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Psychometric Validation of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Questionnaire

Results of the SYMPHONY Trial
Open AccessPublished:April 26, 2018DOI:https://doi.org/10.1016/j.chest.2018.04.027

      Background

      Disease-specific patient-reported outcome (PRO) instruments are important in assessing the impact of disease and treatment. The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is the first instrument for quantifying pulmonary arterial hypertension (PAH) symptoms and impacts developed according to the 2009 US Food and Drug Administration PRO guidance; previous qualitative research in patients with PAH supported its initial content validity.

      Methods

      Content finalization and psychometric validation were conducted by using data from A Study of Macitentan in Pulmonary Arterial Hypertension to Validate the PAH-SYMPACT (SYMPHONY), a single-arm, 16-week trial with macitentan 10 mg in US patients with PAH. Item performance, Rasch analysis, and factor analyses were used to select the final item content of the PRO and to define its domain structure. Internal consistency, test-retest reliability, known-group and construct validity, sensitivity to change, and influence of oxygen on item performance were evaluated.

      Results

      Data from 278 patients (79% female; mean age: 60 years) were analyzed. Following removal of redundant/misfitting items, the final questionnaire has 11 symptom items across two domains (cardiopulmonary and cardiovascular symptoms) and 11 impact items across two domains (physical and cognitive/emotional impacts). Differential item function analysis confirmed that PRO scoring is unaffected by oxygen use. For all four domains, internal consistency reliability was high (Cronbach’s alpha > 0.80), and scores were highly reproducible in stable patients (intraclass correlation coefficient: 0.84-0.94). Correlations with the Cambridge Pulmonary Hypertension Outcome Review questionnaire and the 36-item Medical Outcomes Study Short Form Survey were moderate to high ([r] = 0.34-0.80). The questionnaire differentiated well between patients with varying disease severity levels and was sensitive to improvements in clinician- and patient-reported disease severity.

      Conclusions

      The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is a brief, disease-specific PRO instrument possessing good psychometric properties that can be administered in clinical practice and clinical studies.

      Trial Registry

      ClinicalTrials.gov; No.: NCT01841762; URL: www.clinicaltrials.gov.

      Key Words

      Abbreviations:

      6MWD (6-min walk distance), CAMPHOR (Cambridge Pulmonary Hypertension Outcome Review), CGI-C (Clinician Global Impression of Change), CGI-S (Clinician Global Impression of Severity), ePRO (electronic version of PAH-SYMPACT), FC (functional class), FDA (Food and Drug Administration), HRQoL (health-related quality of life), PAH (pulmonary arterial hypertension), PAH-SYMPACT (Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire), PGA-S (Patient Global Assessment of Disease Severity), PH (pulmonary hypertension), PRO (patient-reported outcome), SF-36 (36-item Medical Outcomes Study Short Form Survey)
      Pulmonary arterial hypertension (PAH) is a rare and debilitating chronic disease of the pulmonary vasculature, characterized by vascular proliferation and remodeling of the small pulmonary arteries, which ultimately leads to right heart failure and death.
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      2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
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      An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from REVEAL.
      Typical symptoms (including shortness of breath, fatigue, chest pain, and lightheadedness)
      • Galiè N.
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      • Vachiery J.L.
      • et al.
      2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
      • Matura L.A.
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      Cluster analysis of symptoms in pulmonary arterial hypertension: a pilot study.
      have a major impact on patients’ functioning and physical, psychological, and social well-being.
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      • et al.
      Understanding the impact of pulmonary arterial hypertension on patients' and carers' lives.
      Because symptom experience is subjective, patient-reported outcome (PRO) instruments are needed to evaluate the effect of both PAH and its treatments on symptoms and the impact of symptoms on patients’ lives.
      • Chen H.
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      • Doyle R.L.
      Health-related quality of life and patient-reported outcomes in pulmonary arterial hypertension.
      Recommendations for PAH trial endpoints now stress the importance of measuring PROs as a secondary endpoint in clinical trials, in addition to clinical endpoints such as change in exercise capacity, cardiac hemodynamic variables, and composite endpoints with morbidity and mortality.
      • McLaughlin V.V.
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      End points and clinical trial design in pulmonary arterial hypertension.
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      New trial designs and potential therapies for pulmonary artery hypertension.
      In 2009, the US Food and Drug Administration (FDA) published a PRO guidance for industry outlining recommended steps for the development of a PRO.

      US Food and Drug Administration. Guidance for Industry. Patient-reported outcome measures: use in medical product development to support labeling claims [Internet]. 2009. http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf. Accessed May 31, 2018.

      Although a number of PRO instruments have previously been developed for and/or used in patients with PAH,
      • Rector T.S.
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      Patients' self-assessment of their congestive heart failure. Part 2: content, reliability and validity of a new measure, the Minnesota Living With Heart Failure Questionnaire.
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      • Doward L.C.
      • Pepke-Zaba J.
      The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR): a measure of health-related quality of life and quality of life for patients with pulmonary hypertension.
      • Yorke J.
      • Corris P.
      • Gaine S.
      • et al.
      emPHasis-10: development of a health-related quality of life measure in pulmonary hypertension.
      • Bonner N.
      • Abetz L.
      • Meunier J.
      • Sikirica M.
      • Mathai S.C.
      Development and validation of the living with pulmonary hypertension questionnaire in pulmonary arterial hypertension patients.
      none of these was developed explicitly according to the FDA PRO guidance. The present article describes the first PRO instrument for use with patients with PAH developed strictly following this guidance, ensuring that items are relevant and meaningful to these patients.
      With the objective of developing a PRO measure that can be used both in clinical trials and in clinical practice, a draft version of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) questionnaire was developed based on qualitative interviews with patients with PAH.
      • McCollister D.
      • Shaffer S.
      • Badesch D.B.
      • et al.
      Development of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT®) questionnaire: a new patient-reported outcome instrument for PAH.
      The development of this questionnaire—which consists of two parts (one assessing PAH symptoms and the other assessing impacts)—has previously been described (Fig 1).
      • McCollister D.
      • Shaffer S.
      • Badesch D.B.
      • et al.
      Development of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT®) questionnaire: a new patient-reported outcome instrument for PAH.
      Here, we report results of the psychometric analyses performed to validate the PAH-SYMPACT based on A Study of Macitentan in Pulmonary Arterial Hypertension to Validate the PAH-SYMPACT (SYMPHONY). This psychometric validation study included patients with PAH who received macitentan 10 mg, an endothelin receptor antagonist approved for the treatment of PAH,

      Actelion Pharmaceuticals US Inc. Opsumit® (macitentan) Prescribing Information [Internet]. 2017. https://opsumit.com/opsumit-prescribing-information.pdf. Accessed May 31, 2018.

