Research ArticleArticle

Analysis of the Validation Status of Quality of Life and Functional Disability Measures in Pulmonary Arterial Hypertension Related to Systemic Sclerosis: Results of a Systematic Literature Analysis by the Expert Panel on Outcomes Measures in Pulmonary Arterial Hypertension Related to Systemic Sclerosis (EPOSS)

OTYLIA KOWAL-BIELECKA, JEROME AVOUAC, DAVID PITTROW, DOERTE HUSCHER, FRANK BEHRENS, CHRISTOPHER P. DENTON, IVAN FOELDVARI, MARC HUMBERT, MARCO MATUCCI-CERINIC, PETER NASH, CHRISTIAN F. OPITZ, LEWIS J. RUBIN, JAMES R. SEIBOLD, VIBEKE STRAND, DANIEL E. FURST and OLIVER DISTLER
The Journal of Rheumatology November 2011, 38 (11) 2419-2427; DOI: https://doi.org/10.3899/jrheum.110344

Abstract

Objective. We aimed to assess the current validity status of the Health Assessment Questionnaire–Disability Index (HAQ-DI) and the 36-item Medical Outcomes Study Short Form Health Survey (SF-36).

Methods. Studies using HAQ-DI and/or SF-36 in patients with pulmonary arterial hypertension (PAH) associated with systemic sclerosis (PAH-SSc) were identified through a systematic literature review and assessed according to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) consensus group criteria.

Results. Both HAQ-DI and SF-36 were considered credible (having face validity) and feasible. Based on expert opinion, neither HAQ-DI nor SF-36 was specific for PAH-SSc since their results may be influenced by other aspects of SSc (judged “unclear” with respect to the content validity criterion). In the overall SSc population, there was significant albeit weak correlation between physical component SF-36 scores and pulmonary artery systolic pressure (PASP) by echocardiography (Kendall tau b = −0.2, p < 0.01). Although HAQ-DI also correlated with PASP by echocardiography, there were no significant correlations in SSc patients with PAH proven by right heart catheterization between changes in HAQ-DI over time and changes in other PAH measures including 6-min walk distance (r = −0.04, p = 0.86), expert global assessment (r = 0.06, p = 0.97), and New York Heart Association functional class (r = 0.38, p = 0.39), indicating lack of construct validity for HAQ-DI in PAH-SSc. No studies enabling assessment of criterion validity or discrimination of HAQ-DI or SF-36 in PAH-SSc could be identified.

Conclusion. Further validation of HAQ and SF-36 in PAH-SSc is needed. Alternatively, more specific assessments for functional disability or quality of life in PAH-SSc might be required.

Key Indexing Terms:

Pulmonary arterial hypertension (PAH) is a serious complication and one of the major causes of death is systemic sclerosis (scleroderma, SSc)1. PAH is defined as a mean pulmonary artery pressure (mPAP) > 25 mm Hg with a pulmonary capillary wedge pressure (PCWP) < 15 mm Hg at rest in the absence of significant lung disease with hypoxemia, thromboembolic, or left heart disease2. PAH develops in about 10%–12% of patients with SSc3,4. Despite recent progress in therapy of PAH, more than 50% of patients with PAH associated with SSc (PAH-SSc) die within 3 years from diagnosis5. Thus, there is an urgent need for clinical studies aimed at evaluation of new therapeutics specifically in patients with PAH-SSc.

Recognizing the importance of appropriate outcome measures for correct evaluation of clinical trials, an Expert Panel on Outcome Measures in PAH-SSc (EPOSS) has undertaken a validation process of endpoints in PAH-SSc. The validation is based on criteria developed by the OMERACT (Outcome Measures in Rheumatology Clinical Trials) consensus group. These criteria are known as the OMERACT filter, and include truth (face, content, construct, and criterion validity), discrimination (reliability/reproducibility and sensitivity to change), and feasibility6. These OMERACT criteria should be fulfilled before a specific outcome measure is fully validated and recommended for use in clinical trials.

PAH manifests itself with dyspnea and impaired exercise tolerance, which lead to functional limitations and decreased quality of life. Measurement tools evaluating functional status/disability and/or health-related quality of life (HRQOL) are therefore considered helpful in assessing patients with PAH and their response to PAH therapies.

