Approaches to the Assessment of Clinical Benefit of Treatments for Conditions That Have Heterogeneous Symptoms and Impacts: Potential Applications in Rare Disease.

OBJECTIVES: Evaluating the clinical benefit of interventions for conditions with heterogeneous symptom and impact presentations is challenging. The same condition can present differently across and within individuals over time. This occurs frequently in rare diseases. The purpose of this review was to identify (1) assessment approaches used in clinical trials to address heterogeneous manifestations that could be relevant in rare disease research and (2) US Food and Drug Administration (FDA)-approved labeling claims that used these approaches. METHODS: A targeted literature review was conducted examining peer-reviewed publications and FDA-approved labeling claims from January 2002 to July 2020, focusing on claims incorporating clinical outcome assessments. Approaches were then assessed for their potential application in rare diseases. RESULTS: A total of 6 assessment approaches were identified: composite or other multicomponent endpoints, multidomain responder index, most bothersome symptom (MBS), goal attainment scaling, sliding dichotomy, and adequate relief. A total of 59 FDA-approved labeling claims associated with these approaches were identified: composite or other multicomponent endpoints (n=49), MBS (n=9), and adequate relief (n=1). A total of 10 FDA-approved labeling claims, all using multicomponent endpoints, were identified for rare diseases. CONCLUSIONS: Multicomponent, MBS, and adequate relief have been included in FDA-approved labeling claims. Multicomponent endpoints, including composite endpoints, were the most frequent way to address heterogeneous manifestations of both common and rare diseases. MBS may be acceptable to regulators, whereas multidomain responder index is unlikely to be. The goal attainment scaling and adequate relief approaches may have potential utility in rare disease trials, assuming the theoretical and statistical challenges inherent in each approach are managed.

Reliability, validity and responsiveness of E-RS:COPD in patients with spirometric asthma-COPD overlap.

BACKGROUND: The Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease (E-RS:COPD) is a patient-reported diary that assesses respiratory symptoms in stable COPD. METHODS: This post hoc analysis of a randomized, double-blind, parallel-arm trial (GSK ID: 200699; NCT02164539) assessed the structure, reliability, validity and responsiveness of the E-RS, and a separate wheeze item, for use in patients with a primary diagnosis of asthma or COPD, but with spirometric characteristics of both (fixed airflow obstruction and reversibility to salbutamol; a subset of patients referred to as spirometric asthma-COPD overlap [ACO]; N = 338). RESULTS: Factor analysis demonstrated that E-RS included Cough and Sputum, Chest Symptoms, and Breathlessness domains, with a Total score suitable for quantifying overall respiratory symptoms (comparative fit index: 0.9), consistent with the structure shown in COPD. The wheeze item did not fit the model. Total and domain scores were internally consistent (Cronbach's alpha: 0.7-0.9) and reproducible (intra-class correlations > 0.7). Moderate correlations between RS-Total and RS-Breathlessness scores were observed with St George's Respiratory Questionnaire (SGRQ) Total and Activity domain scores at baseline (r = 0.43 and r = 0.48, respectively). E-RS scores were sensitive to change when a patient global impression of change and SGRQ change scores were used to define responders, with changes of ≥ - 1.4 in RS-Total score interpreted as clinically meaningful. CONCLUSIONS: E-RS:COPD scores were reliable, valid and responsive in this sample, suggesting the measure may be suitable for evaluating the severity of respiratory symptoms and the effects of treatment in patients with asthma and COPD that exhibit spirometric characteristics of both fixed airflow obstruction and reversibility. Further study of this instrument and wheeze in new samples of patients with ACO is warranted.

Patient-reported Outcomes for the Detection, Quantification, and Evaluation of Chronic Obstructive Pulmonary Disease Exacerbations.