      • Pulido T.
      • Adzerikho I.
      • Channick R.N.
      • et al.
      Macitentan and morbidity and mortality in pulmonary arterial hypertension.
      to enable change in symptoms and impacts. The objectives of the present study were to finalize the item content and domain structure of the PAH-SYMPACT and to show content validity of the final questionnaire, as well as to assess its psychometric properties (including sensitivity to change).
      Figure thumbnail gr1
      Figure 1Development and validation studies of the PAH-SYMPACT. ICF = informed consent form; PAH = pulmonary arterial hypertension; PAH-SYMPACT = Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire; PRO = patient-reported outcome; SYMPHONY = A Study of Macitentan in Pulmonary Arterial Hypertension to Validate the PAH-SYMPACT. aPreviously published by McCollister et al.
      • McCollister D.
      • Shaffer S.
      • Badesch D.B.
      • et al.
      Development of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT®) questionnaire: a new patient-reported outcome instrument for PAH.

      Materials and Methods

       Study Design

      SYMPHONY was a prospective, open-label, single-arm, multicenter, Phase IIIb study in patients with PAH receiving macitentan 10 mg once daily. The study was conducted by Evidera in collaboration with the sponsor and a Steering Committee comprising eight expert clinicians from the United States experienced in treating patients with PAH.
      The present study was conducted in accordance with the amended Declaration of Helsinki. Local institutional review boards or independent ethics committees at each participating institution approved the protocol (e-Table 1), and all patients provided written informed consent.

       Patients

      Eligible patients were 18 to 80 years of age with PAH in one of the following groups as classified by the 4th World Symposium on Pulmonary Hypertension: idiopathic PAH, heritable PAH, or PAH associated with drug or toxin exposure, with HIV infection, with connective tissue disease, or with repaired simple congenital systemic-to-pulmonary shunts.
      • Simonneau G.
      • Robbins I.M.
      • Beghetti M.
      • et al.
      Updated clinical classification of pulmonary hypertension.
      Confirmation of the diagnosis by using right-heart catheterization was required.
      Patients were required to be in functional class (FC) II to IV, according to the World Health Organization classification, and to have a 6-min walk distance (6MWD) of at least 150 m. Patients receiving a phosphodiesterase type-5 inhibitor or inhaled prostacyclin were required to have been receiving stable doses for at least 3 months. Patients had to be able to speak and read English.

       Assessments

      Following screening, patients had a 2-week baseline period followed by a 16-week period of macitentan treatment (Fig 2). Patients completed an electronic version of the PAH-SYMPACT (ePRO)
      • McCollister D.
      • Shaffer S.
      • Badesch D.B.
      • et al.
      Development of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT®) questionnaire: a new patient-reported outcome instrument for PAH.
      using a tablet computer during four study periods (ePRO 1-4). The draft PAH-SYMPACT comprised a yes/no question about oxygen use (assessed daily for 1 week), 16 symptom items with a 24-h recall period (assessed daily for 1 week), and 25 questions about impacts experienced during the past 7 days (assessed on the last day of the week). Each PAH-SYMPACT symptom or impact item was scored by using a 5-point Likert scale.
      Figure thumbnail gr2
      Figure 2Assessment schedule in SYMPHONY. 6MWT = 6-min walk test; CAMPHOR = Cambridge Pulmonary Hypertension Outcome Review; CGI-C = Clinician Global Impression of Change; CGI-S = Clinician Global Impression of Severity; ePRO = electronic version of PAH-SYMPACT; FC = functional class; PGA-S = Patient Global Assessment of Disease Severity; SF-36 = 36-item Medical Outcomes Study Short Form Survey. See legend for expansion of other abbreviations.
      Health-related quality of life (HRQoL), 6MWD, World Health Organization FC, and clinician- and patient-reported disease severity were assessed at screening, baseline, and weeks 8 and 16. HRQoL was assessed by using the 36-item Medical Outcomes Study Short Form Survey (SF-36 v2)
      • Ware Jr., J.E.
      • Sherbourne C.D.
      The MOS 36-item Short-Form Health Survey (SF-36). I. Conceptual framework and item selection.
      and the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)
      • McKenna S.P.
      • Doughty N.
      • Meads D.M.
      • Doward L.C.
      • Pepke-Zaba J.
      The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR): a measure of health-related quality of life and quality of life for patients with pulmonary hypertension.
      questionnaire. Disease severity was measured by using the Clinician Global Impression of Severity (CGI-S) and the Patient Global Assessment of Disease Severity (PGA-S), with a Likert scale ranging from 1 (none) to 6 (very severe). Clinician-reported impression of change in disease severity was also evaluated at weeks 8 and 16 by using the Clinician Global Impression of Change (CGI-C), with a Likert scale ranging from –3 (very much worse) to 3 (very much better).

