Outcomes Multisystemic Impact: Fibromyalgia

1
OutcomesMulti-systemic ImpactFibromyalgia

• George A Wells
• Department of Epidemiology and Community
  Medicine
  
• University of Ottawa

2
Fibromyalgia

• chronic musculoskeletal disorder characterized by
  widespread pain, exquisite tenderness at specific
  anatomic sites and other clinical manifestations
  such as fatigue, sleep disturbance and irritable
  bowel syndrome (Bradley and Alarcon)
• ACR 1990 criteria for classifying patients with
  fibromyalgia
  
• widespread pain for at least 3 months (pain in
  left and right sides of body pain above and
  below waist and axial skeletal pain)
  
• tenderness in at least 11 of 18 tender points

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Fibromyalgia

• Controversy
• medicalization of unrelated symptoms
• syndrome (occurring with other diseases)
• defined disorder
• Controversy
• What are the most appropriate outcome measures?

4
Outcome Measures

• Types of outcome measures (Fibromyalgia)
• Choosing outcomes
• Development and selection of outcomes
• Overall response criteria
• Minimal clinically important difference
• Low disease activity state

5
Outcome Measures

• Types of outcome measures (Fibromyalgia)
• Choosing outcomes
• Development and selection of outcomes
• Overall response criteria
• Minimal clinically important difference
• Low disease activity state

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Types of Outcome Measures(Fibromyalgia)

• Karjalainen K, et al
• Multidisciplinary rehabilitation for
  fibromyalgia and musculoskeletal pain in working
  age adults
  
• Cochrane Collaboration Review 2003
• Busch A, et al
• Exercise for treating fibromyalgia syndrome
• Cochrane Collaboration Review 2002
• Rossy LA, et al
• A meta-analysis of fibromyalgia treatment
  interventions
  
• Ann Behav Med. 1999

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Types of Outcome Measures

• Constructs
• Pain
• Tender points
• Physical function
• Global well being or perceived improvement
• Self efficacy
• Fatigue and sleep
• Psychological function
• Quality of life

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Types of Outcome Measures

• Pain
• visual analogue scale
• ordinal scale
• pain drawings
• Regional Pain Scale (RPS)
• (Wolfe, J Rheumatol 2003)

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Types of Outcome Measures

• Tender points
• pain threshold of tender points using
  dolorimetry
  
• tenderness to thumb pressure

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Types of Outcome Measures

• Physical function
• Self-reported physical function
• FIQ Physical Impairment subscale
• FHAQ
• Musculoskeletal performance
• grip strength
• hip and knee extension strength
• sit and reach test
• Cardiorespiratory fitness
• submaximal or maximal treadmill or cycle
  ergometer tests
  
• 6 minute walk

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Types of Outcome Measures

• Global well being or perceived improvement
• physician rated change
• FIQ total score

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Types of Outcome Measures

• Self efficacy
• Arthritis Self-efficacy Questionnaire

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Types of Outcome Measures

• Fatigue and sleep
• FIQ fatigue subscale
• sleep VAS

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Types of Outcome Measures

• Psychological function
• FIQ subscales for depression and anxiety

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Types of Outcome Measures

• Quality of life / Generic Functional Status
• Short Form 36 (SF36)
• Sickness Impact Profile (SIP)
• Health Assessment Questionnaire (HAQ)

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Fibromyalgia Impact Questionnaire (FIQ)

• brief 10-item self-administered instrument
• measures
• physical functioning
• work status
• depression
• anxiety
• sleep
• pain
• stiffness
• fatigue
• well-being
• (Burckhardt, Clark, Bennett, J Rheumatol 1991)

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• Were you able to
• a. Do shopping
• b. Do laundry with a washer and dryer
• c. Prepare meals
• d. Wash dishes/cooking utensils by hand
• e. Vacuum a rug
• f. Make beds
• g. Walk several blocks
• h. Visit friends/relatives
• I. Do yard work
• j. Drive a car
• 0 Always 1 Most times 2 Occasionally 3 Never

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• Of the days in the past week, how many days did
  you feel good?
  