An exacerbation of chronic obstructive pulmonary disease (COPD) is an acute worsening of respiratory symptoms accompanied by a variable degree of physiological deterioration. The traditional assessment of an exacerbation consists of the reporting of symptoms by the patient to a clinician and subsequent clinical assessment. It would be valuable to also gather symptom reports directly from patients, and thus patient-reported outcome (PRO) tools should be ideally suited to the evaluation of COPD exacerbations. However, most pharmaceutical industry- and large academy-sponsored studies have used a healthcare resource use definition alone, which is based on sustained worsening of a patient's condition from the stable state that requires a change in regular medication. This Review explores the use of PROs for the detection, quantification, and evaluation of COPD exacerbations. It examines symptom diary cards as exacerbation detection tools and their evolution into electronic diaries used in pharmaceutical trials. This paper also describes the development of specifically designed PROs that have been used in exacerbation settings, focusing on the Exacerbations and Symptoms in COPD e-Diary, Exacerbations of Chronic Obstructive Pulmonary Disease Tool, COPD Assessment Test, and Chronic Respiratory Disease Questionnaire, highlighting the strengths and weaknesses of these instruments. We describe the effectiveness of these tools to enhance exacerbation reporting; quantify exacerbation characteristics, including the frequency, duration, and severity of events; and evaluate the outcome. We also explore the potential use of PROs in future studies to discriminate the effect of therapies on different exacerbation phenotypes and thus enhance personalized therapeutic approaches.

Measuring respiratory symptoms of COPD: performance of the EXACT- Respiratory Symptoms Tool (E-RS) in three clinical trials.

BACKGROUND: Symptomatic relief is an important treatment goal for patients with COPD. To date, no diary for evaluating respiratory symptoms in clinical trials has been developed and scientifically-validated according to FDA and EMA guidelines. The EXACT - Respiratory Symptoms (E-RS) scale is a patient-reported outcome (PRO) measure designed to address this need. The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms. METHODS: This study examined the performance of the E-RS in each of 3 controlled trials with common and unique validation variables: one 6-month (N = 235, US) and two 3-month (N = 749; N = 597; international). Subjects completed the E-RS as part of a daily eDiary. Tests of reliability, validity, and responsiveness were conducted in each dataset. RESULTS: In each study, RS-Total score was internally consistent (Cronbach α) (0.88, 0.92, 0.92) and reproducible (intra-class correlation) in stable patients (2 days apart: 0.91; 7 days apart: 0.71, 0.74). RS-Total scores correlated significantly with the following criterion variables (Spearman's rho; p < 0.01, all comparisons listed here): FEV1% predicted (-0.19, -0.14, -0.15); St. George's Respiratory Questionnaire (SGRQ) (0.65, 0.52, 0.51); Breathlessness, Cough, and Sputum Scale (BCSS) (0.89, 0.89); modified Medical Research Council dyspnoea scale (mMRC) (0.40); rescue medication use (0.43, 0.42); Functional Performance Inventory Short-Form (FPI-SF) (0.43); 6-minute walk distance (6-MWT) (-0.30, -0.14) and incremental shuttle walk (ISWT) (-0.18) tests. Correlations between these variables and RS-Breathlessness, RS-Cough and Sputum, RS-Chest Symptoms scores supported subscale validity. RS-Total, RS-Breathlessness, and RS-Chest Symptoms differentiated mMRC levels of breathlessness severity (p < 0.0001). RS-Total and domain scores differentiated subjects with no rescue medication use and 3 or more puffs (p < 0.0001). Sensitivity to changes in health status (SGRQ), symptoms (BCSS), and exercise capacity (6MWT, ISWT) were also shown and responder definitions using criterion- and distribution-based methods are proposed. CONCLUSIONS: Results suggest the E-RS is a reliable, valid, and responsive measure of respiratory symptoms of COPD suitable for use in natural history studies and clinical trials. TRIAL REGISTRATION: MPEX: NCT00739648 ; AZ1: NCT00949975 ; AZ 2: NCT01023516.

The Fatigue Associated with Depression Questionnaire (FAsD): responsiveness and responder definition.

