preference-based measures of health-related quality of

REVIEW Open Access

Preference-based measures of health-related quality of life in congenital mobilityimpairment: a systematic review of validityand responsivenessNathan Bray1,2*, Llinos Haf Spencer1,2 and Rhiannon Tudor Edwards1,2

Abstract

Introduction: Mobility impairment is the leading cause of disability in the UK. Individuals with congenital mobilityimpairments have unique experiences of health, quality of life and adaptation. Preference-based outcomesmeasures are often used to help inform decisions about healthcare funding and prioritisation, however theapplicability and accuracy of these measures in the context of congenital mobility impairment is unclear. Inaccurateoutcome measures could potentially affect the care provided to these patient groups. The aim of this systematicreview was to examine the performance of preference-based outcome measures for the measurement of utilityvalues in various forms of congenital mobility impairment.

Methods: Ten databases were searched, including Science Direct, CINAHL and PubMed. Screening of reference listsand hand-searching were also undertaken. Descriptive and narrative syntheses were conducted to combine andanalyse the various findings. Results were grouped by condition. Outcome measure performance indicators wereadapted from COSMIN guidance and were grouped into three broad categories: validity, responsiveness andreliability. Screening, data extraction and quality appraisal were carried out by two independent reviewers.

Results: A total of 31 studies were considered eligible for inclusion in the systematic review. The vast majority ofstudies related to either cerebral palsy, spina bifida or childhood hydrocephalus. Other relevant conditions includedmuscular dystrophy, spinal muscular atrophy and congenital clubfoot. The most commonly used preference-basedoutcome measure was the HUI3. Reporting of performance properties predominantly centred around constructvalidity, through known group analyses and assessment of convergent validity between comparable measures anddifferent types of respondents. A small number of studies assessed responsiveness, but assessment of reliability wasnot reported. Increased clinical severity appears to be associated with decreased utility outcomes in congenitalmobility impairment, particularly in terms of gross motor function in cerebral palsy and lesion level in spina bifida.However, preference-based measures exhibit limited correlation with various other condition-specific and clinicallyrelevant outcome measures.

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* Correspondence: [email protected] of Health Sciences, Fron Heulog, Bangor University, Gwynedd LL572EF, Wales, UK2Centre for Health Economics and Medicines Evaluation, Ardudwy, BangorUniversity, Gwynedd LL57 2PZ, Wales, UK

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Conclusion: Preference-based measures exhibit important issues and discrepancies relating to validity andresponsiveness in the context of congenital mobility impairment, thus care must be taken when utilising thesemeasures in conditions associated with congenital mobility impairments.

Keywords: Disability, Mobility impairment, Quality of life, Health-related quality of life, Patient reported outcomes,Preference-based outcome measures, Utilities, QALYs

IntroductionMobility impairment and assistive mobility technologyMobility impairment is the leading cause of disability inthe UK, accounting for 52% of reported disabilities [1].Mobility impairments arise from a vast array of differentdisabilities, conditions, injuries and illnesses. However,they can be classified broadly as either congenital (i.e.from birth) or acquired (i.e. occurring later in life).Whether a disability is present from birth or acquiredlater on in life significantly influences individual adapta-tion. For instance, individuals with congenital disabilitiesexhibit higher degrees of life satisfaction, self-identityand self-efficacy (related to their disability) than individ-uals who have had to adapt to acquired disability [2].Adaptation to disability is influenced by self-concept anddisability identity, which in turn are related to the onsetof disability [2].Common congenital conditions which can impact mo-

bility include cerebral palsy (CP) and spina bifida (SB).CP refers to a number of conditions caused by damageto the parts of the brain which control movement, bal-ance and posture, and can be caused either by abnormalbrain development or trauma. CP is symptomized byvarying degrees of permanent movement disorder, in-cluding poor coordination, muscle stiffness/weaknessand involuntary movements. SB affects the developmentof the spine and spinal cord before birth, and can resultin leg weakness and paralysis. There are three types ofSB: myelomeningocele, meningocele and SB occulta.Both congenital and acquired mobility impairments

may necessitate the use of assistive technology to allevi-ate impairments. Assistive technology refers to a widearray of products and services which enhance function-ing, participation and promote independence for peoplewho have disabilities. The Medicines and HealthcareProducts Regulatory Agency defines assistive technologyas any device “intended to compensate for or alleviate aninjury, handicap or illness or to replace a physical func-tion” [3]. Assistive technology, such as wheelchairs, arean “essential component for inclusive sustainable devel-opment” [4], and can enhance the fundamental freedomsand equality of opportunity for people with mobility im-pairments and other disabilities. The United Nations(UN) states that access to appropriate and affordable as-sistive technology is a basic human right [5]; the UN

Convention on the Rights of Persons with Disabilitieshas been ratified by 175 Member States, who are obli-gated to ensure that affordable assistive technology isavailable to all individuals in need. However, The WorldHealth Organization (WHO) estimates that only 10% ofpeople who need assistive technology have access to it[6], and there remain persistent challenges in the equit-able provision of assistive technology, particularly in de-veloping countries. One of the keys issues is in assessingthe costs and benefits of different assistive technologies,and developing evidence-based approaches to provisionwhich make best use of limited resources to maximisethe outcomes of people with disabilities.The National Health Service (NHS) in the UK spends

almost £200million per year on wheelchairs alone [7],thus there is an imperative to ensure that assistive mo-bility technologies (AMTs) such as wheelchairs andother mobility-enhancing interventions are provided inan evidence-based manner, utilising evidence of cost-effectiveness to guide service commissioning.

Economic evaluation and quality-adjusted life yearsMethods of economic evaluation are now routinely em-bedded in the evaluation of health technologies, andused to estimate the cost of incremental benefits associ-ated with new and alternative health interventions. Cost-utility analysis, specifically estimation of cost per quality-adjusted life years (QALYs), has become the predomin-ant form of economic evaluation for new health tech-nologies in the UK, in part due to the National Institutefor Health and Care Excellence’s (NICE) advocacy forthis approach [8]. The QALY framework has become in-creasingly influential in health policy as a theoreticallyuniversal and generic approach to measuring benefits viaa single common outcome.In order to calculate QALYs, health state utility values

are needed. These values are most commonly derivedfrom preference-based measures (PBMs) of health-related quality of life (HRQoL). HRQoL is a subjectiveand multi-dimensional construct defined as the per-ceived impact of health status on quality of life, includ-ing physical, psychological and social functioning. PBMsof HRQoL are used to assess the social desirability andutility values associated with different states of health.

Bray et al. Health Economics Review (2020) 10:9 of 38

As the descriptive systems and value sets of genericPBMs are usually derived from adult samples of the gen-eral population, a common criticism is that their gener-icity limits relevance and sensitivity in certain conditions[9]. Moreover, in health states where quality of life takesprecedent over quantity of life (e.g. chronic illness, life-limiting conditions and disability), QALYs derived fromgeneric PBMs can devalue the effectiveness of an inter-vention [10].

Use of preference-based measures in the context ofmobility impairmentThe accuracy of a QALY estimate is subject to the sensi-tivity and applicability of the measurement tool used togenerate the utility data. PBMs have been found to be in-consistent in both congenital and acquired mobility im-pairments [11–13], furthermore different PBMs producesignificantly different results for AMT users [14, 15].Previous research shows that patients with congenital

mobility impairments do not necessarily consider mobil-ity to have a major impact on their HRQoL when suit-able adaptations (such as AMT) are available [16, 17].However, general population PBM value sets heavily im-pact estimation of HRQoL when ability to walk is af-fected. As an example, using the NICE approved UKvalue set for the EuroQoL five-dimension (three levelversion) (EQ-5D-3 L), the lowest possible mobility level(‘confined to bed’) has a disutility of − 0.664, meaningthat an individual who is unable to walk but is otherwisemobile using AMT can achieve a maximum utility valueof 0.336 (0 = death; 1 = perfect health), even if they haveno other HRQoL impacts. This raises the questions as towhether existing PBMs are a valid source of utility valuesin mobility impaired populations, particularly AMTusers.The validity of PBMs can be tested by comparing re-

sults across groups of patients and by comparing genericPBMs with condition-specific measures. For instance,the EQ-5D-3 L and the Health Assessment Question-naire (HAQ; an outcome measure for rheumatoid arth-ritis) both measure health status in significantly differentways [18], suggesting that the EQ-5D-3 L is lacking con-sideration of important health impacts associated withrheumatoid arthritis. These issues are partly due to theinsensitivity of the EQ-5D-3 L ‘mobility’ dimension toaccurately assess the varied impacts of rheumatoid arth-ritis on mobility [19]. Similarly, the limited level choiceson the EQ-5D-3 L have been found to cause some indi-viduals with mobility impairments to choose levelswhich are more or less severe than their actual state,such as using ‘I am confined to bed’ to substitute beingconfined ‘to an electric wheelchair’ [20]. The updatedfive level version of the EQ-5D (EQ-5D-5 L) is unlikelyto address this issue as the five level choices still focus

on walking and do not take account of alternativemethods of mobility.Even simple generic measures of health status, such as

the single question self-reported health (SRH) scale (i.e.“in general, would you say your health is excellent, verygood, good, fair, or poor?”), exhibit only limited correl-ation with PBMs such as the Health Utilities Index(HUI) 3 and Assessment of Quality of Life (AQoL) inthe context of SB [21] and CP [22]. Likewise, for individ-uals with spinal cord injuries, the wording of the 36-Item Short Form Health Survey (SF-36) (from which theShort-Form Six-Dimension (SF-6D) PBM is calculated)must be modified in order to maintain relevance [23].Considering the potential issues of using generic PBMs

in disability, and congenital mobility impairment specif-ically, it is apparent that there are a number of import-ant considerations when using PBMs to evaluate AMTinterventions and other mobility-enhancing interven-tions for people with congenital mobility impairments.The objective of this systematic review is therefore toexamine the measurement properties of generic utility-based PBMs in various forms of congenital mobility im-pairment. All evidence reporting (or inferring) the valid-ity, reliability and/or responsiveness of PBMs inconditions associated with congenital mobility impair-ment was collated and synthesised. Comparablecondition-specific reviews of PBM performance havebeen conducted in mobility impairments such asrheumatoid arthritis [24], CP [25] and multiple sclerosis[26], however PBM performance has not been systemat-ically summarised and collated across a range of con-genital mobility impairments to date.

MethodsThis systematic review followed the University of YorkCentre for Reviews and Dissemination (CRD) principlesfor conducting searches and extracting data [27]. Inter-net reference database searching was the main strategyfor gathering evidence. Databases included: CochraneCollaboration Register and Library, Science Direct,CINAHL, ASSIA, PsychINFO, PubMed and Web of Sci-ence. Screening of reference lists, hand-searching andtargeted searching via the CRD database (which coversthe Database of Abstracts of Reviews of Effects (DARE),the NHS Economic Evaluation Database (NHS EED) andthe Health Technology Association (HTA) database)were carried out in addition to the primary databasesearches. Due to limited translation resources, only stud-ies written or translated into English or Welsh were eli-gible for inclusion. Search results were managed usingthe online bibliographic management software Refworks(for storage of titles from the systematic searches) andMendeley (for referencing purposes). The systematic


review protocol was registered on PROSPERO(CRD42018088932).

Search termsFor the purpose of this review, mobility impairment wasdefined as any congenital (i.e. present from or shortly afterbirth) condition, impairment, disability or illness whichcauses significant restrictions to mobility for 12months orlonger, and which necessitates the use of AMT, surgery orrehabilitation to maintain, facilitate or substitute ambula-tion, or to reduce complications related to mobility im-pairment. Acquired mobility impairments (i.e. not presentfrom birth) and short-term injuries, such as sprains oracute muscular injuries, were not included under this def-inition of mobility impairment.Search terms included a mixture of MeSH (Medical

Subject Heading) and non-MeSH words and phrases, di-vided into two groups: ‘population’ and ‘outcomes’ (seeTable 1).In order to identify studies referring to interventions ra-

ther than patient groups (e.g. studies examining ‘wheel-chair users’ more generally), the ‘population’ search termsalso covered relevant AMTs and mobility-enhancing in-terventions. The ‘outcomes’ search terms covered relevantPBM keywords, including specific outcome measures(such as the various versions of the EQ-5D and HUI mea-sures). An NHS posture and mobility service manager wasconsulted to refine the search terms. An example of asearch string is shown in Table 2.

Study eligibilityAny study reporting the performance of PBMs ofHRQoL in patient groups with congenital mobility im-pairments was eligible for inclusion. This included stud-ies reporting proxy outcomes. There was no restrictionon study type. Studies focussing solely on non-PBMs ofHRQoL or acquired mobility impairments were ex-cluded. Studies which included patient groups with vary-ing degrees of disability/disease severity were consideredfor inclusion if the majority of patients had a congenitalmobility impairment or if the data for patients with con-genital mobility impairments was reported separately(i.e. sub-group analysis).

ScreeningTwo researchers undertook each stage of the screeningprocess. For the initial screening process, all identifiedstudies were assessed for relevance based on their titleand descriptor terms, the remaining studies were thenassessed by their abstract. All studies considered relevantafter the initial screening process were then obtained infull. Both reviewers screened each study independently.A third researcher was consulted when there was dis-agreement about the inclusion of a specific study.

Quality appraisalAll relevant studies which met the initial inclusion cri-teria were critically appraised for methodological qualityby two researchers. Quality appraisal methods wereadapted from similar systematic reviews in other clinicalareas [28–30]. Quality appraisal was not used to excludestudies, but to illustrate the overall quality of researchconducted in this topic area. Quality appraisal focussedon six key areas:

� Whether tests of statistical significance were carriedout

� Differences between interventions and/or patientgroups (i.e. sub-group analysis)

� Clinical significance and relevance of results� Reporting of missing data� Response and completion rates� Explicit reporting of inclusion/exclusion criteria

Data extractionData extraction criteria included:

� Study characteristics: study type, country, number/composition of study groups, missing data

� Demographics: number of participants, age, gender,type/severity of mobility impairment

� Measures: Generic PBMs used, condition-specificmeasures used, other clinically relevant measuresused

� Outcomes: Mean utility scores, mean utility scoresfor relevant sub-groups, statistical significancebetween groups

� Performance: Known group analyses, convergentvalidity (correlation between outcomes and/orrespondent types), responsiveness, reliability,response/completion rates

Analysis of the performance of preference-basedmeasuresPBM performance indicators were adapted from COS-MIN measurement property guidance for health-relatedpatient-reported outcomes [31].

Assessment of validityIn this context validity refers to the extent to which aPBM can be considered to measure what it has been de-signed to measure (i.e. HRQoL), and whether it does soin a systematic manner. By establishing whether a spe-cific PBM is sufficiently valid in a particular patientgroup, greater confidence can be placed in the generateddata. We focussed predominantly on construct validityin this review.Construct validity was assessed in a number of ways.