The Health Assessment Questionnaire-Disability Index (HAQ-DI) and the 36-item Medical Outcomes Study Short Form Health Survey (SF-36) are patient-oriented assessment tools aimed at evaluation of functional disability and quality of life, respectively. HAQ-DI comprises 20 questions related to different aspects of function, which are divided into 8 domains. Each question/item is scored from 0 (no disability) to 3 (maximal disability). The SSc-related version of the HAQ, the SHAQ, has in addition 5 disease-specific domains concerning SSc-related vascular (Raynaud’s, ulcers), gastrointestinal, pulmonary, and overall complaints. The HAQ-DI has been validated in different SSc populations and is used in clinical trials evaluating treatments for SSc7,8,9,10,11,12,13,14,15,16.

The SF-36 questionnaire covers 8 areas/health dimensions, each scored from 0 (poor health status) to 100 (good health status). These 8 different health dimensions evaluate the degree to which an individual’s health limits or impairs physical functioning, social functioning, bodily pain, activities due to physical problems (role-physical), activities due to emotional problems (role-emotional), emotional well-being (mental health), vitality, and general health perceptions. Scores can also be summarized in 2 aggregates, the physical component score (PCS) and the mental component score (MCS). The SF-36 is one of the most widely used instruments to assess quality of life in chronic diseases14,15.

Recently, based on a Delphi process among 74 interdisciplinary experts, the HAQ-DI and SF-36 were identified by the EPOSS panel as potential endpoints useful for clinical trials in PAH-SSc17. The aim of this study was to assess the current status of validation of the SF-36 and HAQ-DI questionnaires in PAH-SSc according to the OMERACT criteria using a systematic literature search.

MATERIALS AND METHODS

Systematic literature review

The systematic literature search was performed as described18. Briefly, original studies involving ≥ 5 patients with PAH/PH-SSc, in which the HAQ and/or SF-36 questionnaires were used for patient evaluation, were searched in PubMed and Cochrane Controlled Trial Register databases using combinations of predefined key words up to January 31, 2010. The key words used were “systemic sclerosis OR scleroderma OR CREST” AND “pulmonary arterial hypertension OR pulmonary hypertension” AND “HAQ OR SF-36.” Abstracts or congress reports were not included. Studies with mixed populations of patients with PAH or patients with different connective tissue diseases were eligible if the subset of patients with SSc was separately analyzed, or if > 50% of the patients in the study had SSc. The literature analysis was limited to studies published in English and those pertaining to humans and adults only.

Studies were excluded if they were not original, if by definition only patients with other forms of PH than PAH were analyzed, if ≥ 50% of patients had diseases other than SSc, or if the studies did not include a separate analysis of patients with SSc or did not contain information enabling application of the OMERACT filter. Studies including < 5 patients with PAH/PH-SSc and those for which there was no information about whether any patients with PAH/PH-SSc were analyzed were also excluded.

The systematic literature search and the analysis of retrieved documents were performed independently by 2 trained reviewers (OKB, JA). If differences in judgment occurred, they were resolved by discussion.

Quality evaluation according to level of evidence

The level of evidence was assessed according to established criteria based on study design using a hierarchy of evidence in descending order according to qualities19. In brief, meta-analyses of randomized controlled trials (RCT) were considered the highest level of evidence (level 1a), followed by RCT (1b), nonrandomized controlled studies (2a), quasiexperimental studies (2b), descriptive studies (3), and expert committee reports or opinions (4).

Quality evaluation according to the definition of pulmonary hypertension

Because this analysis aimed to look at the validation of HAQ-DI and SF-36 for pulmonary arterial hypertension, and because other forms of pulmonary hypertension have different pathophysiologies, clinical courses, and clinical presentations, we also rated the respective studies according to their definition of PAH. The criteria for this quality assessment have been described in detail18 and are summarized in Table 1. Briefly, studies with PAH confirmed by right heart catheterization (RHC) were assigned category A. Because all studies were performed before the new Dana Point definition was published, the previous World Health Organization (WHO) criteria (according to the consensus conference in Venice) were applied [mean pulmonary artery pressure (PAP) > 25 mm Hg at rest and/or > 30 mm Hg with exercise by RHC]. PAH/PH assessed by echocardiography with pulmonary artery systolic pressure (PASP) ≥ 45 mm Hg, which has 97% specificity versus RHC20, were assigned category B. PAH/PH assessed by echocardiography with 45 mm Hg > PASP/tricuspid gradient ≥ 35 mm Hg was assigned category C, and all other definitions were considered category D.

