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Growing up with hemophilia
Health related quality of life and psychosocial functioning
Limperg, P.F.
Publication date
2017
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Citation for published version (APA):
Limperg, P. F. (2017). Growing up with hemophilia: Health related quality of life and
psychosocial functioning.
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55
Chapter 3
Health-related quality of life questionnaires in
individuals with haemophilia: a systematic review of
their measurement properties
P.F. Limperg, C.B. Terwee, N.L. Young, V.E. Price, S.C. Gouw, M. Peters, M.A. Grootenhuis, V. Blanchette, L. Haverman
Abstract
Background: The evaluation of health related quality of life (HRQOL) is essential for a full assessment of the infl uence of an illness on patients’ lives. The aim of this paper is to critically appraise and compare the measurement properties of HRQOL questionnaires studied in haemophilia.
Methods: Bibliographic databases (Embase, Medline, Cinahl and PsycInfo) were searched for articles evaluating measurement properties of HRQOL questionnaires in haemophilia. Articles were excluded that did not report HRQOL measurement properties, or when <50% of the study population had haemophilia. The methodological quality of the selected studies was evaluated using the COSMIN checklist. The measurement properties of the HRQL questionnaires were rated as ‘positive’, ‘indeterminate’, or ‘negative’, accompanied by levels of evidence.
Results: The search resulted in 1597 unique hits, of which 22 studies were included. These articles evaluated three questionnaires for children (CHO-KLAT, Haemo-QoL and one unnamed measure) and fi ve for adults (Hemofi lia-QoL, Haemophilia Well-Being Index, HAEMO-QoL-A, Haem-A-lia-QoL, and SF-36). The CHO-KLAT was the paediatric measure that showed the strongest measurement properties in high-quality studies. The Haemophilia Well-Being Index and HAEMO-QoL-A performed best among the adult measures. None of the studies reported measurement error and responsiveness.
Conclusion: Our fi ndings suggest that there is no need for new disease specifi c HRQOL questionnaires for haemophilia, but rather that additional research is necessary to document the measurement properties of the currently available questionnaires, specifi cally focusing on the structural validity, measurement error and responsiveness of these questionnaires.
57
Introduction
Haemophilia is an X-linked bleeding disorder, affecting primarily boys, caused by an inherited defi ciency of factor VIII (haemophilia A) or factor IX (haemophilia B) [1]. The bleeding risk is related to the severity of the factor defi ciency, and repeated joint bleeding can cause severe joint damage and pain, leading to disability [2]. Consequently, haemophilia and its treatment impact patients’ health-related quality of life (HRQOL) and daily functioning. Diffi culties and impairments, such as frequent hospital visits, frequent injections and limited participation in (sport) activities are common [3].
Much of the haemophilia outcomes research to date has focused on pathophysiological manifestations of the disease, such as the number and type of bleeds, and evidence of joint damage. However, these outcomes alone are not suffi cient to assess the impact of a health condition on a person’s life. The evaluation of HRQOL is essential for a full understanding of the infl uence of a chronic health condition on individuals and to evaluate the impact of different treatment strategies [4]. HRQOL is a multidimensional concept that refers to the subjective impact of health and illness on an individual’s daily functioning, which encompasses not only physical functioning but also social, cognitive and emotional functioning [5]. It is recommended to include HRQOL as an outcome in research and in assessment of care options in persons with haemophilia [6, 7].
Health-related quality of life questionnaires have been used in adult populations for some time, paediatric questionnaires have also gained acceptance over the years [8-10]. In children, the relevant dimensions and the content of paediatric HRQOL questionnaires can differ substantially from those of adult questionnaires, and may also vary with age of the child [10, 11]. Research shows that children over the age of 7 years are able to reliably report their health status [10, 12, 13].
In general, HRQOL questionnaires are either generic or disease-specifi c. Generic instruments allow for comparison of HRQOL across conditions, where disease-specifi c questionnaires are more responsive to change in the area of interest and more sensitive to the impact of changes in clinical conditions
or treatment [5, 10]. For children and adults with haemophilia, several age and disease-specifi c HRQOL instruments have been developed [14-17]. A challenge in using HRQOL instruments is that adaptation to different cultures and languages is needed to be useful in multisite international studies. Even though generic HRQOL instruments have been used most frequently, such as the SF-36 for adults and the PedsQL for children [7, 18-20], a combination of the two types of measures may provide the most optimal information [5, 10, 21].
Systematic reviews can be useful to select the best measurement instrument for a specifi c purpose [22]. In haemophilia, several systematic reviews on health and patient reported outcome measures (PROMs) have been published [2, 9, 23-25]. However, these reviews have not systematically assessed the methodological quality of studies on measurement properties. Studies of high methodological quality are needed for unbiased assessment of the measurement properties. The ‘COnsensus-based Standards for the selection of health status Measurement INstruments’ (COSMIN) checklist has recently become available to evaluate the methodological quality of studies on measurement properties against a set of standards and to take the methodological quality of studies into account in the evaluation of the measurement properties of HRQOL questionnaires [26, 27].