Firstly, known-group analyses were used to assess


whether specific PBMs were able to detect expected dif-ferences between different patient groups (i.e. variancedue to severity of illness). Secondly, convergent validitywas determined by examining correlation between com-parable outcomes, for instance between PBMs andcondition-specific measures with comparable constructs.Finally, convergent validity was further examined bylooking at correlation between respondents types (i.e.self-reported and proxy utility outcomes). In the interest

of uniformity, the strength of correlations was defined asabsent (r < 0.20), weak (r = 0.20 to 0.35), moderate (r =0.35 to 0.50) and strong (r ≥ 0.50) [32].

Assessment of reliabilityReliability refers to the replicability of results. Reliabilityis commonly assessed by examining test-retest resultsand inter-rater reliability of PBMs in defined unchangingpatient groups.

Table 1 Search terms and phrases

Population Outcomes

Assisted mobility Mobility scooter 15D

Assistive mobility Mobility technolog* AQoL

Brain damage* Motor dis* Assessment of Quality of Life

Brain injur* Motorised scooter Child health utilities

Buggy Neurodisability Child health utility

Caliper Neurological dis* CHU9D

Cane Neuromotor dis* CHU-9D

Cerebral palsy Neuromuscular dis* EQ 5D

Club foot Orthoti* EQ-5D

Clubfoot Osteogenesis imperfecta EuroQoL

Crutch* Paraly* Health utilities

Diplegi* Paraplegi* Health-utilities

Dysmelia Physical disab* HUI

Dystroph* Physical impair* HUI2

Electric chair Physically disab* HUI3

Electric powered indoor outdoor chair Physically impaired Preference based

Electric powered indoor/outdoor chair Power chair Preference-based

Electric scooter Powered chair QALY

Electrically powered indoor outdoor chair Pushchair Quality adjusted life year

Electrically powered indoor/outdoor chair Quadriplegi* Quality-adjusted life year

Electronically powered indoor outdoor chair Rollator Quality of well-being scale

Electronically powered indoor/outdoor chair Scooter QWB-SA

*encephal* Spina bifida Short Form Six Dimension

EPIOC Spinal muscular atrophy Short From 6 Dimension

Functional disab* Talipes SF6D

Handicap* Tetraplegi* SF-6D

Hemiplegi* Walk aid

Hydrocephalus Walk-aid

Knee scooter Walker

Knee walker Walking aid

Mobility aid Walking frame

Mobility device Walking stick

Mobility dis* Walking-aid

Mobility equipment Wheelchair

Mobility impair**Indicates truncated words/phrases


Assessment of responsivenessResponsiveness refers to the extent to which a measurecan identify changes in health status [28]. A responsivemeasure should be able to detect clinically significantchanges in health outcomes over time [29]. Responsive-ness was determined by examining the relationship be-tween outcomes derived from PBMs and other relevantmeasures, before and after an intervention.

Evidence synthesisDescriptive synthesis of search results was conducted[27] and presented in tabulated form. Narrative synthesiswas undertaken to develop a structured narrative of re-sults; extracted results were grouped by type of mobilityimpairment and category of PBM performance.

ResultsSee Fig. 1 for search outcomes and the screening processflowchart. Searches were conducted from March to May2018. In total 1489 study articles were identified: 1332from the bibliographic searches and 157 articles fromother sources (i.e. CRD database, screening of referencelists and hand-searching), of which 410 duplicates wereremoved. After screening of titles and abstracts, 66

Table 2 Example of keyword search string

(“Assisted mobility” Or “Assistive mobility” Or “Brain damage*” Or “Braininjur*” Or Buggy Or Caliper Or Cane Or “Cerebral palsy” Or “Club foot”Or Clubfoot Or Crutch* Or Diplegi* Or Dysmelia Or Dystroph* Or“Electric chair” Or “Electric powered indoor outdoor chair” Or “Electricpowered indoor/outdoor chair” Or “Electric scooter” Or “Electricallypowered indoor outdoor chair” Or “Electrically powered indoor/outdoorchair” Or “Electronically powered indoor outdoor chair” Or “Electronicallypowered indoor/outdoor chair” Or encephal* Or EPIOC Or “Functionaldisab*” Or Handicap* Or Hemiplegi* Or Hydrocephalus Or “Kneescooter” Or “Knee walker” Or “Mobility aid” Or “Mobility device” Or“Mobility dis*” Or “Mobility equipment” Or “Mobility impair*” Or “Mobilityscooter” Or “Mobility technolog*” Or “Motor dis*” Or “Motorised scooter”Or Neurodisability Or “Neurological dis*” Or “Neuromotor dis*” Or“Neuromuscular dis*” Or Orthoti* Or “Osteogenesis imperfect” Or Paraly*Or Paraplegi* Or “Physical disab*” Or “Physical impair*” Or “Physicallydisab*” Or “Physically impaired” Or “Power chair” Or “Powered chair” OrPushchair Or Quadriplegi* Or Rollator Or Scooter Or “Spina bifida” Or“Spinal muscular atrophy” Or Talipes Or Tetraplegi* Or “Walk aid” Or“Walk-aid” Or Walker Or “Walking aid” Or “Walking frame” Or “Walkingstick” Or “Walking-aid” Or Wheelchair) AND (15D OR AQoL OR“Assessment of Quality of Life” OR “Child health utilities” OR “Childhealth utility” OR CHU9D OR “CHU-9D” OR EQ. 5D OR “EQ-5D” OREuroQoL OR “Health utilities” OR “Health-utilities” OR HUI OR HUI2 ORHUI3 OR “Preference-based” OR “Preference based” OR QALY OR “Qualityadjusted life year” OR “Quality of well-being scale” OR “Quality-adjustedlife year” OR “QWB-SA” OR “Short Form Six Dimension” OR “Short From 6Dimension” OR SF6D OR “SF-6D”)

Fig. 1 PRISMA flowchart for search outcomes and screening process


studies were identified as potentially eligible. Followingfull review of full-texts, 35 studies were excluded for avariety of reasons (see Fig. 1). In total 31 studies wereidentified as relevant and eligible for inclusion in the sys-tematic review. Quality appraisal outcomes are presentedin Table 3.

Study and patient characteristicsStudy and participant characteristics are presented inTable 4. Most of the studies (22 of 31) were cross-sectional studies [15, 21, 22, 34, 36–38, 40–45, 47–52,54, 58, 59], six were prospective cohort studies [33, 35,39, 46, 53, 57], two were case-control studies [11, 56]and one was a randomised controlled trial [55]. The se-lected studies were conducted in a range of differentcountries; most were (n = 15) from Canada [21, 22, 33,35, 36, 38–43, 46, 49, 53, 57]. The sample sizes of rele-vant study groups ranged from 13 [15] to 770 [44].Fourteen studies included data relating to CP [22, 33,

35, 36, 39, 46, 48–51, 53, 55, 57, 58], six included datarelating to SB [21, 38, 51, 52, 54, 56] and five includeddata relating to childhood hydrocephalus [40–43, 45].Data for a range of other relevant conditions were alsofound in either single studies or from extractable sub-groups, these included muscular dystrophy [34, 44],spinal muscular atrophy [47], Morquio A syndrome [37],congenital clubfoot [59] and microcephaly [51]. Threestudies focused on multiple conditions where sub-groupdata could not be examined separately [11, 15, 51].The vast majority of studies (23 of 31) included only

child/adolescent participants [11, 15, 33, 35, 36, 38–44,46–54, 56, 58]. Of the remaining studies, six includedchildren/adolescents and adults [21, 22, 34, 37, 55, 57]and two included only adults [45, 59]. PBM reportingwas predominantly from proxies (13 of 23 studies);eleven studies included both self-reported and proxydata [15, 21, 22, 36, 43, 48–50, 53, 54, 57] and sevenstudies included only self-reported PBM data [11, 34, 37,45, 55, 58, 59].In terms of use of PBMs, 22 of the studies used a ver-

sion of the HUI [15, 21, 22, 33, 35, 36, 38–44, 46, 48, 49,51–54, 56, 57], eight used a version of the EQ-5D [11,15, 34, 37, 47, 50, 58, 59], three used a version of AQoLinstrument [21, 22, 57], one used the 15D [45] and oneused the SF-6D [55].

Narrative synthesisUtility outcomes are presented in Table 5 and PBM per-formance outcomes are presented in Table 6. The narra-tive synthesis is categorised by type of mobilityimpairment and PBM performance indicator. No studiesreported PBM reliability outcomes, therefore reliabilityresults have not been presented.

Cerebral palsyKnown-group analysesFive studies reported known-group analyses in CP [22,33, 51, 53, 58]. Petrou and Kupek [51] estimated that theadjusted HUI3 disutility of childhood CP from perfecthealth was − 0.72 (95% confidence interval [CI] -0.61 to− 0.85), and − 0.65 (95% CI − 0.54 to − 0.78) from child-hood norms. Two studies found that as CP severity (i.e.gross motor function) increased, average utility scores(measured using HUI3 or AQoL) decreased in adoles-cents and young adults with CP [22, 53]; Rosenbaumet al. [53] found statistically significant differences inmean utility scores between most Gross Motor FunctionClassification System (GMFCS) levels (p < 0.01). Onestudy demonstrated that the vision, pain and cognitiondimensions of the HUI3 steadily declined as GMFCSlevel increased, however statistical significance was notreported [33]. Vitale et al. [58] found that adolescentswith CP had significantly higher average EQ-5D utilityscores (0.92) compared to adolescents with scoliosis(with comorbidities) (0.73; p > 0.05), although selectionof these patient sub-groups was not explicitly justifiedand the version of the EQ-5D was not reported.

Convergent validity: comparing measuresTwo studies reported that GMFCS level was correlatedwith worsening utility scores [22, 53]. Young et al. [22]found that GMFCS level in childhood was responsiblefor between 45% (AQoL: β = − 0.148; p < 0.001) and 53%(HUI3: β = − 0.205; p < 0.001) of variance in utilityscores. Rosenbaum et al. [53] found a strong negativecorrelation between the HUI3 utility scores of adoles-cents with CP and their GMFCS level (r = − 0.81). Interms of individual PBM dimensions, results from fourstudies were varied [33, 35, 39, 49]; Kennes et al. [39]found that the dimension most associated with GMFCSlevel in children was ambulation (tau-b = 0.82; p < 0.01).Bartlett et al. [33] found that the HUI3 vision, pain andcognition dimensions generally worsened as GMFCSlevel increased in adolescents; however, there was no in-dication that these dimensions were determinants ofmotor capacity decline. Two studies [35, 49] reported asignificant negative association between the HUI3 paindimension and GMFCS level in children with CP, how-ever both of these studies only examined the HUI3 paindimension and not the full HUI3 system.Three studies reported various levels of correlation be-

tween PBMs and other outcome measures in CP [22, 46,53]. Young et al. [22] found moderate correlation be-tween utility score and SRH (r = 0.41; p < 0.001 for boththe HUI3 and AQoL). Two studies compared the Qual-ity of Life Instrument for People with DevelopmentalDisabilities (QOL Instrument) and the HUI3 [46, 53];Rosenbaum et al. [53] reported that adolescents’ HUI3


utility scores explained between 3% (belonging) and 14%(being) of variance in QOL Instrument dimensionscores, while Livingston and Rosenbaum [46] reportedthat the HUI3 and QOL Instrument shared up to 23%variance, thus the relationship between the measureswas considered to be moderate at best.Two studies reported on the relationship between

different PBMs in CP [22, 57]. Although utility scoresderived from the HUI3 and AQoL were strongly cor-related (r = 0.87; p < 0.001) [22], HUI3 derived utilityscores tended to be lower than AQoL derived utilityscores [22, 57].

Convergent validity: comparing respondentsFour studies examined correlation between respondentsin CP [22, 48–50]. Morrow et al. [48] reported moderateagreement between parents and doctors of children withCP for the HUI2/3 dimensions of sensation (63.6%agreement; Kappa 0.41), cognition (70% agreement;Kappa 0.56), self-care (100% agreement; Kappa 1.00) andambulation (63.6% agreement; Kappa 0.46). Good correl-ation was also found between child self-reported HUI3pain scores and equivalent parent proxy scores (Good-man and Kruskal’s y statistic = 0.57; p < 0.001) [49].Perez Sousa et al. [50] reported a high level of dis-

agreement between parents and children on the EQ-5D

Table 3 Quality appraisal outcomes

Study reference (author, year) Tests of statisticalsignificanceconducted

Sub-groupanalysesconducted

Clinicalimplicationsdiscussed

Proportions ofmissing/incorrectdata reported

Response and/orcompletion ratesreported

Inclusion and/orexclusion criteriaexplicitly stated

Bartlett et al. (2010) [33] Y Y Y Y X Y

Bray et al. (2017) [15] Y Y Y Y Y Y

Burstrom et al. (2014) [11] Y Y X Y Y X

Cavazza et al. 2016 [34] X X X X X X

Christensen et al. (2016) [35] Y Y Y X Y X

Findlay et al. (2015) [36] Y Y Y Y Y X

Hendriksz etl al (2014) [37]. Y Y Y Y X Y

Karmur and Kulkarni (2018) [38] Y X Y Y X X

Kennes et al. (2002) [39] Y Y Y Y X Y

Kulkarni et al. (2004) [40] Y X Y X Y Y

Kulkarni (2006) [41] Y Y X Y X Y

Kulkarni et al. (2008) [42] Y X Y Y Y X

Kulkarni et al. (2008) [43] Y Y Y X Y Y

Landfeldt et al. (2016) [44] Y X Y X Y X

Lindquist et al. (2014) [45] Y Y Y X X Y

Livingston and Rosenbaum (2008) [46] Y X Y Y X X

Lopez-Bastida et al. (2017) [47] X X Y Y X X

Morrow et al. (2011) [48]. Y Y Y X Y Y

Penner et al. (2013) [49] Y Y Y X Y X

Perez Sousa et al. (2017) [50] Y Y Y Y Y Y

Petrou and Kupec (2009) [51] Y Y Y Y X Y

Rocque et al. (2015) [52] Y Y Y X X Y

Rosenbaum et al. (2007) [53] Y Y Y Y X Y

Sims-Williams et al. (2016) [54] Y Y Y Y X Y

Slaman et al. (2015) [55] Y X Y X X Y

Tilford et al. (2005) [56] Y X Y X Y X

Usuba et al. (2014) [57] Y Y Y Y Y Y

Vitale et al. (2001) [58] Y Y Y X X Y

Wallander et al. (2009) [59]. Y X Y X Y Y

Young et al. (2010) [22]. Y Y Y Y Y Y

Young et al. (2013) [21] Y Y Y X Y Y


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Con

ditio

n(s)of

interest

Clinicalanddiagno

stic

inform

ation(%

ofsample)

Samplesize

Age

(mean±SD

;range

)and

gend

er(%

ofsample)

Bartlettet

al.

(2010)

[33]

Toexplorepo

ssiblereason

sfortheob

served

declinein

grossmotor

capacity

ofadolescentswith

cerebral

palsyin

GMFC

SlevelsIII,IV

andV

Canada

Prospe

ctive

coho

rtAdo

lescen

tswith

cerebral

palsy

GMFCSlevel

GMFC

SIII:38%

GMFC

SIV:35%

GMFC

SV:27%

Cerebralpalsy

sub-type

Diplegia:24%

Hem

iplegia:1%

Tetraplegia:71%

n=135

Mean14

yrs.(±2.4;rang

e11–17)

44%

female/56%

male

Bray

etal.

