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Table 5 Clinical outcome assessments and considerations for their use in mucopolysaccharidosis clinical studies

From: Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): defining and measuring functional impacts in pediatric patients

COA Age range Disease concepts of interest Additional considerations
2MWT [21]/6MWT [22]  ≥ 3 years Mobility
Endurance
Strength
Fatigue
Self-paced walking test measuring distance walked in 6 min (6MWT) or 2 min (2MWT). An assessment of functional capacity in pulmonary, cardiac, and musculoskeletal systems
Age specific normative data available [23,24,25]
Multibody system assessment; difficult to assess which body system is responsible for change
Previous use in MPS studies [18, 26]
3 Minute Stair Climb (3MSC) Not defined Mobility
Endurance
Strength
Fatigue
Measures number of stairs climbed in 3 min. Assesses ambulatory capacity, strength, and endurance. More challenging motor task than ambulation on a flat surface
Normative data not available (alternative is Timed Up and Down Stair Test for which normative data is available [27])
Variability may be present in the size and number of flights of stairs available at clinical sites
Ceiling effect present if children are able to climb maximum number of available stairs
Multibody system assessment; difficult to assess which body system is responsible for change
Difficult to define meaningful change in the absence of normative data, especially in growing child
Previous use in MPS studies [26, 28,29,30]
BOT-2 [31] 4 to 21 years Strength
Mobility
UE Function
Dexterity
Standardized assessment designed to provide an overview of fine and gross motor skills in people aged 4 to 21 years
Generates norm-referenced scores across individual fine and gross motor subtests and composite scores. Can administer individual subtests that align with MPS VI disease concepts of interest
Assesses higher gross motor function than walk test, with items to measure bilateral extremity coordination, balance, jumping, hopping and running
Assesses numerous fine motor dexterity and precision items, such as cutting with scissors, copying shapes, and placing pegs in a pegboard
Contractures can limit positioning for items such as pushups or sit-ups
Age and functional level should be considered to determine if use is appropriate because floor effect may be present for lower functioning patients
Limited use in MPS studies [32]
NIH Toolbox Pegboard Dexterity Test [21]  ≥ 3 years Dexterity
UE Function
Measures the amount of time required to quickly place 9 small pegs into a pegboard and once completed, remove them
NIH Toolbox provides normative reference data for children ≥ 3 years based on large diverse normative sample
Captures the speed and accuracy of hand movements with manipulation of objects, which has functional relevance to daily activity in MPS VI
Standardized administration, data collection and training materials available on NIH Toolbox app
Use in MPS studies (ClinicalTrials.gov: NCT03370653)
NIH Toolbox Grip Strength
Test [21]
 ≥ 3 years Strength Measures hand grip strength using a grip strength dynamometer
NIH Toolbox provides normative reference data for children ≥ 3 years based on large diverse normative sample
Standardized administration, data collection and training materials available on NIH Toolbox app
Dynamometer must adjust for use with small hands
Use in MPS studies [33, 34]
Passive Range of Motion Any age Limited joint flexibility Normal references values available [35]
Inter-rater reliability can be a challenge; this can be mitigated with training and standardized equipment [36]
Stiffness can vary throughout day
Previous use in MPS studies [6, 18, 37]
PROMIS® [11]  ≥ 5 years
Parent Proxy ≥ 5 years
Self-report ≥ 8 years
Pain
Mobility
UE Function
Dexterity
Fatigue
Patient or parent proxy reported outcomes covers wide range of domains applicable to MPS VI including pain intensity, interference and behavior, fatigue, mobility, and UE function
Normative reference values generated from general population and clinical disease samples
Available in many languages
Pain interference and pain behavior are observable so can be reported by proxy (caregiver) for children < 8 years of age
Pain intensity is a self-report NRS and cannot be assessed in children < 8 years of age
Previous use in MPS studies [38]
PODCI [10] 2 to 18 years
Parent Proxy ≥ 2 years
Self-report ≥ 11 years
Mobility
Dexterity
Pain
Fatigue
HRQoL
Patient or parent proxy reported outcome designed to assess change following pediatric orthopedic interventions in a wide range of diagnoses [39]
Standardized scores calculated from 0 to 100 with higher scores representing less disability and better function. Standard scores were also normed on US population to create normative scores for each scale
PODCI constructs applicable to MPS VI include UE function, transfers and mobility, physical function and sports, and comfort (lack of pain)
The Physical Function and Sports domain provides unique and MPS VI relevant content related to community, sports, and recreation participation
Versions available in Korean, Spanish and English [40]
Previous use in MPS studies [41]
CHAQ [42] Ages for Parent Proxy and Self-report not specified Pain
Mobility
UE Function
Dexterity
Fatigue
Patient or parent proxy reported outcome designed to measure health status and physical function in juvenile arthritis. Has been validated for use in children with chronic musculoskeletal pain [40]
Normative data is not available. A Disability Index (DI) is calculated by pooling domain scores, with higher scores reflecting greater disability. Pooling of domains may limit ability to interpret primary disease concept of change
Items that cannot be completed because they are not developmentally appropriate are left blank resulting in fewer items to detect change in younger patients
CHAQ constructs relevant to MPS VI are physical function, dressing and grooming, eating, walking, hygiene, reach and grip
Includes Visual Analog Pain Scale
Original CHAQ translated and validated in over 40 languages [40]
Previous use in MPS studies [6, 18, 43]
PedsQL™ [44, 45]  ≥ 2 years
Parent Proxy ≥ 2 years
Self-report ≥ 5 years
Pain
Mobility
UE Function
Fatigue
HRQoL
Patient or parent proxy reported outcome designed to measure HRQoL in children and adolescents with acute and chronic health conditions. Numerous modules are available to capture constructs relevant to MPS VI including the Generic Core Scales, the Family Impact Module, and the Multi-Dimensional Fatigue Scale
Scored on a scale of 1 to 100 where higher scale scores indicate better HRQoL and distinguishes healthy children from children with health conditions but does not provide comparison to age specific normative data
Covers many domains with few questions for each, resulting in less information available for each domain
Available in many languages
Previous use in MPS studies [8, 46]
Faces Pain Scale-Revised [47]  ≥ 4 years Pain Self- report of pain intensity developed for children. Children choose the face that best illustrates the pain they are experiencing
Allows self-report of pain for young children
Easy to administer
Available in many languages
Previous use in MPS studies [8]
VAS for Pain  ≥ 7 years Pain Horizontal line 10 cm in length. On one end the descriptor is ‘no pain’ and on the other end the descriptor is ‘very severe pain’. The subject marks a spot on the line that represents their pain level within a given recall period
CHAQ includes a VAS
Appropriate for ages 7 and older [48]
Previous use in MPS studies [8, 42]
NRS for Pain  ≥ 8 years Pain Numeric scale from 0 to 10 on which patients estimate their pain numerically, with higher numbers representing increasing pain severity
PROMIS Pediatric Numeric Rating Scale v1.0-Pain Intensity is a NRS [11]
Appropriate for ages 8 and older [48]
Limited use in children with MPS [49]
  1. 2MWT 2-min walk test, 6MWT 6-min walk test, ADL activities of daily living, BOT-2 Bruininks–Oseretsky Test of Motor Proficiency, 2nd edition, CHAQ childhood health assessment questionnaire, COA clinical outcome assessment, DI disability index, HRQoL health-related quality of life, MPS mucopolysaccharidosis, NIH National Institutes of Health, NRS numeric rating scale, PedsQL pediatric quality of life inventory, PODCI pediatrics outcomes data collection instrument, PROMIS patient-reported outcomes measurement information system, UE upper extremity, VAS visual analog scale