[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.211.168.204. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
Table 1. 
Demographics of 653 Subjects With PDa
Demographics of 653 Subjects With PDa
Table 2. 
Cross-Sectional Analyses of Ratings on the UPDRS by Levels of Disability on the SE Scale
Cross-Sectional Analyses of Ratings on the UPDRS by Levels of Disability on the SE Scale
Table 3. 
Cross-Sectional Analyses of Ratings on the UPDRS by HY Stages
Cross-Sectional Analyses of Ratings on the UPDRS by HY Stages
Table 4. 
Summary of Distribution- and Anchor-Based Analyses of the CID on the UPDRS Total and Motor Scores
Summary of Distribution- and Anchor-Based Analyses of the CID on the UPDRS Total and Motor Scores
Table 5. 
Effect Sizes in Published Clinical Trials in PDa
Effect Sizes in Published Clinical Trials in PDa
1.
Jaeschke  RSinger  JGuyatt  GH Measurement of health status: ascertaining the minimal clinically important difference. Control Clin Trials 1989;10 (4) 407- 415
PubMedArticle
2.
Barrett  BBrown  DMundt  MBrown  R Sufficiently important difference: expanding the framework of clinical significance. Med Decis Making 2005;25 (3) 250- 261
PubMedArticle
3.
Caplan  LR How well does “evidence-based” medicine help neurologists care for individual patients? Rev Neurol Dis 2007;4 (2) 75- 84
PubMed
4.
Fahn  SElton  RLMembers of the UPDRS Development Committee, Unified Parkinson's Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson's Disease., Vol 2. Florham Park, NJ Macmillan Health Care Information1987;153- 164
5.
Movement Disorder Society Task Force on Rating Scales for Parkinson's Disease, The Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. Mov Disord 2003;18 (7) 738- 750
PubMedArticle
6.
Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.  Rockville, MD US Dept of Health and Human Services2006;
7.
Samsa  GEdelman  DRothman  MLWilliams  GRLipscomb  JMatchar  D Determining clinically important differences in health status measures: a general approach with illustration to the Health Utilities Index Mark II. Pharmacoeconomics 1999;15 (2) 141- 155
PubMedArticle
8.
Norman  GRSridhar  FGGuyatt  GHWalter  SD Relation of distribution- and anchor-based approaches in interpretation of changes in health-related quality of life. Med Care 2001;39 (10) 1039- 1047
PubMedArticle
9.
Schrag  ASampaio  CCounsell  NPoewe  W Minimal clinically important change on the Unified Parkinson's Disease Rating Scale. Mov Disord 2006;21 (8) 1200- 1207
PubMedArticle
10.
Copay  AGSubach  BRGlassman  SDPolly  DW  JrSchuler  TC Understanding the minimum clinically important difference: a review of concepts and methods. Spine J 2007;7 (5) 541- 546
PubMedArticle
11.
Laine  CDavidoff  F Patient-centered medicine: a professional evolution. JAMA 1996;275 (2) 152- 156
PubMedArticle
12.
Hoehn  MMYahr  MD Parkinsonism: onset, progression, and mortality. Neurology 1967;17 (5) 427- 442
PubMedArticle
13.
Schwab  JFEngland  AC Projection technique for evaluating surgery in Parkinson's disease. In: Gillingham FJ, Donaldson MC, eds. Third Symposium on Parkinson's Disease., Edinburgh, Scotland E & S Livingston1969;152- 157
14.
Folstein  MFFolstein  SE McHugh  PR “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12 (3) 189- 198
PubMedArticle
15.
Ware  J  JrKosinski  MKeller  SD A 12-Item Short Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996;34 (3) 220- 233
PubMedArticle
16.
Sloan  JA Assessing the minimally clinically significant difference: scientific considerations, challenges and solutions. COPD 2005;2 (1) 57- 62
PubMedArticle
17.
Guyatt  GHOsoba  DWu  AWWyrwich  KWNorman  GRClinical Significance Consensus Meeting Group, Methods to explain the clinical significance of health status measures. Mayo Clin Proc 2002;77 (4) 371- 383
PubMedArticle
18.
Yost  KJCella  DChawla  A  et al.  Minimally important differences were estimated for the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) instrument using a combination of distribution- and anchor-based approaches. J Clin Epidemiol 2005;58 (12) 1241- 1251
PubMedArticle
19.
Revicki  DHays  RDCella  DSloan  S Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes. J Clin Epidemiol 2008;61 (2) 102- 109
PubMedArticle
20.
Redelmeier  DAGuyatt  GHGoldstein  RS Assessing the minimal important difference in symptoms: a comparison of two techniques. J Clin Epidemiol 1996;49 (11) 1215- 1219
PubMedArticle
21.
Cohen  J Statistical Power Analysis for the Behavioral Sciences.  Orlando, FL Academic Press Inc1977;
22.
W right  JGYoung  NL A comparison of different indices of responsiveness. J Clin Epidemiol 1997;50 (3) 239- 246