• 1 2 3 4 5 6 7
• How many days in the past week did you miss work
  because of your fibromyalgia? 1 2 3 4
  5
  
• When you did go to work, how much did pain or
  other symptoms of your fibromyalgia interfere
  with your ability to do your job?
  
• How bad has your pain been?
• How tired have you been?
• How have you felt when you got up in the
  morning?
  
• How bad has your stiffness been?
• How tense, nervous or anxious have you felt?
• How depressed or blue have you been?
• Questions 4 10 assessed using a VAS

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Fibromyalgia Health Assessment Questionnaire
(FHAQ)

• Are you able to (over the past week)
• a. bending
• b. dressing
• c. wash body
• d. getting in and out of car
• e. vacuum
• f. stand up from chair
• g. reach overhead
• h. run errands
• 0 Without any difficulty 1 With some
  difficulty
  
• 2 With much difficulty 3 Unable to do
• (Wolfe et al, J Rheumatol, 2000)

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Outcome Measures

• Types of outcome measures (Fibromyalgia)
• Choosing outcomes
• Development and selection of outcomes
• Overall response criteria
• Minimal clinically important difference
• Low disease activity state

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Choosing Outcomes

• objective measurements (validated and accepted to
  represent appropriate efficacy criteria)
  
• reduced or reversed disease progression
• improved quality of life
• reduced mortality
• clinical global impression (physician, patient)
• improved symptomatology of patient
• biochemical measures (assessing underlying
  disease state)

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Patients desire the following

• 1) to live as long as possible death
• 2) to be normally functioning
  disability
  
• 3) to be free of pain, psychological,
• physical, social and other
• symptoms discomfort
• 4) to be free of iatrogenic
• problems from treatments drug s/e
• 5) to remain solvent destitution

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Identifying the best outcomes

• influence physicians decision
• combination of outcomes thats most practical and
  useful
  
• hard measurement
• change in endpoint that would be clinically
  significant

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Identifying the best outcomes influence
physicians decision

• Outcome measurement procedures in routine
  rheumatology outpatient practice in Canada /
  Australia
  
• How often do you serially use the following
  assessment techniques for longitudinally
  monitoring the efficacy of antirheumatic drug
  therapy in your adult fibromyalgia outpatient
  practice?

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Identifying the best outcomes influence
physicians decision

• Never Occasionally Usually
  Always
  
• Canada
• Quality of sleep 11 11 28
  50
  
• Fatigue 13 13 29 45
• No. tender points 17 15 29
  39
  
• Skinfold tenderness 47 25 19
  9
  
• Australia
• Quality of sleep 18 8 42
  32
  
• Fatigue 21 14 43 23
• No. tender points 38 22 30
  10
  
• (Bellamy J Rheumatol 1998, 1999)

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Outcome Measures

• Types of outcome measures (Fibromyalgia)
• Choosing outcomes
• Development and selection of outcomes
• Overall response criteria
• Minimal clinically important difference
• Low disease activity state

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Criteria for Development and Selection of Outcomes

• Comprehensive (content validity)
• - includes appropriate components of health
• Credibility (face validity)
• - appears sensible and interpretable
• Accuracy (criterion validity)
• - consistently reflects true clinical status of
  patients
  
• Sensitivity to change (discriminant validity)
• - detects smallest clinically important
  difference
  
• Biological sense (construct validity)
• - matches hypothesized expectations when
  compared with other indirect measures

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Health Measurement

• Reliability
• Validity
• Sensitivity to Change

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Reliability

• Reflection of the amount of error, both random
  (mechanical inaccuracy, measurement mistakes) and
  systematic, inherent to any measurement
  
• Determines how reproducible is the scale under
  different conditions
  

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Reliability
The reliability coefficient expresses the
proportion of the total variance in the
measurements (denominator), which is due to true
differences between subjects (numerator)
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Reliability