(2017)

[15]

Tocompare

how

children

with

mob

ility

impairm

ents

andtheirparents(byproxy)

repo

rtHRQ

oLusingstandard

outcom

emeasures

UK

Cross-sectio

nal

Childrenandadolescents

with

impairedmob

ility

(relevant

cond

ition

s:cerebral

palsy,he

miplegia,muscular

dystroph

y)

Mixed

diagno

ses

Cereb

ralp

alsy:85%

Hem

iplegia/stroke:8%

Musculardystroph

y:8%

n=13

Rang

e6-18

yrs.

39%

female/62%

male

Burstrom

etal.

(2014)

[11]

Totestthefeasibility

and

validity

oftheEQ

-5D-Y

ina

Swed

ishpatient

sampleof

childrenandadolescents

with

functio

nalm

otor,ortho

paed

icandmed

icaldisabil

ities

andto

compare

there

sults

with

age

neralp

opula

tionsample

Swed

enCase-control


with

functio

nalm

otor,

orthop

aedicandmed

ical

disabilities(re

levant

cond

ition

s:artrog

rypo

sis

multip

lecong

enital,

myelomen

ingo

cele,cereb

ral

palsy,orthop

aediclower

limb

deform

ities,achon

drop

lasia)

Mixed

diagno

ses

Artrogryposismultip

lecong

enital:14%

Myelomen

ingo

cele:17%

Cereb

ralp

alsy:20%

Ortho

paed

iclower

limb

deform

ities:7%

Achon

drop

lasia:6%

n=71

case

grou

pn=407control

grou

p

Case

group

Mean12

yrs.(±3.1;

rang

e7–17)

61%

female/39%

male

Controlgroup

Mean13

yrs.(±2.7;rang

e8–16)

49%

female/51%

male

Cavazza

etal.

(2016)

[34]

Tode

term

inetheecon

omic

burden

from

asocietal

perspe

ctiveandtheHRQ

oLof

patientswith

Duche

nne

musculardystroph

y,in

Europe

Multin

ational

(Bulgaria,France,

Germany,

Hun

gary,Italy,

Spain,Sw

eden

,UK)

Cross-sectio

nal

Ado

lescen

tsandadultswith

Duche

nnemuscular

dystroph

y

Not

stated

n=268

Meanagevariedby

coun

try,

from

11yrs.(±5.6)

inSw

eden

to23

yrs.(±15.8)inBu

lgaria.

70%

ofsamplewerechildren

(rang

e2–17)

7%female/93%

male

Christensen

etal.

(2016)

[35]

Toiden

tifyfactorsassociated

with

achange

inpain

over

timein

childrenwith

cerebral

palsy

Canada

Prospe

ctive

coho

rtChildrenandadolescents

with

cerebralpalsy

GMFCSlevel

GMFC

SI:21%

GMFC

SII:11%

GMFC

SIII:24%

GMFC

SIV:22%

GMFC

SV:22%

n=148

Mean8yrs.(rang

e3–19)

30%

female/70%

male

Find

layet

al.

(2015)

[36]

Toexplorewhe

ther

HRQ

oLcanbe

pred

ictedby

pain,

age,GMFC

Slevel,andsexin

childrenwith

cerebralpalsy

andwhe

ther

different

pain

aetio

logies

have

varying

effectson

HRQ

oL

Canada

Cross-sectio

nal

Childrenwith

cerebralpalsy

GMFCSlevel

GMFC

SI:26%

GMFC

SII:16%

GMFC

SIII:23%

GMFC

SIV:18%

GMFC

SV:17%

Cerebralpalsy

sub-type

Unilateral:19%

Bilateralspastic:75%

Dyskine

tic:4%

Other

(ataxicand

hypo

tonic):2%

n=248

Mean10

yrs.(±4.3)

37%

female/63%

male


Table

4Stud


mog

raph

icsforinclud

edstud

ies(Con

tinued)

Stud

yreference

Aim

sandob

jectives

Cou

ntry

Stud

ytype

Con

ditio

n(s)of

interest

Clinicalanddiagno

stic

inform

ation(%

ofsample)

Samplesize

Age

(mean±SD

;range

)and

gend

er(%

ofsample)

Hen

driksz

etal.

(2014)

[37]

Toassess

theglob

albu

rden

ofdiseaseam

ongpatients

with

Morqu

ioAsynd

rome,

includ

ingim

pact

onmob

ility/w

heelchairuse,

HRQ

oL,p

ainandfatig

ueand

theinteractionbe

tween

thesefactors

Multin

ational

(Brazil,Colom

bia,

Germany,Spain,

Turkey,U

K)

Cross-sectio

nal

Childrenandadultswith

Morqu

ioAsynd

rome

Comorbidities

Bone

deform

ity:75%

full

sample

Abn

ormalgait:96%

adult

grou

p/75%

child

grou

p

n=36

child

grou

pn=27

adult

grou

p

Child

group

Rang

e5-17

yrs.(47%

aged

10–14)

44%

female/56%

male

Adultgroup

Rang

e18-40yrs.(52%

aged

18–24)

44%

female/56%

male

Karm

urand

Kulkarni

(2018)

[38]

Toun

derstand

thequ

ality

oflifeof

patientswith

myelomen

ingo

celeand

shun

tedhydrocep

halus

Canada

Cross-sectio

nal


with

spinabifid

a(m

yelomen

ingo

cele)and

shun

tedhydrocep

halus

Not

stated

n=131

Mean12

yrs.(±3.7)

51%

female/49%

male

Kenn

eset

al.

(2002)

[39]

Tode

scrib

ethehe

alth

status

ofpre-adolescent

children

with

cerebralpalsy,andto

determ

inethestreng

thof

correlations

betw

eenthe

severityof

grossmotor

functio

nalimpairm

ent

andothe

raspe

ctsof

functio

nalh

ealth

status

(sen

sory,intellectual,

emotionaletc.)

Canada

Prospe

ctive

coho

rtChildrenwith

cerebralpalsy

GMFCSlevel

GMFC

SI:28%

GMFC

SII:12%

GMFC

SIII:20%

GMFC

SIV:20%

GMFC

SV:21%

n=408

Mean8yrs.(±1.9;rang

e5–15)

46%

female/54%

male

Kulkarni

etal.

(2004)

[40]

Tode

velopandtestthe

psycho

metric

prop

ertiesof

theHydroceph

alus

Outcome

Questionn

aire

(HOQ),as

ameasure

ofhe

alth

status

inclinicalresearch

projectsof

paed

iatrichydrocep

halus

Canada

Cross-sectio

nal

Childrenwith

hydrocep

halus

Hydroceph

alus

aetiology

Con

genital/aqu

eductal

sten

osis:36%

Myelomen

ingo

cele:13%

Other:51%

n=90

Mean10

yrs.(±3.5)

Gen

derdistrib

utionno

tstated

Kulkarni

etal.

(2006)

[41]

Tocompare

threeseparate

metho

dsforestablishing

interpretabilityfortheHOQ,

andto

calculatethe

conversion

ofnu

mericalHOQ

scores

into

utility

scores

obtained

from

HUI2

Canada

Cross-sectio

nal

Childrenwith

hydrocep

halus

Hydroceph

alus

aetiology

Con

genital/aqu

eductal

sten

osis:33%

Myelomen

ingo

cele:15%

Intraven

tricular

haem

orrhage:

13%

Other:40%

n=79

Mean10

yrs.(±3.5)

Gen

derdistrib

utionno

tstated

Kulkarni

etal.

(2008)

[42]

Tostud

ythefactors

associated

with

HRQ

oLin

Canadianchildrenwith

hydrocep

halus,usinga

compreh

ensive

mod

elof

determ

inantsof

child

health,

includ

ingsocioe

cono

mic

factors

Canada

Cross-sectio

nal

Childrenwith

hydrocep

halus

Hydroceph

alus

aetiology

Myelomen

ingo

cele:33%

Intraven

tricular

haem

orrhage

ofprem

aturity:9%

Aqu

eductalsteno

sis:10%

Post-in

fection:4%

Posteriorfossacyst:5%

Not

stated

:39%

n=340

Mean11

yrs.(±3.6)

Gen

derdistrib

utionno

tstated

Kulkarni

etal.

Toinvestigatethefeasibility

Canada

Cross-sectio

nal

Childrenwith

hydrocep

halus

Hydroceph

alus

aetiology

n=273

Mean14

yrs.(±2.6)


Table

4Stud


mog

raph

icsforinclud

edstud

ies(Con

tinued)

Stud

yreference

Aim

sandob

jectives

Cou

ntry

Stud

ytype

Con

ditio

n(s)of

interest

Clinicalanddiagno

stic

inform

ation(%

ofsample)

Samplesize

Age

(mean±SD

;range

)and

gend

er(%

ofsample)

(2008)

[43]

andscientificprop

ertiesof

achild-com

pleted

versionof

theHOQ(cHOQ)

Myelomen

ingo

cele:34%

Intraven

tricular

haem

orrhage

ofprem

aturity:11%

Aqu

eductalsteno

sis:10%

Post-in

fection:4%

Con

genitalcom

mun

icating:

3% Intracranialcyst:8%

Other:30%

47%

female/54%

male

Land

feldtet

al.

(2016)

[44]

Toestim

ateHRQ

oLin

patientswith

Duche

nne

musculardystroph

y

Multin

ational

(Germany,Italy,

UK,USA

)

Cross-sectio

nal


with

Duche

nnemuscular

dystroph

y

Ambulatorystatus

Early

ambu

latory

(5-7yrs):

20%

Late

ambu

latory

(8-11yrs):

33%

Early

non-am

bulatory

(12-15

yrs):20%

Late

non-am

bulatory

(≥16

yrs):27%

n=770

Mean14

yrs.(±7.0)

100%

male

Lind

quistet

al.

(2014)

[45]

Toanalysequ

ality

oflifein

avery

long

-term

follow-upof

now

adultindividu

als,treated

forhydrocep

halus(with

out

spinabifid

a)du

ringtheirfirst

year

oflife

Swed

enCross-sectio

nal

Adu

ltswho

expe

rienced

hydrocep

halusin

infancy

31%

ofstud

ygrou

pdiagno

sedwith

cerebralpalsy

and/or

epilepsy;

hydrocep

halusaetio

logies

notrepo

rted

n=29

stud

ygrou

pn=1613

controlg

roup

Studygroup

Mean34

yrs.(rang

e30–41)

38%

female/62%

male

Controlgroup

Matched

ageandge

nder

tocase

grou

p

Living

ston

and

Rosenb

aum

(2008)

[46]

Toassess

thestability

ofmeasuremen

tof

quality

oflifeandHRQ

oLover

the

course

of1year

amon

gadolescentswith

cerebral

palsy

Canada

Prospe

ctive

coho

rtAdo

lescen

tswith

cerebral

palsy

GMFCSlevel

GMFC

SI:30%

GMFC

SII:16%

GMFC

SIII:15%

GMFC

SIV:25%

GMFC

SV:15%

n=185

Mean16

yrs.(±1.75;range

13–20)

47%

female/54%

male

Lope

z-Bastida

etal.(2017)[47]

Tode

term

inetheecon

omic

burden

andhe

alth-related

quality

oflifeof

patientswith

spinalmuscularatroph

yand

theircaregiversin

Spain

Spain

Cross-sectio

nal

Childrenwith

spinalmuscular

atroph

ySpinal

muscularatroph

ytype

Type

I:10%

Type

II:74%

Type

III:16%

n=81

Mean7yrs.(±5.47)

58%

female/42%

male

Morrow

etal.

(2011)

[48]

Toevaluate

differences

betw

eenchildren’s,parents’

anddo

ctors’pe

rcep

tions

ofhe

alth

states

andHRQ

oLin

childrenwith

chronicillne

ssandexplorefactorswhich

explainthesedifferences

Australia

Cross-sectio

nal

Childrenwith

chronic

cond

ition

s(re

levant

cond

ition

:cereb

ralp

alsy)

Allparticipantsin

cerebral

palsysub-grou

pwerecate

gorised

asGMFC

SlevelV

Cerebralpalsy

sub-group

n=1child-

parent

pair

n=1child-

doctor

pair

n=11

parent-

doctor

pairs

Cerebralpalsy

sub-group

36%

aged

>12

yrs.

Gen

derdistrib

utionno

trepo

rted

Penn

eret

al.

(2013)

[49]

Tode

term

inetheim

pact

ofpain

onactivities

andto

iden

tifythecommon

Canada

Cross-sectio

nal


with

cerebralpalsy

GMFCSlevel

GMFC

SI:24%

GMFC

SII:13%

n=252

Mean9yrs.(±4.2;rang

e3–19)

36%

female/64%

male


Table

4Stud


mog

raph

icsforinclud

edstud

ies(Con

tinued)

Stud

yreference

Aim

sandob

jectives

Cou

ntry

Stud

ytype

Con

ditio

n(s)of

interest

Clinicalanddiagno

stic

inform

ation(%

ofsample)

Samplesize

Age

(mean±SD

;range

)and

gend

er(%

ofsample)

physician-iden

tifiedcauses

ofpain

inchildrenandyouth

aged

3to

19yearsacross

all

levelsof

severityof

cerebral

palsy

GMFC

SIII:21%

GMFC

SIV:19%

GMFC

SV:23%

PerezSousaet

al.

(2017)

[50]

Toanalysethelevelo

fagreem

entbe

tweenchildren

with

cerebralpalsyandtheir

parents,usingtheEQ

-5D-Y

questio

nnaire

andits

proxy

version

Spain

Cross-sectio

nal


with

cerebralpalsy

Functiona

lclassification

Grade

1(with

outactivity

limitatio

n):66%

Grade

2(m

ildor

mod

erate

activity

limitatio

n):34%

n=62

Mean10

yrs.(±2.3;rang

e6–17)

44%

female/56%

male

Petrou

andKu

pek

(2009)

[51]

Toaugm

entprevious

catalogu

esof

preferen

ce-

basedHRQ

oLweigh

tsby

estim

atingpreferen

ce-based

HUI3multiattrib

uteutility

scores

associated

with

awide

rang

eof

childho

odcond

ition

s

UK

Cross-sectio

nal

Childrenwith

childho

odcond

ition

s(re

levant

cond

ition

s:microceph

aly,

cerebralpalsy,spinal

muscularatroph

y,muscular

dystroph

y,spinabifid

a)

Not

stated

Relevant

sub-

groups

Microceph

aly

n=40

Cereb

ralp

alsy

n=178

Muscular

dystroph

yor

spinal

muscular

atroph

yn=45

Spinabifid

an=42

Relevant

sub-groups

Microceph

aly:mean11

yrs.

Cereb

ralp

alsy:m

ean11

yrs.

Musculardystroph

yor

spinal

muscularatroph

y:mean

12yrs.

Spinabifid

a:mean13

yrs.

Gen

derdistrib

utionpe

rsub-

grou

pno

trepo

rted

Rocque

etal.

