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Construction and validation of the MG Composite and MG- QOL15

This study outlines the construction and validation of the MG Composite (MGC) and MG-QOL15, user-friendly disease-specific scales that measure direct manifestations and health-related quality of life in Myasthenia Gravis (MG) patients. The MGC evaluated item performance from three scales in three cohorts and considered functional domain representation, while the MG-QOL15 measures HRQOL. Clinical data from various trials and databases were analyzed to hybridize patient and physician-reported data for better understanding of MG manifestations. The study involved multiple centers and validation processes to ensure the accuracy and reliability of the new scales.

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Construction and validation of the MG Composite and MG- QOL15

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  1. 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

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

  3. 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: > 160 pts

  4. Hybrid =exam+history

  5. 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

  6. Normal Mild Moderate Severe Of the same importance??

  7. 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 Women’s – 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.”

  8. 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%

  9. ADL MMT QOL MGFA

  10. 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

  11. Physician + MG-QOL15 change

  12. 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)

  13. Of patients whose MGC improved 3 points… 1. Mean MG-QOL15 improvement = 12 points 2. 39 of 42 MG-QOL scores improved or same

  14. Validation of MG Composite Neurology 2010;74:1434-1440.

  15. Next Stop: “Muscle Study Group” meeting at Beaver Hollow 2010 Reza Sadjadi

  16. “You should do a Rasch analysis on your MGC and MGQOL15.” Reza Sadjadi

  17. “By the way, I applied to your residency program.” Reza Sadjadi

  18. 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.”

  19. 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

  20. Specificity Sensitivity MGC Reproducibility Validity Best cut-point

  21. ? Scale

  22. ? Scale

  23. 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)

  24. 4. Weights are appropriate Item Consensus Rasch • Eyelid strength • Eye gaze • Eye closure • Talking • Chewing • Swallowing • Breathing • Neck flex/ext • Shoulder abduction • 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

  25. Post-script (Rasch of MGC) • Published paper of MGC Rasch analysis • 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)

  26. 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.

  27. Summary of MGC 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

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

  29. Preface: HRQOL are very subjective… • Strength: insight into the patient’s 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

  30. …so keep it simple • No “Rube Goldberg” machines • Make it user-friendly

  31. 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

  32. Self-administered 15-item QOL questionnaire

  33. 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

  34. 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%

  35. e.g. Frustrated:“somewhat”/ “quite a bit” / “very much” 4% 48% 70%

  36. Rasch of MG-QOL15(including developmental pathway) Slightly mis-fitting item • Didn’t hurt “uni-dimensionality of scale.” • Not surprised by this (retired people, disability seekers, etc).

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

  38. Potential roles of MG-QOL15 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

  39. 1. Patient perspective (e.g. in clinic) Masuda M et al. Muscle Nerve 2012;46:166-173 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.”

  40. 2. Following an individual over time(e.g. our 175 subject study) Burns et al. Muscle Nerve 2011;43:14-18 • 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)

  41. 3. Comparing groups in a trial Barnett C et al. J Neurol Neurosurg Psych 2012; in press • 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)

  42. 4. For studying QOL of patients Masuda M et al. Muscle Nerve 2012;46:166-173 • > 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

  43. 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 2012;46:153-154

  44. 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.

  45. 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

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