# Bias in HD-ISS staging introduced by the FreeSurfer cross-sectional stream: Insights from the Huntington's Disease Young Adult Study (HD-YAS)

## TL;DR

This study shows that using the cross-sectional FreeSurfer stream for HD-ISS staging leads to biased results compared to the longitudinal stream, affecting clinical trial eligibility.

## Contribution

The study reveals a bias in HD-ISS staging when using the cross-sectional FreeSurfer stream, suggesting the need for revised cut-offs for clinical trials.

## Key findings

- Cross-sectional stream produces smaller caudate and putamen volumes compared to the longitudinal stream.
- Volume reductions are more pronounced in larger volumes, potentially misclassifying participants into HD-ISS stage 1.
- CS-specific volumetric cut-offs are needed for accurate HD-ISS staging in clinical trials.

## Abstract

Huntington's Disease Integrated Staging System (HD-ISS) stages are likely inclusion criteria in future clinical trials. Stage 1 volumetric cut-offs were derived using the FreeSurfer longitudinal stream (LG). However, trials will require cross-sectional stream (CS) application with one MRI. Volumetric outputs are not robust to software type or version. T1-weighted images from 88 participants with MRIs from baseline and follow-up HD-YAS visits were segmented using both streams. CS calculated smaller caudate and putamen volumes adjusted for total intracranial volume, with greater reduction for larger volumes, shifting towards HD-ISS stage 1. CS-specific cut-offs need to be established before application to clinical trials.