Ranking the Predictive Power of Clinical and Biological Features Associated With Disease Progression in Huntington's Disease.

Naghmeh Ghazaleh,Giuseppe Palermo,Peter A Wijeratne,Richard Houghton,Jeffrey D Long,Scott A Schobel

doi:10.3389/fneur.2021.678484

Naghmeh Ghazaleh, Giuseppe Palermo + Show 4 more

Open Access

https://doi.org/10.3389/fneur.2021.678484

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Abstract

Huntington's disease (HD) is characterised by a triad of cognitive, behavioural, and motor symptoms which lead to functional decline and loss of independence. With potential disease-modifying therapies in development, there is interest in accurately measuring HD progression and characterising prognostic variables to improve efficiency of clinical trials. Using the large, prospective Enroll-HD cohort, we investigated the relative contribution and ranking of potential prognostic variables in patients with manifest HD. A random forest regression model was trained to predict change of clinical outcomes based on the variables, which were ranked based on their contribution to the prediction. The highest-ranked variables included novel predictors of progression—being accompanied at clinical visit, cognitive impairment, age at diagnosis and tetrabenazine or antipsychotics use—in addition to established predictors, cytosine adenine guanine (CAG) repeat length and CAG-age product. The novel prognostic variables improved the ability of the model to predict clinical outcomes and may be candidates for statistical control in HD clinical studies.

Highlights

Huntington’s disease (HD) is a rare, genetic, neurodegenerative disease caused by a cytosine adenine guanine (CAG) repeat expansion variant of the huntingtin gene (HTT) [1] and is characterised by a triad of cognitive, behavioural, and motor symptoms [2, 3]
Other prognostic variables associated with faster progression that ranked in the top 10 for at least three of the five outcomes were: age at diagnosis, being accompanied to clinic visits, history of cognitive impairment, tetrabenazine use and antipsychotics use
The novel variables identified were predictive of progression over multiple clinical domains, measured by motor, cognitive and CAG repeats

Summary

Introduction

Huntington’s disease (HD) is a rare, genetic, neurodegenerative disease caused by a cytosine adenine guanine (CAG) repeat expansion variant of the huntingtin gene (HTT) [1] and is characterised by a triad of cognitive, behavioural, and motor symptoms [2, 3]. Disease onset, defined as the onset of motor signs and symptoms as measured by a Diagnostic Confidence Level of 4 [3, 4], typically occurs in the prime of life, between the ages of 30 and 50 years [2]. With potential disease-modifying therapies for HD in clinical development [11], there is interest in measuring disease progression and characterising prognostic variables in order to improve the efficiency and accuracy of clinical trials [12].

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