D02-00 Database and protocol to evaluate HRQOL of selected ... · HAEMO-SYM [63] Functional Independence Score in Haemophilia (FISH) [72] Short-Form 36 (SF-36) [73] The Personal Adjustment

D02-00

Database and protocol to evaluate HRQOL of selected RD in participating European countries

Document Information

Contract number 20091204

Document Type D02-00

Language GB

Document status IS

Format .PDF

Authors Ola Ghatnekar, Anna H Glenngård, Sara Olofsson, Ulf Persson (The Swedish Institute for Health Economics)

This deliverable arises from the project "Social Economic Burden and Health

Related Quality of Life in Patients with Rare Diseases in Europe" which has

received funding from the European Union in the framework of the Health

Programme.

The Executive Agency is not responsible for any use that may be made of the

information contained in this document.

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Contents 1. Background.......................................................................................................................................... 3

2. Objective.............................................................................................................................................. 4

3. Method................................................................................................................................................ 5

4. Results ................................................................................................................................................. 6

4.1 Search Results................................................................................................................................ 6

4.2 Instruments Used for Measuring HRQoL in Rare Diseases ......................................................... 11

4.2.1 Cystic Fibrosis (CF) ................................................................................................................ 11

4.2.2 Prader-Willi Syndrome (PWS)............................................................................................... 11

4.2.3 Haemophilia ......................................................................................................................... 12

4.2.4 Duchenne Muscular Dystrophy (DMD) ................................................................................ 13

4.2.5 Epidermolysis Bullosa (EB) ................................................................................................... 13

4.2.6 Fragile x Syndrome ............................................................................................................... 13

4.2.7 Scleroderma ......................................................................................................................... 13

4.2.8 Mucopolyaccharidosis .......................................................................................................... 14

4.2.9 Juvenile Idiopathic Arthritis (JIA).......................................................................................... 14

4.2.10 Histiocytosis........................................................................................................................ 15

4.2.11 Summary............................................................................................................................. 15

4.2 Content and Psychometric properties of Selected Instruments................................................. 16

5. Discussion and Conclusion ................................................................................................................ 24

BURQOL RD Grant Agreement No. 2009 12 04

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1. Background

There are two basic approaches and related instruments to measuring QoL, i.e. generic instruments

that provide a summary of HRQL; and specific instruments that focus on problems associated with

specific diseases, patient groups or areas of function. Generic instruments include health profiles and

instruments that generate health utilities (Guyatt et al 1993).

1.1 Generic/general health profiles

Generic or general health status measures are broadly applicable across different types and

severities of diseases and across different types of medical treatments or interventions. They are

thus designed to be able to describe the concept of health or quality of life in many different

conditions, illnesses, patients and populations. One (the main?) advantage of preference-based

measures of health with generic health state descriptive systems (e.g. EQ-5D, SF-6D, HUI) is that they

enable for comparison of health states across different diseases, e.g. for purpose of resource

allocation.

1.2 Disease-specific health profiles

The disadvantage of generic instruments is that general measures of health might be inappropriate

or insensitive for some medical conditions. Disease specific instruments are designed to assess

specific patient groups or illnesses and are very useful in measuring clinically important changes in

response to treatments. They are generally more sensitive than general instruments since they

include elements most relevant to a specific disease. The disadvantage of disease specific instrument

is that they cannot be used to compare health states across different patient populations.


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2. Objective To perform a systematic literature review with the aim to identify instruments used to evaluate

HRQOL and their applicability in the area of 10 rare diseases:

- Cystic fibrosis

- Prader-WilliSyndrom

- Fragile X Syndrome

- Haemophilia

- Duchenne Muscular Dystrophy

- EpidermolysisBullosa

- Sclerodermia

- Mucopolysaccharidosis

- Juvenile idiopathic arthritis

- Histiocytosis


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3. Method

3.1 Search Strategy

A structured literature search of PubMed was performed on 2011-02-23 with the aim to identify

studies using quality of life instruments in patients with 10 different rare diseases, using the

following search criteria:

("Quality of Life"[Mesh]) AND (questionnaire OR survey OR interview OR instrument) AND ("Cystic

Fibrosis"[Mesh] OR "Prader-Willi Syndrome"[Mesh] OR "Hemophilia A"[Mesh] OR "Hemophilia

B"[Mesh] OR "Muscular Dystrophy, Duchenne"[Mesh] OR "EpidermolysisBullosa"[Mesh] OR "Fragile

X Syndrome"[Mesh] OR “Scleroderma, Localized”[Mesh] OR “Scleroderma, Systemic”[Mesh]OR

"Mucopolysaccharidoses"[Mesh] OR "Arthritis, Juvenile Rheumatoid"[Mesh] OR

"Histiocytosis"[Mesh]) AND ((English[lang] OR Swedish[lang]))

A search was also performed adding the search term (EQ-5D OR EQ-5D-Y OR Zarit OR Barthel).

However, the number of identified articles did not change. It can therefore be assumed that all

available literature using these instruments is included in the original search.

An additional search, limited to articles in the following languages ((French[lang] OR German[lang]

OR Italian[lang] OR Spanish[lang] OR Bulgarian[lang] OR Hungarian[lang])) was also performes. This

search identified 9 articles of relevance, including four in German[1-4], one in French[5], two in

Italian[6, 7] and two in Spanish[8, 9].

