Myasthenia gravis - University of Rochester Medical Center

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Construction and validation of the
MG Composite and MG-QOL15
Ted M. Burns, MD
University of Virginia, Neurology
Harrison Distinguished Professor and Vice Chair
Disclosures: MGFA, CSL Behring, Alexion
Outline
1.
2.
MG Composite
 User-friendly, disease-specific scale
that measures direct manifestations
MG-QOL15
 User-friendly, disease-specific scale
that measures HRQOL
Construction of MGC
1.
2.
Evaluated item performance of 3 scales in 3 cohorts
Considered functional domain representation
QMG
13 items
MMT
30 items
ADL
8 items
Clinical data from:
1.
MSG trial of MMF in MG: 80 pts; ~dozen centers
2.
Aspreva trial of MMF in MG: 176 pts; 43 centers
3.
UVA database: > 160 pts
Hybrid = exam + history
Patient-reported + physician-reported =
makes good sense for MG
1.
manifestations fluctuate

2.
manifestations evident to the patient
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3.
Often missed on “snapshot” examination (4pm vs. 9am?)
Diplopia, dysarthria, dysphagia, etc
Many manifestations more evident to
the patient

Dysphagia, chewing weakness
Normal
Mild
Moderate
Of the same
importance??
Severe
Next step: weighting
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University of Virginia – Ted Burns and Larry Phillips  Leiden University – Jan Verschuuren
Duke University – Don Sanders and Vern Juel
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University of Wuerzburg – Klaus Toyka
Indiana University – Bob Pascuzzi
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University of Alberta – Zaeem Siddiqi
Kansas University – Rick Barohn
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Hopital Raymond Poincare, France – Tarek Sharshar
Brigham and Women’s – Tony Amato and Steve
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Karonlinska Institute – Ritva Pirskanen-Matell
Greenberg
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Catholic University, Rome – Luca Padua
West Virginia University – Laurie Gutmann
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University Western Ontario – Mike Nicolle
University of North Carolina – James Howard
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Carlo Besta, Milan – Renato Mantegazza and Carlo
University of Texas, San Antonio – Carlayne Jackson
Antozzi
University of Texas, Southwestern – Gil Wolfe
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University Tubingen – Arthur Melms
University of Illinois at Chicago – Matt Meriggioli
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University Autonoma Barcelona – Isabella Illa
St. Louis University – Henry Kaminski
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Radcliffe Hospital, Oxford – David Hilton-Jones
Ohio State University – John Kissel
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Walton Centre, Liverpool – Ian Hart
University of California Irvine – Tahseen Mozaffar
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Institute Neurological Sciences, Glasgow – Maria Farrugia
University of California Davis – David Richman
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Hadassah-Hebrew, Jerusalem – Zohar Argov
Pittsburgh University – David Lacomis
US, Canada, UK, Netherlands, Germany,
University of Alabama Birmingham – Shin Oh
Yale University – Jonathan Goldstein
France, Sweden, Italy, Spain, Israel
Mayo Jacksonville – Devon Rubin
“Consider QOL, health risk, prognosis, estimated
item validity and reliability and any other
factors you think are important.”
2008 – 2009: validation of MGC
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Validation study:
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11 centers
Consecutive patients
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Outpt and/or inpt
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2 visits per pt
Baseline characteristics
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Age/duration:
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mean – 58 years
duration – 7 years
Serology
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AchR (+) – 78%
MusK (+) – 7%
At least one negative – 10%
Unknown – 5%
Current MGFA Class
Frequency
Percent
0
27
15.34
1
39
22.16
2a
38
21.59
2b
33
18.75
3a
21
11.93
3b
13
7.39
4b
5
2.84
176
100%
Total
ADL
QOL
MMT
MGFA
Is the MGC responsive to change?
We chose physician impression + MG-QOL15 change agreement as “gold
standard” to indicate clinical improvement
AUC of 0.94 = “highly accurate”
McDowell, “Measuring Health”, 2006
Physician + MG-QOL15 change
MGC score cut-off = 3 points
1.
2.
3.
Good sensitivity and specificity
Test-retest reliability results (38 patients)
 Test-retest reliability coefficient was
98%
 Within 3 points 95% of time
“Meaningfulness” of 3-point
improvement in MGC (next slide)
Of patients whose MGC improved 3 points…
1. Mean MG-QOL15 improvement = 12 points
2. 39 of 42 MG-QOL scores improved or same
Validation of MG Composite
Neurology 2010;74:1434-1440.