The aim of this systematic review was to obtain a comprehensive overview of the measurement properties of HRQOL questionnaires in haemophilia across geographic and age boundaries.
Methods
Literature search
The computerized bibliographic databases Medline, Embase, CINAHL, and PsycINFO were searched (January 2016). Variations of the following search terms were used: haemophilia A/B, in combination with the search fi lter PROMs (www.cosmin.nl) and a fi lter for fi nding studies on properties of measurement instruments [28]. This full search strategy is available upon request. Reference lists from included articles were reviewed to identify additional studies.
59
Selection criteria
Two reviewers (PL, MJ) independently assessed all titles, abstracts and full-text articles retrieved by the literature search. Potentially relevant articles were assessed to ensure they were full-text original research articles (e.g. not an abstract or review), published in English, and focused on the development or evaluation of measurement properties of a HRQOL questionnaire. Furthermore, the questionnaire had to be self- or parent proxy-reported, and specifi cally developed or evaluated in individuals with haemophilia (≥50% of the sample with haemophilia A/B). In case of disagreement between the two reviewers, there was discussion to reach consensus. If necessary, a third reviewer (CT) made the decision regarding inclusion of an article.
Methodological quality assessment of included studies
The methodological quality of the included studies was assessed to screen for potential bias; the COSMIN checklist has been designed for this purpose [26, 27]. The COSMIN checklist consists of nine boxes with methodological standards for how each measurement property should be assessed. Each item was scored on a 4-point rating scale (‘excellent’, ‘good, ‘fair or ‘poor’) [26]. An overall score for the methodological quality of a study was determined for each measurement property separately, by taking the lowest rating of any of the items in a box [26]. The methodological quality of each selected study was evaluated by two independent reviewers (PL, MJ). Consensus was reached by discussion or a third reviewer (CT) if there was disagreement.
Quality evaluation of the measurement properties
In addition to assessing the methodologic quality of each included study, the results of the studies were subsequently rated against criteria for good measurement properties (see Table 1) [29]. The measurement properties are divided over three domains: reliability, validity and responsiveness, which will be described briefl y below. In addition, the interpretability is described.
Reliability is defi ned by COSMIN as the extent to which scores for patients who have not changed are the same for repeated measurement under several
Property Rating Quality Criteria Reliability
Internal consistency + (Sub)scale unidimensional AND Cronbach’s alpha(s) ≥ 0.70 ? Dimensionality not known OR Cronbach’s alpha not determined - (Sub)scale unidimensional AND Cronbach’s alpha(s) < 0.70 Measurement error + SDC < MIC OR MIC outside the LOA
? MIC not defined
- SDC ≥ MIC OR MIC equals or inside LOA Test-retest reliability + ICC/weighted Kappa ≥ 0.70 OR Pearson’s r ≥0.80
? Neither ICC/weighted Kappa, nor Pearson’s r determined - ICC/weighted Kappa < 0.70 OR Pearson’s r < 0.80 Validity
Content validity + The target population considers all items in the questionnaire to be relevant AND considers the questionnaire to be complete ? No target population involvement
- The target population considers items in the questionnaire to be irrelevant OR considers the questionnaire to be incomplete Construct validity
Structural validity + Factors should explain at least 50% of the variance ? Explained variance not mentioned
- Factors explain < 50% of the variance
Hypothesis testing + Correlation with an instrument measuring the same construct ≥ 0.50 OR at least 75% of the results are in accordance with the hypotheses AND correlation with related constructs is higher than with unrelated constructs
? Solely correlations determined with unrelated constructs - Correlation with an instrument measuring the same construct
< 0.50 OR < 75% of the results are in accordance with the hypotheses OR correlation with related constructs is lower than with unrelated constructs
Cross-cultural validity + Original factor structure confirmed OR no important DIF ? Confirmation original factor structure AND DIF not mentioned - Original factor structure not confirmed OR important DIF Responsiveness
Responsiveness + Correlation with an instrument measuring the same construct ≥ 0.50 OR at least 75% of the results are in accordance with the hypotheses OR AUC ≥ 0.70 AND correlation with related constructs is higher than with unrelated constructs
? Solely correlations determined with unrelated constructs - Correlation with an instrument measuring the same construct
< 0.50 OR < 75% of the results are in accordance with the hypotheses OR AUC < 0.70 OR correlation with related constructs is lower than with unrelated constructs
Table 1. Quality criteria for good measurement properties.