3.2 Selection Criteria

Titles and abstracts of all identified articles were screened for possible full-text retrieval based on the

following inclusion criteria: (i) use or analysis of a standardized generic or disease-specific health-

related quality of life instrument (articles using or analysing instruments adapted to the specific

study or country setting were excluded); (ii) included patients or their care-takers with one of the

selected ten rare diseases; and (iii) original research article (discussions, reviews, and letters to the

editors were excluded).

3.3 Data Extraction

The following parameters were extracted from the included articles:

(i) The purpose of the instrument (generic index, generic profile, disease-specific profile)

(ii) The domains included in the instrument (e.g. physical health, mental health)

(iii) Reliability (reproducible and internally consistent results)

(iv) Validity (measure what it claims to measure)

(v) Responsiveness (measure changes over time that matters to patients)


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4. Results

4.1 Search Results

The literature search identified 278 articles. Titles and abstracts were reviewed to exclude articles

that did not meet the inclusion criteria. This left 134 articles in which the health-related QoL was

measured in one of the 10 rare diseases.

Table 1 summarizes the included article with respect to the disease studied and the instrument used.

The most frequently studied diseases were cystic fibrosis (37 articles), juvenile idiopathic arthritis (27

articles), scleroderma (27 articles), and haemophilia (27 articles). A few studies were identified for

epidermolysisbullosa (4 articles), Duchenne muscular dystrophy (2 articles), and Prader-Willi

syndrome (2 articles). No relevant articles were found for mucopolyaccharidosis.


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Table 1. Instruments for patient-reported outcomes (quality of life, independence, informal care-giving) in 10 selected rare diseases

Disease Generic Instrument Disease-Specific Instrument

Name of Instrument Ref No. Name of Instrument Ref No.

Child Health Questionnaire (CHQ) [10-14] Cystic Fibrosis Questionnaire (CFQ) [15-28]

Short-Form 36 (SF-36) [12, 14, 29, 30] Hospital Anxiety and Depression Scale (HADS) [17]

EQ-5D-Y [16] Cystic Fibrosis Quality of Life Questionnaire (CFQoL)

[31-34]

Pediatric Quality of Life Inventory (PedsQL)

[35] CF Coping Scale [31]

Questions on Life Satisfaction [4, 30, 36] 16-item Sino-Nasal Outcome Test (SNOT-16) [37]

Quality of Well-Being Scale (QWB) [38] The Caregiver Quality of Life Cystic Fibrosis (CQOLCF) Scale

[39]

King’s Health Questionnaire (KHQ) [40] The Quality of Life Profile for Chronic Diseases (PLC)

[30]

Nottingham Health Profile (NHP) [41] Chronic Respiratory Disease Questionnaire (CRDQ)

[42]

Disease-specific Scale of the Questions on Life Satisfaction

[43]

Cystic Fibrosis

St George’s Respiratory Questionnaire (SGRQ) [9]

Child Health Questionnaire (CHQ) [44] Prader-Willi Syndrome

Short-Form 36 (SF-36) [44, 45]

Health Utilities Index Mark 3 (HUI3) [46] Hemophilia-Specific Quality of Life Index (Haemo-QoL) Questionnaire

[47-54]

Short-Form 36 (SF-36) [48, 55-63] HEP-Test-Q [64]

EQ-5D [58, 62, 65] Hemophilia Pain Coping Questionnaire (HPCQ)

[55, 66]

Health Assessment Questionnaire (HAQ) [48, 57, 63] Chronic Pain Acceptance Questionnaire (CPAQ)

[55]

MOS-36 Health Survey [67] New Hemophilia Disease-Specific Measure [68-70]

Haemophilia

The Canadian Haemophilia Outcomes – Kids Life Assessment Tool (CHO-KLAT)

[71]


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HAEMO-SYM [63]

Functional Independence Score in Haemophilia (FISH)

[72]

Short-Form 36 (SF-36) [73] The Personal Adjustment and Role Skills Questionnaire (GHQ-30)

[74] Duchenne Muscular Dystrophy

The AutoquestionnaireQualite de vie Enfants Image (AUQEI)

[8]

Short-Form 36 (SF-36) [75] Quality of Life in EpidermolysisBullosa (QOLEB)

[76]

General Health Questionnaire-12 (GHQ-12)

[75] Skindex-29 [75]

EQ-5D [75] The Dermatology Life Quality Index (DLQI) [77]

EpidermolysisBullosa

Activities of Daily Living Score (ADL) [78]

Fragile X Syndrome Family-related life quality questionnaire (FLQ)

[3]

Visual Analogue Scale (VAS) [79] The Dermatology Life Quality Index (DLQI) [80]

Short-Form 36 (SF-36) [5, 6, 81-93] Symptom Burden Index (SBI) [94]

SF-12 [95] Saint George’s Respiratory Questionnaire (SGRQ)

[83, 96]

SF-6D [97] The McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR)

[98, 99]

Health Assessment Questionnaire (HAQ) [6, 7, 81, 82, 87, 89, 91-93, 96, 100]

Scleroderma Gastrointestinal Tract 1.0 (SSC-GIT 1.0)

[101]

Activities of Daily Living (ADL) [79] Cochin Hand Function Scale (CHFS) [88]

WHO Quality of Life Instrument [102, 103] Scleroderma Health Assessment Questionnaire (S-HAQ)

[88, 90]

Manchester Short Assessment of Quality of Life (MANSA)

[104] Psychosocial Adjustment to Illness Scale [100]

EQ-5D [7] Satisfaction with Daily Occupations (SDO) [100]

Scleroderma

The Self-administrated Systemic Sclerosis Questionnaire (SySQ)

[105]

Mucopolyaccharidosis No Articles.