Next Stop: “Muscle Study Group”
meeting at Beaver Hollow 2010
Reza Sadjadi
“You should do a Rasch analysis
on your MGC and MGQOL15.”
Reza Sadjadi
“By the way, I applied to your
residency program.”
Reza Sadjadi
1. “I have no idea
what Rasch is… I
guess I’ll think
about it.”
2. “We’ll be sure to
interview you for
residency.”
Rasch analysis
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Type of “item response theory”
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Focuses on the item, looking at relationships of
items to other items
Rasch assesses whether the data is any good (e.g.
the tool that creates the data is any good)
Uses of Rasch with scales: 1) to build; 2) to
evaluate
Sensitivity
Specificity
MGC
Reproducibility
Validity
Best cut-point
Scale
?
Scale
?
Rasch analysis of MGC - summary
1.
2.
3.
4.
Do all the items fit? Yes.
Can we sum the item scores? Yes.
Are the response categories (e.g. mild, moderate,
severe) in the proper order? Yes (except that
moderate and severe ptosis the same).
Are the response categories weighted
appropriately? (next slide)
4. Weights are appropriate
Item
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Eyelid strength
Eye gaze
Eye closure
Talking
Chewing
Swallowing
Breathing
Neck flex/ext
Shoulder abduction
Hip flexion
Consensus
Rasch
0, 1, 2, 3
0, 1, 3, 4
0, 0, 1, 2
0, 2, 4, 6
0, 2, 4, 6
0, 2, 5, 6
0, 2, 4, 9
0, 1, 3, 4
0, 2, 4, 5
0, 2, 4, 5
0.2, 1.3, 2.0, 2.9
0, 1.2, 2.0, 3.23
0, 0, 3.7, 6
0.9, 2.7, 4.0, 5.6
1, 1.7, 3.8, 5.2
1.1, 2.7, 3.8, 5.2
0.8, 2.9, 4.4, 5.8
0.6, 2.1, 3.4, 5.1
0.9, 2.5, 4.2, 6.6
0.7, 2.4, 4.2, 6.6
Post-script (Rasch of MGC)
1.
Published paper of MGC Rasch analysis
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2.
3.
Psychometric evaluation of the MG Composite
using Rasch analysis. Muscle Nerve 2012;45:820-825
Reza Sadjadi is a terrific PGY-2 Neurology
resident at UVA
I think Rasch is worth doing for other scales
(e.g. IBM-FRS, CMTNS-2, CIP-PRO20, etc)
MGC has been recommended by
an MSAB/MGFA “Task Force”
Benatar, M et al. Recommendations for
MG Clinical Trials. Muscle Nerve
2012;45;909-917.
Summary of MGC
1.
2.
3.
4.
5.
Items carefully selected
Validated
3-point change in MGC score appears to
be meaningful and reliable
Rasch analysis of MGC was favorable
MGC is simple and useful for clinical trials
and for everyday practice
Outline
1.
2.
MG Composite
 User-friendly, disease-specific scale
that measures direct manifestations
MG-QOL15
 User-friendly, disease-specific scale
that measures HRQOL
Preface: HRQOL are very subjective…
1.
2.
Strength: insight into the patient’s appraisal of
dysfunction and tolerability of dysfunction
Weaknesses: so many factors at play
1. “Antecedents”
2. Secondary gain issues
3. Response shift
 Changes in values, goals, expectations, etc.
brought on by the disease (or other life events),
changing familiarity with the course over time
…so keep it simple
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No “Rube Goldberg”
machines
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Make it user-friendly
MG QOL scale (2007 – 2008)
60
15
questions
questions
Looked at data from:
1.) MSG MMF study
2.) UVA database
Performance of all 60 items
1) responsiveness, 2) reliability, 3)
duplication, 4) we also thought
about domain representation
Item generation (60)
1. Focus groups
2. Discussions with
specialists
Self-administered 15-item QOL questionnaire
The 15 items of the MG-QOL15
1. Frustrated
2. Eyes
3. Eating
4. Social activities
5. Hobbies and fun
things
6. Needs of family
7. Make plans around
8. Job status
9. Speaking
10. Driving
11. Depressed
12. Walking
13. Getting around
14. Feel overwhelmed
15. Grooming
Physical functioning = 12; Fun stuff > 4; Psych = 3; Social > 2; Income/career > 2
175 subject scale validity study
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11 centers
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Consecutive patients
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2 visits per pt
mean – 58 years
duration – 7 years
Serology
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Frequency
Percent
0
27
15.34
1
39
22.16
2a
38
21.59
2b
33
18.75
3a
21
11.93
3b
13
7.39
4b
5
2.84
176
100%
Outpt and/or inpt
Age/duration:

Current MGFA Class
AchR (+) – 78%
MusK (+) – 7%
At least one negative – 10%
Unknown – 5%
Total
e.g. Frustrated:
“somewhat”/ “quite a bit” / “very much”
4%
48%
70%
Rasch of MG-QOL15
(including developmental pathway)
Slightly mis-fitting
item
1.