• Reproducibility
• Test-retest reliability
• Intra-rater reliability
• Inter-rater reliability
• Internal consistency of a scale (correlation
  among items composing an instrument)
  

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Reliability Reproducibility

• Intra-class correlation (ICC)
• (based on ANOVA)
• Pearsons r
• Kendalls index of concordance
• Kappa coefficient
• Bland and Altman

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Reliability Reproducibility

• Other considerations
• Observations as fixed factor
• test always done by same observers
• same items completed by all
• Observations as random factor
• observer varies

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Reliability Reproducibility

• Other considerations (contd)
• Observer nested within subject
• several subjects evaluated by several observers
• no observer common to more than one subjects
• One-way ANOVA
• subject as grouping factor
• multiple observations within each cell as
  within-subject factor

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Reliability Reproducibility

• Other considerations (contd)
• multiple observations k
• multiple items on questionnaire
• multiple observers
• repeated use of an instrument

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Reliability Internal Consistency

• Represents the average of the correlations among
  all items in the measure
  
• All the items should be tapping different
  aspects of the same attribute
  
• items should be moderately correlate with each
  other
  
• each should correlate with the total scale score

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Reliability Internal Consistency

• Item-total correlation
• checks homogeneity of scale
• correlation of individual item with scale score
  omitting that item
  
• Pearson correlation (working rule 0.2)
• Split-half reliability
• splits scale in half, each half is correlated
  with the other
  
• Spearman-Brown
• Kuder-Richardson 20
• scales with dichotomous items
• Cronbachs aplha
• scales with ordinal items
• should be 0.70 but

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Reliability Improving IT

• Reduce error variance
• observer training
• elimination of extreme observers
• improve scale design
• Increase true variance
• introduce items resulting in performance nearer
  middle of scale
  
• modify descriptors on the scale
• Increase number of items
• as long as items not perfectly correlated

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Validity

• Determine the degree of confidence we can place
  on inferences made based on the scores from the
  scale

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Validity

• Content
• cover all domains of interest
• sufficient number of items
• inferred from experts
• Criterion
• test against a gold standard
• Concurrent
• gold standard and the new instrument are applied
  at the same time
  
• Predictive
• gold standard is applied in the future

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Validity

• Construct
• if no gold standard exists
• based on conceptual definition of construct to be
  measured
  
• defines hypotheses of what should or should not
  correlate
  
• Correlational
• Convergent
• instrument tested should correlate with other
  methods that measure same concept
  
• Divergent
• instrument should not correlate with other
  methods that measure different themes
  

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Validity

• Construct (contd)
• Factorial analysis
• examines how items measure one or more common
  themes
  
• analysis forms the questions into groups or
  factors that appear to measure common themes with
  each factor distinct from the others
  
• Multi-trait multi-method analysis
• method for considering convergent and
  discriminant validity simultaneously
  

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Validity

• Evaluation using
• Correlations
• Receiver operator characteristic (ROC) curves
• 2x2 tables (sensitivity and specificity)

44
Sensitivity to Change

• Ability of an instrument to detect small but
  clinically important clinical
  
• Particularly important where subjective reports
  of health status is one of the primary outcomes
  of the trial

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Sensitivity to Change

• t-test
• compares means at baseline and follow-up
• Effect-size
• relates changes in mean score (from baseline to
  follow-up) to the standard deviation of baseline
  score
  
• ROC Curve
• Evaluate how a given change score can
  discriminate between patients who improve from
  those who do not
  

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FIQ

• (Burckhardt et al, J Rheumatol 1991)
• evidence of reliability and validity
• Reliability
• test-retest reliability correlations for FIQ
  items ranged from 0.56 to 0.95
  
• Content validity
• assessed by calculating percent missing data
  11 washing by hand item, 20 yard work item,
  38 job working items
  
