Table 5 Clinical outcome assessments and considerations for their use in mucopolysaccharidosis clinical studies
COA | Age range | Disease concepts of interest | Additional considerations |
|---|---|---|---|
 ≥ 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 | |
3 Minute Stair Climb (3MSC) | Not defined | Mobility Endurance Strength Fatigue | Measures number of stairs climbed in 3Â 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 |
BOT-2 [31] | 4 to 21Â years | Strength Mobility UE Function Dexterity | Standardized assessment designed to provide an overview of fine and gross motor skills in people aged 4 to 21Â 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 |
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 |
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] |
 ≥ 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 | |
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] |
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] |