PURPOSE: The Fatigue Associated with Depression Questionnaire (FAsD) was developed to assess fatigue and its impact among patients with depression. The purpose of this study was to examine the questionnaire's responsiveness to change and identify a responder definition for interpretation of treatment-related changes. METHODS: Data were collected at baseline and at 6 weeks from patients with depression starting treatment with a new antidepressant. RESULTS: Of the 96 participants, 55.2% were women, with a mean age of 43.4 years. The total score and both subscales demonstrated statistically significant change with moderate to large effect sizes (absolute values ≥ 0.76). FAsD change scores were significantly correlated with change on the Brief Fatigue Inventory (r ≥ 0.73; p < 0.001). FAsD mean change scores discriminated among patient subgroups differing by degree of improvement in patient- and clinician-reported fatigue and depression. Responder definition for the two subscales and total score (0.67, 0.57, 0.62) was estimated primarily based on mean change among patients who reported a small but important improvement in fatigue. DISCUSSION: The FAsD was responsive to change, and the responder definition may be used when interpreting treatment-related change. Results add to previous findings suggesting the FAsD is a useful measure of fatigue among patients with depression.

Patient-reported outcome (PRO) measures for clinical trials of COPD: the EXACT and E-RS.

The precise assessment of treatment efficacy in clinical trials requires scientific instruments that are not only relevant to the target population and treatment, but have been shown to be reliable, valid, and sensitive to change within the intended context of use. This paper describes the background, procedures, and current status of 2 patient-reported outcome (PRO) instruments developed for use in clinical trials of chronic obstructive pulmonary disease (COPD). The first measure, the EXAcerbations of Chronic pulmonary disease Tool (EXACT), was developed under the EXACT-PRO Initiative, a multi-year, multi-sponsor project involving experts in pulmonary medicine, instrument development, and drug development regulatory issues, dedicated to the development of a single, standardized instrument for evaluating the effects of treatment on acute exacerbations of COPD. The second measure, the EXACT-Respiratory Symptoms (E-RS) scale, is a derivative instrument comprising a subset of EXACT items to test the effect of treatment on the severity of respiratory symptoms in stable COPD. The EXACT-PRO Initiative was the first PRO instrument development consortia, and the EXACT and E-RS are the first PRO measures to undergo qualification review by the United States Food and Drug Administration (FDA).

Measuring respiratory symptoms in moderate/severe asthma: evaluation of a respiratory symptom tool, the E-RS®: COPD in asthma populations.

BACKGROUND: Symptom constructs included in the Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease (E-RS®: COPD) tool may be relevant to patients with asthma. The purpose of this study was to evaluate content validity and psychometric performance of the E-RS: COPD in moderate/severe asthma patients. METHODS: Content validity of the E-RS: COPD was evaluated in patients with moderate/severe asthma using concept elicitation and cognitive debriefing interviews. Secondary analyses using data from two clinical trials in patients with moderate/severe asthma evaluated the factor structure of the E-RS: COPD plus two supplementary items (wheeze; shortness of breath with strenuous physical activity) and assessed psychometric properties of the tool, which will be referred to as E-RS®: Asthma when used in asthma populations. RESULTS: Qualitative interviews (N = 25) achieved concept saturation for asthma respiratory symptoms. Concepts in the E-RS: COPD were relevant to patients and instructions were understood. Most patients (19/25; 76%) reported experiencing all concepts in the E-RS: COPD; no patients indicated missing symptoms. Secondary analyses of clinical trial data supported the original factor structure (RS-Total and three symptom-specific subscales). The two supplemental items did not fit with this factor structure and were not retained. RS-Total and subscale score reliability was high (internal consistency [α] > 0.70). Validity was demonstrated through significant (P < 0.0001) relationships with the St George's Respiratory Questionnaire (SGRQ) and Asthma Symptom Severity scale. E-RS: Asthma was responsive to change when evaluated using SGRQ, Patient Global Impression of Change and Asthma Quality of Life Questionnaire as anchors (P < 0.0001). Clinically meaningful change thresholds were also identified (RS-Total: - 2.0 units). CONCLUSIONS: The E-RS: Asthma is reliable and responsive for evaluating respiratory symptoms in patients with moderate/severe asthma.

Development of the EXAcerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT): a patient-reported outcome (PRO) measure.