Based on Terwee et al. [35]. MIC minimal important change; SDC smallest detectable change; LOA limits of agreement; ICC intraclass correlation coefficient; AUC area under the curve; DIF differential item functioning; + positive rating, ? indeterminate rating, - negative rating.
conditions [30]. Three forms of reliability are distinguished: internal consistency (the degree of interrelatedness among items within the same questionnaire, expressed as Cronbach’s α), measurement error (systematic and random error of a patient’s score that is not attributed to true changes in the construct to be measured, expressed by the standard error of measurement (SEM)), and test-retest reliability (the proportion of the total variance in the measurements
3
61 that is due to true differences between patients; expressed by the intraclass correlation coeffi cient (ICC) or Cohen’s Kappa) [30, 31].
Validity is defi ned as the extent to which a questionnaire measures the construct it is supposed to measure. Three aspects of validity are included: content validity (the degree to which the content of a questionnaire is an adequate refl ection of the construct to be measured), criterion validity (the extent to which scores on instruments are an adequate refl ection of a gold standard), and construct validity (the extent to which the scores of an instrument are consistent with hypotheses, based on existing knowledge about the construct) [30, 31]. Additionally, three aspects of construct validity are distinguished; structural validity (the degree to which the scores of an instrument are an adequate refl ection of the (uni)dimensionality of the construct to be measured using factor analysis to confi rm the number of subscales present in a questionnaire), hypotheses testing (the degree to which a measure relates to other measures or measures differences between relevant groups in a way one would expect), and cross-cultural validity (the degree to which the performance of the items on a translated or culturally adapted instrument is an adequate refl ection of the performance of the items of the original version of the instrument) [30].
Responsiveness is defi ned as the ability of an instrument to detect change over time in the construct to be measured [30]. The correlation between change scores of two measures should be in accordance with predefi ned hypotheses [27].
Interpretability is defi ned as the degree to which one can assign qualitative meaning to quantitative scores (i.e. what do scores on an instrument mean). Interpretability is not considered a measurement property, but an important characteristic of a measurement instrument. This means that information should be provided about clinically meaningful differences in scores between subgroups, fl oor and ceiling effects, and the minimal important change (MIC) [30].
Best evidence synthesis: levels of evidence
Level Rating Criteria
Strong +++ or --- Consistent findings in multiple studies of good methodological quality OR in one study of excellent methodological quality
Moderate ++ or -- Consistent findings in multiple studies of fair methodological quality OR in one study of good methodological quality
Limited + or - One study of fair methodological quality Conflicting ± Conflicting findings
Unknown ? Only studies of poor methodological quality
Table 2. Levels of evidence for the overall quality of the measurement property.
Based on the Cochrane Back Review Group [36]. + positive result; - negative result; ? unknown result.
separately, taking into account the total sample size of the available studies, the methodological quality of the studies and the consistency of the results. The quality of the evidence refers to the confi dence that the results are correct. Judgements were not made for individual studies, but based on all available evidence on a measurement property of a questionnaire (see Table 2) [29]. This best evidence synthesis is similar to that used for synthesizing evidence from clinical trials [32].
Results
The number of articles identifi ed through the study selection process and reasons for exclusion are summarized in Fig. 1. In total, 22 articles (of which 15 included children and 7 included adults) reported on eight distinct questionnaires; three for children and fi ve for adults. The general characteristics of these studies and questionnaires are presented in Table 3. The methodological qualities of the studies, based on the COSMIN checklist, are presented in Table 4 for each questionnaire and measurement property assessed. The synthesis of results per questionnaire and their accompanying level of evidence (based on Table 2) are presented in Table 5 (children) and Table 6 (adults). Below, we will discuss the results per questionnaire.
Children
CHO-KLAT
Two studies of poor methodological quality evaluated the internal consistency of the CHO-KLAT [15] (Cronbach’s α of 0.81-0.91), but have not assessed
3
63 unidimensionality of the questionnaire, so the internal consistency was rated as indeterminate [33]. We found strong positive evidence for test-retest reliability of the CHO-KLAT: ICC is 0.74 for children, 0.83 for parents and the child-parent concordance is 0.75 [33-35]. We found strong positive evidence for content
Records identified through database searching
(n = 1,892)
Records after duplicates removed (n=1,597)
Full-text articles assessed for eligibility
(n=34)
Most frequently used HRQOL questionnaires as outcome: Children - Haemo-QoL (15) - KINDLR (2) - PedsQL (2) - CHO-KLAT (1) - KIDSCREEN (1) Adults - SF-36 (18) - EQ-5D (6) - SF-12 (4) - Rand 36 (1) Records excluded (n=1563)
Full-text articles ex-cluded, with reasons (n=12): - No measurement properties (n=7) - Not in English (n=2) - No HRQOL (n=1) - Not hemophilia (n=2)
Studies included in review (n=22)
Instruments included in review (n=8)
Reference checking (n=0) Medline
(n=490) Embase(n=667) (n=171)Cinahl PsycInfo(n=564)
Identifi cation Eligibility Scr eening Included
Table 3.