       Item Reduction and Content Validation

      Analyses were conducted to support finalization of item content and domain structure of the PAH-SYMPACT and to confirm its content validity; namely, to show that it measures symptoms and impacts that are important to patients, without redundancy (ie, without measuring the same concept more than once).
      Distributional characteristics of each of the items were evaluated to test for floor and ceiling effects (ie, the clustering of item scores at the bottom or the top of the response-scale range) that could render the questionnaire unresponsive or insensitive to change, or make it inappropriate for a broad range of patients. Pairwise item-to-item correlations were performed to identify questions measuring the same concept (correlation ≥ 0.7 indicating potential redundancy).
      • Ferketich S.
      Focus on psychometrics. Aspects of item analysis.
      Rasch analysis was undertaken to identify items that did not fit the scoring assumptions
      • Tennant A.
      • McKenna S.P.
      • Hagell P.
      Application of Rasch analysis in the development and application of quality of life instruments.
      (ie, responses did not align with patient-specific severity as expected). Factor analyses were performed to assign items to domains; initially, exploratory factor analysis was conducted to identify the underlying relationships between individual items.
      • Floyd F.J.
      • Widaman K.F.
      Factor analysis in the development and refinement of clinical assessment instruments.
      The exploratory factor analysis was conducted simultaneously with the Rasch analysis to allow identification and examination of items with poor fit (ie, disordered thresholds); these items were flagged for potential deletion. Initial rounds of exploratory factor analysis were set to include three factors for both symptoms and impacts, and were followed by exploration of two- and four-factor solutions.
      Items that had high floor or ceiling effects or high correlations with other items, were misfitting, or had factor loadings < 0.3 (ie, the weight or correlation explaining the relationship between each item and the underlying factor/domain) were flagged for further assessment. The final decision regarding item inclusion or exclusion was based on the previous qualitative research, the psychometric analyses (including the exploratory factor analysis and Rasch analyses), and input from the Steering Committee. Confirmatory factor analysis was performed on the final item content, and the conceptual framework was finalized.
      • Floyd F.J.
      • Widaman K.F.
      Factor analysis in the development and refinement of clinical assessment instruments.
      All psychometric analyses were performed in accordance with the FDA guidance.

      US Food and Drug Administration. Guidance for Industry. Patient-reported outcome measures: use in medical product development to support labeling claims [Internet]. 2009. http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf. Accessed May 31, 2018.

      An analysis of differential item functioning was performed to determine whether performance of the PAH-SYMPACT differs in patients with oxygen use vs those without oxygen use.

       Psychometric Validation

      Internal consistency reliability analysis was performed to assess how well items fit in their hypothesized domains, using data from ePRO period 2. Cronbach’s alpha ≥ 0.70 and ≥ 0.80 indicate good and excellent fit, respectively.
      • Bland J.M.
      • Altman D.G.
      Cronbach's alpha.
      Test-retest reliability analysis assessed the stability of PAH-SYMPACT domain scores between ePRO periods 1 and 2 (ie, the two baseline PAH-SYMPACT assessment periods, from week –2 to week –1 and from week –1 to week 0, respectively) in patients who remained stable between visits 1 and 2 (ie, the screening visit between week –4 and week –2 and the baseline visit at week 0) based on the PGA-S. An intraclass correlation coefficient ≥ 0.70 demonstrates good test-retest reliability.
      To demonstrate construct validity (ie, domain scores correlate well with different measures of the same concept [concurrent validity] and minimally with measures of different concepts [divergent validity]), Pearson product-moment or Spearman’s rank correlation analyses were performed on the PAH-SYMPACT domain scores from ePRO period 2 and scores from visit 2 for the CAMPHOR and the SF-36 v2 domains, as well as the 6MWD.
      Known-groups validity (ie, the ability of domain scores to distinguish between patient groups that differ by key indicators) was tested with 1-way ANOVA using Scheffé post hoc comparisons on domain scores from ePRO period 2 vs scores from visit 2 for FC, PGA-S, and CGI-S.
      The sensitivity to change of the PAH-SYMPACT (ie, the extent to which the domain scores reflect change in the patient’s condition) was evaluated by using ANOVA, with change from visit 2 to visit 4 in PGA-S, CGI-S, and CGI-C scores as the independent variables; change from ePRO period 2 to period 4 in domain score was the dependent variable.

      Results

       Patients

      Between April 2013 and October 2015, a total of 284 patients with PAH were enrolled at 71 centers across the United States. Six patients were excluded from the analysis because of protocol deviations (Fig 1). The 278 patients included in the analyses were generally representative of the PAH population seen in clinical practice
      • Badesch D.B.
      • Raskob G.E.
      • Elliott C.G.
      • et al.
      Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry.
      (Table 1). Overall, 46% were receiving background PAH-specific therapy.
      Table 1Patient Baseline Characteristics
      CharacteristicValues (N = 278)
      Female219 (78.8%)
      Age, mean ± SD, y59.7 ± 13.4
      Race/ethnicity
       White224 (80.6%)
       Black/African-American34 (12.2%)
       Asian8 (2.9%)
       Other12 (4.4%)
      PAH etiology
       Idiopathic PAH136 (48.9%)
       Heritable PAH2 (0.7%)
       Drug- or toxin-induced21 (7.6%)
       PAH-CTD111 (39.9%)
       PAH-CHD7 (2.5%)
       HIV infection1 (0.4%)
      Time since initial PAH diagnosis, mo
       Mean ± SD20.2 ± 35.9
       Median (range)6.0 (0.5-340.9)
      WHO FC
       II110 (39.6%)
       III164 (59.0%)
       IV4 (1.4%)
      6MWD, mean ± SD, m342.3 ± 117.2
      Background PAH therapy129 (46.4%)
      PDE-5i monotherapy115 (41.4%)
      Inhaled/oral prostacyclin monotherapy2 (0.7%)
      PDE-5i + inhaled/oral prostacyclin12 (4.3%)
      Oxygen use (clinician-reported)96 (34.5%)
      6MWD = 6-min walk distance; CHD = congenital heart disease; CTD = connective tissue disease; FC = functional class; PAH = pulmonary arterial hypertension; PDE-5i = phosphodiesterase type-5 inhibitor; WHO = World Health Organization.

