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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