(2015)

[52]

Tocharacterisethequ

ality

oflifeof

paed

iatricpatientswith

spinabifid

a,andto

analyse

factorsthat

influen

ceHRQ

oLandaidin

thede

term

ination

ofwhe

ther

acorrelation

existsbe

tweenvario

usdiseaseand/or

person

alcharacteristicsandHRQ

oLscores

USA

Cross-sectio

nal


with

spinabifid

aUnd

erlyingdiagno

sisMyelomen

ingo

cele:79%

Lipo

myelomen

ingo

cele:16%

Men

ingo

cele:3%

Filum

term

inale-related

patholog

y:2%

Sacralagen

esis:>

1%

n=159

Mean12

yrs.(rang

e5–20)

57%

female/43%

male

Rosenb

aum

etal.

(2007)

[53]

Torepo

rtself-

and

proxy-assessed

quality

oflife

alon

gwith

parentalaccoun

tsof

HRQ

oLof

acoho

rtof

adolescentswith

cerebral

palsyparticipatingin

along

itudinalstudy

chartin

gmob

ility

andself-care

throug

htheadolescent

years

Canada

Prospe

ctive

coho

rtAdo

lescen

tswith

cerebral

palsy

GMFCSlevel

GMFC

SI:30%

GMFC

SII:16%

GMFC

SIII:14%

GMFC

SIV:25%

GMFC

SV:16%

n=203

Mean16

yrs.(±1.75;range

13–20)

45%

female/55%

male

Sims-Williams

etal.(2017)[54]

Toascertainthequ

ality

oflife

ofsurvivingchildrenwith

spinabifid

aandto

determ

ine

whe

ther

thiswas

influen

ced

Ugand

aCross-sectio

nal

Childrenwith

spinabifid

a45%

ofsamplehad

comorbidhydrocep

halus

Walking

ability

Unableto

walk:47%

n=66

(63of

which

completed

HUI3)

Rang

e10-14yrs.

44%

female/56%

male


Table

4Stud


mog

raph

icsforinclud

edstud

ies(Con

tinued)

Stud

yreference

Aim

sandob

jectives

Cou

ntry

Stud

ytype

Con

ditio

n(s)of

interest

Clinicalanddiagno

stic

inform

ation(%

ofsample)

Samplesize

Age

(mean±SD

;range

)and

gend

er(%

ofsample)

bymob

ility,urin

ary

continen

ce,hydroceph

alus,

sex,family

size

andscho

olattend

ance

Walkwith

sticks/crutche

s:14%

Walkun

aide

d:39%

Slam

anet

al.

(2015)

[55]

Toevaluate

thecost-utility

ofalifestyleinterven

tions

amon

gadolescentsand

youn

gadultswith

cerebral

palsy

TheNethe

rland

sRand

omised

controlledtrial

(single-blind)

Ado

lescen

tsandyoun

gadultswith

cerebralpalsy

Interven

tiongrou

pGMFC

Slevel

GMFC

SI:61%

GMFC

SII:32%

GMFC

SIII:7%

GMFC

SIV:0%

Con

trol

grou

pGMFC

Slevel

GMFC

SI:55%

GMFC

SII:31%

GMFC

SIII:10%

GMFC

SIV:4%

n=20

interven

tion

grou

pn=20

control

grou

p

Interventiongroup

Mean20

yrs.(±3.0)

57%

female/43%

male

Controlgroup

Mean20

yrs.(±3.0)

48%

female/52%

male

Tilford

etal.

(2005)

[56]

Toprovideinform

ationon

thepreferen

cescores

ofchildrenwith

spinabifid

aaperta

andto

measure

the

impact

ofcarin

gforachild

with

spinabifid

aconsistent

with

econ

omicevaluatio

ns

USA

Case-control

Childrenwith

spinabifid

aCa

segrouplesio

nlevel

Sacral:42%

Lower

lumbar:34%

Thoracic:25%

n=80

case

grou

pn=30

gene

ral

popu

latio

ncontrolg

roup

Case

group

Mean9yrs.(±4.6)

61%

female/39%

male

Generalpopulationcontrol

group

Mean7yrs.(±4.0)

55%

female/45%

male

Usuba

etal.

(2014)

[57]

Toexplorethemagnitude

andtim

ingof

change

sin

grossmotor

functio

nand

HRQ

oLam

ongpe

rson

swith

cerebralpalsyover

an8-year

perio

d,with

specificinterest

incomparin

gthosewho

madethetransitio

nto

adult

services

Canada

Prospe

ctive

coho

rtAdo

lescen

tsandadultswith

cerebralpalsy

GMFCSlevel(fullsample)

GMFC

SI:22%

GMFC

SII:13%

GMFC

SIII:13%

GMFC

SIV:22%

GMFC

SV:30%

n=31

‘you

nger

adults’g

roup

n=23

‘older

adults’g

roup

‘Young

eradults’group

Mean15

yrs.(rang

e13–17)

‘Olderadults’group

Mean26

yrs.(rang

e23–32)

Fullsample

46%

female/54%

male

Vitaleet

al.

(2001)

[58]

Toexam

inewhe

ther

theSF-

36andEQ

-5Dwou

ldbe

use

fulfor

evaluatin

gqu

ality

oflifein

adolescentswith

ortho

paed

iccond

ition

s

USA

Cross-sectio

nal

Ado

lescen

tswith

orthop

aedic

prob

lems(re

levant

cond

ition

:cerebralpalsy)

Not

stated

n=14

cerebralpalsy

sub-grou

p

Cereb

ralp

alsy

sub-grou

page

data

notrepo

rted

(full

sample:mean14

yrs.

[rang

e10–18])

Gen

derdistrib

utionno

trepo

rted

Walland

eret

al.

(2009)

[59]

Toreview

agrou

pof

patients

over

60yearsof

agewho

had

been

treatedforcong

enital

talipes

equinu

svarus(CTEV)

ininfancy,usingge

neric

instrumen

tsforthe

assessmen

tof

quality

oflife

inge

neraland

aspecificfoot

andankleinstrumen

tfor

assessmen

tof

functio

n

Swed

enCross-sectio

nal

Adu

ltstreatedforCTEVin

infancy

Clubfoot

laterality

Unilateral:54%

Bilateral:46%

n=83

Mean64

yrs.(rang

e62–67)

24%

female/76%

male


Table

4Stud


mog

raph

icsforinclud

edstud

ies(Con

tinued)

Stud

yreference

Aim

sandob

jectives

Cou

ntry

Stud

ytype

Con

ditio

n(s)of

interest

Clinicalanddiagno

stic

inform

ation(%

ofsample)

Samplesize

Age

(mean±SD

;range

)and

gend

er(%

ofsample)

Youn

get

al.

(2010)

[22]

Tode

scrib

ethehe

alth

and

quality

oflifeou

tcom

esof

youthandyoun

gadultswith

cerebralpalsy,andto

explore

theim

pact

of3factors

(cereb

ralp

alsy

severity,age

andsex)on

quality

oflife

outcom

es

Canada

Cross-sectio

nal

Ado

lescen

tsandyoun

gadultswith

cerebralpalsy

‘Youth’group

GMFCSlevel

GMFC

SI:22%

GMFC

SII:12%

GMFC

SIII:18%

GMFC

SIV:25%

GMFC

SV:22%

‘Adult’groupGMFCSlevel

GMFC

SI:23%

GMFC

SII:14%

GMFC

SIII:19%

GMFC

SIV:25%

GMFC

SV:20%

n=129‘you

th’

grou

pn=70

‘adu

lt’grou

p

‘Youth’group

Mean15

yrs.(±1.36)

45%

female/55%

male

‘Adult’group

Mean26

yrs.(±2.63)

40%

female/60%

male

Youn

get

al.

(2013)

[21]

Tode

scrib

ethehe

alth

and

HRQ

oLou

tcom

esof

youths

andyoun

gadultswith

spina

bifid

a

Canada

Cross-sectio

nal

Ado

lescen

tsandyoun

gadultswith

spinabifid

a‘Youth’group

lesio

nlevelTho

racic:25%

High-lumbar:18%

Low-lu

mbar:30%

Sacral:28%

‘Adult’grouplesio

nlevel

Thoracic:15%

High-lumbar:23%

Low-lu

mbar:31%

Sacral:15%

Unkno

wn:15%

n=40

‘you

th’

grou

pn=13

‘adu

lt’grou

p

‘Youth’groupMean16

yrs.

(±1.3;rang

e13–17)65%

female/35%

male

‘Adult’group

Mean26

yrs.(±3.10;

rang

e23–32)

77%

female/23%

male


Table

5Summaryof

utility

outcom

esforinclud

edstud

ies

Stud

yreference

Con

ditio

n(s)of

interest

Respon

dent

type

PBM

(s)

Other

relevant

outcom

emeasures

Overallutility

scores

(mean±SD

)Sub-grou

putility

scores

(mean±SD

)

Bartlettet

al.

(2010)

[33]

Ado

lescen

tswith

cerebral

palsy

Proxy(paren

t)HUI3

Gross

Motor

Functio

nMeasure

66Items(GMFM

-66)

SpinalAlignm

entandRang

eof

MotionMeasure

(SARO

MM)

NA

Overallutility

scores

notrepo

rted

,on

lyvision

,cog

nitio

nandpain

dimen

sion

sused

-am

bulatio

n,he

aring,

speech,d

exterityand

emotiondimen

sion

sallexclude

ddu

eto

concep

tualoverlapwith

othe

rmeasures

NA

Bray

etal.(2017)[15]


with

impairedmob

ility

(relevant

cond

ition

s:cerebral

palsy,he

miplegia,muscular

dystroph

y)

Self-repo

rted

and

proxy(paren

t);

matched

-pairs

HUI2,H

UI3and

EQ-5D-Y

Visualanalog

uescale(VAS)

Child

self-reported

HUI2:0.53(±0.07)

HUI3:0.22(±0.09)

EQ-5D-Y:0.24(±0.30)

Parent

proxy

HUI2:0.49(±0.09)

HUI3:0.16(±0.10)

EQ-5D-Y:0.01(±0.14)

NA

Burstrom

etal.

(2014)

[11]


with

functio

nalm

otor,

orthop

aedicandmed

ical

disabilities(re

levant

cond

ition

s:artrog

rypo

sis

multip

lecong

enital,

myelomen

ingo

cele,cereb

ral

palsy,orthop

aediclower

limb

deform

ities,achon

drop

lasia)

Self-repo

rted

EQ-5D-Y

VAS

KIDSC

REEN

-27

KIDSC

REEN

-10

Self-ratedhe

alth

(SRH

)Life

satisfactionladd

er(LSL)

NA

Overallutility

scores

notrepo

rted

,on

lydimen

sion

scores

repo

rted

NA

Cavazza

etal.

(2016)

[34]

Ado

lescen

tsandadultswith

Duche

nnemuscular

dystroph

y

Self-repo

rted

EQ-5D-Y

VAS

Barthe

lInd

exMean0.24

Variedby

coun

try,rang

ingfro

m−0.71

(±0.41)in

Swed

ento

0.66

(±0.08)in

Bulgaria

NA

Christensen

etal.

(2016)

[35]


with

cerebralpalsy

Proxy(careg

iver)

HUI3

Won

g-BakerFA

CES

Pain

Ratin

gScale

NA

Overallutility

scores

notrepo

rted

,on

lyHUI3pain

dimen

sion

measured

NA

Find

layet

al.

(2015)

[36]

Childrenwith

cerebralpalsy

Self-repo

rted

and

proxy(careg

iver);

prop

ortio

nof

proxy

data

notrepo

rted

HUI3

DISABKIDSChron

icGen

eric

mod

ule(DCGM-37)

DISABKIDSSm

ileymeasure

(DSM

)Won

g-BakerFA

CES

Pain

Ratin

gScale

NA

Overallutility

scores

notrepo

rted

,on

lyHUI3pain

dimen

sion

measured

NA

Hen

driksz

etal.

(2014)

[37]


Morqu

ioAsynd

rome

Self-repo

rted

EQ-5D-5L

BriefPain

InventoryShort

Form

(BPI-SF)

Ado

lescen

tPediatric

Pain

Tool

(APPT)

NA

Overallutility

scores

notrepo

rted

Child

group:utilityscoreby

wheelchairusefrequency

Nouse:0.534

Occasionalu

se:0.664

Full-tim

euse:−0.180

Adultgroup:utilityscoreby

wheelchairusefrequency

Nouse:0.846

Occasionalu

se:0.582

Full-tim

euse:0.057

Karm

urandKu

lkarni

(2018)

[38]


with

spinabifid

a(m

yelomen

ingo

cele)and

Proxy(careg

iver)

HUI2andHUI3

(version

used

tocalculateutility

Hydroceph

alus

Outcome

Questionn

aire

(HOQ)

0.51

(±0.28)

NA


Table

5Summaryof

utility

outcom

esforinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Respon

dent

type

PBM

(s)

Other

relevant

outcom

emeasures

Overallutility

scores

(mean±SD

)Sub-grou

putility

scores

(mean±SD

)

shun

tedhydrocep

halus

scores

notstated

)

Kenn

eset

al.

(2002)

[39]

Childrenwith

cerebralpalsy

Proxy(careg

iver)

HUI3

Functio

nalInd

epen

dence

Measure

forChildren

(WeeFIM)

Streng

thandDifficulties

Questionn

aire

(SDQ)

WideRang

eAchievemen

tTest(W

RAT)

NA

Overallutility

scores

notrepo

rted

,on

lydimen

sion

scores

repo

rted

NA

Kulkarni

etal.

(2004)

[40]

Childrenwith

hydrocep

halus

Proxy(paren

t)HUI2

HOQ

NA

Overallutility

scores

notrepo

rted

NA

Kulkarni

etal.

(2006)

[41]

Childrenwith

hydrocep

halus

Proxy(paren

t)HUI2

HOQ

NA

Overallutility

scores

notrepo

rted

NA

Kulkarni

etal.

(2008)

[42]

Childrenwith

hydrocep

halus

Proxy(careg

iver)

HUI3

HOQ

0.58

(±0.32)

NA

Kulkarni

etal.

(2008)

[43]

Childrenwith

hydrocep

halus

Self-repo

rted

and

proxy(careg

iver);

proxy-repo

rted

HUI3

andHOQ,self-

repo

rted

cHOQ

HUI3

Child-com

pleted

versionof

theHOQ(cHOQ)

0.71

(±0.27)

NA

Land

feldtet

al.

(2016)

[44]


with

Duche

nnemuscular

dystroph

y

Proxy(careg

iver);

althou

ghpatients

includ

edin

data

collection,

only

proxyutility

data

repo

rted

HUI(versionno

tstated

)Pediatric

Qualityof

Life

Inventory(Ped

sQL)

neurom

uscularmod

ule3.0

NA

Overallutility

scores

notrepo

rted

Utility

scoreby

ambulatorystatus

Early

ambu

latory:0.75

Late

non-am

bulatory:0.15

Lind

quistet

al.