       Item Reduction and Content Validation

       Item Performance Analysis

      Across symptom and impact items, ceiling effects were negligible, but floor effects were evident (Table 2), likely reflecting the mild to moderately severe population enrolled in SYMPHONY, many of whom were receiving PAH treatment at baseline. Substantial floor effects (> 50% of patients) were observed for three symptom items and four impact items. All but one symptom item (loss of appetite) and one impact item (maintain relationships) had high correlations (≥ 0.70) with at least one other item measuring similar concepts, indicating potential redundancy.
      Table 2Analysis of Symptom and Impact Items: Floor and Ceiling Effects, Item-to-Item Correlations, and Item Misfit
      Item (24-h Recall Period)Score, Mean (SD)Patients With Floor/Ceiling Effect, %
      Threshold, > 50%.
      Correlated With
      Threshold, ≥ 0.7.
      Misfitting in Rasch Analysis
      Based on item responses being disordered.
      FloorCeiling
      Symptom items (average across day –7 to –1)
       Shortness of breath1.3 (0.8)6.6%0.4%Fatigue
       Tiredness
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      1.4 (0.8)5.5%0.4%Fatigue, lack of energy, weakness
       Fatigue1.3 (0.8)12.0%0.0%Tiredness, lack of energy, weakness
       Lack of energy1.3 (0.8)10.2%0.0%Tiredness, fatigue, weakness
       Weakness
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      1.1 (0.8)19.0%0.0%Tiredness, fatigue, lack of energy
       Swelling in ankles or legs0.6 (0.8)43.8%0.0%Swelling in stomach area
       Swelling in stomach area0.5 (0.7)56.9%0.4%Swelling in ankles or legs
       Heart palpitations (heart fluttering)0.5 (0.7)42.3%0.4%Rapid heartbeat
       Rapid heartbeat0.6 (0.7)35.4%0.0%Heart palpitations
       Chest pain0.4 (0.6)52.2%0.0%Chest tightness
       Chest tightness0.5 (0.6)44.5%0.0%Chest pain
       Cough0.7 (0.7)32.8%0.0%Dry cough
       Dry cough
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      0.6 (0.7)37.2%0.0%Cough
       Loss of appetite
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      0.4 (0.6)56.6%0.0%
       Dizziness
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      0.4 (0.6)49.6%0.0%Lightheadedness
       Lightheadedness0.5 (0.7)39.8%0.0%Dizziness
      Impact items (day –1)
       Walk slowly on a flat surface0.9 (0.9)41.3%0.0%Walk quickly, walk for 5 min
       Walk quickly on a flat surface1.9 (1.2)13.1%13.5%Walk slowly, walk for 5 min
       Walk for 5 min on a flat surface
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      1.4 (1.2)26.2%6.7%Walk slowly, walk quickly, walk for 10 min
       Walk for 10 min on a flat surface
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      2.0 (1.3)15.5%17.9%Walk for 5 min, walk uphill
       Walk up about 6 stairs
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      1.5 (1.2)23.0%6.7%Walk uphill
       Walk uphill2.1 (1.2)7.6%16.7%Walk 6 stairs
       Light exercise(s)
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      1.7 (1.3)18.3%15.5%Light indoor chores
       Carry things1.5 (1.1)22.6%4.8%Light indoor chores
       Light indoor household chores1.1 (1.0)33.7%1.2%Light exercise, carry things, errands
       Heavy indoor household chores
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      2.4 (1.4)10.7%29.8%Walk quickly, carry things, light indoor chores
       Errands
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      1.4 (1.2)29.5%8.4%Light indoor chores, social activities
       Wash or dress self0.7 (0.9)55.6%0.0%Light indoor chores, errands
       Fall asleep
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      1.0 (1.1)42.6%2.4%Stay asleep
       Stay asleep
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      1.2 (1.1)33.3%4.8%Fall asleep
       Go out to social activities
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      1.2 (1.3)40.9%9.1%Errands
       Maintain relationships
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      0.7 (1.0)57.9%2.0%
       Need help from others1.4 (1.0)23.4%2.0%Light indoor chores, heavy indoor chores, errands, social activities
       Think clearly0.5 (0.7)61.1%0.0%Remember things
       Remember things
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      0.7 (0.8)52.4%0.0%Think clearly
       Sad1.0 (1.1)40.1%2.8%Anxious/scared, worried, frustrated, stressed
       Anxious or scared
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      0.9 (1.0)44.8%2.0%Sad, worried, stressed
       Worried1.1 (1.0)31.3%2.0%Sad, anxious/scared, stressed
       Frustrated1.4 (1.2)27.4%4.8%Sad, stressed
       Stressed
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      1.4 (1.1)21.4%4.0%Sad, anxious/scared, worried, frustrated
       Angry
      Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      0.8 (1.0)46.4%1.6%Sad
      a Threshold, > 50%.
      b Threshold, ≥ 0.7.
      c Based on item responses being disordered.
      d Items deleted from final version of Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire.
      Evaluation of the rating scale structure (based on Rasch analysis) indicated disordering of responses for four symptom items and seven impact items (Table 2).

       Item Reduction and Exploratory Factor Analysis

      Based on the item performance analyses, input from the Steering Committee, and the previous qualitative research, five symptom items and 14 impact items were removed (Table 3), leaving 11 symptom items and 11 impact items. Exploratory factor analysis identified two symptom domains and two impact domains.
      Table 3Deletion of Symptom and Impact Items
      Item DeletedMain Reason for Deletion
      Symptoms
       TirednessHighly correlated with fatigue/lack of energy
       WeaknessHighly correlated with fatigue/lack of energy; redundancy with other items based on Rasch
       Dry coughHighly correlated with cough; subset of cough
       Loss of appetiteMay be a side effect of treatment rather than a symptom of PAH
       DizzinessHighly correlated with lightheadedness
      Impacts
       Walk for 5 min/walk for 10 minWalk slowly and walk quickly retained because pace considered more relevant than time
       Walk up 6 stairsStairs not universally relevant to patients
       Light exercise(s)May be interpreted differently by different patients; disordered Rasch thresholds
       Heavy indoor choresModerately correlated with other items; disordered Rasch thresholds
       ErrandsRedundancy based on correlations; disordered Rasch thresholds
       Fall asleep/stay asleepFormed single factor in exploratory factor analysis; likely not specific to PAH
       Social activitiesDisordered Rasch thresholds
       Maintain relationshipsDisordered Rasch thresholds
       Remember thingsConsidered somewhat redundant with think clearly; impaired memory may be associated with older age
       Anxious/scaredItem addresses > 1 concept at the same time; disordered Rasch thresholds
       Stressed/angryOther similar items (sad, worried, and frustrated) retained instead
      See Table 1 legend for expansion of abbreviation.

