Tanya P Garcia1, Yuanjia Wang2, Ira Shoulson3, Jane S Paulsen4, Karen Marder5. 1. Department of Statistics, Texas A&M University, College Station, TX, USA. 2. Department of Biostatistics, Columbia University, New York, NY, USA. 3. Department of Neurology, Georgetown University, Washington, DC, USA. 4. Department of Psychological and Brain Sciences, The University of Iowa, Iowa City, IA, USA. 5. Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Abstract
BACKGROUND: Critical to discovering targeted therapies for Huntington disease (HD) are validated methods that more precisely predict when clinical outcomes occur for different patient profiles. OBJECTIVE: To more precisely predict the probability of when motor diagnosis (diagnostic confidence level 4) on the Unified Huntington's Disease Rating Scale (UHDRS), cognitive impairment (two or more neuropsychological scores on the UHDRS were 1.5 standard deviations below normative means) and Stage II Total Functional Capacity (TFC) first occur by accounting for dependencies between these outcomes. METHODS: Adult premanifest participants with ≥36 CAG repeats were selected from multi-center, longitudinal, observational studies: Prospective Huntington At Risk Observational Study (PHAROS, n = 346), Neurobiological Predictors of Huntington Disease (PREDICT, n = 909); and Cooperative Huntington Observational Research Trial (COHORT, n = 430). Probabilities were estimated for each study, and pooled using the Joint Progression of Risk Assessment Tool (JPRAT) which accounts for dependencies between outcomes. RESULTS: All studies had similar probabilities of when motor diagnosis, cognitive impairment, and Stage II TFC first occurred. Probability estimates from JPRAT were 43% less variable than from models that ignored dependencies between outcomes. The probability of experiencing motor-diagnosis, cognitive impairment, and Stage II TFC within 5 years was 10%, 18%, and 7%, respectively for 45-year-olds with 42 CAG repeats, and was 4%, 10% and 5%, respectively, for 40 year olds with 42 CAG repeats. CONCLUSIONS: Improved predictions from JPRAT may benefit treatment studies of rare diseases and is an alternative to composite outcomes when the objective is interpreting individual outcomes within the same model.
BACKGROUND: Critical to discovering targeted therapies for Huntington disease (HD) are validated methods that more precisely predict when clinical outcomes occur for different patient profiles. OBJECTIVE: To more precisely predict the probability of when motor diagnosis (diagnostic confidence level 4) on the Unified Huntington's Disease Rating Scale (UHDRS), cognitive impairment (two or more neuropsychological scores on the UHDRS were 1.5 standard deviations below normative means) and Stage II Total Functional Capacity (TFC) first occur by accounting for dependencies between these outcomes. METHODS: Adult premanifest participants with ≥36 CAG repeats were selected from multi-center, longitudinal, observational studies: Prospective Huntington At Risk Observational Study (PHAROS, n = 346), Neurobiological Predictors of Huntington Disease (PREDICT, n = 909); and Cooperative Huntington Observational Research Trial (COHORT, n = 430). Probabilities were estimated for each study, and pooled using the Joint Progression of Risk Assessment Tool (JPRAT) which accounts for dependencies between outcomes. RESULTS: All studies had similar probabilities of when motor diagnosis, cognitive impairment, and Stage II TFC first occurred. Probability estimates from JPRAT were 43% less variable than from models that ignored dependencies between outcomes. The probability of experiencing motor-diagnosis, cognitive impairment, and Stage II TFC within 5 years was 10%, 18%, and 7%, respectively for 45-year-olds with 42 CAG repeats, and was 4%, 10% and 5%, respectively, for 40 year olds with 42 CAG repeats. CONCLUSIONS: Improved predictions from JPRAT may benefit treatment studies of rare diseases and is an alternative to composite outcomes when the objective is interpreting individual outcomes within the same model.