PubMedArticle
23.
Hays  RDWoolley  JM The concept of clinically meaningful difference in health-related quality-of-life research: how meaningful is it? Pharmacoeconomics 2000;18 (5) 419- 423
PubMedArticle
24.
Norman  GRSloan  JAWyrwich  KW Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care 2003;41 (5) 582- 592
PubMed
25.
Hawkes  WGWilliams  GRZimmerman  S  et al.  A clinically meaningful difference was generated for a performance measure of recovery from hip fracture. J Clin Epidemiol 2004;57 (10) 1019- 1024
PubMedArticle
26.
Luo  NTan  LZhao  YLau  PNAu  WLLi  SC Determination of the longitudinal validity and minimally important difference of the 8-item Parkinson's Disease Questionnaire (PDQ-8). Mov Disord 2009;24 (2) 183- 187
PubMedArticle
27.
Stewart  ALGreenfield  SHays  RD  et al.  Functional status and well-being of patients with chronic conditions: results from the medical outcomes study. JAMA 1989;262 (7) 907- 913
PubMedArticle
28.
Wiebe  SMatijevic  SEliasziw  MDerry  PA Clinically important change in quality of life in epilepsy. J Neurol Neurosurg Psychiatry 2002;73 (2) 116- 120
PubMedArticle
29.
Bjorner  JBWallenstein  GVMartin  MC  et al.  Interpreting score differences in the SF-36 vitality scale: using clinical conditions and functional outcomes to define the minimally important difference. Curr Med Res Opin 2007;23 (4) 731- 739
PubMedArticle
30.
Glassman  SDCopay  AGBerven  SHPolly  DWSubach  BRCarreon  LY Defining substantial clinical benefit following lumbar spine arthrodesis. J Bone Joint Surg Am 2008;90 (9) 1839- 1847
PubMedArticle
31.
Brunt  ERBrooks  DJKorczyn  ADMontastruc  JLStocchi  F043 Study Group, A six-month multicentre, double-blind, bromocriptine-controlled study of the safety and efficacy of ropinirole in the treatment of patients with Parkinson's disease not optimally controlled by L-dopa. J Neural Transm 2002;109 (4) 489- 502
PubMedArticle
32.
Korczyn  ADBrunt  ERLarsen  JPNagy  ZPoewe  WHRuggieri  S053 Study Group, A 3-year randomized trial of ropinirole and bromocriptine in early Parkinson's disease. Neurology 1999;53 (2) 364- 370
PubMedArticle
33.
Stern  MBMarek  KLFriedman  J  et al.  Double-blind, randomized, controlled trial of rasagiline as monotherapy in early Parkinson's disease patients. Mov Disord 2004;19 (8) 916- 923
PubMedArticle
34.
Parkinson Study Group, Safety and efficacy of pramipexole in early Parkinson disease: a randomized dose-ranging study. JAMA 1997;278 (2) 125- 130
PubMedArticle
35.
Parkinson Study Group, Effect of deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1989;321 (20) 1364- 1371
PubMedArticle
36.
Guttman  MInternational Pramipexole-Bromocriptine Study Group, Double-blind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson's disease. Neurology 1997;49 (4) 1060- 1065
PubMedArticle
37.
Shannon  KMBennett  JP  JrFriedman  JHThe Pramipexole Study Group, Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease. Neurology 1997;49 (3) 724- 728
PubMedArticle
38.
Rascol  OBrooks  DJBrunt  ERKorczyn  ADPoewe  WHStocchi  F056 Study Group, Ropinirole in the treatment of early Parkinson's disease: a 6-month interim report of a 5-year levodopa-controlled study. Mov Disord 1998;13 (1) 39- 45
PubMedArticle
39.
Sethi  KDO’Brien  CFHammerstad  JP  et al. Ropinirole Study Group, Ropinirole for the treatment of early Parkinson disease: a 12-month experience. Arch Neurol 1998;55 (9) 1211- 1216
PubMedArticle
40.
Parkinson Study Group, Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA 2000;284 (15) 1931- 1938
PubMedArticle
41.
Parkinson Study Group, A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol 2002;59 (12) 1937- 1943
PubMedArticle
42.
Parkinson Study Group, A controlled, randomized, delayed start study of rasagiline in early Parkinson's disease. Arch Neurol 2004;61 (4) 561- 566
PubMedArticle
43.
Fahn  SOakes  DShoulson  I  et al. Parkinson Study Group, Levodopa and the progression of Parkinson's disease. N Engl J Med 2004;351 (24) 2498- 2508
PubMedArticle
44.
Parkinson Study Group, A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005;62 (2) 241- 248
PubMedArticle
45.
Perera  SMody  SHWoodman  RCStudenski  SA Meaningful change and responsiveness in common physical performance measures in older adults. J Am Geriatr Soc 2006;54 (5) 743- 749
PubMedArticle
46.
Rascol  O Defining a minimal clinically relevant difference for the Unified Parkinson's Rating Scale: an important but still unmet need. Mov Disord 2006;21 (8) 1059- 1061
PubMedArticle
Original Contribution
January 2010