       Scoring Algorithm and Differential Item Functioning Analysis

      Scores for the individual items and domains ranged from 0 to 4, with higher scores indicating greater symptom severity or worse impact (e-Table 2). Mean weekly symptom item scores are calculated as an average of the daily item scores, and a mean symptom domain score is then calculated as the average of the mean weekly scores for its included items. The mean impact domain scores are calculated as the average of the mean impact item scores.
      Approximately one third of patients self-reported using oxygen on a given day. No significant differences in item functioning were found between patients receiving oxygen and those not receiving oxygen (data not shown), indicating that the PAH-SYMPACT can be scored the same way irrespective of oxygen use.

       Confirmatory Factor Analysis

      Confirmatory factor analysis showed acceptable model fit for symptom items (comparative fit index = 0.861) and good model fit for impact items (comparative fit index = 0.960). The two symptom domains were labeled Cardiopulmonary Symptoms and Cardiovascular Symptoms, and the two impact domains were labeled Physical Impacts and Cognitive/Emotional Impacts (Fig 3). The mean coefficients of determination for these domains were 0.43, 0.50, 0.63, and 0.64, respectively.
      Figure thumbnail gr3
      Figure 3Conceptual framework of the revised PAH-SYMPACT. See legend for expansion of abbreviations.
      Factor loadings for all items (e-Tables 3 and 4) exceeded the acceptable fit threshold of 0.3 except for “swelling in ankles or legs” (0.297). This item was retained on the advice of all eight clinical experts of the Steering Committee because they identified this item to be a key cardiopulmonary symptom that is highly relevant to patients with severe PAH.

       Psychometric Characteristics

       Reliability

      Internal consistency reliability was high for all four domains (ie, Cronbach’s alpha > 0.80) (Table 4), indicating that the items are appropriately placed within their domains.
      Table 4Internal Consistency of Domain Scores (ePRO Period 2)
      PAH-SYMPACT DomainNo.Cronbach's Alpha
      Cronbach’s alpha ≥ 0.70 is considered good; ≥ 0.80 is considered excellent.
      Symptoms
       Cardiopulmonary Symptoms2740.81
       Cardiovascular Symptoms2740.88
      Impacts
       Physical Impacts2500.92
       Cognitive/Emotional Impacts2520.87
      ePRO = electronic version of the Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire (PAH-SYMPACT).
      a Cronbach’s alpha ≥ 0.70 is considered good; ≥ 0.80 is considered excellent.
      Domain scores were highly consistent in patients with stable disease, demonstrating high reproducibility of scores for all four domains in the test-retest reliability analysis (intraclass correlation coefficient: 0.84-0.94) (Table 5).
      Table 5Test-Retest Reliability of Domain Scores in Patients With No Change in PGA-S Score Between Visit 1 and Visit 2
      PAH-SYMPACT DomainNo.ePRO Period 1: Mean ± SDePRO Period 2: Mean ± SDDifference: Mean ± SDICC
      ICC ≥ 0.70 is considered good.
      Symptoms
       Cardiopulmonary Symptoms1211.0 ± 0.50.9 ± 0.60.0 ± 0.20.94
       Cardiovascular Symptoms1210.4 ± 0.50.4 ± 0.5–0.0 ± 0.20.93
      Impacts
       Physical Impacts108
      Smaller No. for impacts vs symptoms reflects missing impact values.
      1.3 ± 0.91.3 ± 0.80.0 ± 0.40.91
       Cognitive/Emotional Impacts108
      Smaller No. for impacts vs symptoms reflects missing impact values.
      0.9 ± 0.80.9 ± 0.8–0.0 ± 0.50.84
      See Figure 2 for definitions of visits. ICC = intraclass correlation coefficient; PGA-S = Patient Global Assessment of Disease Severity. See Table 4 legend for expansion of other abbreviations.
      a ICC ≥ 0.70 is considered good.
      b Smaller No. for impacts vs symptoms reflects missing impact values.

