Motor onset and diagnosis in Huntington disease using the diagnostic confidence level
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Huntington disease (HD) is a neurodegenerative disorder characterized by motor dysfunction, cognitive deterioration, and psychiatric symptoms, with progressive motor impairments being a prominent feature. The primary objectives of this study are to delineate the disease course of motor function in HD, to provide estimates of the onset of motor impairments and motor diagnosis, and to examine the effects of genetic and demographic variables on the progression of motor impairments. Data from an international multisite, longitudinal observational study of 905 prodromal HD participants with cytosine–adenine–guanine (CAG) repeats of at least 36 and with at least two visits during the followup period from 2001 to 2012 was examined for changes in the diagnostic confidence level from the Unified Huntington’s Disease Rating Scale. HD progression from unimpaired to impaired motor function, as well as the progression from motor impairment to diagnosis, was associated with the linear effect of age and CAG repeat length. Specifically, for every 1-year increase in age, the risk of transition in diagnostic confidence level increased by 11 % (95 % CI 7–15 %) and for one repeat length increase in CAG, the risk of transition in diagnostic confidence level increased by 47 % (95 % CI 27–69 %). Findings show that CAG repeat length and age increased the likelihood of the first onset of motor impairment as well as the age at diagnosis. Results suggest that more accurate estimates of HD onset age can be obtained by incorporating the current status of diagnostic confidence level into predictive models.
KeywordsHuntington disease Hidden Markov model Diagnostic confidence level Prediction Diagnosis Onset
This research is supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke (5R01NS040068) awarded to Jane Paulsen; CHDI Foundation, Inc (A6266; A2015) awarded to Jane Paulsen; and Cognitive and Functional Brain Changes in Preclinical Huntington’s Disease (HD) (5R01NS054893) awarded to Jane Paulsen. We thank the PREDICT-HD sites, the study participants, the National Research Roster for Huntington Disease Patients and Families, the Huntington’s Disease Society of America, and the Huntington Study Group. This publication was supported by the National Center for Advancing Translational Sciences, and the National Institutes of Health (NIH), through Grant 2 UL1 TR000442-06. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
PREDICT-HD Investigators, Coordinators, Motor Raters, Cognitive Raters
Isabella De Soriano, Courtney Shadrick, and Amanda Miller (University of Iowa, Iowa City, IA, USA); Edmond Chiu, Joy Preston, Anita Goh, Stephanie Antonopoulos, and Samantha Loi (St. Vincent’s Hospital, The University of Melbourne, Kew, VIC, Australia); Phyllis Chua and Angela Komiti (The University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia); Lynn Raymond, Joji Decolongon, Mannie Fan, and Allison Coleman (University of British Columbia, Vancouver, BC, Canada); Christopher A. Ross, Mark Varvaris, Maryjane Ong, and Nadine Yoritomo (Johns Hopkins University, Baltimore, MD, USA); William M. Mallonee and Greg Suter (Hereditary Neurological Disease Centre, Wichita, KS, USA); Ali Samii, Emily P. Freney, and Alma Macaraeg (University of Washington and VA Puget Sound Health Care System, Seattle, WA, USA); Randi Jones, Cathy Wood-Siverio, and Stewart A. Factor (Emory University School of Medicine, Atlanta, GA, USA); Roger A. Barker, Sarah Mason, and Natalie Valle Guzman (John van Geest Centre for Brain Repair, Cambridge, UK); Elizabeth McCusker, Jane Griffith, Clement Loy, Jillian McMillan, and David Gunn (Westmead Hospital, Sydney, NSW, Australia); Michael Orth, Sigurd Süβmuth, Katrin Barth, Sonja Trautmann, Daniela Schwenk, and Carolin Eschenbach (University of Ulm, Ulm, Germany); Kimberly Quaid, Melissa Wesson, and Joanne Wojcieszek (Indiana University School of Medicine, Indianapolis, IN, USA); Mark Guttman, Alanna Sheinberg, Albie Law, and Irita Karmalkar (Centre for Addiction and Mental Health, University of Toronto, Markham, ON, Canada); Susan Perlman and Brian Clemente (UCLA Medical Center, Los Angeles, CA, USA); Michael D. Geschwind, Sharon Sha, Joseph Winer, and Gabriela Satris (University of California, San Francisco, San Francisco, CA, USA); Tom Warner and Maggie Burrows (National Hospital for Neurology and Neurosurgery, London, UK); Anne Rosser, Kathy Price, and Sarah Hunt (Cardiff University, Cardiff, Wales, UK); Frederick Marshall, Amy Chesire, Mary Wodarski, and Charlyne Hickey (University of Rochester, Rochester, NY, USA); Peter Panegyres, Joseph Lee, Maria Tedesco, and Brenton Maxwell (Neurosciences Unit, Graylands, Selby-Lemnos & Special Care Health Services, Perth, WA, Australia); Joel Perlmutter, Stacey Barton, and Shineeka Smith (Washington University, St. Louis, MO, USA); Zosia Miedzybrodzka, Daniela Rae, Vivien Vaughan, and Mariella D’Alessandro (Clinical Genetics Centre, Aberdeen, Scotland, UK); David Craufurd, Judith Bek, and Elizabeth Howard (University of Manchester, Manchester, UK); Pietro Mazzoni, Karen Marder, and Paula Wasserman (Columbia University Medical Center, New York, NY, USA); Rajeev Kumar, Diane Erickson, Christina Reeves, and Breanna Nickels (Colorado Neurological Institute, Englewood, CO, USA); Vicki Wheelock, Lisa Kjer, Amanda Martin, and Sarah Farias (University of California, Davis, Sacramento, CA, USA); Wayne Martin, Oksana Suchowersky, Pamela King, Marguerite Wieler, and Satwinder Sran (University of Alberta, Edmonton, AB, Canada); and Anwar Ahmed, Stephen Rao, Christine Reece, Alex Bura, and Lyla Mourany (Cleveland Clinic Foundation, Cleveland, OH, USA).
Principal Investigator Jane S. Paulsen, Jeffrey D. Long, Hans J. Johnson, Thomas Brashers-Krug, Phil Danzer, Amanda Miller, H. Jeremy Bockholt, and Kelsey Montross.
Deborah Harrington (University of California, San Diego); Holly Westervelt (Rhode Island Hospital/Alpert Medical School of Brown University); Elizabeth Aylward (Seattle Children’s Research Institute); Stephen Rao (Cleveland Clinic); David J. Moser, Janet Williams, Nancy Downing, Vincent A. Magnotta, Hans J. Johnson, Thomas Brashers-Krug, Jatin Vaidya, Daniel O’Leary, and Eun Young Kim (University of Iowa).
Biostatistics: Jeffrey D. Long, Ji-In Kim, Spencer Lourens (University of Iowa); Ying Zhang and Wenjing Lu (University of Indiana).
Ethics: Cheryl Erwin (Texas Tech University Health Sciences Center); Thomas Brashers-Krug, Janet Williams (University of Iowa); and Martha Nance (University of Minnesota).
Biomedical Informatics: H. Jeremy Bockholt, Jason Evans, and Roland Zschiegner (University of Iowa).
Compliance with ethical standards
Conflicts of interest
J. Paulsen is the principal investigator for PREDICT-HD and has therefore received grant funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke as detailed above. J. Paulsen has also served on an advisory board for Lundbeck, LLC, and has a consulting agreement with ProPhase, LLC. J. Long has a consulting agreement with NeuroPhage, LLC. All other authors declare no conflicts of interest.
PREDICT-HD was approved by the institutional review boards at the University of Iowa and each participating site, and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from each participant.
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