The Clinically Important Difference on the Unified Parkinson's Disease Rating Scale

Author Affiliations

Author Affiliations: Departments of Neurology (Drs Shulman, Anderson, Fishman, Reich, and Weiner), Epidemiology and Preventive Medicine (Dr Gruber-Baldini), and Psychiatry (Dr Anderson), University of Maryland School of Medicine, Baltimore.

Arch Neurol. 2010;67(1):64-70. doi:10.1001/archneurol.2009.295
Abstract

Objective  To determine the estimates of minimal, moderate, and large clinically important differences (CIDs) for the Unified Parkinson's Disease Rating Scale (UPDRS).

Design  Cross-sectional analysis of the CIDs for UPDRS total and motor scores was performed on patients with Parkinson disease (PD) using distribution- and anchor-based approaches based on the following 3 external standards: disability (10% on the Schwab and England Activities of Daily Living Scale), disease stage (1 stage on the Hoehn and Yahr Scale), and quality of life (1 SD on the 12-Item Short Form Health Survey).

Setting  University of Maryland Parkinson Disease and Movement Disorders Center,

Patients  Six hundred fifty-three patients with PD.

Results  A minimal CID was 2.3 to 2.7 points on the UPDRS motor score and 4.1 to 4.5 on the UPDRS total score. A moderate CID was 4.5 to 6.7 points on the UPDRS motor score and 8.5 to 10.3 on the UPDRS total score. A large CID was 10.7 to 10.8 points on the UPDRS motor score and 16.4 to 17.8 on the UPDRS total score.

Conclusions  Concordance among multiple approaches of analysis based on subjective and objective data show that reasonable estimates for the CID on the UPDRS motor score are 2.5 points for minimal, 5.2 for moderate, and 10.8 for large CIDs. Estimates for the UPDRS total score are 4.3 points for minimal, 9.1 for moderate, and 17.1 for large CIDs. These estimates will assist in determining clinically meaningful changes in PD progression and response to therapeutic interventions.

A clinically important difference (CID) is the amount of change on a measure that patients can recognize and value.1 Growing interest in CIDs stems from a greater emphasis on evidence-based and patient-centered medicine.2 Large randomized clinical trials frequently show significant differences on outcome measures that are so small that clinicians are unsure how to apply them to clinical decision making.3 The Movement Disorder Society Task Force on Rating Scales for Parkinson's Disease highlighted the importance of identifying thresholds on the Unified Parkinson's Disease Rating Scale (UPDRS) that represent clinically relevant differences.4,5 The US Food and Drug Administration also described the need to define minimally important differences on patient-reported outcome measures used to support the labeling claims of medical products.6

The 2 key methods of CID assessment are the distribution- and anchor-based approaches.7,8 The distribution-based approach relies on the empirical distribution of a measure in a population and the derived effect size. The anchor-based approach uses a familiar and relevant external standard to determine the corresponding magnitude of change. This study uses both of these approaches and relies on 3 different external standards (anchors) to assess the CID on the UPDRS total scale and its motor subscale.

The minimal clinically important change on the UPDRS was previously determined based on data from 2 clinical trials of dopamine agonist monotherapy in early Parkinson disease (PD).9 Study limitations included the inability to generalize the results to more advanced PD and the reliance on a clinician-based measure (Clinical Global Impression of Improvement) as the anchor for assessing clinical relevance. Assessments by clinicians do not always match patient evaluations because of limitations in awareness of the patient experience.6,10 The belief that clinically relevant differences in health should be defined by patients is fundamental to patient-centered medicine.11

The primary objective of this study was to determine the CID for the UPDRS by using multiple methods of assessment and a large patient sample representing all stages of PD. The goal was to create estimates of minimal, moderate, and large CIDs by looking for concordance of the results from multiple approaches of CID analysis.

METHODS

The sample consists of patients diagnosed as having PD by a movement disorder specialist (L.M.S., P.S.F., S.G.R., or W.J.W.) at the University of Maryland Parkinson Disease and Movement Disorders Center who underwent assessment during routine office visits from April 1, 2003, through August 31, 2006. The criteria for the diagnosis of PD were asymmetrical onset of at least 2 of the following 3 cardinal signs: resting tremor, rigidity, and bradykinesia, with no atypical signs or exposure to dopamine-blocking drugs. Patients attending the movement disorders center are routinely asked to enroll in the University of Maryland Quality of Life and Function Study. During the study period, 86% of patients with PD agreed to participate and signed an informed consent form approved by the University of Maryland institutional review board. The treating neurologist completed the UPDRS, staging with the Hoehn and Yahr Scale (HY),12 the Schwab and England Activities of Daily Living Scale (SE Scale),13 and the Mini-Mental State Examination14 for all subjects. Patients with a Mini-Mental State Examination score of less than 26 required the assistance of a caregiver for consent and questionnaire completion. Patients completed the 12-Item Short Form Health Survey, version 2 (SF-12)15 during the office visit. The HY data reported herein are based on a combination of the single rating for patients for whom the stage did not fluctuate and the “on” rating for those whose stage did fluctuate (30% of the sample consisted of patients whose stage fluctuated and the results were similar when “off” ratings were analyzed).