• Construct validity
• (1) correlational analysis comparing FIQ
  items/scales to corresponding ones of AIMS
  physical functioning item 0.67 pain 0.69
  depression 0.73 anxiety 0.76
• (2) correlational analysis comparing FIQ items
  with measures of symptom severity AIMS impact
  analog (0.17 to 0.48), AIMS syndrome activity
  (0.28 to 0.83) and tender points (0.14 to 0.74)
• (3) factor analysis to determine if items of
  physical functioning loaded on single factor (eg.
  10 items of FIQ loaded on same factor)

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FIQ

• (Dunkl et al, J Rheumatol 2000)
• responsive to perceived clinical improvement
• Sensitivity to Change
• Patient Global
• Improvement FIQ mean (sd)
• Improved 34.11 (17.48)
• Unchanged 46.92 (15.44)
• Worsened 57.92 (15.23)
• (Wolfe et al, J Rheumatol 2000)
• FIQ systematically underestimates functional
  impairment by its handling of activities not
  usually performed

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6 Minute Walk (6-MWT)

• (Pankoff et al, J Rheumatol 2000)
• not a valid predictor of cardiorespiratory
  fitness sensitive to change related to FIQ
  score
  
• Sensitivity to Change
• Before After
• Exercise Exercise p-value
• 6-MWT, m 487 (75) 565 (58)
• PVO2, ml/kg/min 19.6 (4.5) 21.4 (4.8) 0.001
• FIQ Total 47.9 (12.1) 38.0 (12.9) 0.012
• FIQ Phys 3.1 (1.7) 2.3 (1.9) 0.0.62
• Validity
• Correlation of change scores 6-MWT, PVO2
  (r0.081)
  
• 6-MWT, FIQ Total (r0.592)
• 6-MWT, FIQ Phys (r0.245)

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Generic versus Specific

• The use of generic and specific quality of life
  measures in fibromyalgia patients (Wolfe et al, J
  Rheumatol 2000)
  
• Instruments
• Generic SF-36, HAQ, MHAQ, IHAQ
• Specific FIQ, FHAQ
• Methods
• FM patient (FIQ Boston 1928, San Antonio 233, US
  multicenter 333, Beer Sheva 100 HAQ National
  Data Bank for Rheumatic Diseases 1438 SF-36
  Wichita 760)
• Rasch analysis (based on item response theory)
• Results
• no functional assessment questionnaire works
  well
  
• FIQ underestimates functional impairment by
  handling activities not usually performed
  
• developed FHAQ (subset of HAQ) with appropriate
  metric properties and should function well need
  to assess sensitivity to change
  

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Outcome Measures

• Types of outcome measures (Fibromyalgia)
• Choosing outcomes
• Development and selection of outcomes
• Overall response criteria
• Minimal clinically important difference
• Low disease activity state

51
Improvement Criteria

• Core set of outcome measures
• reliable, valid, sensitive to change
• consider in combination (patient profiles)
• Conduct survey of clinicians providing
  information on randomly selected patients from
  clinical trials near thresholds of improvement
  
• for outcome measures, data at baseline, end of
  study and percentage change provided for each
  patient
  
• surveyed clinicians indicated whether each
  patient improved
  
• analysis focused on patients characterized
  improved by vast majority of surveyed
  clinicians
  

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Improvement Criteria

• Statistical analysis of clinical trial data for
  selecting definition of improvement
  
• data sets assembled of appropriate placebo
  controlled trials with very efficacious
  interventions and included outcome measures
  
• improvement criteria selected that best
  discriminates an efficacious intervention from
  placebo
  
• Evaluate definition of improvement in large
  comparative trials
  
• Improvement definition selected based on ease of
  use and credibility
  
• with experienced trialists ranking face validity

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Preliminary Criteria for Response to Treatment in
Fibromyalgia