BACKGROUND: This article describes the qualitative methods used to develop the EXAcerbation of Chronic Pulmonary Disease Tool (EXACT), a new patient-reported outcome (PRO) instrument for evaluating frequency, severity, and duration of exacerbations of chronic obstructive pulmonary disease (COPD). METHODS: Focus groups and interviews were conducted in the United States with COPD patients treated for exacerbations during the past 6 months. Participants were asked to describe exacerbation attributes, care-seeking cues, and indications of progression and recovery. An iterative process was used to identify themes in the data to inform instrument content and structure. Cognitive debriefing interviews were performed to evaluate and revise the draft item pool. Experts in COPD, instrument development, and clinical research participated in the process. RESULTS: Eighty-three subjects participated in elicitation focus groups or interviews (n=48); elicitation interviews with cognitive debriefing (n=23), or cognitive interviews alone (n=12). Mean age of the sample was 65 years (SD=10); 45% were male; mean FEV-1% predicted was 44% (SD=16). Participants characterized exacerbations as a persistent increase in the severity of respiratory symptoms and other systemic manifestations accompanied by a dramatic reduction in activity. Specific attributes included shortness of breath, chest congestion, cough, sputum, chest discomfort, feeling weak or tired, sleep disturbances, and concern or worry. The diary card of 23 candidate items was debriefed in booklet and electronic format. CONCLUSIONS: Qualitative data from patients and input from experts formed the basis of the EXACT's structure and item pool, ready for empirically based item reduction and reliability and validity testing.

Clinically Important Deterioration Among Patients with Chronic Obstructive Pulmonary Disease (COPD) Treated with Nebulized Glycopyrrolate: A Post Hoc Analysis of Pooled Data from Two Randomized, Double-Blind, Placebo-Controlled Studies.

Purpose: Using a composite endpoint, pooled data from two 12-week Phase III placebo-controlled trials (GOLDEN 3, NCT02347761; GOLDEN 4, NCT02347774) were analyzed to determine whether glycopyrrolate inhalation solution (25 mcg and 50 mcg) administered twice daily (BID) via the eFlow® Closed System nebulizer (GLY) reduced the risk of clinically important deterioration (CID) in patients with moderate-to-very-severe COPD. Methods: CID was defined as ≥100-mL decrease from baseline in post-bronchodilator trough forced expiratory volume in one second (FEV1), or ≥4-unit increase in baseline St. George's Respiratory Questionnaire (SGRQ) total score, or moderate/severe exacerbation. The relative treatment effect of GLY versus placebo on the odds of CID (any and by component endpoints) was expressed as the odds ratio (OR) and 95% confidence interval (CI). Subgroups categorized by age (<65/≥65 years), sex, smoking status (current/former), long-acting beta agonist (LABA) use, FEV1 (<50%/≥50%), and peak inspiratory flow rate (PIFR) (<60 L/min/≥60 L/min) were analyzed. Results: Compared to placebo, GLY 25 mcg and 50 mcg BID over 12 weeks significantly reduced the risk of CID by 50% (OR: 0.50 [0.37-0.68]) and 40% (OR: 0.60 [0.44-0.80]), respectively. Subjects treated with GLY 25 mcg BID were 59% less likely to experience CID in FEV1 (OR: 0.41 [0.27-0.62]) and 48% less likely to perceive CID in health status (OR: 0.52 [0.37-0.73]). Statistically significant reductions were also observed at the higher dose. The incidence of moderate/severe exacerbations was low and comparable among the cohorts. GLY 25 mcg BID was significantly more effective than placebo (p<0.05) in preventing CID irrespective of age, smoking status, LABA use, COPD severity, or PIFR. Subjects <65 years (OR 0.45 [0.29-0.68]) and those with PIFR <60 L/min (OR 0.36 [0.20-0.67]) exhibited the largest benefit. Conclusion: Nebulized GLY over 12 weeks significantly reduced the risk of CID and provided greater short-term stability in patients with moderate-to-very-severe COPD.

Development of the neurotrophic keratopathy questionnaire: qualitative research.