View this table:
Table 1.

Quality assessment of studies according to the definition of pulmonary arterial hypertension (PAH) and exclusion of other forms of pulmonary hypertension.

In addition, studies were analyzed for whether clinically significant interstitial lung disease (ILD) and postcapillary PH/left heart disease were excluded. ILD and left heart disease are considered the most frequent causes of PH other than PAH in SSc. ILD was considered clinically significant when restrictive ventilatory defects and/or advanced radiological changes were present (according to the assessment of the authors of the respective studies). A judgment of postcapillary PH was based on the wedge pressure > 15 mm Hg on RHC. Accordingly, studies in which the definition of PAH included these exclusions were assigned category 1, while all other studies were considered category 2.

Application of the OMERACT filter

To assess the current status of validation of the HAQ-DI and SF-36, the OMERACT criteria were used. These include truth (face, content, construct, and criterion validity), discrimination (reliability/reproducibility and sensitivity to change), and feasibility6. Definitions of the OMERACT criteria are given in Table 2.

View this table:
Table 2.

The OMERACT filter criteria.

The OMERACT criteria were applied on reports retrieved from the systematic literature review. For the final assessment of validation, the quality of the report was taken into consideration as follows (Table 1). HAQ-DI and/or SF-36 were considered valid (V) or not valid (NV) only if high-quality studies were available with a definition of PAH according to the WHO criteria (i.e., A1 definition); HAQ-DI/SF-36 were considered partially validated (PV) if lower-quality studies (i.e., A2 or B to D definition of PAH/PH) indicated these outcome measures were valid. These strict criteria were used because these studies might include patients with forms of PH other than PAH (e.g., associated with left heart disease, interstitial fibrosis) and a number of false positives (PAH not confirmed by RHC). The validation status of HAQDI/SF-36 was considered unclear/possibly not valid (U), if “lower-quality studies” indicated these outcome measures were not valid. Again, lower-quality studies were defined as those with quality assessment below A1.

Moreover, validation of HAQ-DI/SF-36 with respect to the sensitivity to change over time required longitudinal studies for which parallel data on RHC and HAQ-DI/SF-36 at 2 different timepoints were available. In addition, validation of sensitivity to change over treatment required data from RCT.

Application of the OMERACT criteria was discussed at 3 face-to-face meetings of the EPOSS steering committee. If there was disagreement on the status of validation, it was resolved by discussion.

RESULTS

Results of the systematic literature search and quality assessment of articles

The literature search revealed 19 studies, out of which 15 were excluded based on predefined inclusion/exclusion criteria. The remaining 4 studies were included for further analysis15,21,22,23. The systematic literature search strategy including reasons for exclusions is presented in Figure 1. Three out of these 4 studies included information on SF-36 and all 4 studies on the HAQ-DI and/or the SHAQ. Detailed characteristics of the studies selected for analysis, including PAH/PH definition, total number of subjects, percentage of patients with SSc, and major data on SF-36 and/or HAQ/SHAQ are given in Table 3.

Figure 1.
Figure 1.

Results of the systematic literature search for quality of life and functional disability measures. HAQ: Health Assessment Questionnaire; SF-36: 36-item Medical Outcomes Study Short Form Health Survey; OMERACT: Outcome Measures in Rheumatology Clinical Trials.

View this table:
Table 3.

Characteristics of studies selected for analysis including the definition of pulmonary artery hypertension/pulmonary hypertension (PAH/PH), total number of subjects and the percentage of patients with SSc, information concerning SF-36 scores, and/or HAQ-DI score.

Two studies21,23 included well-defined PAH-SSc subgroups according to the WHO criteria (quality level A1). One study22 included patients with PAH/PH based on echocardiography with continuous Doppler measurements (quality level B2), and 1 study15 did not provide definition of PAH/PH (quality level D).

No RCT fulfilling the inclusion criteria could be identified. One uncontrolled study21 represented level of evidence 2b, while the remaining studies were classified as level of evidence 3.

