title: Limited responsiveness related to the minimal important difference of patient-reported outcomes in rare diseases.
abstract: To explore the responsiveness of patient-reported outcomes (PROs) in interventional studies involving patients with rare lysosomal storage diseases (LSDs).
  
  
  
  We searched eight databases for experimental and nonexperimental studies. Pairs of trained reviewers independently screened articles and subsequently extracted data from the eligible studies. Among studies with 10 or more patients using a valid PRO, we assessed the responsiveness of PROs based on a reanalysis of the data using minimal important difference estimates. Our analyses focused on statistically significant within-group differences in PROs for observational studies or the statistically significant between-group differences in PRO scores for controlled studies.
  
  
  
  Of 2,679 unique records, 62 interventional studies addressing patients with Fabry (55%), Gaucher (19%), Pompe (16%), and mucopolysaccharidoses (11%) proved eligible. The most frequently used PROs were the Short-Form-36 (25 studies), Brief Pain Inventory (20 studies), EuroQoL-5D (9 studies), and the Fatigue Severity Scale (6 studies). Observational studies suggest that PROs sometimes detect significant within-group changes when present. Randomized trials raise questions regarding the responsiveness of PROs to small differences between groups.
  
  
  
  Most studies have relied on generic PROs to evaluate quality of life and symptoms in patients with rare LSDs. PROs appear more responsive in observational studies than randomized trials.
authors.affiliation: Systematic Overviews through advancing Research Technology, Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, University of Toronto, 686 Bay St, Toronto, Ontario, Canada M5G 0A4; Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, Ontario, Canada M5G 1X8; Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, 155 College St, Toronto, Ontario, Canada M5T 3M6. Electronic address: bradley.johnston@sickkids.ca.
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Johnston
authors.affiliation: School of Rehabilitation Science, McMaster University, 1400 Main St. W., Hamilton, Ontario, Canada L8S 1C7.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Miller
authors.affiliation: Department of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada M5S 1A8.
authors.forename: Arnav
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada L8S 4K1.
authors.forename: Sohail
authors.initials: S
authors.lastname: Mulla
authors.affiliation: Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada L8S 4K1.
authors.forename: Rabia
authors.initials: R
authors.lastname: Khokhar
authors.affiliation: School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Kyle
authors.initials: K
authors.lastname: De Oliveira
authors.affiliation: Systematic Overviews through advancing Research Technology, Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, University of Toronto, 686 Bay St, Toronto, Ontario, Canada M5G 0A4.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hitchcock
authors.affiliation: Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada L8S 4K1; HIV/STI Surveillance Research Center and WHO Collaborating Centre for HIV Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, 1 Haft Bagh St, Kerman 76169, Iran.
authors.forename: Behnam
authors.initials: B
authors.lastname: Sadeghirad
authors.affiliation: Department of Research & Scientific Affairs, American Academy of Orthopaedic Surgeons, 9400 West Higgins Road, Rosemont, IL 60018, USA.
authors.forename: Mukarram
authors.initials: M
authors.lastname: Mohiuddin
authors.affiliation: Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada L8S 4K1.
authors.forename: Nigar
authors.initials: N
authors.lastname: Sekercioglu
authors.affiliation: Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Gregórzecka 20, 31-351, Krakow, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Seweryn
authors.affiliation: Public Health and Health Promotion Department, Province Sanitary-Epidemiological Station of Lesser Poland, Pradnicka 76, 31-202, Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Koperny
authors.affiliation: Department of Hygiene and Dietetics, Jagiellonian University Medical College, Kopernika 7, 31-034, Krakow, Poland.
authors.forename: Malgorzata M
authors.initials: MM
authors.lastname: Bala
authors.affiliation: Hospital Library, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Thomasin
authors.initials: T
authors.lastname: Adams-Webber
authors.affiliation: Sanofi Genzyme, 500 Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Granados
authors.affiliation: Sanofi Genzyme, 500 Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Alaa
authors.initials: A
authors.lastname: Hamed
authors.affiliation: Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Crawford
authors.affiliation: Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
authors.forename: Ans T
authors.initials: AT
authors.lastname: van der Ploeg
authors.affiliation: Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada L8S 4K1.
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Guyatt
mesh_terms: D006801:Humans; D016464:Lysosomal Storage Diseases / Q000628:therapy*; D000071066:Patient Reported Outcome Measures; D035583:Rare Diseases / Q000628:therapy*
keywords: Lysosomal storage disease; Minimal important difference; Patient-reported outcomes; Rare disease; Responsiveness