• (Simms et al, J Rheumatol 1991)
• Methods
• clinical trial of amitriptyline vs placebo for
  treating fibromyalgia (amitriptyline was found to
  be significantly more efficacious)
  
• proxy response treatment with effective
  medication (amitripyline)
  
• outcome measures available physician global,
  patient global, pain, fatigue, sleep, tender
  point score
  
• used logistic regression(s) to determine
  predictors of response
  
• considered combinations of outcome measures and
  plotted ROC curves to determine criteria with
  optimal sensitivity / specificity
  
• applied criteria to unreported trial
  (cyclobenzaprine vs placebo)
  

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Preliminary Criteria for Response to Treatment in
Fibromyalgia

• Criteria
• (1) physician global assessment score
• (0 extremely well, 10 extremely poorly)
• (2) patient sleep
• (0 sleeping extremely well, 10 sleeping
  extremely poorly)
  
• (3) tender point score
• (maximum possible 20)
• Future Work
• as sensitive and clinically relevant outcomes
  are developed, can apply this methodology to
  refine criteria
  

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Outcome Measures

• Types of outcome measures (Fibromyalgia)
• Choosing outcomes
• Development and selection of outcomes
• Overall response criteria
• Minimal clinically important difference
• Low disease activity state

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Two Steps

• Studies of Responsiveness
• A classification system (Beaton, Bombardier et
  al, J Rheumatol 2003)
  
• Minimal Clinically Important Differences
• A review of methods (Wells, Tugwell et al, J
  Rheumatol 2003)
  

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Studies of Responsiveness

• clinical studies are often aimed at
  discriminating between groups of interest
  
• differences are often change over time (eg.
  response to therapy)
  
• change (within-patient change over time)
• differences (between patients)
• hybrid (between group differences of
  within-patient change)
  
• studies of responsiveness evaluate the ability of
  an outcome measure to accurately detect change
  when it has occurred

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Construct of change in studies of responsiveness

• Each study defines the change/difference it is
  examining
  
• Defined by three key features (axes)
• Setting individual versus group-level?
• Which data is being compared?
• What kind of change is being quantified?

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Key features addressed in defining
change/difference
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Key features addressed in defining
change/difference
61
Key features addressed in defining
change/difference
Minimum potentially detectable
Observed in those estimated to have an important
difference/ change
Observed in those estimated to differ/ to have
changed
Observed in population
Minimum actually detectable beyond error
62

• These 3 features are mutually independent and fit
  together into a cube with each cell describing
  the construct of change built into the study
  of responsiveness
• The cube becomes a classification system,
  classifying the nature of discrimination (either
  differences of changes) built into studies of
  responsiveness

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Classification of discrimination (differences
and changes) in studies
3. both differences between changes within
2. changes within
Which?
1. differences between
2. - individual
Setting Who is the focus?
1. - group
1. 2. 3.
4. 5.
Minimum potentially detectable
Observed in those estimated to have an important
difference/ change
Observed in those estimated to differ/ to have
changed
Observed in population
Minimum actually detectable beyond error
What kind of change/difference
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Summary

• Responsiveness studies look at varying kinds of
  change/difference
  
• Some will be helpful in pursuit of MCID
• Cube of discrimination helps to sort through
  the literature
  
• Point to those articles that might be useful
• Separates out those that will not help

65
Two Steps

• Studies of Responsiveness
• A classification system (Beaton, Bombardier et
  al, J Rheumatol 2003)
  
• Minimal Clinically Important Differences
• A review of methods (Wells, Tugwell et al, J
  Rheumatol 2003)
  

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• MCID
• a MCID can be considered as the smallest change
  or difference in an outcome measure that is
  perceived as beneficial and would lead to a
  change in the patients management, assuming an
  absence of excessive side effects and costs
• Purpose
• to consider and classify the different methods
  that have been used in detecting important
  changes or differences for the purposes of
  developing the MCID or an outcome measure
• Method
• extensive literature search to retrieve all
  relevant articles related to specific topics on
  MCID
  