Status of validation according to the OMERACT criteria

The current status of validation of HAQ-DI and SF-36 according to the OMERACT criteria and based on the systematic literature review and its quality assessment is summarized in Tables 4 and 5.

View this table:
Table 4.

Validation of HAQ and SF-36 in PAH-SSc according to the OMERACT filter.

View this table:
Table 5.

Studies required for further validation of HAQ and SF-36 as an outcome measure in PAH-SSc.

I. Truth

1. Face validity

The HAQ-DI and the SF-36 were selected by the experts during the Delphi study17 as appropriate measures of the influence of PAH on functional status and HRQOL in patients with PAH-SSc. Indeed, dyspnea and impaired exercise tolerance are major clinical attributes of PAH that lead to restriction of all kinds of daily activities including those investigated by the HAQ-DI and SF-36 questionnaires. Thus, by definition, all these measures were considered credible (having face validity).

2. Content validity

In 2 studies15,22 in which patients with PAH-SSc accounted for only 10%, the HAQ-DI/SHAQ scores ranged from 0.69 to 1.07 for the overall SSc population; while in 2 other studies21,23 including only patients with PAH-SSc and/or PAH-connective tissue disease, of whom 80% were PAH-SSc, the mean HAQ-DI score was higher, ranging from 1.17 to 1.4, which suggests greater functional impairment in PAH-SSc than in the overall SSc population. Since different populations of patients with SSc were studied, it cannot be excluded that differences in HAQ-DI are due to aspects of the disease other than PAH/PH.

The mean SF-36 physical component scores (PCS) ranging from 37.5 to 43.8 indicated diminished HRQOL in the overall SSc population15,22. In contrast to the PCS, in the overall population of patients with SSc, the SF-36 mental component scores (MCS) of 49.3 to 50.7 were close to what are considered normal values15,22.

Only 1 study21 reported SF-36 scores in patients with PAH, 80% of whom were PAH-SSc. In that study, scores for particular SF-36 health areas ranged from 27.47 for physical role and 28.76 for physical functioning to 43.00 for pain and 45.11 for mental health (Table 3), suggesting that HRQOL is lower in those with PAH-SSc than in the overall SSc population. Again, it cannot be excluded that the differences in SF-36 PCS scores are due to aspects of the disease other than PAH/PH.

In the study by Baron, et al22 of 195 patients with SSc, 11% of whom had PAH/PH as defined by PASP > 50 mm Hg by echocardiography, overall disease severity measured by the Medsger severity index and dyspnea were independent predictors of HAQ scores and the PCS of SF-36. The disease severity scores incrementally predicted 18.4%, 7.8%, and 2.8% of the variance in the HAQ, SF-36 PCS, and SF-36 MCS, respectively. For comparison, the dyspnea scores predicted an additional 15.7%, 27.0%, and 10.2% of the variances of the respective outcome measures22. Because the Medsger severity index was calculated in that study based on the involvement of 8 systems, including heart (but without pulmonary system), these data suggest that neither HAQ nor SF-36 PSC is specific for assessment of PAH/PH. Disease severity appears to have greater effect on HAQ scores compared with SF-36 scores. Indeed, in the same study22, forced vital capacity (FVC) was an independent variable in the models predicting HAQ and SF-36 PCS, indicating that pulmonary diseases, including SSc-ILD, might have significant influence on both these measures.

Together, these results show that the presence of PAH/PH is associated with diminished function (indicated by higher HAQ-DI scores) and HRQOL (indicated by lower SF-36 scores). However, both HAQ-DI and SF-36 are also decreased in the overall SSc population and in SSc patients with other organ manifestations. They are thus not specific for SSc-PAH and do not fulfill this aspect of the content validity criterion of the OMERACT filter. Since the quality level of the study21 reporting on relationships between HAQ-DI and SF-36 scores and SSc severity was B2, the validity status for the HAQ-DI and SF-36 was judged as “unclear.” However, the expert group agreed that it is very unlikely that content validity will be fully validated even when high-quality A1 studies are performed.

3. Criterion validity

None of the studies included for analysis allowed comparisons of HAQ-DI or SF-36 results with measurements of RHC, which is considered a “gold standard” for evaluation of PAH. Therefore it was not possible to judge the criterion validity for any of HAQ-DI or SF-36.