DETERMINING THE CID WITH DISTRIBUTION- AND ANCHOR-BASED ANALYSES

There are many accepted methods of assessing CID; because all methods have strengths and weaknesses, it is preferable to rely on several methods.7,10,1619 There is also no single response or precise threshold for the CID of a measure; instead it is best to represent the CID of a measure as a range (eg, small, moderate, or large).1,7,17,20 Therefore, in this cross-sectional study we used a combination of distribution- and anchor-based approaches, and we designated predetermined cut points of small, moderate, and large CIDs for the UPDRS.

For the distribution-based approach, means and standard deviations were derived from the current sample of data, and effect sizes were calculated relative to 1 SD. The most common approach to the analysis of the distribution-based CID in the literature relies on the Cohen effect size, in which an effect size of 0.2 (0.2 of an SD) is small, 0.5 is moderate, and 0.8 is large.7,10,18,2126

In anchor-based methods, the measures chosen as anchors should be familiar to clinicians in the field, relevant, interpretable, and significantly correlated with the instrument being explored.7,18 Three measures were used as anchors in this study: (1) the SF-12,15 (2) the SE Scale,13 and (3) the HY stages.12 Pearson correlations were performed, showing that the UPDRS total and motor scores have moderate to large correlations with the SE Scale (r = −0.64 to −0.78), HY stages (r = 0.70 to 0.75), and SF-12 (physical health [PH], r = −0.44 to −0.52; mental health [MH], r = −0.35 to −0.45) (for all, P < .001). Previously accepted thresholds for the CID have been published for the 36-Item Short Form Health Status Survey (SF-36) and the SF-12, but thresholds have not been defined for the SE Scale or the HY stages.

CUT POINTS FOR THE SF-36 AND SF-12

The SF-36 and SF-12 have 2 summary scores—PH and MH—that yield t scores based on a US normative population in which the average score is the 50th percentile and 10 units is 1 SD. An analysis of effect sizes for the SF-36 was performed by Samsa et al7 for about 25 medical conditions. Conforming to clinical intuition, conditions such as congestive heart failure or emphysema were associated with large effect sizes on the SF-36, conditions such as arthritis had moderate effect sizes, and conditions such as hypertension had small effect sizes. Based on the published literature, the small CID for the SF-36 or the SF-12 is in the range of 3 to 5 points, whereas the moderate CID is 9 to 10 points.7,2730 These ranges for small and moderate CID were used in our study.

CUT POINTS FOR THE SE SCALE AND HY STAGES

In the absence of previous analysis of thresholds for effect sizes on the SE Scale or the HY stages, we used a combination of clinical judgment and analysis of each scale's distribution (based on the standard deviation). Specifically, we made a predetermined judgment of small, medium, or large CID on the SE Scale and the HY stages based on our clinical experience. Then we analyzed the SE Scale and HY stage distributions in our sample to assess whether they conformed to our clinical impressions. On the SE Scale, clinicians assign scores based on descriptors that coincide with 10% increments on the scale; therefore, a 10% change (10 points on the SE Scale) is clinically relevant. Furthermore, the standard deviation on the SE Scale for our sample was 18.7 (Table 1). Therefore, our criterion for a 10% change is 0.53 SD (10 per 18.7) or approximately half of an SD for every 10% change: a moderate CID based on the Cohen effect size. On the HY stages, clinicians assign the 5 stages based on the clinical descriptions at each stage. Because PD is a gradually progressive disorder, moving from one stage to another generally takes several years. Therefore, the HY stages are clinically relevant and represent a relatively large change in disease severity. The standard deviation on the HY stages for our sample was 0.9 (Table 1). Therefore, a change of 1 stage on the HY stages is equivalent to 1.1 SD (1 stage per 0.9 SD), or greater than the large effect size (0.8) based on the Cohen effect size.

DATA ANALYSIS

Because the HY stages and SE Scale are not normally distributed (and because the HY scale is not an interval or ratio scale but rather an ordinal scale), general linear model analyses (using SAS statistical software, version 9.1; SAS Institute Inc, Cary, North Carolina) were performed to calculate averaged groups for the UPDRS total and motor scores by the SE and HY groups (analysis of variance model). Average differences between these group means were then calculated. Regression models (general linear model and ordinary least squares) were run to examine linear changes for the UPDRS measures by differences on the SF-12 because the SF-12 is a normally distributed interval scale. We reported the regression weight change per specified unit on the SF-12 (eg, 5 units as a small change and 10 units as a moderate change). A separate general linear model was run for every predictor (HY stages, SE Scale, and SF-12 PH and MH) on each outcome (UPDRS total and motor scores), resulting in 8 separate analyses. The critical P value for interpretation was set to P < .01 to adjust for multiple comparisons. Unless otherwise indicated, scores are expressed as mean (SD).