BACKGROUND: Neurotrophic keratopathy/keratitis (NK) is a rare disease of the cornea that can lead to anatomical loss of the eye. Little is known about the NK experience from the patients' perspective. The objectives of this study were to examine the symptomatic experience and impacts of NK on patients and assess the overall comprehension, relevance, and content validity of a new questionnaire. METHODS: This was a cross-sectional, qualitative study conducted with NK patients with varying levels of disease severity, recruited from one clinical site. One-on-one interviews using concept elicitation and cognitive interviewing techniques were conducted. RESULTS: Fourteen NK patients participated; 64.3% were female (n = 9), mean age was 65.7 ± 13.3, and 14.3% (n = 2), 21.4% (n = 3), and 64.3% (n = 9) were classified as Mackie stage I, stage II, or stage III, respectively. Participants reported 24 concepts, including: redness (n = 12, 86%), sensitivity to light (n = 11, 79%), general discomfort (n = 9, 64%), dry eye (n = 9, 64%), reduced visual acuity (n = 9, 64%), blurred vision (n = 8, 57%), and eye fatigue (n = 8, 57%). No new concepts were reported after the 13th interview. The most frequently reported impacts included frustration (n = 10, 71%), driving impairment (n = 8, 57%), reading impairment (n = 7, 50%), difficulty watching television (n = 7, 50%), and concern with potentially losing their eyesight due to NK (n = 6, 43%). Participants provided positive feedback on the draft NK Questionnaire (NKQ) and felt that it was comprehensive and relevant to their experience with NK. Additionally, the recall period, instructions, item concepts, and response options were well-understood by participants. Minor revisions were made to the tool for consistency (i.e., the timeframe "in the past 7 days" was added to items 12-14); item 14 was modified to include "how often"; examples were added to item 9. CONCLUSIONS: The results of the concept elicitation portion of the qualitative study support the content validity of the draft NKQ. The clinically significant concepts identified in the literature and raised during concept elicitation are included as items in the questionnaire. Further assessment of the psychometric properties should be conducted in support of this new tool to measure the effect of new treatments on symptoms and impacts associated with NK.

Older peoples' attitudes to mental illness.

Despite the prevalence of mental health problems in later life, older people markedly underutilize mental health services. A greater awareness of factors influencing older peoples' attitudes to mental illness may therefore improve awareness and treatment of mental disorders in this population. A mixed methodology approach was used to explore and compare older peoples' attitudes to mental illness in a sample of clinical and non-clinical participants. Results indicated that, similar to younger people, older people endorsed a range of positive and negative attitudes to mental illness. However, when attitudes to mental illness were considered within the context of ageing and experience a more complex pattern of results emerged. Although negative attitudes to mental illness were associated with negative attitudes to ageing across the entire sample, clinical participants (and those with prior experience of mental illness) reported more positive attitudes to mental illness and more negative attitudes to ageing than non-clinical participants, for whom the reverse was true. Attitudes were also differentially related to health behaviour outcomes. Results suggest that attitudes to mental illness and ageing may be linked and mediated by personal experience and capacity for psychological self-regulation in the face of age-associated adversity.

The Impact of Twice-Daily Indacaterol/Glycopyrrolate on the Components of Health-Related Quality of Life and Dyspnea in Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic cough, dyspnea, and excessive sputum production, the characteristic symptoms of chronic obstructive pulmonary disease (COPD), can negatively affect patients' health-related quality of life (HRQoL). The fixed-dose combination of a long-acting beta2-adrenergic agonist and a long-acting muscarinic antagonist (LABA/LAMA) have been shown to improve HRQoL and COPD symptoms as measured by the St George's Respiratory Questionnaire (SGRQ) and the Transition Dyspnea Index (TDI) total scores. However, the impact of a LABA/LAMA on the individual components of HRQoL and dyspnea with daily activities is unknown. METHODS: Secondary analysis of pooled data from 2 replicate, phase 3, 12-week, randomized, placebo, and active-controlled trials of twice-daily indacaterol/glycopyrrolate (IND/GLY) were analyzed. Change from baseline in HRQoL and dyspnea was measured by SGRQ and TDI, respectively. Total and component scores were evaluated using linear mixed models. Logistic regression was used to analyze the proportion of patients achieving minimum clinically important difference. Study outcomes were further explored in patient subgroups. RESULTS: A total of 2038 patients from FLIGHT1/FLIGHT2 studies were evaluated. IND/GLY significantly improved SGRQ component scores (symptoms [-7.3], activity [-3.6], and impacts [-5.0]); all P < 0.001 compared with placebo. IND/GLY also significantly improved symptoms scores compared with IND and GLY (-3.5 and -3.7, respectively; both P < 0.001). Patients treated with IND/GLY also had significant improvements in TDI component scores compared with placebo: functional impairment (0.48), magnitude of task (0.61), and magnitude of effort (0.54); all P < 0.001. All component scores were significantly higher for IND/GLY compared with IND and GLY (P ≤ 0.002 for all). CONCLUSIONS: Twice-daily IND/GLY significantly improved total scores as well as components of HRQoL and dyspnea in patients with COPD. These data demonstrate multiple clinical benefits of LABA/LAMA maintenance therapy in the COPD population. ClinicalTrials.gov: NCT01727141 and NCT01712516.