(2014)

[45]

Adu

ltswho

expe

rienced

hydrocep

halusin

infancy

Self-repo

rted

15D

NA

Stud

ygrou

p:0.92

Con

trol

grou

p:0.95

Living

ston

and

Rosenb

aum

(2008)

[46]

Ado

lescen

tswith

cerebral

palsy

Proxy(paren

t)HUI3

Qualityof

Life

Instrumen

tfor

Peop

lewith

Develop

men

tal

Disabilities(QOLInstrumen

t)

NA

Overallutility

scores

notrepo

rted

NA

Lope

z-Bastidaet

al.

(2017)

[47]

Childrenwith

spinalmuscular

atroph

yProxy(careg

iver)

EQ-5D-3L

VAS

Barthe

lInd

ex0.16

(±0.44)

Utility

scoreby

spinal

muscular

atroph

ytype

Type

IIspinalmuscularatroph

ysub-grou

p:−0.01

(±0.35)

Scores

forType

Iand

IIIno

trepo

rted

Morrow

etal.

(2011)

[48]

Childrenwith

chronic

cond

ition

s(re

levant

cond

ition

:cereb

ralp

alsy)

Self-repo

rted

and

proxy(paren

tand

doctor);matched

grou

ps

HUI2andHUI3

NA

NA

Overallutility

scores

notrepo

rted

forrelevant

sub-grou

p

NA

Penn

eret

al.

(2013)

[49]


with

cerebralpalsy

Self-repo

rted

and

proxy(paren

tand

physician);p

roxy-

repo

rted

HUI3pain

score,self-repo

rted

Won

g-BakerFA

CES

Pain

Scale

HUI3

Won

g-BakerFA

CES

Pain

Ratin

gScale

NA

Overallutility

scores

notrepo

rted

,on

lyHUI3pain

dimen

sion

measured

NA

PerezSousaet

al.


Self-repo

rted

and

EQ-5D-Y

VAS

NA

NA


Table

5Summaryof

utility

outcom

esforinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Respon

dent

type

PBM

(s)

Other

relevant

outcom

emeasures

Overallutility

scores

(mean±SD

)Sub-grou

putility

scores

(mean±SD

)

(2017)

[50]

with

cerebralpalsy

proxy(m

othe

rand

father);matched

grou

ps

Overallutility

scores

notrepo

rted

,on

lydimen

sion

scores

repo

rted

Petrou

andKu

pek

(2009)

[51]

Childrenwith

childho

odcond

ition

s(re

levant

cond

ition

s:microceph

aly,


muscularatroph

y,muscular

dystroph

y,spinabifid

a)

Proxy(careg

iver)

HUI3

NA

Meanutilityby

cond

ition

Microceph

aly:0.141

Cereb

ralp

alsy:0.276

Musculardystroph

yor

spinal

muscularatroph

y:0.386

Spinabifid

a:0.452

NA

Rocque

etal.

(2015)

[52]


with

spinabifid

aSelf-repo

rted

and

proxy(careg

iver);

pred

ominantly

proxy

(11%

self-repo

rted

)

HUI3

NA

NA

Overallutility

scores

notrepo

rted

Utility

scoreby

type

ofspinabifida

Myelomen

ingo

cele:0.51

Closedspinaldysraphism

:0.77

Utility

scoreby

treatm

enthistory

Nohistoryof

shun

tor

CM-II

decompression

:0.74

Shun

tbu

tno

CM-II

decompression

:0.49

Shun

tandCM-II

decompression

:0.29

Rosenb

aum

etal.

(2007)

[53]

Ado

lescen

tswith

cerebral

palsy

Self-repo

rted

and

proxy(paren

t);

proxy-repo

rted

HUI3,

34%

self-repo

rted

QOLInstrumen

t

HUI3

QOLInstrumen

t0.42

(±0.41)

Utility

scoreby

GMFCSlevel

GMFC

SI:0.84

(±0.20)

GMFC

SII:0.50

(±0.31)

GMFC

SIII:0.39(±0.31)

GMFC

SIV:0.16(±0.26)

GMFC

SV:−0.08

(±0.23)

Sims-Williamset

al.

(2017)

[54]

Childrenwith

spinabifid

aSelf-repo

rted

and

proxy(careg

iver);

matched

pairs

HUI3

VAS

Child

self-reported

0.58

(95%

CI0.49–0.66)

Caregiverproxy

0.55

(95%

CI0.47–0.63)

NA

Slam

anet

al.

(2015)

[55]

Ado

lescen

tsandyoun

gadultswith

cerebralpalsy

Self-repo

rted

SF-6D

36-Item

ShortForm

Survey

(SF-36)-SF-6Dutility

out

comes

derived

from

SF-36

Baseline

Con

trol:0.74(±0.12)

Interven

tion:

0.75

(±0.10)

6mon

thspostintervention

Con

trol:0.77(±0.12)

Interven

tion:

0.80

(±0.03)

NA

Tilford

etal.

(2005)

[56]

Childrenwith

spinabifid

aProxy(careg

iver)

HUI2

Qualityof

Well-Being

scale

(QWB)

Casegrou

p:0.55

(±0.24)

Utility

bycase

grouplesio

nlevel

Sacrallesion

:0.61(±0.26)

Lower

lumbarlesion

:0.54(±0.19)

Thoraciclesion

:0.45(±0.25)

Gen

eralpo

pulatio

ncontrol

grou

p:0.93

(±0.11)

Usuba

etal.

(2014)

[57]

Ado

lescen

tsandadultswith

cerebralpalsy

Self-repo

rted

and

proxy(und

efined

);pred

ominantly

proxy

(40%

self-repo

rted

)

HUI3andAQoL

SRH

Baseline(bothgroups)

HUI3:0.29(±0.39)

AQoL:0.35(±0.33)

8-year

follow-up(bothgroups)

HUI3:0.29(±0.38)

AQoL:0.35(±0.32)

NA

Vitaleet

al.

(2001)

[58]

Ado

lescen

tswith

orthop

aedicprob

lems

(relevant

cond

ition

:cereb

ral

palsy)

Self-repo

rted

EQ-5D(version

not

stated

)SF-36

Cereb

ralp

alsy

sub-grou

p:0.922

NA


Table

5Summaryof

utility

outcom

esforinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Respon

dent

type

PBM

(s)

Other

relevant

outcom

emeasures

Overallutility

scores

(mean±SD

)Sub-grou

putility

scores

(mean±SD

)

Walland

eret

al.

(2009)

[59]

Adu

ltstreatedforCTEVin

infancy

Self-repo

rted

EQ-5D(version

not

stated

)SF-36

VAS

American

Acade

myof

Ortho

paed

icSurgeo

nsFoot

andAnkleQuestionn

aire

NA

Overallutility

scores

notrepo

rted

NA

Youn

get

al.

(2010)

[22]

Ado

lescen

tsandyoun

gadultswith

cerebralpalsy

Self-repo

rted

and

proxy(careg

iver);

pred

ominantly

self-

repo

rted

(45%

proxy)

HUI3andAQoL

SRH

Health

Assessm

ent

Questionn

aire

(HAQ)

Com

bine

dagegrou

psHUI3:0.30(±0.42)

AQoL:0.28(±0.33)

Utility

scoreby

agegroup

(HUI3/AQ

oL)

‘You

th’g

roup

:0.30(±0.43)/

0.28

(±0.34)

‘Adu

lt’grou

p:0.31

(±0.40)/

0.28

(±0.314)

Youthgroup:utilityscoreby

GMFCSlevel(HUI3/AQ

oL)

GMFC

SI:0.67

(±0.32)/0.58

(±0.31)

GMFC

SII:0.59

(±0.35)/0.53

(±0.34)

GMFC

SIII:0.43(±0.39)/0.31

(±0.32)

GMFC

SIV:0.08(±0.25)/0.06

(±0.12)

GMFC

SV:−0.13

(±0.19)/0.01

(±0.07)

Adultgroup:utilityscoreby

GMFCS

level(HUI3/AQ

oL)GMFC

SI:0.64

(±0.30)/0.52

(±0.32)

GMFC

SII:0.50

(±0.39)/0.33

(±0.24)

GMFC

SIII:0.53(±0.27)/0.39

(±0.27)

GMFC

SIV:0.06(±0.21)/0.10

(±0.20)

GMFC

SV:−0.14

(±0.20)/0.02

(±0.06)

Youn

get

al.

(2013)

[21]

Ado

lescen

tsandyoun

gadultswith

spinabifid

aSelf-repo

rted

and

proxy(careg

iver);

pred

ominantly

self-

repo

rted

(15%

proxy)

HUI3andAQoL

SRHHAQ

Com

bine

dagegrou

psHUI3:0.52(±0.28)

AQoL:0.34(±0.24)

Utility

scoreby

agegroup(HUI3/

AQoL)

‘You

th’g

roup

:0.58(±0.27)/0.37

(±0.26)

‘Adu

lt’grou

p:0.36

(±0.27)/0.25

(±0.17)

Utility

scoreby

lesio

nlevel(HUI3/

AQoL)

Thoracic:0.29(±0.14)/0.22

(±0.14)

High-lumbar:0.44

(±0.31)/0.28

(±0.23)

Low-lu

mbar:0.63

(±0.23)/0.39

(±0.21)

Sacral:0.76(±0.20)/0.51

(±0.33)

Unkno

wn:

0.22

(±0.02)/0.09

(±0.04)


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

Bartlettet

al.

(2010)

[33]

Ado

lescen

tswith

cerebral

palsy

HUI3vision

,cog

nitio

nandpain

dimen

sion

ssteadilyde

clined

asGMFC

Slevel

increased,

statistical

sign

ificanceno

trepo

rted

.

Exam

iningcorrelation

coefficients,therewas

noindicatio

nthat

theHUI3

vision

(r=0.01;p

=0.92),

cogn

ition

(r=−0.05;p

=0.59)or

pain

dimen

sion

s(r=0.16;p

=0.07)w

ere

determ

inantsof

motor

capacity,asmeasured

usingtheGMFM

-66.

NA

NA

Individu

alswith

aGMFC

Slevelo

fVexhibitedthe

largestmeande

creasesin

HUI3dimen

sion

levels

over

time,rang

ingfro

m−0.2(±1.2)

fortheHUI3

vision

dimen

sion

to−0.3

(±1.3)

fortheHUI3

cogn

ition

andpain

dimen

sion

s.

Bray

etal.

(2017)

[15]


with

impairedmob

ility

(relevant

cond

ition

s:cerebralpalsy,

hemiplegia,muscular

dystroph

y)

NA

NA

Largevariancebe

tween

meanutility

scores

derived

from

different

PBMs,rang

ingfro

m0.24

(EQ-5D-Y)to0.53

(HUI2)

forchild

self-repo

rted

utility,and

from

0.01

(EQ-

5D-Y)to

0.49

(HUI2)for

parent-rep

ortedproxy

utility.

Asign

ificant

respon

dent

type

effect

was

foun

d,with

meanchild

self-

repo

rted

utility

scores

sign

ificantly(p

≤0.021)

high

erthan

equivalent

proxieson

allP

BMs.

Sign

ificant

strong

correlations

werefoun

dbe

tweenutility

scores

for

children/parent

proxies

usingallm

easures:EQ

-5D

-Y(r=0.67;p

=0.026),

HUI2(r=0.73;p

=0.005)

andHUI3(r=0.84;p

<0.001).

Using

Bland-Altm

anplots,

sufficien

tagreem

ent

betw

eenutility

scores

for

children/parent

proxies

was

foun

dfortheHUI2

(CL=0.22)andHUI3

(CL=0.22).EQ

-5D-Y

exhibitedclinically

impo

rtantdiscrepancies

betw

eenchild

andparent

proxyrespon

ses

(CL=1.04).

NA

Burstrom

etal.

(2014)

[11]


with

functio

nalm

otor,

orthop

aedicandmed

ical

disabilities(re

levant

cond

ition

s:artrog

rypo

sis

multip

lecong

enital,

myelomen

ingo

cele,

cerebralpalsy,

orthop

aediclower

limb

deform

ities,

Statisticallysign

ificant

(p≤0.001)

differences

betw

eencase

and

controlg

roup

son

all

dimen

sion

s.Mean

dimen

sion

scores

not

repo

rted

,propo

rtions

ofpatientschoo

sing

each

dimen

sion

level

indicate

case

grou

p

Strong

sign

ificant

correlationwas

foun

dbe

tweentheEQ

-5D-Y

anxiety/de

pression

dimen

sion

andthe

KIDSC

REEN

-27psycho

logicalw

ell-b

eing

dimen

sion

(r=−0.51;p

=0.001);

KIDSC

REEN

-27ph

ysical

well-b

eing

dimen

sion

NA

NA

NA


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

acho

ndroplasia)

repo

rted

more

prob

lemson

all

dimen

sion

sthan

the

controlg

roup

:83%

ofcase

grou

prepo

rted

some/alotof

prob

lemson

any

dimen

sion

,com

pared

to37%

ofcontrol

grou

p;likew

ise21%

ofcase

grou

prepo

rted

extrem

eprob

lemson

any

dimen

sion

,com

pared

to2%

ofcontrol

grou

p.

(r=−0.53;p

=0.001);and

lifesatisfactionladd

er(LSL)(r=

−0.54;p

<0.001).M

oderatecorrel

ationalso

foun

dbe

tween

thisdimen

sion

andthe

KIDSC

REEN

-10HRQ

oLinde

xscore(r=−0.50;

p=0.001)

andself-

repo

rted

health

(SRH

)(0.42;p=0.007).

Theself-care

EQ-5D-Y

dimen

sion

exhibitedmod

eratecorrelationwith

the

KIDSC

REEN

-27ph

ysical

wellbeing

dimen

sion

(r=

−0.37;p

=0.028)

andthe

usualactivities

EQ-5D-Y

dimen

sion

was

mod

eratelycorrelated

with

theKIDSC

REEN

-27

psycho

logicalw

ellbeing

dimen

sion

(r=−0.35;p

=0.027).A

llothe

rcorrelations

were

weakor

absent.

Cavazza

etal.

(2016)

[34]

Ado

lescen

tsandadults

with

Duche

nnemuscular

dystroph

y

NA

NA

NA

NA

NA

Christensen

etal.

(2016)

[35]


with

cerebralpalsy

NA

Using

multivariate

linear

regression

,asign

ificant

associationwas

foun

dbe

tweentheHUI3pain

dimen

sion

scoreat

baselineandGMFC

Slevel

(b=−0.11,β

=−0.15;

p<0.036;95%

CI−

0.21

to−0.01):high

erpain

scoreat

baselinewas

associated

with

greater

improvem

entin

pain

status

inGMFC

SlevelI

comparedto

levelV

.

NA

NA

Using

one-way

ANOVA

analysis,a

sign

ificant

associationwas

foun

dbe

tweenph

ysician

prim

arypain

aetio

logy

andchange

inHUI3pain

status

(p=0.001):children

with

musculoskeletalpain

atbaselineshow

edsig

nificantim

provem

ents

(meanchange

0.55;95%

CI0.053

to1.05)com

paredto

childrenwith

out

pain

atbaseline(m

ean

change

−0.39;95%

CI−

0.62

to−0.15)(p=0.006).