       Construct and Known-Groups Validity

      PAH-SYMPACT domain scores correlated with those of generic and PH-specific HRQoL questionnaires (Table 6), with correlations highest for measures of similar constructs (concurrent validity). Within this study population, the internal consistency reliability for the two multi-item HRQoL questionnaires used to test construct validity of the PAH-SYMPACT (CAMPHOR and SF-36) was acceptable (e-Tables 5 and 6). Correlations between PAH-SYMPACT Physical Impacts domain scores and 6MWD were highest (r = –0.57; P < .0001), demonstrating the ability of this domain to assess physical functioning. Correlations between other domain scores and 6MWD were low to moderate, confirming that these domains reveal patient-relevant information about symptoms and impacts not captured by exercise capacity.
      Table 6Correlation of Domain Scores (ePRO Period 2) With Scores for CAMPHOR, SF-36, and 6MWD (Visit 2)
      VariableCorrelation Coefficient
      Cardiopulmonary SymptomsCardiovascular SymptomsPhysical ImpactsCognitive/Emotional Impacts
      CAMPHOR
       Total Symptom Score0.68
      P < .0001.
      0.48
      P < .0001.
      0.75
      P < .0001.
      0.62
      P < .0001.
       Activities0.59
      P < .0001.
      0.38
      P < .0001.
      0.80
      P < .0001.
      0.46
      P < .0001.
       Quality of life0.59
      P < .0001.
      0.40
      P < .0001.
      0.67
      P < .0001.
      0.65
      P < .0001.
      SF-36
       PCS–0.56
      P < .0001.
      –0.39
      P < .0001.
      –0.73
      P < .0001.
      –0.34
      P < .0001.
       MCS–0.48
      P < .0001.
      –0.36
      P < .0001.
      –0.47
      P < .0001.
      –0.72
      P < .0001.
      6MWD–0.36
      P < .0001.
      –0.14
      P < .05.
      –0.57
      P < .0001.
      –0.22
      P < .001.
      CAMPHOR = Cambridge Pulmonary Hypertension Outcome Review; MCS = Mental Component Summary; PCS = Physical Component Summary; SF-36 = 36-item Medical Outcomes Study Short Form Survey. See Table 1 and 4 legends for expansion of other abbreviations.
      a P < .0001.
      b P < .05.
      c P < .001.
      The questionnaire differentiated well between patients with different baseline disease severity levels (FC II vs III/IV) (Fig 4) and between patient groups on the basis of baseline PGA-S (Table 7) and CGI-S (overall F test, P = .0039 for Cardiovascular Symptoms, P < .0001 for the three other domains) (e-Table 7).
      Figure thumbnail gr4
      Figure 4Domain scores (ePRO period 2) according to functional class (visit 2). LS = least squares. Data are presented as least squares mean ± SE. Pairwise comparisons between least squares means were performed by using the Scheffé test, adjusting for multiple comparisons; only statistically significant pairwise comparisons are shown. *P < .05. **P < .001. ***P < .0001. See and legends for expansion of abbreviations.
      Table 7Domain Scores (ePRO Period 2) According to Patient-reported Disease Severity (PGA-S, Visit 2)
      PAH-SYMPACT DomainLeast Squares Mean (SE)Overall F-testPairwise Comparison
      Pairwise comparisons between least squares means were performed by using the Scheffé test, adjusting for multiple comparisons: 1 = none vs very mild; 2 = none vs mild; 3 = none vs moderate; 4 = none vs severe; 5 = none vs very severe; 6 = very mild vs mild; 7 = very mild vs moderate; 8 = very mild vs severe; 9 = very mild vs very severe; 10 = mild vs moderate; 11 = mild vs severe; 12 = mild vs very severe; 13 = moderate vs severe; 14 = moderate vs very severe; 15 = severe vs very severe. Nonsignificant comparisons are not presented in this table.
      None (1)Very Mild (2)Mild (3)Moderate (4)Severe (5)Very Severe (6)FP ValueP Value
      Symptomsn = 25n = 55n = 81n = 89n = 18n = 5
       Cardiopulmonary Symptoms0.43 (0.36)0.60 (0.42)0.90 (0.43)1.21 (0.45)1.55 (0.57)1.89 (0.78)30.51< .00012
      P < .0001.
      , 3
      P < .0001.
      , 4
      P < .0001.
      , 5
      P < .0001.
      , 6
      P < .05.
      , 7
      P < .0001.
      , 8
      P < .0001.
      , 9
      P < .0001.
      , 10
      P < .001.
      , 11
      P < .0001.
      , 12
      P < .0001.
       Cardiovascular Symptoms0.15 (0.17)0.24 (0.34)0.48 (0.42)0.66 (0.54)1.00 (0.94)0.86 (0.63)12.13< .00013
      P < .0001.
      , 4
      P < .0001.
      , 7
      P < .0001.
      , 8
      P < .0001.
      , 11
      P < .001.
      Impactsn = 22n = 53n = 75n = 81n = 16n = 4
       Physical Impacts0.47 (0.59)0.80 (0.69)1.27 (0.70)1.81 (0.71)2.13 (0.79)2.79 (0.43)28.35< .00012
      P < .0001.
      , 3
      P < .0001.
      , 4
      P < .0001.
      , 5
      P < .0001.
      , 6
      P < .05.
      , 7
      P < .0001.
      , 8
      P < .0001.
      , 9
      P < .0001.
      , 10
      P < .0001.
      , 11
      P < .001.
      , 12
      P < .001.
       Cognitive/Emotional Impacts0.72 (0.69)0.65 (0.71)0.96 (0.79)1.21 (0.85)1.53 (1.08)1.38 (1.53)5.10.00027
      P < .05.
      , 8
      P < .05.
      See Table 4 and 5 legends for expansion of abbreviations.
      a Pairwise comparisons between least squares means were performed by using the Scheffé test, adjusting for multiple comparisons: 1 = none vs very mild; 2 = none vs mild; 3 = none vs moderate; 4 = none vs severe; 5 = none vs very severe; 6 = very mild vs mild; 7 = very mild vs moderate; 8 = very mild vs severe; 9 = very mild vs very severe; 10 = mild vs moderate; 11 = mild vs severe; 12 = mild vs very severe; 13 = moderate vs severe; 14 = moderate vs very severe; 15 = severe vs very severe. Nonsignificant comparisons are not presented in this table.
      b P < .0001.
      c P < .05.
      d P < .001.

       Sensitivity to Change

      Domain scores were sensitive to improvement in patient-reported disease severity, with significant associations between improvements in PAH-SYMPACT domain scores and improvements in PGA-S scores from baseline to week 16 (Fig 5). Domain scores were also sensitive to improvement in clinician-reported disease severity as measured by improvement in CGI-S scores from baseline to week 16 (P < .0001 for all domains except Cognitive/Emotional Impacts, P = .0061), and CGI-C scores from baseline to week 16 (P < .01 for all domains except Cognitive/Emotional Impacts, P = .0665).
      Figure thumbnail gr5
      Figure 5Change over time in domain scores (ePRO period 2 to period 4) by change in PGA-S score (visit 2 to visit 4). Data are presented as least squares mean ± SE. Pairwise comparisons between least squares means were performed by using the Scheffé test, adjusting for multiple comparisons; only statistically significant pairwise comparisons are shown. **P < .001. ***P < .0001. See for definitions of visits and ePRO periods. See and legends for expansion of abbreviations.