The measurement of physical functioning among patients with Tenosynovial Giant Cell Tumor (TGCT) using the Patient-Reported Outcomes Measurement Information System (PROMIS).

BACKGROUND: Tenosynovial giant cell tumor (TGCT), a rare, locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, pain and swelling. Impacts on physical function (PF) vary depending on tumor size and location. The aim of this study was to identify relevant items, and demonstrate the content validity of custom measures of lower extremity PF from the Patient-Reported Outcomes Measurement Information System Physical Function Physical Function (PROMIS-PF) item bank among patients with TGCT. METHODS: Patients were recruited for qualitative research interviews to identify predominant TGCT symptoms and impacts. Patients completed a checklist to evaluate the relevance of each PROMIS-PF item. The publicly available PROMIS-PF item response theory (IRT) parameters were used to select items representing the range of the latent PF trait. RESULTS: Participants (n = 20) were 75% female, mean age 42.5 years. TGCTs were located in the knee (n = 15), hip (n = 3), and ankle (n = 2). Fifty-four PROMIS-PF items were identified as relevant by ≥20% of the participants. PF concepts discussed by participants during the qualitative interviews were also used to select relevant items. Selected items (n = 13) were used to create a physical function subscale specific to lower extremity tumors. CONCLUSIONS: We describe a novel method of combining qualitative research and IRT-based item information to select a relevant and content valid subset of PROMIS-PF items to assess heterogeneous impacts on PF in TGCT, a rare disease population.

The Short-term Impact of Symptom-defined COPD Exacerbation Recovery on Health Status and Lung Function.

Background: This study examined the short-term effects of symptom-defined exacerbation recovery on health status and pulmonary function in moderate to severe chronic obstructive pulmonary disease (COPD) patients. Methods: Secondary analyses of pooled data from two 12-week Phase II international, randomized controlled trials using the EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) to identify symptom-defined exacerbations were conducted. Recovery was categorized as recovered, unrecovered (persistent worsening), or censored. Multiple regression analyses were used to test the effect of recovery status on change in the St George's Respiratory Questionnaire (SGRQ) and forced expiratory volume in 1 second (FEV1) from baseline to Week 12. Evaluating Respiratory Symptom scale (E-RS) scores were used to evaluate change in stable-state respiratory symptoms from baseline to Week 12. Results: Of 1346 eligible patients, 414 (31%) experienced ≥1 symptom-defined exacerbation; 260 patients recovered from their events, 80 experienced an unrecovered event (persistent worsening), 74 patients had only censored events (excluded). Groups were similar at baseline, with the recovered group reporting significantly worse symptoms (p<0.01). Recovery group and baseline SGRQ were significant predictors of change in health status over 12 weeks (p=0.04; p<0.01); no effects were observed for lung function. Significant between-group differences in change in respiratory symptom severity from baseline to Week 12 were observed (p<0.01), with the persistent worsening group experiencing clinically meaningful deterioration in breathlessness and chest symptoms. Conclusions: Results suggest some patients have difficulty recovering from symptom-defined exacerbations, leading to a deterioration in health status, dyspnea, and chest symptoms without short-term effects on lung function. Further study of symptom-defined exacerbation recovery and health outcomes is warranted.

Evaluation of a respiratory symptom diary for clinical studies of idiopathic pulmonary fibrosis.