• methods section of the retrieved articles was
  reviewed
  
• methodology followed was used to categorize study
  according to the cube classification

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Methods for Determining Minimal Clinically
Important Differences
Which?
Patient Perspective
3. both differences between changes within
Clinical Perspective

• 1. Comparison to global rating
• Patients global ratings
• Clinical assessments
• Change scale MCID small change

• 2. Patient conversation
• Patients comparative ratings
• Clinical assessments
• Comparative ratings MCID small change

• 3. Consensus Development
• Clinicians examine statistics
• Compare groups
• MCID hypothetical RCT

• 4. Patient scenario scoring
• Clinicians suggest change
• Average response
• Assess change using options MCID chosen option
  vs initial

• 5. Patient scenario comparison
• Clinicians contrast scenarios
• Average assessment
• Assess change using option. MCID small change

• 6. Prognostic rating scale
• Clinicians describe changes
• ROC analysis
• Prognostic rating

• 7. Data driven
• SEM
• Longitudinal change score
• SEM proxy for MCID

• 8. Improvement criteria
• Survey clinicians
• Patients near improvement threshold
• Improved if indicated by vast majority RCT data

• 9. Achieving treatment goals
• Patients followed
• Best improvement cut-point
• Treatment goals achieved ROC analysis

2. changes within
Clinician Perspective
1. differences between
Individual
Group
Minimum potentially detectable
Observed in those estimated to differ/ to have
changed
Observed in population
Minimum actually detectable beyond error
Setting
Observed in those estimated to have an important
difference/ change
Discerning important improvement
Type of Change/Difference
68
Methods for Determining Minimal Clinically
Important Differences
Which?
Patient Perspective
3. both differences between changes within
Clinical Perspective
2. changes within
Clinician Perspective
1. differences between
Individual
Group
Minimum potentially detectable
Observed in those estimated to differ/ to have
changed
Observed in population
Minimum actually detectable beyond error
Setting
Observed in those estimated to have an important
difference/ change
Discerning important improvement
Type of Change/Difference
69
Summary

• most methods consider important change form the
  viewpoint of a group of patients
  
• contrast of groups considered from all
  perspectives
  
• for setting, only a few methods considered within
  individuals
  
• need more development of methods that focus on
  individuals

70
Outcome Measures

• Types of outcome measures (Fibromyalgia)
• Choosing outcomes
• Development and selection of outcomes
• Overall response criteria
• Minimal clinically important difference
• Low disease activity state

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Low Disease Activity State Workshop

• Objectives of workshop
• to meet the many challenges that exist in
  determining a low disease activity state by
  reviewing the concepts and terminologies
  associated with a low disease activity state and
  determining the processes for developing an
  operational definition of low disease activity
  state
• working definition for low disease activity
  state
  
• a state that is deemed a useful treatment
  target by patients and physicians
  

72
Research Agenda Overview

• Review and obtain consensus on the specific
  outcomes that should be considered in the
  definition of low disease activity state for RA
  
• Design and conduct an assessment of evaluating
  the outcomes sleep and energy /fatigue using
  valid and reliability measuring instruments
  
• Design and conduct an opinion-based and
  observation-based approach for the determining a
  low disease activity state for RA
  
• Design and conduct a study to compare the
  attributes of a weighted, unweighted and tree
  approach for formulating a low disease activity
  state for RA

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Next Steps

• To come to a concrete definition
• opinions of physicians and patients will be
  collected
  
• based on these opinions, candidate definitions
  will be composed and tested in datasets
  
• results of this work will be collated and
  circulated prior to the workshop
  
• at the workshop, discussions will continue in
  plenary and small group sessions to resolve
  remaining issues, and come up with one or a
  limited number of top candidates that can then
  be validated

74
George A. Wells Department of Epidemiology a
nd Community Medicine University of Ottawa Ott
awa, Ontario, Canada e-mail gwells.uottawa.c
a