      Discussion

      The final PAH-SYMPACT is a valid and reliable instrument that is sensitive to improvement. The questionnaire measures important, patient-relevant aspects of PAH symptoms (which are a direct consequence of the disease) and impacts (which are a consequence of the symptoms) that are not captured by other clinical endpoints (eg, change in exercise capacity).
      Recall periods are clearly defined and align with relevant time frames for assessment; that is, daily recall for symptoms, which may vary from day to day, vs weekly recall for impacts, which may not be experienced every day. With 11 symptom items and 11 impact items (plus one item on oxygen use), this brief questionnaire is easy to apply in clinical practice and PAH trials. To ensure its suitability as an efficacy endpoint in future PAH clinical trials, its development has rigorously followed the FDA PRO guidance from the outset, including being based on patient input using patients’ language, with input from clinical experts throughout its development.

      US Food and Drug Administration. Guidance for Industry. Patient-reported outcome measures: use in medical product development to support labeling claims [Internet]. 2009. http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf. Accessed May 31, 2018.

      In contrast, the development of other PH-specific PRO instruments has followed different approaches to meet specific needs. For example, the emPHasis-10 was developed primarily as a short, simple scoring system for HRQoL in patients with PH in clinical practice; it is scored on a single dimension, and its items are assessed using a recall period of “recent experience of living with PH.”
      • Yorke J.
      • Corris P.
      • Gaine S.
      • et al.
      emPHasis-10: development of a health-related quality of life measure in pulmonary hypertension.
      CAMPHOR differs from the PAH-SYMPACT in being developed on the theoretical basis of the needs-based model of quality of life,
      • Doward L.C.
      • McKenna S.P.
      Defining patient-reported outcomes.
      rather than a measure of symptoms and impacts.
      • McKenna S.P.
      • Ratcliffe J.
      • Meads D.M.
      • Brazier J.E.
      Development and validation of a preference based measure derived from the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) for use in cost utility analyses.
      • Meads D.M.
      • McKenna S.P.
      • Doughty N.
      • et al.
      The responsiveness and validity of the CAMPHOR Utility Index.
      Measures of internal consistency reliability found in this study for CAMPHOR were high and similar to those reported in the original CAMPHOR development study, which included patients with PAH in the validation population.
      • McKenna S.P.
      • Doughty N.
      • Meads D.M.
      • Doward L.C.
      • Pepke-Zaba J.
      The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR): a measure of health-related quality of life and quality of life for patients with pulmonary hypertension.
      However, CAMPHOR has fewer response options than the PAH-SYMPACT (yes/no questions and 3-point Likert scales vs 5-point Likert scales), which could make the instrument less sensitive to change. CAMPHOR poses a higher patient burden to complete (it has 65 items), which may make it less practical for use in clinical practice than in clinical trials.
      Development populations for the CAMPHOR and the emPHasis-10 included patients with PAH and other forms of PH, primarily chronic thromboembolic PH.
      • McKenna S.P.
      • Doughty N.
      • Meads D.M.
      • Doward L.C.
      • Pepke-Zaba J.
      The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR): a measure of health-related quality of life and quality of life for patients with pulmonary hypertension.
      • Yorke J.
      • Corris P.
      • Gaine S.
      • et al.
      emPHasis-10: development of a health-related quality of life measure in pulmonary hypertension.
      Although all forms of PH share symptoms in common,
      • McLaughlin V.V.
      • Archer S.L.
      • Badesch D.B.
      • et al.
      ACCF/AHA 2009 expert consensus document on pulmonary hypertension. A report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association.
      there may be differences between types of PH in the relative importance of symptoms and their effects on patients,
      • Cenedese E.
      • Speich R.
      • Dorschner L.
      • et al.
      Measurement of quality of life in pulmonary hypertension and its significance.
      and potentially also in the types of symptoms. In contrast, the development of the Living With Pulmonary Hypertension questionnaire, an adaptation of the Minnesota Living With Heart Failure Questionnaire
      • Rector T.S.
      • Kubo S.H.
      • Cohn J.N.
      Patients' self-assessment of their congestive heart failure. Part 2: content, reliability and validity of a new measure, the Minnesota Living With Heart Failure Questionnaire.
      for use in populations with PAH,
      • Bonner N.
      • Abetz L.
      • Meunier J.
      • Sikirica M.
      • Mathai S.C.
      Development and validation of the living with pulmonary hypertension questionnaire in pulmonary arterial hypertension patients.
      was based on interviews of patients with PAH exclusively. However, the development process for the Living With Pulmonary Hypertension questionnaire did not incorporate the potential for addition of new symptoms and impacts, and its 1-week recall period for both symptoms and impacts could introduce recall bias for symptoms, given their potential for daily variation.
      Substantial floor effects were observed for several PAH-SYMPACT items. This finding was likely attributable (at least in part) to the relatively small number of patients with FC IV as well as the fact that many patients in SYMPHONY were already receiving background PAH-specific therapy, which may have led to a lower symptom burden than would have been seen in untreated patients. Floor effects are unlikely to have an impact on the overall performance of the questionnaire, especially considering that one of the three symptom items and two of the four impact items that had floor effects in > 50% of patients were deleted during item reduction. Those items with floor effects that were retained were of clear importance in PAH, especially for patients with more severe disease, as indicated by the qualitative research and confirmed by the clinical experts.
      The main limitations of SYMPHONY include the lack of untreated patients and the fact that few patients had heritable PAH, PAH associated with congenital heart disease or HIV infection, or severe disease (FC IV), reflecting the difficulty of recruiting patients from these less common subgroups. The low number of patients in FC IV in SYMPHONY represents a limitation only in terms of evaluating the psychometric characteristics of the instrument in this subgroup, as the qualitative development of the PAH-SYMPACT included patients in FC IV,
      • McCollister D.
      • Shaffer S.
      • Badesch D.B.
      • et al.
      Development of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT®) questionnaire: a new patient-reported outcome instrument for PAH.
      and the item content of the questionnaire was designed to cover the full spectrum of symptom severity. A Steering Committee of clinical experts provided input on item retention and removal, taking into account the full spectrum of PAH severity. However, the study did not include a formal method of quantifying the experts’ level of agreement on content relevance, such as the Content Validity Index.
      • Lynn M.R.
      Determination and quantification of content validity.
      The absence of a control arm also limits the ability to fully determine the effect of macitentan on PAH symptoms and impacts. Results of analyses of responder/clinically meaningful change thresholds are forthcoming.

