1. Parkinson’s Disease: Updating the UPDRS February 20, 2014 Glenn T. Stebbins, PhD Department of Neurological Sciences Rush University Medical Center Chicago, IL USA American Society for Experimental NeuroTherapeutics | 16 th Annual Meeting

2. Disclosures Consulting and Advisory Board Memberships: Adamas Pharmaceuticals, Inc., Ceregene, Inc., CHDI Management, Inc., Ingenix Pharmaceutical Services (i3 Research), Neurocrine Biosciences, Inc.. Grants and Research: National Institutes of Health, Michael J. Fox Foundation for Parkinson’s Research, Dystonia Coallition, Parkinson Disease Foundation. Honoraria: Movement Disorder Society, National Institutes of Health, American Academy of Neurology, Michael J. Fox Foundation for Parkinson’s Research. American Society for Experimental NeuroTherapeutics | 16 th Annual Meeting

3. Learning Objectives 1 Describe the process of modifying, validating and translating clinical scales 2 Use this information in research and clinical practice American Society for Experimental NeuroTherapeutics | 16 th Annual Meeting

4. Structure of the original Unified Parkinson’s Disease Rating Scale (UPDRS) Part I: Mentation, Behavior and Mood Part II: Activities of Daily Living Part III: Motor part Part IV Complications Answer options: 0-4 or yes/no

5. Development of the MDS-UPDRS 2001: MDS Task Force on PD rating scales 2003: Published UPDRS critique 2004: Initiation of MDS-UPDRS revision 2006: Preliminary testing and revision 2007: Clinimetric program 2008: MDS-UPDRS published

6. UPDRS - Critique Strengths Single scale for research and practice Generally comprehensive for motor issues Good clinimetrics for Part II and Part III Weaknesses Ambiguities in instructions Poor inter-rater reliability on some items Not all aspects (non-motor) covered Floor effects Recommendation Modify UPDRS to address weaknesses

7. MDS-UPDRS Development Steering Committee 2004 Chairperson:CG Goetz Part I:W Poewe Part II:MB Stern Part III:S Fahn Part IV:P Martinez-Martin AppendixC Sampaio Scale development:GT Stebbins Statistical issues:B Tilley

8. MDS-UPDRS Development Process Delphi Panel Review domains of interest Select scaling metric Generate items Cognitive Pretesting Qualitative testing with examiners and patients Objective is to assess comprehension and comfort with questions and response options

9. Delphi – Domains of Interest Original four component design retained Part I ‘‘nonmotor experiences of daily living’’ Part II ‘‘motor experiences of daily living’’ Part III ‘‘ motor examination’’ Part IV ‘‘motor complications’’ Scoring options: 0-4

10. Delphi – Format and Approach Patient completed: (Part IB and) Part II completed by patient/caregiver as questionnaire Examiner completed: Some of Part 1A and all of Part IV: interview Part III: Motor Examination - details instructions to avoid ambiguities Non-attributional

11. Delphi – Scoring Metric Old Scoring: Mild/moderate/severe/marked became slight/mild/moderate/severe New Scoring Metric: Slight (1) =low frequency or intensity causing no impact on function Mild (2) =frequency or intensity sufficient to cause modest impact on function Moderate (3) = frequency or intensity causing considerable impact, but do not prevent function Severe (4) = prevent function

12. Cognitive Pretesting Each item reviewed qualitatively by 10 raters and 30 patients. Focused on comprehension, comprehensiveness, and comfort with items and response options Required three rounds of cognitive pretesting, Delphi modifications and cognitive pretesting again.

13. Large Clinimetric Study 877 patients examined 560 males/317 females Caucasian (682); Other diverse groups (195) 49 African-American 87 Hispanics 43 Asian 1 native Hawaiian 15 Other ethnicities Drug treated: 805 Untreated: 57 Patients with dyskinesia: 304 Patients with motor fluctuations: 483

14. Statistical Methods Clinimetric PropertyStatistic Internal Consistency Cronbach’s  Concurrent ValiditySpearman Correlation Coefficient ρ, Lin’s CCC Exploratory and Confirmatory Factor Analyses of Parts CFI (≥0.90) DIF by race, age and gender IRT Sensitivity to changeMinimal Clinically Important Change

15. Teaching Tape Similar to original UPDRS Teaching Tapem but… Instruct on all parts (not just Part III) with teaching examples Visual anchors for all items on Part III Expert panel: S Fahn, C Tanner, W Poewe Certificate program hosted on MDS website

16. Certificate Program Raters rate 4 test cases Expert panel ranges (95% CI) are used as the standard MDS members can do this without charge as a member benefit Clinical trial sponsors can purchase access rights and support MDS through this venue Master list of certified MDS members may reduce need to repeat the certification exercise for each study

17. Non-English translations Language teams initiate process with an application Translation/back translation of English version Cognitive pretesting of translated scale Full clinimetric program required (350 PD patients) To qualify as official, each new translation must meet factor structure similarity to original (English) version (CFI > 0.90) Currently 9 translations approved and 11 in progress

18. Impact on Clinical Care and Practice The MDS-UPDRS maintains the overall structure of the original scale, but has improved scale design and clinimetric properties Whereas the UPDRS used to be the “gold standard” in assessing PD severity, the MDS-UPDRS is rapidly becoming the standard. Calibration between the old and new scale allows for legacy data to be incorporated into the new scale.