Noothe

rassociations

wererepo

rted

.HUI3pain

dimen

sion

scores

didno

t


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

change

sign

ificantlyover

time:med

ianscoreof

2(out

of5)

atbo

thvisits.

How

ever,55%

ofchildren

change

dpain

status

over

time:34%

worsening

,21%

improving.

Find

layet

al.

(2015)

[36]

Childrenwith

cerebral

palsy

NA

NA

NA

NA

NA

Hen

driksz

etal.

(2014)

[37]


Morqu

ioAsynd

rome

Asign

ificant

effect

ofwhe

elchairuseon

utility

outcom

eswas

repo

rted

;significant

differences

repo

rted

betw

een:adultno

n-whe

elchairusersand

occasion

alwhe

elchair

users(p

=0.0115);

adultoccasion

alwhe

elchairusersand

full-tim

ewhe

elchair

users(p

=0.0007);

child

occasion

alwhe

elchairusersand

full-tim

ewhe

elchair

users(p=0.0018);and

child

non-whe

elchair

usersandfull-tim

ewhe

elchairusers(p

=0.0018).Childrenwho

occasion

allyused

awhe

elchairhada

high

ermeanutility

scoreon

averagethan

non-whe

elchairusers,

althou

ghbo

thgrou

pshadhigh

eraverage

utility

scores

than

full-

timewhe

elchairusers.

NA

NA

NA

NA

Karm

urand

Kulkarni

(2018)

[38]


with

spinabifid

a(m

yelomen

ingo

cele)and

shun

tedhydrocep

halus

Using

multivariate

regression

analysis,

anatom

icallevelo

fmyelomen

ingo

cele

hadasign

ificant

effect

onutility

score

(p=0.01):lower

anatom

icallevelo

fmyelomen

ingo

cele

NA

NA

NA

NA


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

was

associated

with

ahigh

erutility

score.

Kenn

eset

al.

(2002)

[39]

Childrenwith

cerebral

palsy

NA

Using

Kend

all’s

tau-btest

ofassociation,theHUI3

dimen

sion

mostassoci

ated

with

GMFC

Slevel

was

ambu

latio

n(tau-b

=0.82;p

<0.01):high

erGMFC

Slevelw

asassociated

with

increased

mob

ility

impairm

ent.

Mod

eratecorrelations

(rang

ingfro

mtau-b=

0.36

to0.58;p

<0.01)

werefoun

dbe

tween

GMFC

Sleveland

the

vision

,spe

echand

dexterity

dimen

sion

s.Overallpatterns

were

similarto

theam

bulatio

ndimen

sion

,but

correlations

wereweaker.

Hearin

g(tau-b

=0.16;p

=0.04)andcogn

ition

(tau-

b=0.27;p

<0.01)

dimen

sion

shad

statisticallysign

ificant

but

low

associationwith

GMFC

Slevel.The

emotion(tau-b

=0.03;

p=0.24)andpain

(tau-b

=0.07;p

=0.37)

dimen

sion

swereno

tsign

ificantlyassociated

with

GMFC

Slevel.

NA

NA

NA

Kulkarni

etal.

(2004)

[40]

Childrenwith

hydrocep

halus

NA

Strong

correlationwas

foun

dbe

tweenutility

scoreandtheHOQ

overallh

ealth

(r=0.81),

physicalhe

alth

(r=0.88),

social-emotional(r=

0.56)

andcogn

itive

(r=0.57)

scores.

NA

NA

NA

Kulkarni

etal.

(2006)

[41]

Childrenwith

hydrocep

halus

NA

Correlatio

nbe

tween

utility

scoreandHOQ

overallh

ealth

scorewas

high

(r=0.81),a

scatterplotde

mon

strated

NA

NA

NA


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

astrong

linear

relatio

nship.

Simpleand

complex

linearregression

mod

elsbo

thaccoun

ted

foralargeprop

ortio

nof

HUI2variability(adjusted

R2=0.66

and0.80

respectively).

Kulkarni

etal.

(2008)

[42]

Childrenwith

hydrocep

halus

NA

Meanutility

score(0.58±

0.63)closeto

cHOQ

meanscores

foroverall

health

(0.65±0.20),

Physicalhe

alth

(0.66±

0.25),Cog

nitivehe

alth

(0.55±0.28)andSocial-

emotionalh

ealth

(0.71±

0.19).Statistical

sign

ificanceno

trepo

rted

.

NA

NA

NA

Kulkarni

etal.

(2008)

[43]

Childrenwith

hydrocep

halus

NA

Sign

ificant

correlationwas

foun

dbe

tweenthecH

OQ

overallh

ealth

score(self-

repo

rted

)and

utility

score

(proxy-rep

orted)

(r=0.60;

p<0.001).

NA

NA

NA

Land

feldtet

al.

(2016)

[44]


with

Duche

nnemuscular

dystroph

y

Ambu

latory

classwas

sign

ificantly

associated

with

proxy-

repo

rted

utility

scores

(p<0.001),d

ecreasing

from

early

ambu

latory

class(m

ean0.75)to

late

non-am

bulatory

class(m

ean0.15).

Careg

iver

assessmen

tsof

health

andmen

tal

status

weresign

ificantlyassociated

with

utility

score

(p<0.001).

NA

NA

NA

NA

Lind

quistet

al.

(2014)

[45]

Adu

ltswho

expe

rienced

hydrocep

halusin

infancy

Thestud

ygrou

phad

sign

ificantly(p

≤0.004)

lower

dimen

sion

scores

comparedto

the

controlg

roup

invision

,eating,

usual

activities,m

ental

NA

NA

NA

NA


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

functio

ndimen

sion

s.Themostrepo

rted

prob

lemswere

associated

with

the

neuroimpairm

ent

subg

roup

(mean

utility

score0.87

comparedto

0.94

intheno

neuroimpairm

ent

subg

roup

).The

subg

roup

with

out

neuroimpairm

ent

wereno

tsign

ificantly

different

tothe

controlinterm

sof

meanutility

score

(0.94and0.95

respectively,pvalue

notrepo

rted

).

Living

ston

and

Rosenb

aum

(2008)

[46]

Ado

lescen

tswith

cerebralpalsy

NA

Disattenu

ated

correlation

coefficientsbe

tween

utility

scores

andQOL

Instrumen

tscores

demon

stratedweakto

mod

eratecorrelationfor

thebe

ing(r=0.48);

belong

ing(r=0.35);

becoming(r=0.29)and

overallq

ualityof

life

(r=0.35)scales.The

two

measure

shared

upto

23%

variance.

NA

NA

Gen

eralizability

coefficientswere

calculated

toassess

variabilityof

scores

over

time.Dim

ension

swith

greaterstability

(i.e.larger

Gscores)hadless

variabilitybe

tween

individu

alsover

time.The

ambu

latio

ndimen

sion

(G=0.94)andoverall

utility

(G=0.91)were

foun

dto

behigh

lystable;

whilethespeech

(G=

0.87),vision

(G=0.87);

dexterity

(G=0.82),

cogn

ition

(G=0.81),and

hearing(G

=0.72)

dimen

sion

swere

mod

eratelystable.The

pain

(G=0.48)and

emotion(G

=0.24)

dimen

sion

swerefoun

dto

have

low

stability.

Lope

z-Bastida

etal.(2017)[47]

Childrenwith

spinal

muscularatroph

yChildrenwith

Type

IIspinalmuscular

atroph

ywerefoun

dto

have

alower

NA

NA

NA

NA


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

averageutility

score

(−0.012)

than

the

combine

daverageof

childrenwith

alltypes

ofspinalmuscular

atroph

y(0.158).

Statisticalsign

ificance

was

notrepo

rted

.

Morrow

etal.

(2011)

[48]

Childrenwith

chronic

cond

ition

s(re

levant

cond

ition

:cereb

ralp

alsy)

NA

NA

NA

Agreemen

tbe

tween

respon

dentswas

assessed

usingCoh

en’skapp

acoefficient.M

oderate

agreem

entwas

foun

dbe

tweenparentsof

childrenwith

cerebral

palsyanddo

ctorsforthe

HUI2dimen

sion

sof

sensation(63.6%

agreem

ent;Kapp

a0.41),

cogn

ition

(70%

;Kappa

0.56)andself-care

(100%;

Kapp

a1).O

nlytheHUI3

ambu

latio

ndimen

sion

(63.6%

;Kappa

0.46)de

mon

stratedmod

erate

agreem

ent.Allothe

rdi

men

sion

sexhibitedslight

orfairagreem

ent

NA

Penn

eret

al.

(2013)

[49]


with

cerebralpalsy

Asign

ificant

negative

correlationwas

foun

dbe

tweentheHUI3pain

dimen

sion

andGMFC

Slevel(r=

0.36;p

<0.001).

NA

Goo

dcorrelationwas

foun

dbe

tweenchild

self-

repo

rted

pain

(Won

g-Bakerscale)

andproxyre

ported

pain

(HUI3pain

dimen

sion

)(Goo

dman

andKruskall’sy=0.57;

p<0.001).U

sing

the

HUI3pain

dimen

sion

,ph

ysicians

iden

tifiedpain

in4.4%

ofcaseswhe

reparent

proxiesdidno

tiden

tifypain.In17.4%

ofcases,parent

proxies

iden

tifiedpain

whe

nph

ysicians

didno

t.Statisticalsign

ificance

notrepo

rted

.

NA

PerezSousaet

al.

(2017)

[50]


with

cerebralpalsy

NA

NA

NA

Child/fathe

ragreem

ent

was

poor

forallEQ-5D-Y

NA


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

dimen

sion

s(Kappa

rang

e0.016–0.067;no

n-sign

ificant).Child/m

othe

ragreem

entbe

tweendi

men

sion

swas

mostly

poor

(Kappa

rang

e0.057–

0.389;no

n-sign

ificant),

however

forthemob

ility

dimen

sion

sagreem

ent

was

good

(Kappa

0.713;

p=0.000)

andforthe

usualactivities

dimen

sion

agreem

entwas

mod

erate

(Kappa

0.436;p=0.000).

Mothe

rsandfather

both

tend

edto

repo

rtfewer

prob

lems(byproxy)than

thechild.

Petrou

andKu

pek

(2009)

[51]

Childrenwith

childho

odcond

ition

s(re

levant

cond

ition

s:microceph

aly,


muscularatroph

y,musculardystroph

y,spina

bifid

a)

Microceph

aly:

Adjusteddisutility

from

perfe

cthe

alth

was

estim

ated

tobe

−0.820(95%

CI−

0.670to

−0.970).

Adjusteddisutility

from

childho

odno

rmswas

estim

ated

tobe

−0.745(95%

CI

−0.598to

−0.899).

Cereb

ralp

alsy:

Adjusteddisutility

from

perfe

cthe

alth

was

estim

ated

tobe

−0.726(95%

CI−

0.607to

−0.846).

Adjusteddisutility

from

childho

odno

rmswas

estim

ated

tobe

−0.652(95%

CI

−0.536to

−0.775).

Musculardystroph

yandspinalmuscular

atroph

y:Adjusted

disutility

from

perfe

cthe

alth

was

estim

ated

tobe

−0.616(95%

CI

−0.471to

−0.761).

Adjusteddisutility

from

childho

od

NA

NA

NA

NA


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

norm

swas

estim

ated

tobe

−0.541(95%

CI

−0.400to

−0.690).

Spinabifid

a:Adjusted

disutility

from

perfe

cthe

alth

was

estim

ated

tobe

−0.552(95%

CI

−0.404to

−0.701).

Adjusteddisutility

from

childho

odno

rmswas

estim

ated

tobe

−0.478(95%

CI

−0.333to

−0.630).

Rocque

etal.

(2015)

[52]


with

spinabifid

aDiagn

osisandtype

ofspinabifid

ahada

sign

ificant

effect

onoverallu

tility

and

certaindimen

sion

scores.O

verallutility

was

foun

dto

besign

ificantlylower

(p<0.001)

inchildren

andadolescentswith

myelomen

ingo

cele

comparedto

individu

alswith

closed

dysraphism

.TheHUI3am

bulatio

ndimen

sion

was

sign

ificantlylower

(p<0.001)

inindividu

alswith

open

myelomen

ingo

cele

comparedto

individu

alswith

closed

neuraltube

defects.TheHUI3

cogn

ition

dimen

sion

was

sign

ificantly

lower

(p=0.039)

inindividu

alswith

open

myelomen

ingo

cele

comparedto

individu

alswith

closed

neural

tube

defects

Utility

andam

bulatio

nscores

were

sign

ificantly

NA

NA

NA

NA


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

associated

with

bowel/bladd

ercontinen

ce(p

<0.05).

Thosewith

bowel

continen

cehad

high

eraverageutility

scores.

Utility

scores

were

sign

ificantlylower

for

patientswith

ahistory

ofreceivingshun

tand/or

CM-II

decom

pression

interven

tions

(p<0.005).The

dimen

sion

sof

cogn

ition

(p=0.17)

andam

bulatio

n(p=

0.002)

werefoun

dto

besign

ificantlylower

forindividu

alswith

ahistoryof

shun

ting,

whilethedimen

sion

sof

speech

(p=0.01)

andcogn

ition

(p=

0.005)

weresign

ificantlylower

for

individu

alswith

ahistoryof

CM-II

decompression

.The

results

remaine

dsign

ificant

whe

ncontrolledforage;

shun

tstatus

accoun

tedfor10.5%

ofvariabilityin

overall

utility

scores.Shu

ntrevision

status

weakly

correlated

with

utility

score(r=−0.197;p=

0.048)

anddimen

sion

scores

forvision

,speech,ambu

latio

n(coe

fficien

tsno

tgiven;pvalues

rang

edfro

m0.01

to0.05).

Rosenb

aum

etal.

(2007)

[53]

Ado

lescen

tswith

cerebral

palsy

GMFC

Slevelw

asfoun

dto

have

asign

ificant

impact

on

Astrong

negative

correlationwas

foun

dbe

tweenutility

scoreand

NA

NA

NA


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

utility

score(p

<0.01);

averageutility

scores

decreasedsteadilyas

GMFC

Slevel

increased.

Post-hoc

Bonferon

icorrection

confirm

edsign

ificant

differences

inmean

overallu

tility

scores

betw

eenallG

MFC

Slevels(p

values

not

repo

rted

),except

betw

eenlevelsIIandIII

(p=0.82).HUI3di

men

sion

levelswere

also

sign

ificantly

associated

with

GMFC

Slevelfor

all

dimen

sion

s(p

<0.05).

GMFC

Slevel(r=

−0.81;p

valueno

trepo

rted

)Ado

lescen

ts’abilityto

self-repo

rtusingtheQOL

Instrumen

twas

sign

ificantlyassociated

(p<0.01)with

parent-rep

ortedHUI3

ratin

gsof

speech

(tau-b

=0.52);cogn

ition

(tau-b

=0.50);de

xterity

(tau-b

=0.35);am

bulatio

n(tau-b

=0.31);vision

(tau-b

=0.22)and

hearing(tau-b

=0.19).