4. Construct validity

In the study by Baron, et al22, SHAQ scores and SF-36 PCS scores showed a moderate correlation with dyspnea, while SF-36 MCS scores correlated only weakly with dyspnea (Kendall tau b = 0.30, p < 0.001, for HAQ; Kendall tau b = −0.46, p < 0.001, for SF-36 PCS; and Kendall tau b = −0.17, p = 0.002, for SF-36 MCS). In multivariate analysis, the dyspnea score was an independent predictor of function, as indicated by HAQ scores and physical and mental components of SF-3622. In the same study, HAQ scores and SF-36 PCS scores showed significant, although weak, correlations with PASP by echocardiography (Kendall tau b = 0.2, p < 0.01, for HAD-DI; Kendall tau b = −0.2, p < 0.01, for PCS). However, in multiple linear regression analysis, the independent contribution of PASP to predict HAQ or SF-36 PCS scores was found to be insignificant. Moreover, both HAQ-DI and SF-36 scores correlated weakly with the FVC values (Kendall tau b = −0.17, p < 0.01, and Kendall tau b = 0.20, p < 0.01, respectively)22. There were no significant correlations between SF-36 MCS and PASP in bivariate or multivariate analyses (Kendall tau b = 0.01)21.

In another study23, with 41 SSc patients with PAH (defined according to the Venice standards) and dyspnea, there was moderate although not significant correlation between the changes in HAQ-DI score over time and changes in other PAH variables including Borg dyspnea index (r = 0.60, p = 0.37), while there was no correlation with changes in 6-min walk distance (r = −0.04, p = 0.86) and expert physician global assessment of PAH (r = 0.06, p = 0.97). The changes in HAQ-DI scores again correlated not significantly but moderately with changes in New York Heart Association (NYHA) functional class (r = 0.38, p = 0.39), and percentage predicted DLCO (r = 0.31, p = 0.25), but did not correlate with changes in percentage predicted FVC (r = 0.02, p = 0.93) in pulmonary function tests23.

There are few data concerning convergent and divergent validity of the HAQ-DI and SF-36 in PAH-SSc. Moreover, there are some discrepancies in the results of available studies. There is only 1 study22 evaluating convergent validity of SF-36 scores. The results indicate that SF-36 total and SF-36 PCS and MCS correlate significantly with dyspnea and/or PASP in the overall SSc population22. Since the quality level of that study was only B2, the SF-36 was judged as partially validated with regard to the construct validity criterion of the OMERACT filter.

The same study22 showed significant correlation between HAQ-DI scores and dyspnea and PASP. However, another study of patients with PAH-SSc defined according to the WHO criteria (level A1) showed a lack of correlation between change in HAQ-DI and change in other PAH measures23. In view of these data and according to predefined criteria, the HAQ-DI must be judged nonvalid regarding construct validity.

II. Discrimination

Because of the lack of appropriate studies it was not possible to validate the HAQ-DI or SF-36 regarding discriminant capacity or reliability criteria.

III. Feasibility

The HAQ-DI and SF-36 questionnaires are broadly used in clinical trials. They are widely available, easy to use, and cost-effective. Therefore, the HAQ-DI and SF-36 questionnaires were considered feasible in the clinical assessment of patients with PAH.

DISCUSSION

Evaluation of HRQOL is increasingly considered by regulatory agencies as an important element of assessment of effectiveness of new therapies, and also in PAH. This is the first study addressing the validity of self-related measures of function (HAQ) and HRQOL (SF-36) as outcome measures in PAH-SSc according to a systematic literature review.

Our literature search revealed only a few studies in which HAQ-DI and/or SF-36 questionnaires were used in patients with PAH/PH-SSc. The results allowed evaluation of some aspects of the content and construct validity criteria of the OMERACT filter for HAQ-DI and/or SF-36.