BACKGROUND: There are no validated patient diaries for evaluating respiratory symptoms in idiopathic pulmonary fibrosis (IPF). PURPOSE: To evaluate the performance properties of the chronic obstructive pulmonary disease (COPD) Evaluating Respiratory Symptoms™ (E-RS™: COPD) measure in patients with IPF. METHODS: Concept elicitation and cognitive interviews were conducted with IPF patients to evaluate content validity, including comprehensiveness, relevance, and interpretability of E-RS™ items in this patient population. Secondary analyses of IPF clinical study data were performed to evaluate the scoring structure of the tool. With modifications, reliability, validity, and responsiveness of the instrument (E-RS™: IPF) were evaluated. RESULTS: Qualitative interviews (n = 30) were conducted. During the elicitation interviews (n = 20), concept saturation for IPF respiratory symptoms was achieved; all respiratory symptoms covered by the E-RS™ were endorsed by ≥ 30% of the sample. During cognitive interviews (n = 10), all participants found the items interpretable and relevant. Factor analyses conducted via secondary analysis of IPF clinical study data identified no total score and four symptom scales: Chest, Breathlessness, Cough, and Sputum. Reliability of each scale was high (internal consistency [α] >0.85); 2-day reproducibility (ICC >0.88). Validity was supported through significant (P < 0.0001) relationships with the St. George's Respiratory Questionnaire (SGRQ), the University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ), and other variables. The scales were responsive to change when evaluated using SGRQ Symptoms, UCSD-SOBQ, and Patient Global Impression of Change as anchors (P < 0.01 to P < 0.0001). CONCLUSION: The E-RS™: IPF is a valid, reliable, and responsive tool for evaluating respiratory symptoms in patients with IPF.

Development of the Diabetes Injection Device Experience Questionnaire (DID-EQ) and Diabetes Injection Device Preference Questionnaire (DID-PQ).

BACKGROUND: Previous research has examined patient perceptions of insulin injection devices. However, injectable medications other than insulin are increasingly used to treat type 2 diabetes, including GLP-1 receptor agonists. No patient-reported outcome (PRO) instruments have been developed taking into account the experiences of patients using newer injection devices, which are often different from devices used for insulin. Therefore, the purpose of this qualitative study was to develop two draft PRO instruments focusing on patients' experiences with these newer injection devices (one instrument assessing perceptions of a single injection device, and another assessing preferences between two devices). METHODS: Questionnaire development proceeded in six steps: literature review, interviews with six device experts, concept elicitation interviews with patients (N = 32), preliminary translatability assessment, cognitive interviews with patients (N = 20), and final translatability assessment. RESULTS: Literature review and expert interviews were conducted to inform a concept elicitation interview guide. In concept elicitation in the US, UK, and Germany, patients with type 2 diabetes reported a range of injection features that influenced their perceptions of non-insulin injection devices (e.g., requirements for preparation of the medication/device, issues related to the needle, ease-of-use, portability). Two draft "item pools" were developed based on the literature review, expert interviews, and concept elicitation results. In cognitive interviews, patients recommended minor revisions and indicated that the draft instruments were generally clear, comprehensible, and relevant to their experience with non-insulin injectable medication. The instruments were refined based on the cognitive interviews and translatability assessment, resulting in two questionnaires. CONCLUSIONS: The various steps of qualitative research support the content validity of these new PRO instruments, which are the first developed specifically to assess perceptions of non-insulin injection delivery systems. Despite some overlap with insulin-focused questionnaires, the new instruments are distinct from previous instruments (omitting content that would not be relevant to patients receiving non-insulin injectable treatment, while including content that is not included in the insulin focused instruments). This qualitative research yielded two draft questionnaires that are grounded in patient perceptions and ready for psychometric validation studies with larger samples of patients with type 2 diabetes.

Qualitative evaluation of the St George's Respiratory Questionnaire in patients with severe asthma.