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Child Health Questionnaire (CHQ) [106-110] Juvenile Arthritis Quality of Life Questionnaire (JAQQ)

[111-113]

Visual Analogue Scale (VAS) [106, 114-119] Arthritis Impact Measurement Scales [120]

Childhood Health Assessment Questionnaire (CHAQ)

[1, 107, 111, 113, 116-119, 121-128]

DISABKIDS [2]

Health Utilities Index Mark 3 (HUI3) [107] KINDL-R-Questionnaire [1]

Short-Form 36 (SF-36) [114, 124, 129-132]

EQ-5D [130]

EQ-5D-Y [129]


[35, 116, 122, 123, 125]

Health Assessment Questionnaire (HAQ) [114, 115, 126, 132]

The General Health Questionnaire (GHQ-30)

[114, 115]

Juvenile Idiopathic Arthritis

Quality of My Life [119]

Short-Form 36 (SF-36) [133] No name [134] Histiocytosis


[133]


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4.2 Instruments Used for Measuring HRQoLin Rare Diseases

4.2.1 Cystic Fibrosis (CF)

Thirty-eightof the included articles studied the HRQoL in patiets with CF, whereof more than half (21

articles) used only disease-specific instruments. The most common disease-specific instrument was

“the Cystic Fibrosis Questionnaire (CFQ)”, which was applied by 14 studies. 4 studies used “the Cystic

Fibrosis Quality of Life Questionnaire (CFQoL)”. 11 articles used only generic instruments, whereof 6

applied “the Child Health Questionnaire (CHQ)”.

Fourteen of the included studies investigated the psychometric properties of instruments for

measuring health-related quality of life. Half of these studies did investigate the properties of the

Cystic Fibrosis Questionnaire (CFQ), a HRQoL instrument which was developed by Quittner in 2000, in

a German, English, French, Danish and US setting. All of these studies found it to be a reliable and

valid instrument for measuring HRQoL in CF patients. Four additional disease-specific instruments

were evaluated with regard to their psychometric properties, including the Cystic Fibrosis Quality of

Life Questionnaire (CFQoL), developed by Gee in 2003 (has as of today only been applied in a UK

setting), the Questions of Life Satisfaction for adolescents with cystic fibrosis (FLZ(M)-CF), the St

George’s Respiratory Questionnaire (SGRQ), and the Caregiver Quality of Life Cystic Fibrosis

(CQOLLCF). All of these instruments showed good psychometric properties.

Three studies evaluated the psychometric properties of generic instruments for measuring HRQoL in

CF patients, whereof one studied the use of EQ-5D-Y, one investigated the SF-36, and the remaining

compared three generic instruments to each other with respect to their properties (SF-36, the quality

of life profile for chronic diseases (PLC) and the questions on life satisfaction (FLZ(M))). Eidt-Koch

(2009) performed a study in four cystic fibrosis centres in Germany where quality of life data from 96

patients between 8 and 17 years was collected using the CFQ and the EQ-5D-Y. Results of both

instruments were compared by statistical analysis. The analysis showed several correlations between

different dimensions and the visual analogue scale of the EQ-5D and the scales of the different CFQ

versions for children, their parents and adolescents. Therefore, the authors concluded, the EQ-5D-Y

can be considered a cross-sectional valid generic health outcome measure which reflects differences

in health according to the progression of the lifelong chronic disease CF.

The SF-36 has been evaluated for its psychometric properties in a CF population by Gee et al 2002

and by Goldbeck et al 2001 (along with two other generic instruments). Gee et al found that the

domain structure of SF-36 was robust. However, the discriminatory ability of the measure was

disappointing. Goldbeck et al did not reach any conclusion on the feasibility of using SF-36 in patients

with CF but they concluded that all of the generic instruments evaluated showed similar reliability,

but different validity.

4.2.2 Prader-Willi Syndrome (PWS)

A longitudinal study of 13 GH-treated adult patients used the SF-36 and Psychological General Well-

Being Index (PGWBI) for the assessment of QoL and psychological well-being (Bertella 2007). The

instruments were responsive in that they detected improvements in both HRQoL and well-being,

although parents were less optimistic than children. Caliandro and colleagues (2007) used the SF-36

and the Child Health Questionnaire-Parent Form-50 (CHQ-PF50). They concluded that physical


12


aspects of QoLwerecorrelated toweight whereas mental aspects were affected by facial features. No

psychometric tests were performed.

4.2.3 Haemophilia

The most frequently used and studied generic HRQoL instrument was SF-36. It has shown to have

very good responsiveness, concurrent and clinical criterion validity when validated against a disease

specific instrument. The EQ-5D has been less studied but seems to relate well to the SF-36.

