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Observational Study
. 2016 Jan;73(1):102-10.
doi: 10.1001/jamaneurol.2015.2736.

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials

Huntington Study Group PHAROS InvestigatorsKevin Michael Biglan  1 Ira Shoulson  2 Karl Kieburtz  1 David Oakes  3 Elise Kayson  1 M Aileen Shinaman  1 Hongwei Zhao  4 Megan Romer  5 Anne Young  6 Steven Hersch  6 Jack Penney  6 Karen Marder  7 Jane Paulsen  8 Kimberly Quaid  9 Eric Siemers  10 Caroline Tanner  11 William Mallonee  12 Greg Suter  13 Richard Dubinsky  13 Carolyn Gray  13 Martha Nance  14 Scott Bundlie  14 Dawn Radtke  14 Sandra Kostyk  15 Corrine Baic  15 James Caress  16 Francis Walker  16 Victoria Hunt  16 Christine O'Neill  16 Sylvain Chouinard  17 Stewart Factor  18 Timothy Greenamyre  18 Cathy Wood-Siverio  18 Jody Corey-Bloom  19 David Song  19 Guerry Peavy  19 Carol MoskowitzMelissa Wesson  9 Ali Samii  20 Thomas Bird  20 Hillary Lipe  20 Karen Blindauer  21 Frederick Marshall  1 Carol Zimmerman  1 Jody Goldstein  1 Diana Rosas  6 Peter Novak  6 John Caviness  22 Charles Adler  22 Amy Duffy  22 Vicki Wheelock  23 Teresa Tempkin  23 David Richman  23 Lauren Seeberger  24 Roger Albin  25 Kelvin L Chou  25 Brad Racette  26 Joel S Perlmutter  26 Susan Perlman  27 Yvette Bordelon  27 Wayne Martin  28 Marguerite Wieler  28 Blair Leavitt  29 Lynn Raymond  29 Joji Decolongon  29 Lorne Clarke  29 Joseph Jankovic  30 Christine Hunter  30 Robert A Hauser  31 Juan Sanchez-Ramos  31 Sarah Furtado  32 Oksana Suchowersky  32 Mary Lou Klimek  30 Mark Guttman  33 Rustom Sethna  33 Andrew Feigin  34 Marie Cox  34 Barbara Shannon  34 Alan Percy  35 Leon Dure  35 Madaline Harrison  36 William Johnson  37 Donald Higgins  38 Eric Molho  38 Constance Nickerson  38 Sharon Evans  38 Douglas Hobson  39 Carlos Singer  40 Nestor Galvez-Jimenez  40 Kathleen Shannon  41 Cynthia Comella  41 Christopher Ross  42 Marie H Saint-Hilaire  43 Claudia Testa  44 Adam Rosenblatt  44 Penelope Hogarth  45 William Weiner  46 Peter Como  47 Rajeev Kumar  48 Candace Cotto  49 Julie Stout  50 Alicia Brocht  1 Arthur Watts  1 Shirley Eberly  3 Christine Weaver  1 Tatiana Foroud  9 James Gusella  6 Marcy MacDonald  6 Richard Myers  43 Stanley Fahn  7 Clifford Shults  19
Affiliations
Observational Study

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials

Huntington Study Group PHAROS Investigators et al. JAMA Neurol. .

Abstract

Importance: 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.

Objective: To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).

Design, setting, and participants: 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.

Exposure: Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion.

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

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