Characteristics o
f the included questionnair
es. Questionnair e N o f studies included Scope Tar get population Recall period Response options Domains and items (n)
Scor e range Original language Translations Childr en CHO-KL AT [15] 9
To assess quality of life in boys with hemophilia, and their parents
Childr en 4-18 year s S,P Last 4 weeks Five-point Liker t Scale 1 (35 items) 0-100 (best) English (Canada) 20 languages Haemo-QoL [14] 5
To assess quality of life in childr
en/
adolescents with hemophilia and their parents
Childr en 4-16 year s S,P Last 4 weeks Five-point Liker t Scale 1 (8 items),
8 (21 items), 10 (64 items), 12 (77 items)*
0-100 (wor
st)
Dutch (the Netherlands) English (UK) French (France)
Ger
man (Ger
many)
Italian (Italy) Spanish (Spain)
28 languages ‘Toddler ’ questionnair e [44] 1
To assess disease- specific
Childr en 2-6 year s P Last week Five-point Liker t Scale 9 (39 items) Unknown English (USA) Unknown Adults Hemo filia-QoL [16] 2 To assess quality o f
life in adults living with hemophilia
>18 year s S Unknown Unknown 9 (36 items) Unknown Spanish (Spain) 9 languages
Haemophilia Well-Being Index [45]
1
Assessment o
f
subjective well- being o
f men with hemophilia >18 year s S Last month Five-point Liker t Scale 1 (8 items) 0–100 (best) Spanish (Spain) 3 languages HAEMO-QoL-A [46] 1 To assess quality o f
life in adults living with hemophilia
>18 year s S Last month Six-point Liker t Scale 6 (41 items) 0–100 (best) English (USA) 4 languages Haem-A-QoL [47] 3
To assess health- related quality o
f life
in adult patients with hemophilia
>18 year s S Last 4 weeks Five-point Liker t Scale 10 (46 items) 0-100 (wor st)
English (UK) Italian (Italy)
57 languages
SF-36 [19]
1
To measur
e generic
health concepts relevant acr
oss
age, disease, and treatment gr
oups >16 year s S Last 4 weeks Six-point Liker t Scale 8 (36 items) 0–100 (best) English (USA) 161 languages
* Haemo-QoL: the ver
sion for age gr
oup I (4–7 year
s) contains 21 items in 8 domains, the age gr
oup II (8-12 year
s) ver
sion contains 64 items
in 10 domains, and the age gr
oup III (13-16 year
s) ver
sion contains 77 items in 12 domains. Fur
ther mor e, two shor t for m measur es containing
16 and 35 items wer
e developed for ages 4-7 and 8-16 year
s. P: par ent -r epor ted S: self -r epor ted
3
65 Study Int er nal consist ency Measur ement err or Test -r et est reliability Cont ent validity Structural validity Hypotheses testing Translation Cr oss-cultural validity Responsiv eness Childr en CHO-KL AT Young et al. (2004) [15] -Excellent -Bradley et al. (2006) [33] Poor -Fair -Excellent -Young et al. (2006) [34] -Good -Fair -Young et al. (2012)[38] -Fair Fair -Wu et al. (2012) [36] -Excellent -Good -Villaca et al. (2013) [48] -Fair -Young et al. (2013) [35] -Good Excellent -Fair -Wu et al. (2014) [49] -Excellent -Fair -McCusker et al. (2015) [37] Poor -Good -Fair Good -Haemo-QoL Bullinger et al. (2002) [39] Excellent -Excellent Poor Fair -von Mackensen et al. (2004) [14] Fair -Fair -Poor Fair -Bradley et al. (2006)[33] Poor -Fair -Excellent -Pollak et al. (2006) [42] Excellent -Fair -Excellent Fair -Mer can et al. (2010) [43] -Good -von Mackensen et al. (2013) [51] -Poor -‘Toddler questionnair e’ Manco-Johnson et al. (2004) [44] Good -Excellent -Fair -Adults Hemo filia-QoL Arranz et al. (2004) [16] Excellent -Excellent -Remor et al. (2005) [52] Excellent -Fair Excellent -Fair -Haemophilia W ell-Being Index Remor (2013) [45] Excellent -Good Excellent Excellent Fair -Table 4. Methodological quality o
f each study per measur
ement pr
oper
ty and questionnair
e (C
Table 4.
