group PHAROS Investigators
- Resource Type
- Journal article
- Publication Details
- JAMA neurology, Vol.73(1), pp.102-110
- DOI
- 10.1001/jamaneurol.2015.2736
- PMID
- 26569098
- ISSN
- 2168-6149
- eISSN
- 2168-6157
- Grant note
- P30 CA091842 / NCI NIH HHS UL1 TR000040 / NCATS NIH HHS 5R01-HG-02449 / NHGRI NIH HHS
- Language
- English
- Date published
- 01/2016
- Academic Unit
- Psychiatry; Psychological and Brain Sciences
- Record Identifier
- 9984383299702771
Metrics
6 Record Views