Of the 27 articles identified studying HRQoL in haemophilia, 14 articles used disease-specific

instruments. The most frequently used disease-specific measure were “the Hemophilia Specific

Quality of Life Index (Haemo-QoL) Questionnaire”, which was used by 8 studies. 14 studies used

generic instruments, where the SF-36 combined with EQ-5D (3 articles), HAQ (3 articles), or a

disease-specific instrument (3 articles) were the most frequently used.

The EQ-5D indices showed a statistically significant correlation with each dimension of the SF-36

(Trippoli 2001). Both theEQ-5D and SF-36 were discriminant to patients’ orthopedic status (Scalone

2006) andresponsive to prophylaxis treatment (Royal 2002, Hoots 2008). The SF-36 has excellent

concurrent validity with Haemo-QOL and external clinical criterion validity (haemophilia clinical

status) and sensitivity (health status changes) (Remor 2005, Arranz 2004). The SF-36 instrument

detected differences in general health and vitality in hepatitis C virus infected patients (Posthouwer

2005). Among severe patients, physical functioning, role-physical, bodily pain and general health

were reduced (P<0.001), whereas vitality, social functioning, role-emotional and mental health were

similar to controls (Hartl 2008). In spite of no difference in HAQ score between males with mild

haemophilia and controls, they reported lower on six out of eight SF-36 domains as well as on the

physical component summary score (Walsh 2008). Severity of musculoskeletal morbidity was

predictors of physical role, bodily pain, vitality and social functioning (Solovieva 2001). The Health

Utility Index 2 and 3 were discriminant in severity (mild, moderate, severe), hepatitis and HIV (Barr

2002).

The Haemo-QOL disease specific instrument was developed by Bullinger(2003), and tested in several

European countries. It has acceptable internal consistency and retest reliability values. Young

children were impaired mainly in the dimensions 'family' and 'treatment', whereas older children had

higher impairments in the so-called 'social' dimensions, such as 'perceived support' and 'friends'

(Gringeri 2004). However, the psychometric indicators were less favourable for the youngest age

group (von Mackensen 2004).

The Haemophilia and Exercise Project Test Questionnaire (HEP-Test-Q) was accepted and found easy

to fill in by the patients (von Mackensen 2010). Psychometric testing revealed good values for

reliability in terms of internal consistency and test-retest reliability as well as for convergent validity

correlating highly with Haem-A-QoL, HAL and SF-36. Discriminant validity for certain clinical variables

was shown. Concurrent validity between the haemophilia-specific health-related quality of life

questionnaire for adults (HAEMO_QOL-A) total and subscale scores and all SF-36 subscale scores

were generally good (correlations range: 0.13-0.87) (Rentz 2008)


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4.2.4 Duchenne Muscular Dystrophy (DMD)

We found three studies in the literature search. The SF-36 physical function scores were massively

reduced but QoL was not correlated with the need for noninvasivepositive-pressure ventilation.

Vitality, role-emotional, social function, and mental health scores were nearly normal (Kohler 2005).

Personal psychological dimensions were fairly normal to general population or other chronic diseases

when measured with the Adjustment and Role Skills Scale (PARS-III) among parents andalpha

coefficients and factor analysis indicated good reliability and validity(Hendriksen 2009). Physical

function, family and leisure activity were important domains for QoL in the Autoquestionnaire

Quality de vie Enfant Image (AUQEI) and the agreement between child and caregiver reported QoL

was good(Longo-Araujo 2007).

4.2.5 EpidermolysisBullosa (EB)

We found four studies in the literature search whereof one studied impairment in Activities of Daily

Living” (ADL) and pain (Fine 2004). The other three studies used disease specific instruments

(Dermatology Life Quality Index (DLQI), Children's Dermatology Life Quality Index (CDLQI), Quality of

life - EpidermolysisBullosa (QOLEB) and General Health Questionnaire-12 (GHQ-12)) and two generic

instruments (SF-36 and EQ-5D (Tabolli 2009)). Quality of life varied depending on disease subtype

and women had lower QoL than men (Horn 2002, Frew 2009, Tabolli 2009). Patients with EB Simplex

had similar QoL as those with moderate to severe psoriasis (Horn 2002) and impairment was mainly

physical. Mental components of the SF-36 were similar to the general population. Caregiver stress

was related to the perceived disease severity (Tabolli 2009). No psychometric tests were performed

on the generic instruments.

4.2.6 Fragile x Syndrome

Only one study on Fragile X Syndrome was identified in the literature search (Sarimski 2010). This

study used the Family-Related Life Quality (FLQ) questionnaire to evaluate the QoL among mothers.

Child temperament and atypical behaviour, individual and social coping of the mothers had effect on

parenting stress. No psychometric tests were performed.

4.2.7 Scleroderma

Several studies indicate that SF-36 is a valid, responsive and reliable instrument for scleroderma.

There is one study on SF-6D, the instrument for estimating preference based HRQoL on the basis on

SF-36, which showed good test-retest reliability but poor to moderate agreement with other

preference measures. One study demonstrated good acceptability, feasibility and validity for EQ-5D.