Methodological quality o
f each study per measur
ement pr oper ty and questionnair e (C OSMIN). (Continued) HAEMO-QoL-A Rentz et al. (2008) [53] Excellent -Good Excellent Good Fair Good Good - Young et al. (2012) [38] -Fair Fair -Haem-A-QoL Mer can et al. (2010) [43] -Good -Von Mackensen et al. (2012) [47] Good -Good Excellent -Fair Good -Varaklioti et al. (2014) [54] Good -Fair -Fair -SF-36 Solovieva et al. (2004) [55] Excellent -Good -Table 5. Quality o f the measur ement pr oper
ties per questionnair
e in childr en. Questionnair e Int er nal consist ency Measur ement err or Test -r et est reliability Cont ent v alidity Structural validity Hypothesis testing Cr oss-cultural validity Responsiv eness CHO-KL AT ? NIA +++ +++ NIA +++ NIA NIA Haemo-QoL I (4-7) NIA NIA ? + NIA Physical health -+++ Feeling + +++ View -+++ F amily -+++ Friends ? +++ ? Other s -+++ + Spor t and school -+++ ? T reatment -+++ ? T otal + Haemo-QoL II (8-12) NIA ? + NIA NIA Physical health + + +++ Feeling -+ +++ View + + +++ F amily -+ +++ Friends + + +++ ? Other s + + +++ ? Spor t and school -+ +++ ?
3
67
+++ or --- = str
ong evidence positive/negative r
esult, ++ or -- = moderate evidence positive/negative r
esult, + or - = limited evidence
positive/negative r
esult, +/- = conflicting evidence, ? = unknown, due to poor methodological quality
, NIA = no infor mation available. T reatment -+++ ? P er ceived suppor t -+ +++ Dealing -+++ T otal + + Haemo-QoL III (13-16) NIA ? + NIA NIA Physical health + + +++ Feeling + + +++ + View + + +++ + F amily -+ +++ + Friends -+ +++ Other s + + +++ ? Spor t and school + + +++ T reatment -+++ P er ceived suppor t -+++ + Dealing -+ +++ ? Futur e -+++ Relationship + + +++ T otal + + Haemo-QoL Index ? NIA + NIA ---+ NIA NIA ‘T oddler questionnair e’ NIA NIA NIA + NIA NIA Somatic symptoms ++ +++ + Physical functioning ++ +++ + Sleep disturbance ++ +++ + Stigma ++ +++ + Social functioning ++ +++ + Fear/r esentment ++ +++ + T reatment upset ++ +++ + Haemophilia concer n ++ +++ + Ener gy level ++ +++ + Mood/behaviour ++ +++ + Restrictions ++ +++ + Table 5.
Quality of the measurement properties per questionnaire in children.
validity of the CHO-KLAT [15, 35, 36]. We also found strong evidence for positive construct validity, showing that the CHO-KLAT has positive correlations with instruments measuring generic as well as disease-specifi c HRQOL (r=0.52– 0.82) [33-35, 37, 38]. There were no studies evaluating the measurement error or responsiveness of the CHO-KLAT. With regard to interpretability, no ceiling or fl oor effects were detected; the MIC has not been published.
Haemo-QoL
The internal consistency of the Haemo-QoL was 0.85 (Cronbach’s α) for the total scale in age group I (4-7 years), Cronbach’s α was 0.90 in age group II (8-12 years) and in age group III (13-16) the Cronbach’s α was 0.91. Two studies of poor quality assessed structural validity [14, 39]. The test-retest reliability of the Haemo-QoL has not been assessed for age group I, and we found confl icting evidence for test-retest reliabilities varying from poor to excellent for most scales in age group II and III (0.57-0.90) and excellent scores for the total scale (.90 and .92) [14]. Strong evidence was found for positive content validity. We found confl icting evidence for the construct validity of the Haemo-QoL [14, 40]. No studies were found assessing measurement error and responsiveness has only been studied in a clinical trial population [41]. With regard to interpretability, substantial fl oor and low ceiling effects were found; the MIC has not been studied [14].
The Haemo-QoL Index (short version) represents the core content as well as the multidimensional structure of the original Haemo-QoL versions [42, 43]. One study of excellent quality carried out confi rmatory factor analysis (CFA) and reported a comparative fi t index (CFI) of 0.92, which is just below the threshold for a positive rating for unidimensionality of the scale. A Cronbach’s α of 0.70 was found in children and a Cronbach’s α of 0.78 in parents, but since unidimensionality could not be confi rmed, internal consistency was rated as indeterminate. We found limited evidence for positive test-retest reliability in children (0.76) and for test-retest reliability in parents (0.27). Content validity was not assessed. We found limited evidence for the positive construct validity of the Haemo-QoL Index in correlations (r=-0.22-0.51) with instruments
3
69 measuring generic HRQOL [42]. Responsiveness and measurement error have not been assessed. Floor and ceiling effects, differences in scores between subgroups and the MIC have not been reported.
