Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS)

Abstract

The Huntington Study Group PHAROS Investigators 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 (Ն37 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.

HDQLIFE: development and assessment of health-related quality of life in Huntington disease (HD)

“…With regard to education, our prodromal participants were more highly educated than the manifest participants. This is not surprising given that individuals with greater education also have greater medical genetic knowledge [80] and are more likely to get medical testing [81] and that individuals with higher education are more likely to participate in HD research studies [36, 37, 82]. Rates for race/ethnicity were consistent with established prevalence rates [83–86] and other large HD research cohorts [75, 76, 87].…”

Sample enrichment for clinical trials to show delay of onset in huntington disease

“…Our findings suggest that a sample enrichment approach is advantageous for recruitment of HD gene‐mutation carriers for disease‐modifying clinical trials designed to demonstrate a delay of disease onset. To date, a preventive clinical trial design comparing onset rates has been a concern because of the large number of research participants required . Alternative approaches using composite disease indexes, progression‐free survival, and ongoing detection of new disease markers are also being developed to facilitate the feasibility of preventive trials in CNS.…”

Statistical Approaches to Longitudinal Data Analysis in Neurodegenerative Diseases: Huntington’s Disease as a Model

“…It has been frequently used in analyses of prospective, observational, multi-center longitudinal studies such as COHORT [27], PHAROS [3], PREDICT [2•], and TRACK-HD [19]. Dorsey and colleagues [27] used a MER model to reveal a monotonic decline of movement, cognition, behavior and function using data from COHORT consisting of measures from participants and controls who had at least 3 consecutive years of longitudinal data.…”

“…Dorsey and colleagues [27] used a MER model to reveal a monotonic decline of movement, cognition, behavior and function using data from COHORT consisting of measures from participants and controls who had at least 3 consecutive years of longitudinal data. For PHAROS [3], Biglan and colleagues used a MER model, adjusted for age and sex, to differentiate linear trends of motor, cognitive, psychiatric, and functional decline between individuals with and without the HD mutation. Paulsen and colleagues [2•] used a MER model on PREDICT data to reveal that imaging variables based on regional brain volumes had the largest effect sizes in detecting differences between premanifest HD participants and controls.…”

“…In Huntington’s disease (HD), for example, longitudinal studies have assessed the effect of medication use on performance of motor, cognitive, and neuropsychiatric function over time [1]. Longitudinal assessments of motor and cognitive impairments have also revealed insights into the natural progression of HD [2•, 3]. …”