Large-scale screening of clinical assessments to distinguish between states in the Integrated HD Progression Model (IHDPM)

TL;DR

This study identifies which clinical assessments best distinguish different stages of Huntington's disease, helping to improve trial design and endpoint selection.

Contribution

The paper provides ranked effect sizes for 2,472 clinical measures across nine Huntington's disease states, highlighting their discriminative power.

Findings

UHDRS Motor items, especially TMS, best distinguish early disease states and post-transition states.

Cognitive assessments show strong discrimination except between the first two disease states.

Non-UHDRS assessments like SF-12 are effective for specific disease phases.

Abstract

Understanding the sensitivity and utility of clinical assessments across different HD stages is important for study/trial endpoint selection and clinical assessment development. The Integrated HD Progression Model (IHDPM) characterizes the complex symptom progression of HD and separates the disease into nine ordered disease states.

To generate a temporal map of discriminatory clinical measures across the IHDPM states.

We applied the IHDPM to all HD individuals in an integrated longitudinal HD dataset derived from four observational studies, obtaining disease state assignment for each study visit. Using large-scale screening, we estimated Cohen’s effect sizes to rank the discriminative power of 2,472 clinical measures for separating observations in disease state pairs. Individual trajectories through IHDPM states were examined. Discriminative analyses were limited to individuals with observations in both states of the pairs compared (N = 3,790).

Discriminative clinical measures were heterogeneous across the HD life course. UHDRS items were frequently identified as the best state pair discriminators, with UHDRS Motor items – most notably TMS – showing the highest discriminatory power between the early-disease states and early post-transition period states. UHDRS functional items emerged as strong discriminators from the transition period and on. Cognitive assessments showed good discriminative power between all state pairs examined, excepting state 1 vs. 2. Several non-UHDRS assessments were also flagged as excellent state discriminators for specific disease phases (e.g., SF-12). For certain state pairs, single assessment items other than total/summary scores were highlighted as having excellent discriminative power.

By providing ranked quantitative scores indicating discriminatory ability of thousands of clinical measures between specific pairs of IHDPM states, our results will aid clinical trial designers select the most effective outcome measures tailored to their study cohort. Our observations may also assist in the development of end points targeting specific phases in the disease life course, through providing specific conceptual foci.

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