A proxy disease-specifi c HRQOL questionnaire (‘Toddler questionnaire’)
Cronbach’s α of 0.73-0.94 were found for the ‘Toddler questionnaire’. However, structural validity was not studied [44]. Strong evidence was found for a positive content validity. Limited evidence was found for positive construct validity, showing that this questionnaire has negative as well as positive correlations with instruments measuring generic HRQOL (r=0.25-0.70) [44]. There were no studies evaluating the measurement error, test-retest reliability or responsiveness of this instrument. Floor and ceiling effects, differences in scores between subgroups; and the MIC have not been reported.
Adults
Hemofi lia-QoL
Cronbach’s α of 0.95 was found for the Hemofi lia-QoL total scale [16, 52]. Limited evidence was found for positive test-retest reliability (ICC: 0.79-0.92) [52]. Strong evidence is available for a positive content validity. Limited evidence was found for a positive construct validity; showing that the Hemofi lia-QoL questionnaire has negative as well as positive correlations with instruments measuring generic HRQOL (r=0.17-0.77) [16, 52]. No studies were found assessing responsiveness or measurement error. With regard to interpretability, small fl oor and low ceiling effects have been detected. Differences in scores between subgroups were found, the MIC has not been studied [52].
Haemophilia Well-Being Index
One study of excellent quality has shown the unidimensionality (with factor loadings of ≥0.70) of the Haemophilia Well-Being Index [45], showing strong evidence for a positive internal consistency (Cronbach’s α 0.91) and moderate evidence for positive test-retest reliability (ICC: 0.82) [45]. Strong evidence is available for a positive content validity and structural validity. Limited evidence was found for a positive construct validity; showing that the Haemophilia Well-Being Index has limited correlations with instruments measuring generic HRQOL (r=0.24-0.42) [45]. Responsiveness, measurement error and cross-cultural validity have not been assessed. Floor and ceiling effects, differences in scores between subgroups, and the MIC has not been reported.
HAEMO-QoL-A
We found strong evidence for positive internal consistency of the HAEMO-QoL-A [38, 53] (Cronbach’s α 0.95) and moderate evidence for positive test-retest reliabilities (ICC >0.80), except for the Emotional Impact domain (0.79). Strong evidence is available for the positive content validity and moderate evidence for structural validity. Associations with other generic HRQOL measures provided limited positive evidence for the instrument’s construct validity (r=0.13-0.87) [53]. Moderate positive evidence was found for cross-cultural validity. Responsiveness and measurement error have not been assessed. No fl oor or ceiling effects have been detected; differences in scores between subgroups have been reported. There is no information regarding the MIC.
Haem-A-QoL and Haem-A-QoLElderly
Cronbach’s α of 0.87 was found for the Haem-A-QoL total scale. However, structural validity was not studied [43, 54]. Limited evidence for positive test-retest reliability was found (ICC >0.80). Associations with other generic HRQOL measures provide limited evidence for the instrument’s positive construct validity (r=0.25-0.75) [53]. Measurement error has not been assessed; responsiveness has only been recently studied in a clinical trial population [56]. With regard
3
71 Table 6. Quality o f the measur ement pr oper
ties per questionnair
e in adults. Questionnair e Inter nal consistency Measur ement err or Test -r etest reliability Content validity Structural validity Hypothesis testing Cr oss-cultural validity Responsiveness Hemo filia-QoL NIA NIA NIA NIA Physical health +++ + +++ + Daily activities +++ + +++ Joint damage +++ + +++ P ain +++ + +++ + T reatment satisfaction ---+ +++ + T reatment difficulties ---+ +++ + Emotional functioning +++ + +++ + Mental health +++ + +++ +
Relationships and social activity
+++ + +++ + T otal scor e +++ + +++ + Haemophilia W ell-Being Index +++ NIA ++ +++ +++ + NIA NIA HAEMO-QoL-A NIA ++ + ++ NIA Physical functioning +++ ++ +++ + Role functioning +++ ++ +++ + W orr y +++ ++ +++ + Consequences o f bleeding +++ ++ +++ + Emotional impact +++ ++ +++ + T reatment Concer ns +++ ++ +++ T otal scor e +++ ++ + Haem-A-QoL NIA NIA NIA NIA NIA Physical Health ++ + + Feelings ++ + + View ++ + + Spor ts/leisur e ++ + + W ork/school ++ + + Dealing --+ + T reatment ++ + + Futur e ++ + + F amily planning ++ + + Relationship/par tner ++ + + T otal scor e ++ + +
Table 6.
Quality o
f the measur
ement pr
oper
ties per questionnair
e in adults.