With regard to the content validity criterion, the status of both HAQ-DI and SF-36 questionnaires was judged as “unclear” based on the results of 1 study22 (B2 definition of PAH/PH), indicating that comorbidities other than PAH-SSc-related ones might have influenced HAQ-DI and SF-36 results significantly. Indeed, in a multisystem disease such as SSc, disease-nonspecific questionnaires such as HAQ-DI or SF-36 reflect overall severity of the disease rather than specific organ involvement. This limitation might be overcome by careful selection of patients with SSc in whom PAH is the major health problem and thus the main factor influencing HAQ-DI or SF-36 scores. However, it must be considered that in SSc as a multisystem disease, improving the accuracy of the outcome measure is a better solution than selection of a subgroup of patients with SSc. Thus, introduction of more specific questionnaires might be required. The St. George’s Respiratory Questionnaire (SGRQ) is a respiratory disease-specific instrument yielding scores related to symptoms, activity, and effects of the disease on social and psychological functions. The SGRQ has been validated in respiratory diseases including obstructive and ILD24,25, and has recently been used in PAH26. The Minnesota Living with Heart Failure (MLHF) questionnaire is another self-reported disease-specific tool that was recently used for assessment of PAH27. The MLHF was developed and validated for assessment of disease-specific HRQOL in patients with left heart failure28. Since both the symptoms and outcomes of patients with PAH are mainly determined by development of right heart failure, a simple modification of the MLHF has recently been validated in patients with PH29. However, it should be recognized that even these disease-specific instruments might be influenced by other than PAH pulmonary and/or heart complications of SSc.

On the other hand, dyspnea, function, and HRQOL measures are self-reported by patients, and can also be affected by factors such as depression and individual perception of the significance of the illness, etc. Indeed, in a study evaluating the MLHF in a group of 93 patients with PAH, MLHF scores correlated with WHO class, fatigue, weakness, and abdominal discomfort, but showed no correlation with hemodynamic measures except right atrial pressure27.

A single study showed no significant correlation between change in HAQ-DI scores over time and changes in other PAH measures, including dyspnea, the 6-min walk test, NYHA functional class, overall assessment, or lung function23. Since that study involved patients with the high-quality definition of PAH, the HAQ-DI was considered not valid for construct validity. Another single study involving patients with PAH/PH-SSc defined by echocardiography (B2 definition) showed significant correlations between SF-36 PCS and dyspnea and PASP values22. However, SF-36 PCS scores correlated significantly with FVC values as well, indicating that ILD might influence SF-36 PCF scores; and correlation between SF-36 scores and echocardiography disappeared in multivariate analysis.

Criterion validity, assessed as the ability of the outcome measure to yield the best available estimate of the patient’s true clinical status, is the most important part of the validation among the OMERACT criteria. However, there were no studies comparing the results of HAQ-DI or SF-36 questionnaires with direct measurements of PAH by RHC, considered a gold standard in measurement of PAH. Thus, it was not possible to evaluate criterion validity for HAQ-DI or SF-36 in PAH-SSc.

The discriminant capacity and the reliability criteria of the OMERACT filter could not be evaluated for HAQ-DI/SF-36 in PAH-SSc because of lack of appropriate studies.

Face validity is the only OMERACT criterion that is fully validated based on the consensus of experts who selected the HAQ and SF-36 as appropriate outcome measures for evaluation of PAH-SSc17. Therefore both HAQ-DI and SF-36 were considered as having face validity. Both measures were also considered feasible with regard to ease of use, cost-effectiveness, and broad availability.

The systematic literature search for this study was performed using PubMed and Cochrane Controlled Trial Register databases and was limited to studies published in English. These restrictions might have biased the results toward studies published in North America and Western Europe. However, screening these databases for articles published in languages other than English showed only a small number of candidate reports. In addition, the effectiveness of such an approach was confirmed by experience from previous systematic literature searches by members of the EPOSS group. Moreover, contributions from PAH or SSc experts from different parts of the world to the work of the EPOSS group, as well as hand searches of reference lists of retrieved articles, further reduced potential bias in identification of studies relevant for the assessment of validation of HAQ-DI and SF-36 questionnaires in PAH-SSc.

The data available did not allow full validation, according to the OMERACT criteria, of HAQ-DI and SF-36 questionnaires in PAH-SSc. Further studies are required to allow full validation of the HAQ-DI/SF-36 as outcome measures in PAH-SSc. These studies are summarized in Table 5. Alternatively, more specific assessments for functional disability or quality of life in PAH-SSc might be required.

Footnotes

  • Supported in part by unrestricted educational grants from Actelion, Encysive, Pfizer, Bayer-Schering, and United Therapeutics.

  • Accepted for publication June 10, 2011.

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