      Conclusions

      The PAH-SYMPACT is a new PAH-specific PRO instrument that contains the symptoms and impacts most relevant from a clinical and patient perspective. The domains have good psychometric properties, including sensitivity to improvement. The questionnaire enhances our ability to assess patient outcomes, following FDA guidance. This questionnaire is now available for use in clinical practice and in clinical trials.

      Acknowledgments

      Author contributions: K. M. C. takes responsibility for the content of this article, including the data and analysis. K. M. C., M. G.-M., R. N. C., A. F., R. P. F., C. E. M., R. T. Z., and D. B. B. participated in study design, data acquisition, and data analysis/interpretation. M. J. C., J. W. M., V. V. M., and M. S. Z. participated in data acquisition, and data analysis/interpretation. E. H. and L. K. conceived of the study and participated in study design and data analysis/interpretation. All authors contributed to manuscript drafting and/or critical revision, approved the final manuscript, and agree to be held accountable for all aspects of the work.
      Financial/nonfinancial disclosures: The authors have reported to CHEST the following: K. M. C. has received consultant fees from Actelion and United Therapeutics; and has received research support from Actelion, Bayer, United Therapeutics, and the National Institutes of Health. The University of Chicago has received research funding from Actelion Pharmaceuticals Ltd, Bayer, Gilead Sciences, Inc, Lung Biotechnology, Medtronic, and Reata Pharmaceuticals, Inc for M.G.-M. to participate in clinical trials; M.G.-M has participated as a consultant (steering committees, Data and Safety Monitoring Boards, and/or event committees) for Actelion Pharmaceuticals Ltd, Arena, Bayer, Gilead Sciences, Inc, Liquidia, Medtronic, Merck, St. Jude’s Medical Inc, UCB, and United Therapeutics. R. N. C. has received fees/grants from Actelion Pharmaceuticals Ltd, Bayer, and United Therapeutics. M. J. C. has received consulting fees and honoraria from Actelion Pharmaceuticals Ltd, Bayer, Gilead, and United Therapeutics. A. F. has received consultant fees from Actelion Pharmaceuticals Ltd, aTyr Pharma, Inc, Boehringer Ingelheim, Genentech-Roche Inc, and Gilead Sciences, Inc. R. P. F. reports steering committee and advisory board participation for Actelion Pharmaceuticals Ltd; steering committee and Data and Safety Monitoring Board participation for United Therapeutics; consulting participation for Bayer Corporation; and has received consulting fees from St. Jude Medical, Inc. E. H. and M. S. Z. were employees of Actelion when this research was conducted and previously had stock options or bond holdings in Actelion. L. K. is a salaried employee of Evidera; Evidera has received payments from Actelion Pharmaceuticals Ltd for services related to the conduct of this research. J. W. M. has received honoraria and acted as a consultant for Actelion Pharmaceuticals Ltd, Bayer, and Reata Pharmaceuticals; has advisory board participation for Actelion Pharmaceuticals Ltd, Bayer, and United Therapeutics; has speakers bureau participation for Actelion Pharmaceuticals Ltd, Bayer, and Genentech; and has received research funding from Actelion Pharmaceuticals Ltd, Bayer, Bellerophon, Eiger BioPharmaceuticals, Gilead Pharmaceuticals, Lung Rx, Reata Pharmaceuticals, and United Therapeutics. V. V. M. has received fees from Actelion Pharmaceuticals US, Inc, Bayer, Gilead Sciences, Inc, St. Jude Medical, and United Therapeutics Corporation for advisory board participation and/or consulting; the University of Michigan has received research funding from Actelion Pharmaceuticals US, Inc, Arena, Bayer, Eiger BioPharmaceuticals, Gilead, Ikaria, and Novartis for V. V. M. to participate in clinical trials. C. E. M. has received fees from Actelion Pharmaceuticals Ltd for speakers bureau and clinical trial participation. R. T. Z. has received grants from Actelion Pharmaceuticals Ltd, Reata Pharmaceuticals, Inc, and United Therapeutics; has received consulting fees from Actelion Pharmaceuticals Ltd, Bayer, and United Therapeutics; and holds shares in Genentech, Inc and Selten Pharma, Inc. D. B. B. has served as a consultant (on steering committees and advisory boards) for Acceleron, Actelion, Arena, Bellerophon, Gilead, Liquidia, and United Therapeutics/Lung LLC; and has received grant support from Actelion, Arena, Bellerophon, Eiger BioPharmaceuticals, Gilead, Reata, and United Therapeutics/Lung LLC.
      Role of sponsor: The PAH-SYMPACT is copyright protected and owned by the sponsor, Actelion Pharmaceuticals Ltd. Actelion Pharmaceuticals Ltd provided the study design and statistical analysis plan, and participated in data analysis and interpretation, preparation of the manuscript, and the decision to publish the manuscript. The psychometric study was conducted by Evidera, funded by Actelion Pharmaceuticals Ltd. Medical writing and editorial support were provided by W. Mark Roberts, PhD, Montreal, QC, Canada, funded by Actelion Pharmaceuticals Ltd.
      Other contributions: The SYMPHONY investigators are listed in e-Table 8.
      Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.

      Supplementary Data

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