(Continued)
+++ or --- = str
ong evidence positive/negative r
esult, ++ or -- = moderate evidence positive/negative r
esult, + or - = limited evidence positive/negative r
esult, +/- = conflicting evidence, ? = unknown, due to
poor methodological quality
, NIA = no infor mation available Haem-A-QoL Elderly NIA NIA + NIA NIA Physical ++ ++ +++ Feeling ++ ++ +++ View ++ ++ +++ F amily --+++ Other s ++ ++ +++
Physical activity & leisur
e ++ --+++ W ork ++ ++ +++ Dealing ++ --+++ T reatment ++ ++ +++ Futur e ++ ++ +++ Relationship ++ --+++ T otal ++ ++ + SF-36 NIA NIA NIA NIA NIA NIA Physical functioning +++ ++ Role physical +++ ++ Bodily pain +++ ++ General health +++ ++ Vitality +++ ++ Social functioning +++ ++ Role emotional +++ ++ Mental health +++ ++
3
73 to interpretability, reductions of 7.1 points in the ‘Total Score’ appeared to be reasonable estimates of meaningful change over 6 months, and provided practical thresholds for identifying subjects with notable improvements in HRQOL [57].
Cronbach’s α of 0.96 was found for the Haem-A-QoLElderly total scale. However, structural validity was not studied. Moderate evidence for positive test-retest reliabilities was found (ICC=0.24-0.93) [58]. Strong evidence is available for the positive content validity. With regard to construct validity, limited positive evidence was found that the Haem-A-QoLElderly questionnaire correlates with instruments measuring generic HRQOL (r=0.68-0.76) [58]. Responsiveness and measurement error have not been assessed. With regard to interpretability, no fl oor or ceiling effects were detected. Differences in scores between subgroups have been reported. There is no information regarding the MIC [54].
Short Form-36 (SF-36)
Cronbach’s α of 0.88-0.92 were found for the SF-36, but structural validity was not studied [55]. Strong evidence was found for good internal consistency of the SF-36, a generic HRQOL instrument (Cronbach’s α 0.88-0.92) [19, 55]. The result of the only methodologically sound study evaluating measurement error is indeterminate, because information is needed on the MIC for judging the measurement error. Also, test-retest reliability has not been assessed [55]. With regard to construct validity, there is limited evidence for positive correlation of the SF-36 with other generic HRQOL instruments for individuals with haemophilia (r=0.03-0.75) [55]. Responsiveness has not been assessed. With regard to interpretability, substantial ceiling effects were detected for three subscales. Differences in scores between subgroups (patients vs controls) have been studied. There is no information regarding the MIC.
Discussion
In this systematic review about the measurement properties of HRQOL questionnaires in haemophilia, eight different HRQOL measures have been identifi ed. Most measures are scaled in a similar way (0-100; best) and have good psychometric properties. However, information regarding some of the measurement properties (e.g. structural validity, measurement error and responsiveness) is still lacking, or of poor methodological quality, mostly due to small sample sizes. Additional studies can potentially provide more information on these measurement properties and consequently improve the evidence regarding the instruments (e.g. in new studies with repeated psychometric evaluation, with revised scoring, or in other patient subgroups).
Many different disease-specifi c HRQOL questionnaires have been developed, especially in adults, which complicates the choice of which questionnaire to use and makes comparisons across studies diffi cult. By critically appraising and comparing the measurement properties of HRQOL questionnaires studied in haemophilia, we hope to facilitate the choice of a HRQOL measure. The standardized assessment of HRQOL is important from the patient perspective (e.g. early detection of psychosocial problems or evaluation of a treatment), as well as from the research perspective (e.g. studying the long-term outcomes of different treatments at a group level) [6, 7, 59].
For children, the CHO-KLAT [15] shows strong evidence for content validity, test-retest reliability, and construct validity. The other questionnaires show positive results as well, but the evidence is slightly weaker. Structural validity, measurement error and responsiveness is lacking for most questionnaires.
For adults, fi ve HRQOL questionnaires have been evaluated of which the Haemophilia Well-Being Index and HAEMO-QoL-A seem to perform best [45, 53]. The other questionnaires also show positive results, but the evidence for the measurement properties is more limited. The measurement error and responsiveness have not been assessed.
Measuring HRQOL in children presents unique challenges compared to adults, including the age dependency within some aspects of quality of life domains as well as diffi culties obtaining self-report from children <7 years of
3
75 age [60]. In addition, when there are age-specifi c versions, it is critical to know how the various age versions relate to each other to support pooling of data across age groups or follow-up over time [10, 61]. A questionnaire can cover an age range from 7 to 18 years, because the items generated and retained by different age groups are suffi ciently similar. For example, the CHO-KLAT has been developed for children and has a proxy-report version (4-8 years) and a self-report version (7-18 years). Breaking measures into age ranges is a viable option only when there is extensive testing done to understand how one version relates statistically to the other. This is rarely done, and is often challenging in disease-specifi c and longitudinal studies for children because of limited samples sizes. Thus, multiple age ranges introduces more complex psychometric requirements that often cannot be met [10, 14].