Thirty articles were identified studying the HRQoL in patients with scleroderma. The majority (21

articles) used generic measures, where the SF-36 alone (3 articles) or combined with Health

Assessment Questionnaire (HAQ; 7 articles) or a disease-specific instrument (3 articles) were the

most frequently used. Six articles analysed the HRQoL of patients with scleroderma, using only

disease-specific instruments. The “Saint George’s Respiratory Questionnaire (SGRQ)” and the

“Scleroderma Health Assessment Questionnaire (S-HAQ)” were the only disease-specific instruments

that were used by more than one study.

Systemic scleroderma patients have impaired HRQoL compared to the general population. In the

Symptom Burden Index, symptoms are mainly found in pain, hand mobility, and skin and correlated


14


well to the SF-36 (Kallen 2010). Good to excellent correlation between HAQ Disability Index and SF-

36 has been shown (Khanna 2005). The instrument is responsive. Digital ulcers mainly affect the

mental component of the SF-36Mouthon 2010). Clinical manifestations such as abdominal pain and

bloating, dyspnoea, itch were associated with reduced QoL measured by SF-36 (El-Baalbaki 2010,

Franck-Larsson 2009, Baron 2008, Georges 2006). Joint involvement affected mainly the physical

dimension (Johnson 2006). Lower HRQoL was detected with SF-36 for patients with diffuse

cutaneous involvement compared with limited involvement (Geroges 2006, Khanna 2007). Compared

to rheumatoid arthritis and psoriasis arthritis, joint involvement was more disabling in scleroderma

patients in one study but not in another (Johnson 2006, Danieli 2006). One study concluded that SF-

36 aggregate scores may be of less value (Rannou 2007).

The SF-6D showed good test-retest reliability but poor to moderate agreement with SG, Rating Scale

and TTO (Khanna 2007). It was showed responsive to treatment intervention with small effect size

(Khanna 2007). One study demonstrated good acceptability, feasibility and validity for EQ-5D in

scleroderma patients. Conceptually equivalent domains of EQ-5D demonstrated a good correlation

with HAQ correspondent domains (Gualtierotti 2010).

The McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR) has good

construct validity, weak correlation to HAQ but responsive to changes (Nguyen 2010, Moutho 2008).

In the WHO QoL short form questionnaire arthritis pain and elevated psychological distress and

certain personality traits were associated with reduced HRQoL (Hyphantis 2007).

4.2.8 Mucopolyaccharidosis

No articles were found on Mucopolysaccharidosis.

4.2.9 Juvenile Idiopathic Arthritis (JIA)

Thirty articles studied the HRQoL in patients with JIA, whereof the majority (24 articles) used generic

measures. The generic instruments used included the “Childhood Health Assessment Questionnaire

(CHAQ)”, used by 17 articles, the SF-36, used by 6 articles, the “Pediatric Quality of Life Inventory

(PedsQL), used by 5 articles, and the “Child Health Questionnaire (CHQ)”, used by 5 articles. Four

articles applied a disease-specific questionnaire, whereof 3 used the “Juvenile Arthritis Quality of Life

Questionnaire (JAQQ)”. Only two studies used the EQ-5D on small patient samples.

EQ-5D and SF-36 showed impairment compared to general population (Bruns 2008, Jolles 2008,

Duarte-Salazar 2007). The SF-36 revealed pain, mental health,social and emotional impairments

(Bruns 2008, Foster 2003).However, impaired physical health but not in psychosocial has also been

reported with SF-36 (Ostile 2010, Arkela-Kautiainen 2005).EQ-5D and SF-36 were not able to

discriminate between JIA and juvenile ankylosing spondylitis (Duarte-Salazar 2007).HUI3 showed

responsiveness to treatment (Prince 2010).No psychometric tests were performed.

Child Health Questionnaire (CHQ) was shown to be responsive to treatment changes, reliable and

valid instrument with correlation between children and parents responses although differing

(Ruperto, 2010, Prince 2010, Norrby 2006, Sawyer 2004, Selvaag 2003).

The Childhood Health Assessment Questionnaire (CHAQ) has good psychometric properties, and is

responsive (Rostom 2010, Prince 2010). However, it did not manage to detect a difference in


15


HRQoLbetween active and inactive polyarticular JIA (Ringold 2009). The physical functioning is well

covered in CHAQ (Bekkering 2007).

In five studies caregivers were surveyed as well but only in one study the Caregiver Burden Scale was

used. It showed that emotional more than physical aspects of the patients’ condition determined the

disease burden (Bruns 2008).

4.2.10 Histiocytosis

Two articles were found on Langerhans Cell Histiocytosis (LCH), whereof one used three different

generic instruments (SF-36,PedsQL and LHC DUX) and the other applied a disease-specific instrument

DUX 25. Compared with controls, children with LCH have lower HRQoL (Vrijmoet-Wiersma 2009).

However, when compared to only survivors with LCH no such difference was detected (Lau 2008).

This may be a result of different instruments (DUX 25 and LHC DUX vs. SF-36 and PedsQL). No

psychometric tests were performed.

4.2.11 Summary

Table 2 describes what type of instruments was most frequently used for measuring HRQoL in the

included articles by type of disease. Only generic Instruments were used in more than half of all

studies, while 39 percent used only disease-specific instruments and 10 percent applied both generic

and disease-specific instruments.

The most frequently used generic instrument was the Medical Outcome Study (MOS) Short-Form

Health Survey (SF-36).Other instruments of frequent use were HAQ and CHAQ, the CHQ and PedsQL.

