Construction and validation of the MG Composite and MG-QOL15

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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

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Outline

• MG Composite
• User-friendly, disease-specific scale that
  measures direct manifestations
• MG-QOL15
• User-friendly, disease-specific scale that
  measures HRQOL

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• Construction of MGC
• 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
• MSG trial of MMF in MG 80 pts dozen centers
• Aspreva trial of MMF in MG 176 pts 43 centers
• UVA database gt 160 pts

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Hybrid exam history
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Patient-reported physician-reported makes
good sense for MG

• manifestations fluctuate
• Often missed on snapshot examination (4pm vs.
  9am?)
• manifestations evident to the patient
• Diplopia, dysarthria, dysphagia, etc
• Many manifestations more evident to the patient
• Dysphagia, chewing weakness

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Normal Mild Moderate
Severe
Of the same importance??
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Next step weighting

• University of Virginia Ted Burns and Larry
  Phillips
• Duke University Don Sanders and Vern Juel
• Indiana University Bob Pascuzzi
• Kansas University Rick Barohn
• Brigham and Womens Tony Amato and Steve
  Greenberg
• West Virginia University Laurie Gutmann
• University of North Carolina James Howard
• University of Texas, San Antonio Carlayne
  Jackson
• University of Texas, Southwestern Gil Wolfe
• University of Illinois at Chicago Matt
  Meriggioli
• St. Louis University Henry Kaminski
• Ohio State University John Kissel
• University of California Irvine Tahseen
  Mozaffar
• University of California Davis David Richman
• Pittsburgh University David Lacomis
• University of Alabama Birmingham Shin Oh
• Yale University Jonathan Goldstein
• Mayo Jacksonville Devon Rubin

• Leiden University Jan Verschuuren
• University of Wuerzburg Klaus Toyka
• University of Alberta Zaeem Siddiqi
• Hopital Raymond Poincare, France Tarek Sharshar
• Karonlinska Institute Ritva Pirskanen-Matell
• Catholic University, Rome Luca Padua
• University Western Ontario Mike Nicolle
• Carlo Besta, Milan Renato Mantegazza and Carlo
  Antozzi
• University Tubingen Arthur Melms
• University Autonoma Barcelona Isabella Illa
• Radcliffe Hospital, Oxford David Hilton-Jones
• Walton Centre, Liverpool Ian Hart
• Institute Neurological Sciences, Glasgow Maria
  Farrugia
• Hadassah-Hebrew, Jerusalem Zohar Argov

US, Canada, UK, Netherlands, Germany, France,
Sweden, Italy, Spain, Israel
Consider QOL, health risk, prognosis, estimated
item validity and reliability and any other
factors you think are important.
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2008 2009 validation of MGC

• Validation study
• 11 centers
• Consecutive patients
• Outpt and/or inpt
• 2 visits per pt
• Baseline characteristics
• Age/duration
• mean 58 years
• duration 7 years
• Serology
• 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
Total 176 100
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ADL
MMT
QOL
MGFA
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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
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Physician MG-QOL15 change
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MGC score cut-off 3 points

• 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)

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Of patients whose MGC improved 3 points
1. Mean MG-QOL15 improvement 12 points 2. 39
of 42 MG-QOL scores improved or same
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Validation of MG Composite
Neurology 2010741434-1440.
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Next Stop Muscle Study Group meeting at Beaver
Hollow 2010
Reza Sadjadi
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You should do a Rasch analysis on your MGC and
MGQOL15.
Reza Sadjadi
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By the way, I applied to your residency program.
Reza Sadjadi
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1. I have no idea what Rasch is I guess Ill
think about it. 2. Well be sure to interview
you for residency.
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Rasch analysis

• Type of item response theory
• 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

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Specificity
Sensitivity
MGC
Reproducibility
Validity
Best cut-point
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?
Scale
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?
Scale
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Rasch analysis of MGC - summary

• 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)

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4. Weights are appropriate
Item
Consensus
Rasch

1. Eyelid strength
2. Eye gaze
3. Eye closure
4. Talking
5. Chewing
6. Swallowing
7. Breathing
8. Neck flex/ext
9. Shoulder abduction
10. Hip flexion

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
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Post-script (Rasch of MGC)