RESULTS

The study sample of 653 subjects with PD is described in Table 1. The sample was predominantly white, male, and married, with relatively high education and income.

UPDRS MOTOR SCORE

The mean UPDRS motor score (subscale III) was 27.2 (13.4). Based on the SE Scale ratings, the mean UPDRS motor scores ranged from a low of 15.3 (8.2) for the subjects reporting no disability (SE Scale, 100% [completely independent]) to a high of 60.0 (7.1) for subjects rated as totally dependent (SE Scale, 10% [bedridden]) (Table 2). Based on the HY stages, the mean UPDRS motor scores ranged from a low of 11.2 (4.9) for subjects with unilateral parkinsonism (stage 1) to a high of 54.4 (11.4) for subjects assessed as wheelchair bound or bedridden (stage 5) (Table 3). Regression analysis showed the average difference on the UPDRS motor score to be 4.5 points for a 10% change on the SE Scale and 10.8 points for a 1-stage change on the HY stages. On the SF-12, 1 unit on the PH or the MH summary score was equivalent to a change of 0.47 points on the UPDRS motor score. Therefore, a difference of 1 SD (defined as 10 units) was 4.7 points on the UPDRS motor score and half of a standard deviation was equivalent to 2.3 or 2.4 points (Table 4). The distribution-based analysis showed that the minimal CID was 2.7 points, the moderate CID was 6.7, and the large CID was 10.7 (Table 4). Based on a combination of the anchor- and distribution-based analyses (averaging across the results), 2.5 points is an appropriate estimate for the minimal CID, 5.2 points for the moderate CID, and 10.8 points for the large CID (Table 4).

UPDRS TOTAL SCORE

The mean UPDRS total score (subscales I, II, and III) was 41.0 (20.5). Based on the SE Scale ratings, the mean UPDRS total score ranged from a low of 19.9 (9.5) for subjects reporting no disability (SE Scale, 100%) to a high of 107.5 (7.2) for subjects rated as bedridden (SE Scale, 10%) (Table 2). Based on the HY stages, the mean UPDRS total score ranged from a low of 16.6 (6.6) for subjects with unilateral parkinsonism (stage 1) to a high of 90.2 (25.0) for subjects assessed as wheelchair bound or bedridden (stage 5) (Table 3). Regression analysis showed the average change on the UPDRS total score to be 8.6 points for a 10% change on the SE Scale and 17.8 points for a 1-stage change on the HY stage. On the SF-12, 1 unit on the PH summary score was equivalent to a change of 0.85 points on the UPDRS total score, and 1 unit on the MH summary score was 0.91 points on the UPDRS total score. Therefore, a change of 1 SD (defined as 10 units) was 8.5 (PH) or 9.1 points (MH) on the UPDRS total score, and half of an SD was equivalent to 4.2 or 4.5 points, respectively (Table 4). The distribution-based analysis showed that the minimal CID was 4.1 points, the moderate CID was 10.3 points, and the large CID was 16.4 points on the UPDRS total score (Table 4). Based on a combination of the anchor- and distribution-based analyses, a change of 4.3 points is an appropriate estimate for the minimal CID, 9.1 points for the moderate CID, and 17.1 points for the large CID on the UPDRS total score (Table 4).

COMMENT

Concordance across a combination of distribution- and anchor-based approaches for analysis of the CID demonstrates that the moderate CID for the UPDRS motor score is approximately 5 points and for the UPDRS total score it is 9 points. Variability across sample populations and clinical settings suggests that a range of CID values is likely to be more useful than a single estimate.18,23 This study describes a range from minimal to moderate to large CID, corresponding to about 2.5, 5, and 11 points for the UPDRS motor score and 4.5, 9, and 17 points for the UPDRS total score.

The minimal clinically important change on the UPDRS was previously studied in a sample of individuals with early PD who participated in 2 clinical trials of dopamine agonist monotherapy.9 An anchor-based analysis using the Clinical Global Impression of Improvement found that the minimal clinically important change was 5 points on the UPDRS motor score and 8 points on the UPDRS total score.9 Our results show that the minimal CID was smaller: 2.5 points on the UPDRS motor score and 4.5 points on the UPDRS total score. Because the CID may vary at different stages of disease, this discrepancy may indicate that the CID is larger in earlier PD. Samsa et al7 questioned whether the initial decrement from perfect health to early symptoms may be more meaningful than the impact of similar decrements in the middle part of the scale. The discrepancies in the results between the present and earlier studies underscore the importance of replicating these analyses in different sample populations and in longitudinal studies. There were several differences between these 2 studies, including stage of disease, the anchor chosen, and the clinical setting (naturalistic vs clinical trial).