Didn’t hurt “uni-dimensionality
of scale.”
2.
Not surprised by this (retired
people, disability seekers, etc).
Rasch of MG-QOL15
(including developmental pathway)
Discriminate
well for more
severe disease
Discriminate
well for milder
disease
Potential roles of MG-QOL15
1.
2.
3.
4.
Tell us something about the patients
perspective at the time of the visit
For following an individual patient over time
For comparing groups of patients (e.g.
treatment, placebo)
For studying real patients and learning
from/about them
Burns et al. The MGQOL15 for following the health-related QOL
of patients with myasthenia gravis. Muscle Nerve 2010
1. Patient perspective (e.g. in clinic)
Patient: “When I complete the QOL scale, I sense
that I’m part of the assessment and part of the
decision-making. I’m not a passive object of
your treatment. Completing it forces me to think
about how I’m doing in a structured way. I think
it’s in my best interest—and all patients’best
interests—to complete the scale during their
clinic visits.”
Masuda M et al. Muscle
Nerve 2012;46:166-173
2. Following an individual over time
(e.g. our 175 subject study)
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Point change as indicator of improvement:
6-point: 81% sensitivity; 69% specificity
 7-point: 76% sensitivity; 71% specificity
 8-point: 71% sensitivity; 73% specificity
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My caveat: be cautious, as there are many things
at play here (e.g. response shift, mood that day,
duration between visits)
Burns et al. Muscle Nerve
2011;43:14-18
3. Comparing groups in a trial
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e.g. RCT of PLEx vs. IVIg (Bril and colleagues)
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“Responders” 9-point improvement
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“Non Responders” 2-point improvement
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95% CI: -12 to -6
95% CI: -5 to +1
Authors suggest 7-point change in meaningful
My caveat: both groups knew they were getting a
treatment (i.e. no placebo)
Barnett C et al. J Neurol Neurosurg
Psych 2012; in press
4. For studying QOL of patients
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> 300 consecutive MG patients at 6 centers in
Eastern Japan
What matters for MG-QOL15-J:
1. disease status
2. depressive symptom score
3. dose of prednisone
 e.g. MM patients ≤ 5 mg = PR patients =
CSR patients
Masuda M et al. Muscle
Nerve 2012;46:166-173
Effect of steroids of MG-QOL
1.
Side effect?
e.g. direct effect on mood?
 e.g. side effect of a side effect? (e.g. related to
insomnia, body image?
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2.
Response shift?
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Those on lower doses had disease longer, allowing
time for:
1.
2.
dose to be tapered
response shift to happen (e.g. coping mechanisms to
take hold)
Burns TM. Muscle Nerve
2012;46:153-154
There’s an app for that
(as of Oct 3, 2012)
• We might also learn that:
• a 5-point worsening is urgent issue; many patients react
strongly when first diagnosed (and thus would benefit from
education/ counseling); response shift is a big player; etc.
Acknowledgments
1.
2.
3.
4.
5.
Mark Conaway, PhD (UVA), Don Sanders, MD
(Duke), Gary Cutter (UVA), Reza Sadjadi (UVA)
MG Composite and MG-QOL15 Study Group:
Guillermo Solorzano, Maria E. Farrugia, Janice M. Massey,
Vern C. Juel, Lisa D. Hobson-Webb, Bernadette TuckerLipscomb, Carlo Antozzi, Renato Mantegazza, David Lacomis,
Elliot Dimberg, Srikanth Muppidi, Gil Wolfe, Mazen M.
Dimachkie, Richard J. Barohn, Mamatha Pasnoor, April L.
McVey, Laura Herbelin, Tahseen Mozaffar, Vinh Q. Dang,
Sandhya Rao, Robert Pascuzzi, Riley Snook, Tony A. Amato
Muscle Study Group
Specialists who assisted in the weighting of items
Myasthenia Gravis Foundation of America
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