Utility

scorewas

sign

ificantly(p

valueno

trepo

rted

)but

weakly

correlated

with

scores

ontheQOLInstrumen

tfor

Being(r=0.37),

Belong

ing(r=0.17),

Becoming(r=0.20),and

Overallqu

ality

oflife

(r=0.28).Utility

scores

explaine

dbe

tween2.9%

(Belon

ging

)and14%

(Being

)of

variancein

QOLInstrumen

tscores.

Sims-Williams

etal.(2016)[54]

Childrenwith

spinabifid

aMod

eratecorrelationwas

foun

dbe

tweenchild-

repo

rted

(r=0.49)and

proxy-repo

rted

(r=0.38)

utility

scores

andchild-

repo

rted

VAS-theau

thorsde

scrib

ethisas

a‘poo

r’correlation,p

values

notrepo

rted

.

NA

Child

self-repo

rted

and

caregiverproxyutility

scores

werehigh

lycorrelated

(r=0.85;p

valueno

trepo

rted

).

NA

Slam

anet

al.

(2015)

[55]

Ado

lescen

tsandyoun

gadultswith

cerebralpalsy

NA

NA

NA

NA

Nosign

ificant

difference

betw

eenthecontroland

interven

tiongrou

psat

theen

dof

thetrial(p=

0.42).QALYsgained

equatedto

0.78

forthe

controlg

roup

,and

0.79

fortheinterven

tion

grou

p;theincrem

ental

differenceof

0.013was


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

notsign

ificant

(p=0.76)

Tilford

etal.

(2005)

[56]

Childrenwith

spinabifid

aATren

dtestacross

thecase

grou

prevealed

that

lesion

levelh

adasign

ificant

effect

(atp=0.01

level)on

average

utility

score,with

individu

alswith

thoraciclesion

sscoringthelowest

utility

scores

onaverage.

NA

NA

NA

NA

Usuba

etal.

(2014)

[57]

Ado

lescen

tsandadults

with

cerebralpalsy

NA

NA

Average

utility

scores

variedde

pend

ingon

PBM

used

;HUI3de

rived

utility

scores

werelower

atbaseline(0.29)

and8-

year

follow-up(0.29)

than

equivalent

AQoL

derived

utility

scores

(0.35and

0.32

respectively);statis

ticalsign

ificanceno

trepo

rted

.

NA

The‘older

adult’grou

pweremorelikelyto

repo

rtutility

deterio

ratio

nthan

the‘you

nger

adult’grou

p(HUI3:Relativerisk[RR]=

1.19;95%

CI0.66–2.15

/AQoL:RR=3.17;95%

CI

1.12–9.00).

Asign

ificant

interaction

was

foun

dbe

tweenage

grou

pandtim

eof

survey

usingtheAQoL

(p=

0.002);A

QoL

derived

utility

improved

over

time

inthe‘you

nger

adult’

grou

pbu

ttheop

posite

occurred

inthe‘older

adult’grou

p.Thedistrib

utionof

PBM

dimen

sion

scores

was

stableacross

the8-year

follow-up,

except

forthe

AQoL

socialrelatio

nships,

AQoL

inde

pend

entliving

andHUI3am

bulatio

ndi

men

sion

s,which

allim

proved

inthe‘you

nger

adult’grou

pbu

tde

terio

ratedin

‘older

adult’grou

p.

Vitaleet

al.

(2001)

[58]

Ado

lescen

tswith

orthop

aedicprob

lems

(relevant

cond

ition

:cerebralpalsy)

Therewas

foun

dto

beasign

ificant

difference(p

>0.05)

betw

eenthemean

utility

scores

of

NA

NA

NA

NA


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

childrenwith

cerebral

palsy(m

ean0.92)and

childrenwith

scoliosis

with

comorbidities

(mean0.725),b

utno

tchildrenwith

idiopathicscoliosis

(mean0.889).

Justificatio

nforthese

grou

ping

swas

based

onsamplesize,thu

sthereisno

explicit

explanationas

towhy

utility

differences

betw

eenthese

grou

pswou

ldbe

expe

cted

.

Walland

eret

al.

(2009)

[59]

Adu

ltstreatedforCTEVin

infancy

Maleparticipantshad

sign

ificantlyhigh

eraverageutility

score

than

thecomparable

norm

grou

p(p

=0.027).M

ale

participantsrepo

rted

sign

ificantlyless

mod

erate/extrem

eprob

lemswith

anxiety/de

pression

than

thecomparable

norm

grou

p(6.3%

vs21.2%;p

=0.007).

Femaleparticipants

hadworse

utility

onaveragethan

acomparableno

rmgrou

p,bu

tno

tsign

ificantly.Fem

ale

participantsrepo

rted

sign

ificantlymore

mod

erate/extrem

eprob

lemswith

mob

ility

(45%

vs12.2%;p

<0.001)

and

usualactivities

(35%

vs12.5%;p

=0.006)

than

acomparable

norm

grou

p.

NA

NA

NA

NA

Youn

get

al.

(2010)

[22]

Ado

lescen

tsandyoun

gadultswith

cerebralpalsy

Inbo

ththe‘you

th’

and‘adu

lt’grou

ps,

Line

arregression

analysis

revealed

that

GMFC

SUtility

scores

derived

from

HUI3wereon

Proxyutility

scores

were

gene

rally

lower

(by0.16)

NA


Table

6Summaryof

PBM

perfo

rmance

forinclud

edstud

ies(Con

tinued)

Stud

yreference

Con

ditio

n(s)of

interest

Know

n-grou

panalyses

Con

struct

validity:

comparin

gou

tcom

esCon

struct

validity:

comparin

gPBMs

Con

struct

validity:

comparin

grespon

dents

Respon

sivene

ss

utility

scores

deterio

ratedsteadily

asGMFC

Slevel

increased.

Statistical

sign

ificanceno

trepo

rted

levelinchildho

odwas

themostim

portant

influen

ceon

utility

scores;

respon

siblefor53.2%

ofvariancein

HUI3utility

outcom

es(β=−0.205;

p<0.001)

and45.2%

ofvariancein

AQoL

utility

outcom

es(β=−0.148;

p<0.001).

TheSRHwas

foun

dto

bemod

eratelycorrelated

with

utility

scores

derived

from

theHUI3(r=0.41;

p<0.001)

andAQoL

(r=0.41;p

<0.001).

averagehigh

erthan

thosede

rived

from

AQoL

across

allG

MFC

Slevels;

however

strong

correlationwas

foun

dbe

tweentheHUI3and

AQoL

(r=0.87;p

<0.001).

whe

nadjusted

for

cogn

ition

,gen

eralhe

alth

andCPseverity.Statistical

sign

ificanceno

trepo

rted

.

Youn

get

al.

(2013)

[21]

Ado

lescen

tsandyoun

gadultswith

spinabifid

aUtility

scores

derived

from

both

HUI3and

AQoL

variedin

the

sameway

according

tolesion

level,with

thoraciclesion

sassociated

with

lowestutility.Linear

regression

analysis

revealed

that

the

mostim

portantsing

lefactor

contrib

utingto

utility

outcom

eswas

surgicallesion

level;

respon

siblefor40%

ofvariancein

HUI3

utility

scores

and18%

inAQoL

utility

scores.

Both

lesion

leveland

agewereim

portant

whe

ncombine

d,accoun

tingfor48%

variancein

HUI3utility

scores

and22%

variancein

AQoL

utility

scores.

TheSRHwas

foun

dto

bemod

erately/strong

lycorrelated

with

utility

scores

derived

from

the

HUI3(r=−0.45;p

<0.001)

andAQoL

(r=−

0.58;p

<0.001).The

HAQ

was

also

strong

lycorrelated

with

utility

scores

derived

from

the

HUI3(r=0.79;p

<0.001)

andAQoL

(r=0.70;p

<0.001).

Utility

scores

derived

from

theAQoL

were

high

erthan

from

the

HUI3across

alllesion

levelsub

-group

s;ho

wever

theAQoL

andHUI3

exhibitedstrong

correl

ation(r=0.73;p

<0.001).

Meanutility

scores

were

slightlyhigh

erin

theself-

repo

rted

grou

p(HUI3

mean+0.04;A

QoL

mean+0.03)ho

wever

thiswas

basedon

the

comparison

ofyouthand

adultdata

andtheregres

sion

mod

elsremaine

dun

change

d.

NA


youth version (EQ-5D-Y); parents reported a lower fre-quency of problems on all EQ-5D-Y proxy dimensions,particularly fathers.

ResponsivenessFive studies allowed analysis of PBM responsiveness inCP [33, 35, 46, 55, 57]. Adolescents with a GMFCS levelof V exhibited the largest decreases in HUI3 dimensionlevels over time, compared to adolescents with GMFCSlevels of III and IV [33]. Christensen et al. [35] reporteda significant association between physicians’ primarypain aetiology and change in HUI3 pain status (p =0.001). Conversely, in two studies utility outcomes didnot change significantly over time; HUI3 utility out-comes were found to be stable over a 1 year period foradolescents with CP (G = 0.91) [46], likewise utility out-comes (derived from HUI3 and AQoL) did not signifi-cantly change over an 8 year follow-up period [57].Slaman et al. [55] utilised the SF-6D in a randomisedcontrolled trial, but did not find a significant differencebetween the control and intervention groups at the endof the trial (p = 0.42).

Spina bifidaKnown-group analysesThree studies reported known-group analyses in SB [51,52, 56], two of which found that clinical factors had asignificant impact on utility scores. Petrou and Kupek[51] estimated that the adjusted HUI3 disutility of child-hood SB from perfect health was − 0.55 (95% CI − 0.40to − 0.70), and − 0.48 (95% CI − 0.33 to − 0.63) fromchildhood norms. A statistically significant effect of SBdiagnosis on HUI3 utility score (p < 0.001) was reported[52]; children diagnosed with myelomeningocele (meanutility score = 0.51) tended to have lower utility scorescompared to children with closed dysraphism (meanutility score = 0.77). Tilford et al. [56] reported that le-sion location in childhood SB had a significant impacton overall utility (p < 0.01); individuals with sacral le-sions had the highest overall mean utility (0.61; ±0.26).Two studies reported correlation between clinical fac-

tors and utility scores in SB [21, 38]. Anatomical myelo-meningocele level was found to have a significant effecton the HUI utility scores of children with myelomenin-gocele and shunted hydrocephalus (mean HUI score =0.03; 95% CI 0.01 to 0.05; p = 0.01) [38], with lower mye-lomeningocele level showing association with higherutility scores. A similar trend was reported by Younget al. [21], who found that the most important single fac-tor contributing to utility outcomes in SB was surgicallesion level, which was responsible for between 18%(AQoL) and 40% (HUI3) of variance in utility scores.

Convergent validity: comparing measuresTwo studies reported various levels of correlation betweenPBMs and other outcome measures in SB [21, 54]. Childself-reported HUI3 utility scores were not found to behighly correlated with VAS scores (r = 0.488) [54]. Like-wise, the SRH was only moderately correlated with utilityscores in SB (HUI3: r = − 0.45; p < 0.001 / AQoL: r = −0.58; p < 0.001) [21]. Only the HAQ was found to bestrongly correlated with utility score (HUI3: r = 0.79; p <0.001 / AQoL: r = 0.70; p < 0.001) [21].Young et al. [21] compared results from different

PBMs in SB, and found that mean utility scores on theAQoL were lower than mean utility scores on the HUI3for all sub-groups, despite strong correlation betweenthese measures (r = 0.73; p < 0.001).

Convergent validity: comparing respondentsSims-Williams et al. [54] reported that proxy and self-reported HUI3 utility scores were highly correlated forchildren with SB (r = 0.85; significance not reported).Young et al. [21] found that mean self-reported utilityscores were slightly higher than equivalent proxy scores(HUI3 mean + 0.04; AQoL mean + 0.03) however re-spondent type was not influential in their regressionanalysis.PBM responsiveness outcomes in SB were not found

in the literature.

Mixed patient groups and mobility impairmentsThis section includes results from studies which did notfocus on specific conditions, and where sub-group datacould not be examined separately. Relevant conditions/mobility impairments included muscular dystrophy,spinal muscular atrophy, CP, SB, orthopaedic lower limbdeformities, artrogryposis multiple congenital, achondro-plasia and hemiplegia.

Known-group analysesTwo studies reported known-group analyses in studies ofmixed patient groups [11, 51]. Petrou and Kupek [51]found that children with muscular dystrophy or spinalmuscular atrophy had a mean utility score of 0.39, equat-ing to an adjusted disutility from perfect health of − 0.62(95% CI − 0.471 to − 0.761), and an adjusted disutilityfrom childhood norms of − 0.54 (95% CI − 0.400 to −0.690). Burstrom et al. [11] reported that children with afunctional disability (64% congenital; see Table 4 for pa-tient characteristics) had significantly lower EQ-5D-Y di-mension scores than the general population (p < 0.001).

Convergent validity: comparing outcomesModerate correlation was found between the individualdimensions of the EQ-5D-Y and the dimensions of othermeasures (KIDSCREEN-27 and KIDSCREEN-10) and


the life satisfaction ladder (LSL), when completed bychildren with functional disabilities [11] . The EQ-5D-Yanxiety/depression dimension exhibited significant cor-relation with the KIDSCREEN-27 psychological well-being dimension (r = − 0.51; p = 0.001), theKIDSCREEN-27 physical well-being dimension (r = −0.53; p = 0.001), and the LSL (r = − 0.54; p < 0.001) [11].Large variance was observed between utility scores de-

rived from different PBMs for young wheelchair users;mean utility scores ranged from 0.24 (EQ-5D-Y) to 0.53(HUI2) for self-reporting children, and from 0.01 (EQ-5D-Y) to 0.49 (HUI2) for parent proxies [15].

Convergent validity: comparing respondentsA significant strong correlation was observed betweendyads of young wheelchair users (84.6% children withCP, see Table 4 for patient characteristics) and parentproxies for a number of utility measures: EQ-5D-Y (r =0.67; p = 0.026), HUI2 (r = 0.73; p = 0.005) and HUI3(r = 0.84; p < 0.001) [15]. Using Bland-Altman plots [60],sufficient agreement was observed between dyads for theHUI2 (CL = 0.22) and HUI3 (CL = 0.22), but not the EQ-5D-Y (CL = 1.04). A significant respondent type effectwas found for all measures, with child self-reported util-ity scores significantly higher for the EQ-5D-Y (p =0.012), HUI2 (p = 0.021) and HUI3 (p = 0.009) thanequivalent proxy measures [15].PBM responsiveness outcomes were not found in the

literature for this patient group.

Childhood hydrocephalus (mixed aetiology)Known-group analysesLindquist et al. [45] found that adults with a history ofhydrocephalus (with or without neuro-impairment) hadsignificantly lower 15D dimension scores, compared to acontrol group, in the dimensions of vision (p = 0.001),eating (p = 0.000), usual activities (p = 0.004) and mentalfunction (p = 0.000).