EQ-5D was used by 3 studies in haemophilia, 1 study in EB and 1 study in JIA. EQ-5D-Y was used by 1

study in CF and 1study in JIA. We did not identify any articles on the Barthel Index or the Zarit Scale.

Disease-specific instruments were most frequently used for cystic fibrosis and haemophilia. The

instruments used in these articles were primarily the CFQ and the Haemo-QoL.

Table 2.Number of Articles (%) Using Different Type of Instruments by Type of Disease Studied

Only Generic

Instruments

Only Disease-

Specific Instruments

Both Generic and

Disease-Specific

Instruments

Cystic Fibrosis (CF) 12 (30) 23 (57) 5 (13)

Prader-Willi Syndrome (PWS) 2 (100) 0 (0) 0 (0)

DuchenneMyscular Dystrophy

(DMD)

2 (67) 1 (33) 0 (0)

EpidermolysisBullosa(EB) 1 (25) 2 (50) 1 (25)

Fragile X Syndrome 1(100) 0 (0) 0 (0)

Haemophilia 15 (56) 9 (33) 3 (11)

Scleroderma 20 (69) 5 (17) 4 (14)

Juvenile Idiopathic Arthritis

(JIA)

27 (87) 2 (6.5) 2 (6.5)

Histiocytosis 1 (50) 1 (50) 0 (0)

TOTAL 81 (61) 43 (32) 10 (7)


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4.2 Content and Psychometric properties of Selected Instruments

4.2.1 Characteristics of the Instruments

Short introduction with description of different types of instruments.

Preference-based Health Utility Index

Three different types of preference-based health utility index were identified, including the EuroQol

(EQ-5D), the Health Utilities Index (HUI), and the Short-Form 6 Dimensions (SF-6D) adapted from the

Medical Outcome Survey (MOS) Short-Form (SF-36).

EQ-5D is the most preferred instrument in health-economic research. It is a 5-item questionnaire

with 3 levels, allowing 243 different health states to be identified. The EQ-5D is translated to 150

different languages, and there is a youth version available for children and adolescents aged 7-12

years (the EQ-5D-Y). 5 of the included articles used the EQ-5D, whereof one in juvenile idiopathic

arthritis[130], one in epidermolysisbullosa[75], and three in haemophilia[58, 62, 65]. 2 of the

included articles used the EQ-5D-Y, whereof one in cystic fibrosis[16] and one in juvenile idiopathic

arthritis[129].

The HUI is available in 3 different versions, the HUI Mark 1 (HUI1), HUI Mark 2 (HUI2) and the HUI

Mark 3 (HUI3). Two of the included articles used the HUI3, whereof one in haemophilia[46] and one

in juvenile idiopathic arthritis[107].

The SF-6D provides a means for using the SF-36 and SF-12 in economic evaluation by estimating a

preference-based single index measure for health from these data using general population values.

One of the included articles used the SF-6D in scleroderma[97].

Generic Health Profiles

Functional Health

The Medical Outcome Survey (MOS) Short-Form 36 (SF-36) has become the most widely used

measure of general health in clinical studies throughout the world.It yields an 8-scale profile of

functional health and well-being scores as well as psychometrically-based physical and mental health

summary measures and a preference-based utility index (through the SF-6D). Since the physical and

mental component summary scales capture about 85 % of the reliable variance in the eight scale SF-

36, a twelve-items version has been developed as a simplified version, the Short-Form 12 (SF-12). 39

of the included articles used the SF-36, whereof four in cystic fibrosis[12, 14, 29, 30], two in prader-

willi syndrome[44, 45], 11 in haemophilia[48, 55-63, 67], one in duchenne muscular syndrome[73],

one in epidermolysisbullosa[75], 13 in scleroderma[81-93], six in juvenile idiopathic arthritis[114,

124, 129-132], and one in histiocytosis[133]. One of the included articles used the SF-12 in

scleroderma[95].

The Nottingham Health Profile (NHP) was developed to be used in epidemiological studies of health

and disease, and consists of two parts. Part I contains 38 yes/no items in 6 dimensions which is

scored using weighted values which give a range of possible scores from zero (no problem at all) to

100 (presence of all problems within a dimension). Part II contains 7 general yes/no questions

concerning daily living problems. 1 of the included articles used the NHP in cystic fibrosis.[41]


17


The World Health Organization has developed two instruments for measuring quality of life (the

WHOQOL-100 and the WHOQOL-BREF), that can be used in a variety of cultural settings whilst

allowing the results from different populations and countries to be compared. The WHOQOL-100 is

constructed in 6 broad domains of quality of life, with 24 facets and 100 items. The WHOQOL-100

produces scores relating to particular facets of quality of life, scores relating to larger domains, and a

score relating to overall quality of life and general health. The WHOQOL-BREF is an abbreviated 26

item version of the WHOQOL-100. 2 of the included articles used the WHOQOL in scleroderma[102,

103].

