Utility of the Huntington's Disease Prognostic Index Score for a Perimanifest Clinical Trial.
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ABSTRACT: Background
Subtle neurodegenerative motor and cognitive impairments accumulate over a prodromal period several years before clinical diagnosis of Huntington's disease (HD). The inclusion of prodromal individuals in therapeutic trials would facilitate testing of therapies early in the disease course and the development of treatments intended to prevent or delay disability.Objectives
We evaluate the normalized prognostic index (PIN) score as a tool to select participants for a perimanifest trial. We explore anticipated PIN-based inclusion rates from the preHD screening population and estimate sample-size requirements based on PIN threshold, trial duration, and outcome measure.Methods
Individual participant data from ENROLL-HD were used to fit mixed effect linear models to assess longitudinal changes in clinical metrics for participants with early-manifest HD and PIN-stratified preHD subcohorts.Results
A PIN threshold of 0.0 was met by 40% of the preHD participants in ENROLL-HD; 39.4% and 55.2% progressed to new diagnoses of early-manifest HD within 2 and 3 years, respectively. Various PIN thresholds also enabled the selection of specified ratios of prodromal preHD to early manifest HD participants for a perimanifest trial. Estimated sample sizes for a trial enrolling prodromal preHD (PIN > 0.0) and stage 1 and 2 motor-diagnosed participants varied depending on the composition of the screening pool, the length of follow-up (1, 2, or 3 years), and outcome measure.Conclusions
The composition of a perimanifest clinical trial population can be defined using preselected PIN thresholds, facilitating the assessment of potential disease-modifying therapies in HD. © 2022 Voyager Therapeutics, Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
SUBMITTER: Langbehn DR
PROVIDER: S-EPMC9306552 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective: Early and accurate diagnosis of multiple sclerosis (MS) remains a clinical challenge. The main objective is to evaluate the diagnostic and prognostic value of the routinely performed immunoglobulin G (IgG) index for MS patients in the Asian population. Methods: A retrospective study was conducted among a cohort of clinically isolated syndrome (CIS) patients in China with known oligoclonal band (OCB) status and IgG index at baseline. We first evaluated the predictive value of IgG index for OCB status. Secondly, the diagnostic utility and prognostic value of IgG index alone were tested. Lastly, we incorporated IgG index into the 2017 McDonald criteria by replacing OCB with either "IgG index or OCB" (modified criteria 1), "IgG index and OCB" (modified criteria 2), or "IgG index" (modified criteria 3). The diagnostic utility of different criteria was calculated and compared. Results: In a CIS cohort in China (n = 105), IgG index > 0.7 forecasted OCB positivity (X 2 = 22.90, P < 0.001). An elevated IgG index was highly prognostic of more clinical relapses [1-year adjusted odds ratio [OR] = 1.32, P = 0.015; 2-years adjusted OR = 1.69, P = 0.013] and Expanded Disability Status Scale worsening (1-year adjusted OR = 1.76, P = 0.040; 2-years adjusted OR = 1.85, P = 0.032). Under the 2017 McDonald criteria (Positive Likelihood Ratio = 1.54, Negative Likelihood Ratio = 0.56), an IgG index > 0.7 in CIS patients increased the likelihood of developing MS within 2 years, either when OCB status was unknown (Positive Likelihood Ratio = 2.11) or with OCB positivity (Positive Likelihood Ratio = 2.11) at baseline; An IgG index ≤ 0.7, along with a negative OCB, helped rule out the MS diagnosis (Negative Likelihood Ratio = 0.53). Conclusions: IgG index > 0.7 predicts OCB positivity at the initial attack of MS and is prognostic of early disease activity. IgG index serves as an easily-obtainable and accurate OCB surrogate for MS diagnosis in the Asian population.
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