Strikingly, for adults, several different disease-specifi c HRQOL instruments have been developed with similar names. All these questionnaires address concepts of HRQOL in haemophilia, however contain different items [62]. The existence of several disease-specifi c HRQOL questionnaires in combination with a lacking overview of what questionnaires are available (for free use) and in what languages, complicate the choice of which questionnaire to use.
Since cross-cultural adaptation is limited for many of the questionnaires included, only one of the included studies performed a cross-cultural validation (i.e. no other studies performed multiple-group factor analysis or differential item functioning) [53], no new disease-specifi c HRQOL measures should be developed. Instead, translations for existing measures are needed in order to increase sample sizes and perform studies in multi-cultural societies and internationally [63]. Besides the availability of different languages, the purpose and design of the instrument should be included in the decision about the use of an instrument as well. This adds to the challenge, especially in rare disorders such as haemophilia [2, 34, 63].
Choosing an HRQOL questionnaire can be challenging due to the abundance of different instruments, user fees and limited use in research and clinical settings, which makes it diffi cult to obtain enough empirical data
about specifi c instruments’ performance [60]. The measures presented in this systematic review have been tested and shown to have good group-level measurement properties. Still, none of them are suffi ciently strong to be able to make individual clinical decisions and most information on interpretability is lacking. However, many other clinical tools in haemophilia lack evidence for clinical decision making as well although they are widely used in patient care (e.g. the Haemophilia Joint Health Score (HJHS) [64]). In order to use PROMs in daily clinical practice, the measurement error (i.e. the error of a patient’s score that is not attributed to true changes in the construct) is an important measurement property, which has not been studied in the questionnaires included. However, the questionnaires all have the potential to offer information that can be of value in clinical decision making if used in combination with other outcomes (e.g. joint scores assessed by physical examination or imaging). In essence, HRQOL tools can be an additional aspect of clinical assessment [34]. Our results support the challenge that it is not the availability of suitable instruments, but the lack of awareness in both patients and physicians to implement these tools and document outcomes over time, in order to collect data [7].
In order to minimize respondent burden and to enhance international agreement, the use of core sets of instruments across studies would be optimal [60]. Another option to decrease the respondent burden is the use of Computer Adaptive Testing (CAT), e.g. the Patient-Reported Outcomes Measurements Information System (PROMIS). PROMIS aims to develop self-reported item banks using CAT and Item Response Theory that are applicable across a wide variety of chronic disorders. PROMIS includes generic and disease-specifi c item banks for adults and children (e.g. gastrointestinal, dyspnoea or asthma). However, no disease-specifi c item banks for haemophilia are developed so far. In the future, it would be useful to develop a haemophilia-specifi c PROMIS item bank, so patients only need to answer 4-8 items per item bank, without losing reliability [65, 66].
One of the strengths of this systematic review is the independent literature search and rating of the methodological quality of studies by two independent researchers. The COSMIN checklist was chosen as a guideline to
3
77 assess the methodological quality of the included studies, which is in line with the methodology of systematic reviews of clinical trials [26, 27, 67]. Although there are some limitations to these standards (e.g. high standards that often cannot be met in research in rare diseases, or not being able to distinguish between low reporting and low methodological quality of studies), they offer a strong starting point for a methodological assessment of outcomes. Moreover, exclusion of non-English papers may have introduced selection bias. For example, some instruments were excluded from the analysis because the study was not published in journals in English [68, 69]. Also, we found some instruments that have been developed or evaluated in individuals with haemophilia, but have not been published as full-text in a peer-reviewed journal [70, 71].
The different studies showed similar methodological shortcomings. Small sample sizes, for example, frequently led to poor or fair rating for the quality of the study. Unfortunately this is often the reality with disease-specifi c questionnaires in rare diseases. Another problem we encountered was that most studies do not formulate hypotheses regarding expected correlations in advance when testing construct validity. Most studies also do not report specifi cally on missing items or on how they were handled. Moreover, with regard to the level of construct validity, the measurement properties or quality of comparator instruments are hardly mentioned.
The results of this systematic review are intended to be used by researchers, clinicians and policy makers in choosing the best questionnaires for research purposes, development of guidelines, evidence-based care and policy making [31]. Our fi ndings suggest that additional research using the existing measures is necessary to support and document the measurement properties of currently available questionnaires. New studies could assist in documenting the structural validity, responsiveness and measurement error of existing measures. No new disease specifi c HRQOL questionnaires in haemophilia are required.
Acknowledgements
We would like to thank Joost Daams (clinical librarian at the Academic Medical Centre Amsterdam) for assisting with the literature search and the PROM Group for making the PROMs search fi lter available. We are also very thankful to Mala Joosten (MJ) who assisted in data extraction and assessment of the quality of the studies.
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