The Child Health Questionnaire (CHQ) is a family of generic quality of life instruments that have been

designed and normed for children 5 to 18 years of age. The CHQ measures 14 unique physical and

psychosocial concepts. The parent form is available in two lengths – 50 or 28 items. The youth self-

report version is 87 items and has been developed for ages 10 and older. Scores can be analyses

separately (the CHQ Profile Scores), or combined to derive an overall physical and psychosocial score

(the CHQ Summary Score). 11 of the included articles used the CHQ, whereof five in cystic

fibrosis[10-14], five in juvenile idiopathic arthritis[106-110], and one in prader-willi syndrome[44].

Pediatric Quality of Life Inventory (PedsQL) is designed to measure health-related quality of life in

healthy children and adolescents and those with acute and chronic health conditions 2 to 18 years of

age. It includes four scales and 23 items, yielding a Physical Health Summary Score, a Psychosocial

Health Summary Score, and a Total Scale Score. PedsQL is available in parent form and for child self-

report version adapted to different age intervals (2-4, 5-7, 8-12, 13-18). 6 of the included articles

used the PedsQL, whereof four in juvenile idiopathic arthritis[116, 122, 123, 125], one in cystic

fibrosis[35], and one in histiocytosis[133].

Well-Being

Questions on Life Satisfaction Questionnaire.

The General Health Questionnaire (GHQ) is one of the most common assessments of mental well-

being. It was developed as a screening tool to detect those likely to have or be at risk of developing

psychiatric disorders. It consists of four domains, and is available in a variety of versions using 12, 28,

30, or 60 items. The 28-item version is used most widely. Each item is accompanied by four possible

responses (0-3), yielding a total possible score on the GHQ28 ranging from 0 to 84. 3 of the included

articles used the GHQ, whereof two used the GHQ30 in juvenile idiopathic arthritis[114, 115], and

one used the GHQ12 in epidermolysisbullosa[75].

The General Well Being (GWB) Schedule is a self-administered questionnaire that focuses on one’s

subjective feelings of psychological well-being and distress. It consists of 18 items covering six

dimensions, yielding a total score running from 0 to 110 with lower scores indicating more severe

distress. EJ


18



19


Table 3.Characteristics of Selected HRQoL Instruments for Rare Diseases

Instrument Domains Number of

Items

Number of Levels Respondents

Intended for

(age/disease)

Language

Preference-based Health Utility Index

EuroQol (EQ-5D)1

Mobility, Self-care, Main/Daily Activity, Pain, Mood

5 3 243 health states

General and specific populations

150 translated versions (see web-page)

EuroQol – youth version (EQ-5D-Y)2

Mobility, Self-care, Main/Daily Activity, Pain, Mood

5 3 243 health states

Children and adolescents aged 7-12 years

9 translated versions (see web-page)

Health Utilities Index Mark 3(HUI3)3

Vision, Hearing, Speech, Ambulation, Dexterity, Emotion, Cognition, Pain

8 5/6 General and specific populations (5 years+)

English, French, Spanish, Italian, German, Dutch, Japanese

Short-Form 6D (SF-6D)4

Pain, Mental Health, Physical Functioning, Social Functioning, Role Limitation, Vitality

11 4-6 18,000 health states


At least 50 translated versions. See web-page

Generic Health Profile

Short-Form 36 (SF-36)5

Physical Component: Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH). Mental Component: Vitality (VT), Social Functioning (SF), Role-Emotional (RE), Mental Health (MH).

36 ? General and specific populations

At least 54 translated versions (see web-page)

1http://www.euroqol.org/ 2http://www.euroqol.org/

3http://fhs.mcmaster.ca/hug/ 4http://www.shef.ac.uk/scharr/sections/heds/mvh/sf-6d 5http://www.sf-36.org/


20


Short-Form 12 (SF-12)6

Physical Health, Mental Health 12 ? General and specific populations

See web-page

Health Assessment Questionnaire (HAQ) Disability (HAQ Disability Index): Dressing, Arising, Eating, Walking, Hygiene, Reach, Grip, Common Activities Discomfort and Pain (HAQ Pain Scale)(VAS) Drug Side Effects (Toxicity) Dollar Costs

Disability Index: 8

Disability Index: 4 degree of difficulty, 4 need of assistance Disability Index


Questions on Life Satisfaction (FLZM; FragenzurLebenzufriedenheitModule)

General Life Satisfaction, Satisfaction with Health

8 per domain

Rating of Subjective importance, Degree of Satisfaction “Weighted satisfaction score”


Nottingham Health Profile (NHP)7

Energy Level, Pain, Emotional Reaction, Sleep, Social Isolation, Physical Abilities

38 Yes/No Score:1-100

General and specific populations (16 years+)

Translated to 21 languages (See web-page)

General (Mental) Health Questionnaire (GHQ) (Goldberg)

Depression, Anxiety, Somatic Symptoms, Social Withdrawal

12/28/30/60 0-3 Total: 0-84


At least 38 different languages

Katz Basic Activities of Daily Living (ADL) Scale

Bathing, Dressing, Toileting, Transferring, Continence, Feeding

6 Independent Yes/No

6http://www.sf-36.org/ 7http://www.proqolid.org/instruments/nottingham_health_profile_nhp


21


WHO Quality of Life(WHOQOL)-100/BREF8

Physical Health, Psychological Health, Social Relationships, Environment, Level of Independence Sprituality/Religion/Personal Beliefs (WHOQOL-100)

26/100 5


Translated to at least 20different languages (see web-page)