The presence of a larger CID in early PD is not supported by our analysis of UPDRS ratings by 10% decrements on the SE Scale (Table 2). If this were the case, one would anticipate larger increments in the UPDRS ratings between SE levels associated with earlier disability. However, the largest increment in the UPDRS motor score was associated with the change in SE Scale ratings from 30% to 20% in advanced PD, corresponding to the change in SE responses from “With effort, now and then does a few chores alone. . . . Much help needed” to “Nothing alone. Can be a slight help. . . . Severe invalid.” These larger UPDRS score increments associated with selected levels of 10% change on the SE Scale may simply identify SE Scale cut points that signal clinical distinctions more clearly. A single aberration is seen between SE Scale scores of 60% and 50%, where the UPDRS motor score goes down rather than up. The reason is unclear and requires further investigation.

Clinical trials in PD have applied arbitrary definitions of responders such as improvement of 20%, 30%, 3 points, and 5 points on the UPDRS motor scale.3134 Three to 5 points on the UPDRS motor scale is precisely the minimal to moderate CID range in this analysis.

Establishing the CID for a measure is particularly meaningful when this magnitude of improvement can be realistically achieved. In fact, the CID results in this study are consistent with effect sizes on the UPDRS found in recent clinical trials (Table 5). For example, in the Earlier vs Later Levodopa Therapy in Parkinson Disease study,43 in which 3 dosages of levodopa were studied (150, 300, and 600 mg/d), the change in UPDRS total score was 5.9 points for the low and moderate doses and 9.2 for the highest dose, corresponding to the minimal to moderate CID in this study. However, UPDRS score changes of 1 to 2 points for selegiline hydrochloride35 and rasagiline mesylate42 were below the minimal CID. Although the effect sizes in different trials described in Table 5 are not comparable owing to differences in study duration and variable adjustment for placebo, the range of effect sizes (1.1-8.4 for the UPDRS motor score and 1.8-9.2 for the UPDRS total score) are in the range of the CIDs found in this study.

This study relied on a combination of patient-reported (SF-12) and clinician-reported (SE Scale and HY stage) assessments. Similarly, the UPDRS has elements of patient and clinician assessment, with subscales I (mentation, behavior, and mood) and II (activities of daily living) based on patient responses by history and subscale III (motor examination) based on clinical observation. The CID analysis was initially developed as a tool for patient-reported outcomes, particularly quality-of-life measures,7 and more recently has been applied to a greater diversity of measures, including physical performance measures.25,45

Clinically important differences may vary across diseases, ethnicity, and socioeconomic status. Therefore, these findings may not be applicable to patients who are nonwhite, have lower socioeconomic status, or have other forms of parkinsonism. The CID in a cross-sectional sample is conceptually distinct from CID analysis in a longitudinal sample, although cross-sectional and longitudinal analyses have yielded similar results in previous studies.7 The predetermined estimates of minimal, moderate, and large CID for each of 3 anchors may be subject to criticism as inaccurate representations of a clinically meaningful difference in PD. However, the results compare favorably with the calculated values of CID based on accepted standard effect sizes21 in the distribution-based analysis, and the ranges of computed values of CID based on each of the methods were in close agreement.

The minimum CID was originally defined as “the smallest difference in score in the domain of interest which patients perceive as beneficial and which would mandate, in the absence of troublesome side effects and excessive cost, a change in the patient's management.”1 The role of a CID in clinical decision making is highlighted in this definition, although there is controversy about whether the CID is more applicable to the interpretation of group or individual differences.8,10,18,46 Indeed, assessing the risk to benefit ratio may be more straightforward on the individual level, where the treatment response may need to be especially robust to compensate for troublesome adverse effects or financial limitations. A range of CID values as demonstrated in this study (minimal, moderate, and large) may help meet the needs of individual and group variability. For example, the use of the moderate to large CID range may be more suitable for interpreting change on the individual level, whereas the low end of the range (minimal to moderate) may be preferable when interpreting group differences.18

Establishing CID estimates for common outcome measures such as the UPDRS will not only influence patient management and clinical trials but also influence decision making by government and industry. Clinically important differences are a tool to aid clinicians in translating the results of statistically significant differences in large clinical trials to their individual patients. From a broader perspective, CIDs can facilitate the calculation of sample sizes in trials and may serve as a benchmark for interpreting treatment effects. This study shows that concordance of estimates of the CID on the UPDRS score can be achieved using multiple approaches of analysis and a large PD sample. Changes of 2.5 to 5.2 points on the UPDRS motor score and 4.5 to 9.1 points on the UPDRS total score represent clinically meaningful differences based on a combination of objective and subjective analyses and should be used to assess therapeutic interventions in PD.

Back to top
Article Information

Correspondence: Lisa M. Shulman, MD, Department of Neurology, University of Maryland School of Medicine, 110 S Paca St, Room 3-S-127, Baltimore, MD 21201 (lshulman@som.umaryland.edu).

Accepted for Publication: August 11, 2009.

