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


Kevin Michael Biglan
Ira Shoulson
Karl Kieburtz
David Oakes
Elise Kayson
M Aileen Shinaman
Hongwei Zhao
Megan Romer
Anne Young
Steven Hersch
Jack Penney
Karen Marder
Jane Paulsen
Kimberly Quaid
Eric Siemers
Caroline Tanner
William Mallonee
Greg Suter
Richard Dubinsky
Carolyn Gray
Martha Nance
Scott Bundlie
Dawn Radtke
Sandra Kostyk
Corrine Baic
James Caress
Francis Walker
Victoria Hunt
Christine O'Neill
Sylvain Chouinard
Stewart Factor
Timothy Greenamyre
Cathy Wood-Siverio
Jody Corey-Bloom
David Song
Guerry Peavy
Carol Moskowitz
Melissa Wesson
Ali Samii
Thomas Bird
Hillary Lipe
Karen Blindauer
Frederick Marshall
Carol Zimmerman
Jody Goldstein
Diana Rosas
Peter Novak
John Caviness
Charles Adler
Amy Duffy
Vicki Wheelock
Teresa Tempkin
David Richman
Lauren Seeberger
Roger Albin
Kelvin L Chou
Brad Racette
Joel S Perlmutter
Susan Perlman
Yvette Bordelon
Wayne Martin
Marguerite Wieler
Blair Leavitt
Lynn Raymond
Joji Decolongon
Lorne Clarke
Joseph Jankovic
Christine Hunter
Robert A Hauser
Juan Sanchez-Ramos
Sarah Furtado
Oksana Suchowersky
Mary Lou Klimek
Mark Guttman
Rustom Sethna
Andrew Feigin
Marie Cox
Barbara Shannon
Alan Percy
Leon Dure
Madaline Harrison
William Johnson
Donald Higgins
Eric Molho
Constance Nickerson
Sharon Evans
Douglas Hobson
Carlos Singer
Nestor Galvez-Jimenez
Kathleen Shannon
Cynthia Comella
Christopher Ross
Marie H Saint-Hilaire
Claudia Testa
Adam Rosenblatt
Penelope Hogarth
William Weiner
Peter Como
Rajeev Kumar
Candace Cotto
Julie Stout
Alicia Brocht
Arthur Watts
Shirley Eberly
Christine Weaver
Tatiana Foroud
James Gusella
Marcy MacDonald
Richard Myers
Stanley Fahn
Clifford Shults

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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.

Medical Subject Headings

Adult; Cohort Studies; Female; Genetic Association Studies; Humans; Huntington Disease; Longitudinal Studies; Male; Middle Aged; Mutation; Prospective Studies; Randomized Controlled Trials as Topic; Single-Blind Method; Trinucleotide Repeat Expansion

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JAMA Neurol







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