Manchester Short Assessment of Quality of Life (MANSA)

16

The General Well-Being (GWB) Schedule Anxiety, Depression, General Health, Positive Well-Being, Self-Control, and Vitality

18 0-5 Total: 0-110


Pediatric Generic Health Profile

Children’s Health Assessment Questionnaire (CHAQ)

Dressing & Personal Care, Getting Up, Eating, Walking, Hygiene, Reach, Grip, Activities (VAS: pain, general health)

X 5 Parents

Child Health Questionnaire (CHQ) (Parent and Child Form)9

Physical Functioning, Social Functioning, Bodily/Discomfort, General Behavior, Mental Health, General Health Perception, Self Esteem, Parental Impact (time & emotional), Family Functioning (activities & cohesion)

Parent Form: 28/50 Child Form: 87

CHQ Summary Score

Children 5-18 years of age. 5-13 years, parent responders. 10-18 years, child responders.

Pediatric Quality of Life Inventory (PedsQL)10

Physical Functioning, Emotional Functioning, Social Functioning

23 Psychosocial Health Summary Score, Physical Health Summary Score, Total Scale Score

Children 8-12 years of age (2-7, 8-12, 13-18) 2-18 years, parent responders

See web-page.

8http://www.who.int/substance_abuse/research_tools/whoqolbref/en/ 9http://www.healthact.com/survey-chq.php


22


5-18 years, child responders.

Disease-Specific Health Profile

Cystic Fibrosis Questionnaire (CFQ)11 Physical Functioning, Vitality,

Emotional State, Social Limitations, Role Limitationes/School Performance, Embarrassment, Body Image, Eating Disturbances, Treatment Constraints

CFQ Teen/Adult: 50 CFQ Parent: 44 CFQ Child: 35

Scores for each HRQoL domain (1-100)

CFQ Teen/Adult: 14 years+ CFQ Partent/Child: 6-13 years

American English, German, Dutch, Portuguese, (ongoing translations in Spanish, Italian, Greek, Hebrew, Turkish).

Cystic Fibrosis Quality of Life Questionnaire (CFQoL)

The Caregiver Quality of Life Cystic Fibrosis (CQOLCF) Scale

The Quality of Life Profile for Chronic Diseases (CRDQ)

Hemophilia-Specific Quality of Life Index (Haemo-QoL) Questionnaire

New Haemophilia Measure

The Canadian Haemophilia Outcomes – Kids Life Assessment Tool (CHO-KLAT)

Functional Independence Score in Haemophilia (FISH)

Quality of Life in EpidermolysisBullosa (QOLEB)

The Dermatology Life Quality Index (DLQI)

Scleroderma Health Assessment Questionnaire (S-HAQ)

Juvenile Arthritis Quality of Life

10http://www.pedsql.org/ 11http://qol.thoracic.org/sections/instruments/ae/pages/cfq-cfq-r.html


23


Questionnaire (JAQQ)

The McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR)

The Self-administrated Systemic Sclerosis Questionnaire (SySQ)

King’s Health Questionnaire (KHQ) Global Health Perceptions, Incontinence Impact, Role Limitations, Physical Limitations, Social Limitations, Personal Relationsships, Emotions, Sleep/Energy , Severity Measures

20 4 Patients with an overactive bladder


24


5. Summary This review identified 134 abstracts on generic- or disease specific health related quality of life

(HRQoL) for nine out of ten identified rare diseases. There was a wide range in the number of studies

performed on each disease (0 for mucopolysaccharidosis and 40 for cystic fibrosis). Also the use of

generic and disease specific instruments varied between conditions – disease specific instruments

only was used in 6.5% of the studies on juvenile idiopathic arthritis and 57% of the studies on cystic

fibrosis.The size of the studies also showed great variation – from 10 patients in haemophilia to 3364

patient in JIA. The reasons for these variations are probably plenty but the prevalence /incidence of

the condition, study purpose and the development of treatments with clinical studies may explain

some.

The results have mainly focused on the psychometric aspects of preference based generic

instruments as these can be used to compare outcomes between diseases for economic purposes.

Formal tests for reliability, validity and responsiveness of the instruments were rather scarce. The

associations between certain dimensions of instruments and clinical measures were more frequent,

sometimes with diverging conclusions between studies.

The SF-36 instrument was the most frequently used generic instrument. Although this is not a

preference based instrument it can easily be converted to one using conversion algorithms. Using

this instrument to estimate the HRQoL would therefore provide information that can be validated

with other studies as well as estimating QALY-weights. However, the interpretation of the QALY-

weights obtained through conversion algorithms may not be straight forward [Mortimer, Segal. Med

Decis Making 2008(28):66-89].Other indirect instruments for estimating QALY-weights were the EQ-

5D and HUI2/3 which were used much less in the reviewed studies.

In general there were only few studies analysing the HRQoLmeasured by caregivers. Caregivers, or

proxies, tended to estimate the patient’s HRQoL lower than the child. Especially the physical

dimensions were lower rated by the proxy than the patient. The other important question, namely

how the caregiver’s HRQoL was impaired by the patient’s condition, was only studied in very few

studies. It is therefore difficult to determine which, if any, of the preference based instruments are

suitable for estimating this burden for the studied conditions. This is an area where more research is

needed.


25


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