Author Contributions:Study concept and design: Shulman, Gruber-Baldini, and Anderson. Acquisition of data: Shulman, Anderson, Fishman, Reich, and Weiner. Analysis and interpretation of data: Shulman, Gruber-Baldini, and Anderson. Drafting of the manuscript: Shulman, Gruber-Baldini, and Weiner. Critical revision of the manuscript for important intellectual content: Shulman, Gruber-Baldini, Anderson, Fishman, Reich, and Weiner. Statistical analysis: Gruber-Baldini. Obtained funding: Shulman and Weiner. Administrative, technical, and material support: Shulman, Fishman, and Weiner. Study supervision: Shulman, Anderson, and Weiner.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the Rosalyn Newman Foundation.

Previous Presentation: This study was a platform presentation at the American Academy of Neurology Annual Meeting; May 1, 2007; Boston, Massachusetts.

References
1.
Jaeschke  RSinger  JGuyatt  GH Measurement of health status: ascertaining the minimal clinically important difference. Control Clin Trials 1989;10 (4) 407- 415
PubMedArticle
2.
Barrett  BBrown  DMundt  MBrown  R Sufficiently important difference: expanding the framework of clinical significance. Med Decis Making 2005;25 (3) 250- 261
PubMedArticle
3.
Caplan  LR How well does “evidence-based” medicine help neurologists care for individual patients? Rev Neurol Dis 2007;4 (2) 75- 84
PubMed
4.
Fahn  SElton  RLMembers of the UPDRS Development Committee, Unified Parkinson's Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent Developments in Parkinson's Disease., Vol 2. Florham Park, NJ Macmillan Health Care Information1987;153- 164
5.
Movement Disorder Society Task Force on Rating Scales for Parkinson's Disease, The Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. Mov Disord 2003;18 (7) 738- 750
PubMedArticle
6.
Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.  Rockville, MD US Dept of Health and Human Services2006;
7.
Samsa  GEdelman  DRothman  MLWilliams  GRLipscomb  JMatchar  D Determining clinically important differences in health status measures: a general approach with illustration to the Health Utilities Index Mark II. Pharmacoeconomics 1999;15 (2) 141- 155
PubMedArticle
8.
Norman  GRSridhar  FGGuyatt  GHWalter  SD Relation of distribution- and anchor-based approaches in interpretation of changes in health-related quality of life. Med Care 2001;39 (10) 1039- 1047
PubMedArticle
9.
Schrag  ASampaio  CCounsell  NPoewe  W Minimal clinically important change on the Unified Parkinson's Disease Rating Scale. Mov Disord 2006;21 (8) 1200- 1207
PubMedArticle
10.
Copay  AGSubach  BRGlassman  SDPolly  DW  JrSchuler  TC Understanding the minimum clinically important difference: a review of concepts and methods. Spine J 2007;7 (5) 541- 546
PubMedArticle
11.
Laine  CDavidoff  F Patient-centered medicine: a professional evolution. JAMA 1996;275 (2) 152- 156
PubMedArticle
12.
Hoehn  MMYahr  MD Parkinsonism: onset, progression, and mortality. Neurology 1967;17 (5) 427- 442
PubMedArticle
13.
Schwab  JFEngland  AC Projection technique for evaluating surgery in Parkinson's disease. In: Gillingham FJ, Donaldson MC, eds. Third Symposium on Parkinson's Disease., Edinburgh, Scotland E & S Livingston1969;152- 157
14.
Folstein  MFFolstein  SE McHugh  PR “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12 (3) 189- 198
PubMedArticle
15.
Ware  J  JrKosinski  MKeller  SD A 12-Item Short Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996;34 (3) 220- 233
PubMedArticle
16.
Sloan  JA Assessing the minimally clinically significant difference: scientific considerations, challenges and solutions. COPD 2005;2 (1) 57- 62
PubMedArticle
17.
Guyatt  GHOsoba  DWu  AWWyrwich  KWNorman  GRClinical Significance Consensus Meeting Group, Methods to explain the clinical significance of health status measures. Mayo Clin Proc 2002;77 (4) 371- 383
PubMedArticle
18.
Yost  KJCella  DChawla  A  et al.  Minimally important differences were estimated for the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) instrument using a combination of distribution- and anchor-based approaches. J Clin Epidemiol 2005;58 (12) 1241- 1251
PubMedArticle
19.
Revicki  DHays  RDCella  DSloan  S Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes. J Clin Epidemiol 2008;61 (2) 102- 109
PubMedArticle
20.
Redelmeier  DAGuyatt  GHGoldstein  RS Assessing the minimal important difference in symptoms: a comparison of two techniques. J Clin Epidemiol 1996;49 (11) 1215- 1219
PubMedArticle
21.
Cohen  J Statistical Power Analysis for the Behavioral Sciences.  Orlando, FL Academic Press Inc1977;
22.
