Multivariate prediction of motor diagnosis in Huntington's disease: 12 years of PREDICT-HD.
BACKGROUND
It is well known in Huntington's disease that cytosine-adenine-guanine expansion and age at study entry are predictive of the timing of motor diagnosis. The goal of this study was to assess whether additional motor, imaging, cognitive, functional, psychiatric, and demographic variables measured at study entry increased the ability to predict the risk of motor diagnosis over 12 years.


METHODS
One thousand seventy-eight Huntington's disease gene-expanded carriers (64% female) from the Neurobiological Predictors of Huntington's Disease study were followed up for up to 12 y (mean = 5, standard deviation = 3.3) covering 2002 to 2014. No one had a motor diagnosis at study entry, but 225 (21%) carriers prospectively received a motor diagnosis. Analysis was performed with random survival forests, which is a machine learning method for right-censored data.


RESULTS
Adding 34 variables along with cytosine-adenine-guanine and age substantially increased predictive accuracy relative to cytosine-adenine-guanine and age alone. Adding six of the common motor and cognitive variables (total motor score, diagnostic confidence level, Symbol Digit Modalities Test, three Stroop tests) resulted in lower predictive accuracy than the full set, but still had twice the 5-y predictive accuracy than when using cytosine-adenine-guanine and age alone. Additional analysis suggested interactions and nonlinear effects that were characterized in a post hoc Cox regression model.


CONCLUSIONS
Measurement of clinical variables can substantially increase the accuracy of predicting motor diagnosis over and above cytosine-adenine-guanine and age (and their interaction). Estimated probabilities can be used to characterize progression level and aid in future studies' sample selection.
Department of Psychiatry, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.|Department of Biostatistics, College of Public Health, The University of Iowa, Iowa City, IA, USA.
Jeffrey D
JD
Long
Department of Psychiatry, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.|Department of Neurology, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.|Department of Psychology, The University of Iowa, Iowa City, IA, USA.
Jane S
JS
Paulsen
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003072:Cognition Disorders / Q000175:diagnosis / Q000209:etiology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D008137:Longitudinal Studies; D000069550:Machine Learning; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009483:Neuropsychological Tests; D016016:Proportional Hazards Models; D012720:Severity of Illness Index; D018911:Trinucleotide Repeats / Q000235:genetics*; D055815:Young Adult
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins
Huntington's disease; assessment of cognitive disorders/dementia; clinical trials methodology/study design; prognosis