• Published paper of MGC Rasch analysis
• Psychometric evaluation of the MG Composite using
  Rasch analysis. Muscle Nerve 201245820-825
• 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)

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MGC has been recommended by an MSAB/MGFA Task
Force
Benatar, M et al. Recommendations for MG Clinical
Trials. Muscle Nerve 201245909-917.
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Summary of MGC

1. Items carefully selected
2. Validated
3. 3-point change in MGC score appears to be
   meaningful and reliable
4. Rasch analysis of MGC was favorable
5. MGC is simple and useful for clinical trials and
   for everyday practice

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Outline

• MG Composite
• User-friendly, disease-specific scale that
  measures direct manifestations
• MG-QOL15
• User-friendly, disease-specific scale that
  measures HRQOL

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Preface HRQOL are very subjective

• Strength insight into the patients appraisal of
  dysfunction and tolerability of dysfunction
• Weaknesses so many factors at play
• Antecedents
• Secondary gain issues
• Response shift
• Changes in values, goals, expectations, etc.
  brought on by the disease (or other life events),
  changing familiarity with the course over time

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so keep it simple

• No Rube Goldberg machines

• Make it user-friendly

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MG QOL scale (2007 2008)
60 questions
15 questions
Looked at data from 1.) MSG MMF study 2.) UVA
database
Item generation (60) 1. Focus groups 2.
Discussions with specialists
Performance of all 60 items 1) responsiveness, 2)
reliability, 3) duplication, 4) we also thought
about domain representation
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Self-administered 15-item QOL questionnaire
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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 gt 4 Psych
3 Social gt 2 Income/career gt 2
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175 subject scale validity study

• 11 centers
• Consecutive patients
• Outpt and/or inpt
• 2 visits per pt
• Age/duration
• mean 58 years
• duration 7 years
• Serology
• 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
Total 176 100
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e.g. Frustratedsomewhat/ quite a bit /
very much
4
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70
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Rasch of MG-QOL15(including developmental
pathway)
Slightly mis-fitting item

1. Didnt hurt uni-dimensionality of scale.
2. Not surprised by this (retired people, disability
   seekers, etc).

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Rasch of MG-QOL15(including developmental
pathway)
Discriminate well for more severe disease
Discriminate well for milder disease
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Potential roles of MG-QOL15

1. Tell us something about the patients perspective
   at the time of the visit
2. For following an individual patient over time
3. For comparing groups of patients (e.g. treatment,
   placebo)
4. 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
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1. Patient perspective (e.g. in clinic)

• Patient When I complete the QOL scale, I sense
  that Im part of the assessment and part of the
  decision-making. Im not a passive object of your
  treatment. Completing it forces me to think about
  how Im doing in a structured way. I think its
  in my best interestand all patientsbest
  intereststo complete the scale during their
  clinic visits.

Masuda M et al. Muscle Nerve 201246166-173
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2. Following an individual over time(e.g. our
175 subject study)

• Point change as indicator of improvement
• 6-point 81 sensitivity 69 specificity
• 7-point 76 sensitivity 71 specificity
• 8-point 71 sensitivity 73 specificity
• 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 20114314-18
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3. Comparing groups in a trial

• e.g. RCT of PLEx vs. IVIg (Bril and colleagues)
• Responders 9-point improvement
• 95 CI -12 to -6
• Non Responders 2-point improvement
• 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
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4. For studying QOL of patients

• gt 300 consecutive MG patients at 6 centers in
  Eastern Japan
• What matters for MG-QOL15-J
• disease status
• depressive symptom score
• dose of prednisone
• e.g. MM patients 5 mg PR patients CSR
  patients

Masuda M et al. Muscle Nerve 201246166-173
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Effect of steroids of MG-QOL

• Side effect?
• e.g. direct effect on mood?
• e.g. side effect of a side effect? (e.g. related
  to insomnia, body image?
• Response shift?
• Those on lower doses had disease longer, allowing
  time for
• dose to be tapered
• response shift to happen (e.g. coping mechanisms
  to take hold)

Burns TM. Muscle Nerve 201246153-154
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Theres 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.

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Acknowledgments

• 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
  Tucker-Lipscomb, 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