W right  JGYoung  NL A comparison of different indices of responsiveness. J Clin Epidemiol 1997;50 (3) 239- 246
PubMedArticle
23.
Hays  RDWoolley  JM The concept of clinically meaningful difference in health-related quality-of-life research: how meaningful is it? Pharmacoeconomics 2000;18 (5) 419- 423
PubMedArticle
24.
Norman  GRSloan  JAWyrwich  KW Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care 2003;41 (5) 582- 592
PubMed
25.
Hawkes  WGWilliams  GRZimmerman  S  et al.  A clinically meaningful difference was generated for a performance measure of recovery from hip fracture. J Clin Epidemiol 2004;57 (10) 1019- 1024
PubMedArticle
26.
Luo  NTan  LZhao  YLau  PNAu  WLLi  SC Determination of the longitudinal validity and minimally important difference of the 8-item Parkinson's Disease Questionnaire (PDQ-8). Mov Disord 2009;24 (2) 183- 187
PubMedArticle
27.
Stewart  ALGreenfield  SHays  RD  et al.  Functional status and well-being of patients with chronic conditions: results from the medical outcomes study. JAMA 1989;262 (7) 907- 913
PubMedArticle
28.
Wiebe  SMatijevic  SEliasziw  MDerry  PA Clinically important change in quality of life in epilepsy. J Neurol Neurosurg Psychiatry 2002;73 (2) 116- 120
PubMedArticle
29.
Bjorner  JBWallenstein  GVMartin  MC  et al.  Interpreting score differences in the SF-36 vitality scale: using clinical conditions and functional outcomes to define the minimally important difference. Curr Med Res Opin 2007;23 (4) 731- 739
PubMedArticle
30.
Glassman  SDCopay  AGBerven  SHPolly  DWSubach  BRCarreon  LY Defining substantial clinical benefit following lumbar spine arthrodesis. J Bone Joint Surg Am 2008;90 (9) 1839- 1847
PubMedArticle
31.
Brunt  ERBrooks  DJKorczyn  ADMontastruc  JLStocchi  F043 Study Group, A six-month multicentre, double-blind, bromocriptine-controlled study of the safety and efficacy of ropinirole in the treatment of patients with Parkinson's disease not optimally controlled by L-dopa. J Neural Transm 2002;109 (4) 489- 502
PubMedArticle
32.
Korczyn  ADBrunt  ERLarsen  JPNagy  ZPoewe  WHRuggieri  S053 Study Group, A 3-year randomized trial of ropinirole and bromocriptine in early Parkinson's disease. Neurology 1999;53 (2) 364- 370
PubMedArticle
33.
Stern  MBMarek  KLFriedman  J  et al.  Double-blind, randomized, controlled trial of rasagiline as monotherapy in early Parkinson's disease patients. Mov Disord 2004;19 (8) 916- 923
PubMedArticle
34.
Parkinson Study Group, Safety and efficacy of pramipexole in early Parkinson disease: a randomized dose-ranging study. JAMA 1997;278 (2) 125- 130
PubMedArticle
35.
Parkinson Study Group, Effect of deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1989;321 (20) 1364- 1371
PubMedArticle
36.
Guttman  MInternational Pramipexole-Bromocriptine Study Group, Double-blind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson's disease. Neurology 1997;49 (4) 1060- 1065
PubMedArticle
37.
Shannon  KMBennett  JP  JrFriedman  JHThe Pramipexole Study Group, Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease. Neurology 1997;49 (3) 724- 728
PubMedArticle
38.
Rascol  OBrooks  DJBrunt  ERKorczyn  ADPoewe  WHStocchi  F056 Study Group, Ropinirole in the treatment of early Parkinson's disease: a 6-month interim report of a 5-year levodopa-controlled study. Mov Disord 1998;13 (1) 39- 45
PubMedArticle
39.
Sethi  KDO’Brien  CFHammerstad  JP  et al. Ropinirole Study Group, Ropinirole for the treatment of early Parkinson disease: a 12-month experience. Arch Neurol 1998;55 (9) 1211- 1216
PubMedArticle
40.
Parkinson Study Group, Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA 2000;284 (15) 1931- 1938
PubMedArticle
41.
Parkinson Study Group, A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol 2002;59 (12) 1937- 1943
PubMedArticle
42.
Parkinson Study Group, A controlled, randomized, delayed start study of rasagiline in early Parkinson's disease. Arch Neurol 2004;61 (4) 561- 566
PubMedArticle
43.
Fahn  SOakes  DShoulson  I  et al. Parkinson Study Group, Levodopa and the progression of Parkinson's disease. N Engl J Med 2004;351 (24) 2498- 2508
PubMedArticle
44.
Parkinson Study Group, A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005;62 (2) 241- 248
PubMedArticle
45.
Perera  SMody  SHWoodman  RCStudenski  SA Meaningful change and responsiveness in common physical performance measures in older adults. J Am Geriatr Soc 2006;54 (5) 743- 749
PubMedArticle
46.
Rascol  O Defining a minimal clinically relevant difference for the Unified Parkinson's Rating Scale: an important but still unmet need. Mov Disord 2006;21 (8) 1059- 1061
PubMedArticle
×