Authors: J S Paulsen; H Zhao; J C Stout; R R Brinkman; M Guttman; C A Ross; P Como; C Manning; M R Hayden; I Shoulson Journal: Neurology Date: 2001-08-28 Impact factor: 9.910
Authors: K Duff; J Paulsen; J Mills; L J Beglinger; D J Moser; M M Smith; D Langbehn; J Stout; S Queller; D L Harrington Journal: Neurology Date: 2010-07-07 Impact factor: 9.910
Authors: Kevin Michael Biglan; Ira Shoulson; Karl Kieburtz; David Oakes; Elise Kayson; M Aileen Shinaman; Hongwei Zhao; Megan Romer; Anne Young; Steven Hersch; Jack Penney; Karen Marder; Jane Paulsen; Kimberly Quaid; Eric Siemers; Caroline Tanner; William Mallonee; Greg Suter; Richard Dubinsky; Carolyn Gray; Martha Nance; Scott Bundlie; Dawn Radtke; Sandra Kostyk; Corrine Baic; James Caress; Francis Walker; Victoria Hunt; Christine O'Neill; Sylvain Chouinard; Stewart Factor; Timothy Greenamyre; Cathy Wood-Siverio; Jody Corey-Bloom; David Song; Guerry Peavy; Carol Moskowitz; Melissa Wesson; Ali Samii; Thomas Bird; Hillary Lipe; Karen Blindauer; Frederick Marshall; Carol Zimmerman; Jody Goldstein; Diana Rosas; Peter Novak; John Caviness; Charles Adler; Amy Duffy; Vicki Wheelock; Teresa Tempkin; David Richman; Lauren Seeberger; Roger Albin; Kelvin L Chou; Brad Racette; Joel S Perlmutter; Susan Perlman; Yvette Bordelon; Wayne Martin; Marguerite Wieler; Blair Leavitt; Lynn Raymond; Joji Decolongon; Lorne Clarke; Joseph Jankovic; Christine Hunter; Robert A Hauser; Juan Sanchez-Ramos; Sarah Furtado; Oksana Suchowersky; Mary Lou Klimek; Mark Guttman; Rustom Sethna; Andrew Feigin; Marie Cox; Barbara Shannon; Alan Percy; Leon Dure; Madaline Harrison; William Johnson; Donald Higgins; Eric Molho; Constance Nickerson; Sharon Evans; Douglas Hobson; Carlos Singer; Nestor Galvez-Jimenez; Kathleen Shannon; Cynthia Comella; Christopher Ross; Marie H Saint-Hilaire; Claudia Testa; Adam Rosenblatt; Penelope Hogarth; William Weiner; Peter Como; Rajeev Kumar; Candace Cotto; Julie Stout; Alicia Brocht; Arthur Watts; Shirley Eberly; Christine Weaver; Tatiana Foroud; James Gusella; Marcy MacDonald; Richard Myers; Stanley Fahn; Clifford Shults Journal: JAMA Neurol Date: 2016-01 Impact factor: 18.302
Authors: J S Paulsen; D R Langbehn; J C Stout; E Aylward; C A Ross; M Nance; M Guttman; S Johnson; M MacDonald; L J Beglinger; K Duff; E Kayson; K Biglan; I Shoulson; D Oakes; M Hayden Journal: J Neurol Neurosurg Psychiatry Date: 2007-12-20 Impact factor: 10.154
Authors: Jeffrey D Long; James A Mills; Blair R Leavitt; Alexandra Durr; Raymund A Roos; Julie C Stout; Ralf Reilmann; Bernhard Landwehrmeyer; Sarah Gregory; Rachael I Scahill; Douglas R Langbehn; Sarah J Tabrizi Journal: JAMA Neurol Date: 2017-11-01 Impact factor: 18.302
Authors: Christopher A Ross; Ralf Reilmann; Francisco Cardoso; Elizabeth A McCusker; Claudia M Testa; Julie C Stout; Blair R Leavitt; Zhong Pei; Bernhard Landwehrmeyer; Asuncion Martinez; Jamie Levey; Teresa Srajer; Jee Bang; Sarah J Tabrizi Journal: Mov Disord Clin Pract Date: 2019-08-23