Convergent validity: comparing measuresFour studies examined the relationship between theHydrocephalus Outcome Questionnaire (HOQ) andPBMs [40–43], however only three of these studies per-formed relevant statistical analyses [40, 41, 43]. Kulkarni[41] reported strong correlation (0.81) and a strong lin-ear relationship between HUI2 utility score and HOQoutcomes for children with hydrocephalus. Simple andcomplex linear regression models both accounted for alarge proportion of HUI2 variability (adjusted R2 = 0.66and 0.80 respectively). Similarly, a strong correlation wasfound between HUI2 utility score and the HOQ scoresfor overall health (r = 0.81), physical health (r = 0.88),social-emotional (r = 0.56) and cognitive (r = 0.57) [40].Furthermore, a significant positive correlation was

exhibited between self-reported scores on the child-completed version of the HOQ (cHOQ) and proxy-reported utility scores on the HUI3 (r = 0.60; p < 0.001)[43].PBM responsiveness outcomes in childhood hydro-

cephalus were not found in the literature.

Other conditions and mobility impairmentsOnly known-group analyses were reported for the fol-lowing conditions associated with mobility impairment:

Muscular dystrophyLandfeldt et al. [44] reported that ambulatory status andage were significantly associated with HUI utility scoresin muscular dystrophy (HUI version not stated; p <0.001); young ambulators (5–7 years old) had the highestutility scores on average (0.75), whilst older non-ambulators (≥16 years old) had the lowest utility scoreson average (0.15).

Spinal muscular atrophyLopez-Bastida et al. [47] reported that children with TypeII spinal muscular atrophy tended to have lower meanproxy utility scores (− 0.01; ±0.35) than the combinedaverage for all forms of spinal muscular atrophy (0.16; ±0.44), however statistical analysis was not undertaken.

Morquio A syndromeOne study found that for both adults and children withMorquio A syndrome, wheelchair use was significantlyassociated with lower utility scores [37]. Significant dif-ferences were reported in the adult group between non-wheelchair users and occasional wheelchair users (p =0.0115) and between occasional wheelchair users andfull-time wheelchair users (p = 0.0007). In the childgroup significant differences were reported betweennon-wheelchair users and full-time wheelchair users(p = 0.0018) and occasional wheelchair users and full-time wheelchair users (p = 0.0007).

Congenital clubfootWallander et al. [59] found that male adult patients withcongenital clubfoot (CCF) had significantly better overallutility scores than the male norm group (p = 0.027). Thefemale CCF group had a lower average utility score thanthe norm group, but not significantly (significance levelnot reported).

MicrocephalyPetrou and Kupek [51] found that children with micro-cephaly had a mean utility score of 0.14, equating to anadjusted disutility from perfect health of − 0.82 (95% CI− 0.67 to − 0.97), and an adjusted disutility from child-hood norms of − 0.75 (95% CI − 0.60 to − 0.90).


DiscussionThe results from this systematic review demonstrate thatPBMs have been used in a relatively small number ofstudies relating to congenital mobility impairments. Inconditions such as CP and SB, increased clinical severityappears to be associated with decreased utility. This isparticularly evident using the HUI3, which was also themost commonly used PBM found in this review. In par-ticular, there appears to be a relationship between utilityoutcomes and GMFCS level in CP, and clinical factorssuch as lesion level in SB. In case-control studies, utilityoutcomes tended to be significantly lower in the casegroups, although it is worth noting that in one study themale case-group had significantly higher utility out-comes compared to the control [59].In order to demonstrate sufficient applicability and

sensitivity in a specific disease or disability, associationbetween PBMs and validated clinical/condition-specificoutcomes is of key importance. In this respect existingPBMs show weakness in various conditions associatedwith congenital mobility impairments; exhibiting gener-ally limited correlation with measures such as the QOLInstrument, VAS, SRH, KIDSCREEN-27, KIDSCREEN-10 and LSL. Only the GMFCS and HOQ/cHOQ ap-peared to be well correlated with PBMs across a numberof studies, although it is important to note that GMFCSis a classification system of gross motor function andnot an outcome measure.The results from this systematic review highlight im-

portant considerations for the use of PBMs in healthstates associated with congenital mobility impairment. Itis first of note that the use of PBMs has been dominatedby studies in CP, followed by SB. This is somewhat un-surprising given that these are two of the most prevalentcongenital disabilities which affect mobility. Secondly, itis important to acknowledge that only two studies fo-cussed on adults alone, and that both of these studieswere measuring utility outcomes in adults following con-ditions experienced in childhood [45, 59]. This focus onchildren and adolescents is again unsurprising, as manycongenital conditions can be life-limiting, thus examin-ing health outcomes at a young age becomes particularlyimportant. However, this also shows a lack of focus onthe health outcomes of adults who have life-long experi-ence of mobility impairment, and the potential ways inwhich their health outcomes could change over time orbe improved.There is some evidence to demonstrate that different

PBMs vary in their estimation of utility outcomes instates of impaired mobility. For instance, Bray et al. [15]found large variation between the EQ-5D-Y and HUI2/3utility scores for wheelchair users. Likewise, Usuba et al.[57] and Young et al. [21, 22] found that utility out-comes were generally higher when derived from the

AQoL than the HUI3 for individuals with CP, but viceversa for individuals with SB. This is despite the strongcorrelation between the AQoL and HUI3 in these popu-lations [21, 22]. Unfortunately, statistical differences be-tween these measures were not reported, but it is stillimportant to consider the implications that these differ-ences could have on subsequent QALY outcomes. Forinstance, if one PBM were to produce significantlyhigher utility scores than another, this would mean sig-nificantly different estimates of cost per QALYs and thusestimates of cost-effectiveness. At present there is lim-ited evidence to enable health economists and re-searchers to choose between these different PBMs foruse in congenital mobility impairments.Despite documented limitations [61], QALYs have be-

come increasingly influential in health policy as a meansto determine the cost-effectiveness of new treatments andservices, and therefore guide healthcare funding and pri-oritisation decisions. It is therefore imperative that thePBMs used to develop QALYs are accurate. Otherwise,the cost-effectiveness of certain interventions in certainpatient groups could be underestimated. This in turncould impact funding and prioritisation decisions. In thecontext of congenital mobility impairment, this could im-pact the provision of AMT and other mobility-enhancinginterventions, and subsequently impact patient outcomes.This is particularly important considering the ongoing is-sues of unmet need in assistive technology provision. TheWHO Priority Assistive Products List (APL) was launchedin 2016 to help tackle unmet need [62]. The APL contains50 priority assistive technology products, and was pro-duced through consultation with users, experts and otherkey stakeholders. Appropriate PBM data, and subsequentestimates of cost-effectiveness, could help to inform theAPL and ensure that the most effective and cost-effectiveAMTs are prioritised.Considering that the majority of evidence found in this

review related to children, the relationship between self-reported and proxy utility outcomes is particularly sig-nificant. The results from various studies in this reviewdemonstrate that proxy-reporting of utility is consist-ently different to that of self-reporters, including signifi-cant respondent-type effects and limited agreementbetween respondents. Interestingly, proxy respondentswere found to both underestimate and overestimate util-ity outcomes compared to self-reporters. It is thereforeimportant to prioritise outcome measurement from thepatient, although this can be challenging in populationswho may lack capacity, such as young children and indi-viduals with cognitive impairments.

Methodological implicationsDue to the underlying trade-off between quantity andquality of life in the calculation of utility values and


subsequent QALYs, there is a tendency for lower valueto be placed on extending the length of life of peoplewith long-term disabilities [10, 63], as their quality of lifeis routinely considered to be worse than that of an able-bodied person. Thus, when using the QALY frameworkto assess the outcomes of individuals with disabilities, itis difficult to achieve substantially higher quality of lifewhen compared to individuals without disabilities, rais-ing concerns about bias [10]. To some extent these is-sues could be a result of using generic PBMs to valuedisabled health states.One of the underlying issues of using PBMs in disabil-

ity is that the definition of HRQoL differs profoundly be-tween people with disabilities and the general public[64]. When asked to define HRQoL, young wheelchairusers focus on a number of concepts not explicitly mea-sured using generic PBMs, such as ability to adapt,achievement and independence [17]. The experience ofdisability also affects HRQoL perceptions. Mechanismsof adaptation, coping and adjustment can help individ-uals with disabilities to experience diminishing effects totheir HRQoL over time. These processes are also influ-enced by the onset of disability, as individuals with con-genital disabilities demonstrate better adaptation thanindividuals with acquired disabilities [2]. The evaluationof states of disability by non-disabled individuals maytherefore cause such states to have an exaggerated per-ceived impact on HRQoL and health status [65], particu-larly with regards to congenital disability.When assessing the desirability of hypothetical health

states, individuals focus on the transition from their ownhealth state to the hypothetical health state, thus generalpublic beliefs about the impact of disability do not al-ways reflect the lived experience [66, 67]. Focus on per-sonal transition means that processes such as adaptationare not accounted for, causing a discrepancy in howstates of disability impact HRQoL [9].An alternative approach is to use more sensitive

condition-specific measures to model utility values ongeneric PBMs. Although this approach is advocated byNICE [68] there are serious concerns about the validityof modelled utility values [69], as it cannot be assumedthat modelled utility values are representative of directlymeasured utility values [70]. Using modelled utility datato guide funding and resource allocation decisions istherefore controversial. For instance, Sidovar et al. [71]mapped the 12-Item Multiple Sclerosis Walking Scale(MSWS-12) onto the EQ-5D-3 L. While prediction esti-mates were relatively precise for patients with moder-ately impaired mobility, they were significantly lessaccurate for individuals with severe impairments.Neilson et al. [72] suggest supplementing PBMs with

additional questions relating to functional activitieswhich have a large impact on overall quality of life, such

as ‘sitting’ for AMT users. For instance, Persson et al.[73] added complimentary mobility and social relation-ship items to the EQ-5D-3 L to increase sensitivity indisabled populations. However, this approach assumesthat supplemental questions can be mapped on to thehealth state preference values of existing measures with-out impacting accuracy.

Limitations and challengesDefining the term congenital mobility impairment wasone of the key challenges of designing this systematic re-view. An NHS posture and mobility service manager wasconsulted to help construct the search terms, and anumber of preliminary searches were carried out to testsearch terms for both sensitivity and scope. A multitudeof conditions and disabilities can affect mobility frombirth or early infancy, thus we attempted to cover a widevariety of these in our search terms, but accept thatthere are likely to be conditions and disabilities whichwere missed. Given the search results, we are confidentthat we have captured the vast majority of relevant stud-ies relating to at least the most common forms of con-genital mobility impairment. One key issue wasconsidering whether to include studies relating to hydro-cephalus in this review. Although hydrocephalus is notalways associated with mobility impairment, it can causemovement issues and is commonly related to relevantconditions such as CP and SB. We therefore chose to in-clude studies related to childhood hydrocephalus.We chose specifically to focus on congenital mobility

impairment due to the significant differences in life sat-isfaction, self-identity and self-efficacy experienced bypeople with congenital disabilities compared to peoplewith acquired disabilities [2]. Further research couldcompare PBM performance in congenital and acquiredmobility impairments. Previous reviews have reportedmixed results regarding the validity and responsivenessof existing PBMs in the assessment of health states asso-ciated with acquired mobility impairments, such asrheumatoid arthritis [24] and multiple sclerosis [26].

ConclusionTo our knowledge, this is the first systematic review ofthe use of PBMs in congenital mobility impairment. Evi-dence suggests that existing generic PBMs exhibit im-portant issues relating to validity and responsiveness,and thus care must be taken when selecting a PBM asan outcome measure in this context. Condition or dis-ability specific approaches to utility measurement, suchas the mobility and quality of life (MobQoL) outcomemeasure [74], could improve the sensitivity and applic-ability of utility measurement in this context.


AbbreviationsAMT: Assistive mobility technologies; APL: WHO Priority Assistive ProductsList; APPT: Adolescent Pediatric Pain Tool; AQoL: Assessment of Quality ofLife; BPI-SF: Brief Pain Inventory Short Form; CCF: Congenital clubfoot;cHOQ: Child-completed version of the Hydrocephalus OutcomeQuestionnaire; CI: Confidence interval; CP: Cerebral palsy; CRD: Centre forReviews and Dissemination; CTEV: Congenital talipes equinus varus;DARE: Database of Abstracts of Reviews of Effects; DCGM-37: DISABKIDSChronic Generic Module; DSM: DISABKIDS Smiley Measure; EQ-5D: EuroQoLFive-Dimension; EQ-5D-Y: EuroQoL Five-Dimension - Youth version; EQ-5D-3L: EuroQoL Five-Dimension - Three Level version; EQ-5D-5 L: EuroQoL Five-Dimension - Five Level version; GMFCS: Gross Motor Function ClassificationSystem; GMFM-66: Gross Motor Function Measure 66 Items; HAQ: HealthAssessment Questionnaire; HOQ: Hydrocephalus Outcome Questionnaire;HUI: Health Utilities Index; HRQoL: Health-related quality of life; HTA: HealthTechnology Assessment; LSL: Life Satisfaction Ladder; MeSH: Medical SubjectHeadings; MSWS-12: 12-Item Multiple Sclerosis Walking Scale; NHS: NationalHealth Service; NHS EED: NHS Economic Evaluation Database; NICE: NationalInstitute for Health and Care Excellence; PBM: Preference-based measure;PedsQL: Pediatric Quality of Life Inventory; QALY: Quality-adjusted life year;QOL Instrument: Quality of Life Instrument for People with DevelopmentalDisabilities; QWB: Quality of Well-Being scale; RR: Relative risk;SAROMM: Spinal Alignment and Range of Motion Measure; SB: Spina bifida;SD: Standard deviation; SDQ: Strength and Difficulties Questionnaire; SF-36: 36-Item Short Form Health Survey; SF-6D: Short-Form Six-Dimension;SRH: Self-reported health; UN: United Nations; VAS: Visual analogue scale;WeeFIM: Functional Independence Measure for Children; WHO: World HealthOrganization; WRAT: Wide Range Achievement Test

AcknowledgementsThe author’s would like to acknowledge the support of Dr. Hareth Al-Janabi,Professor Joanna Coast, Professor Deborah Fitszimmons, Ms. Krys Jarvis andProfessor Katherine Payne for acting as advisors to the project.

Authors’ contributionsAll authors were responsible for designing the systematic review, developingthe original review protocol and editing the manuscript. NB devised thesystematic review, prepared the manuscript and synthesised extracted data.LHS conducted the review searches and led the study appraisal process. NBand LHS screened papers for eligibility and quality, and extracted evidencewith support from RTE. All author(s) read and approved the final manuscript.

FundingThis systematic review was funded by the Welsh Government throughHealth and Care Research Wales. The funding body had no role in thedesign, conduct or reporting of this systematic review.

Availability of data and materialsAs this is a systematic review, there was no primary data generated as partof this research. All of the data utilised in this review is available from thecited literature, and has been summarised in Tables 4, 5 and 6.

Ethics approval and consent to participateNot applicable, this is a systematic review.

Consent for publicationNot applicable, this is a systematic review.

Competing interestsThe authors declare that they have no competing interests.

Received: 4 December 2019 Accepted: 8 April 2020

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