PURPOSE: Content validity is the extent to which a patient-reported outcome measure evaluates the concepts most relevant to a patient's condition and treatment. The St George's Respiratory Questionnaire (SGRQ) has been validated in a range of respiratory conditions. This study evaluated the content validity of the SGRQ in patients with severe asthma. METHODS: A qualitative study, guided by a protocol, which included concept elicitation and cognitive debriefing of the SGRQ, was conducted in patients aged ≥18 years with history of severe asthma and blood eosinophil counts of ≥150/µL (past month) or ≥300/µL (past 12 months). Patients were recruited until saturation for concept elicitation was achieved (i.e. no additional concepts identified). Concepts identified by the patients were then mapped to the SGRQ. RESULTS: 18 patient interviews provided concept saturation. Concept elicitation confirmed that the SGRQ includes the commonly reported asthma symptoms and their impact on daily life. In total, 89-100% of patients routinely experienced cough, nighttime awakenings, shortness of breath, chest tightness, sleep difficulty, phlegm/mucus, and wheezing. Patients reported asthma impacting daily and physical activities, mood and sleep. Cognitive interviewing confirmed that patients understood the instructions, items and response options in the SGRQ. Nearly half of the concepts in the SGRQ were endorsed by ≥12 patients; of the 17 items with scoring weights ≥85, 11 were mentioned by ≥12 patients. CONCLUSIONS: This study demonstrates that the SGRQ is a relevant, comprehensive and content-valid instrument to assess health status in patients with severe asthma.

Qualitative Research on Fatigue Associated with Depression: Content Validity of the Fatigue Associated with Depression Questionnaire (FAsD-V2).

BACKGROUND: Fatigue is one of the most common symptoms of major depressive disorder (MDD). The Fatigue Associated with Depression Questionnaire (FAsD) was developed to assess fatigue and its impact in patients with MDD. The current article presents the qualitative research conducted to develop and examine the content validity of the FAsD and FASD-Version 2 (FAsD-V2). METHODS: Three phases of qualitative research were conducted with patients recruited from a geographically diverse range of clinics in the US. Phase I included concept elicitation focus groups, followed by cognitive interviews. Phase II employed similar techniques in a more targeted sample. Phase III included cognitive interviews to examine whether minor edits made after Phase II altered comprehensibility of the instrument. Concept elicitation focused on patients' perceptions of fatigue and its impact. Cognitive interviews focused on comprehension, clarity, relevance, and comprehensiveness of the instrument. Data were collected using semi-structured discussion guides. Thematic analyses were conducted and saturation was examined. RESULTS: A total of 98 patients with MDD were included. Patients' statements during concept elicitation in phases I and II supported item development and content. Cognitive interviews supported the relevance of the instrument in the target population, and patients consistently demonstrated a good understanding of the instructions, items, response options, and recall period. Minor changes to instructions for the FAsD-V2 did not affect interpretation of the instrument. CONCLUSIONS: This qualitative research supports the content validity of the FAsD and FAsD-V2. These results add to previous quantitative psychometric analysis suggesting the FAsD-V2 is a useful tool for assessing fatigue and its impact in patients with MDD.

Identifying cases of undiagnosed, clinically significant COPD in primary care: qualitative insight from patients in the target population.

BACKGROUND: Many cases of chronic obstructive pulmonary disease (COPD) are diagnosed only after significant loss of lung function or during exacerbations. AIMS: This study is part of a multi-method approach to develop a new screening instrument for identifying undiagnosed, clinically significant COPD in primary care. METHODS: Subjects with varied histories of COPD diagnosis, risk factors and history of exacerbations were recruited through five US clinics (four pulmonary, one primary care). Phase I: Eight focus groups and six telephone interviews were conducted to elicit descriptions of risk factors for COPD, recent or historical acute respiratory events, and symptoms to inform the development of candidate items for the new questionnaire. Phase II: A new cohort of subjects participated in cognitive interviews to assess and modify candidate items. Two peak expiratory flow (PEF) devices (electronic, manual) were assessed for use in screening. RESULTS: Of 77 subjects, 50 participated in Phase I and 27 in Phase II. Six themes informed item development: exposure (smoking, second-hand smoke); health history (family history of lung problems, recurrent chest infections); recent history of respiratory events (clinic visits, hospitalisations); symptoms (respiratory, non-respiratory); impact (activity limitations); and attribution (age, obesity). PEF devices were rated easy to use; electronic values were significantly higher than manual (P<0.0001). Revisions were made to the draft items on the basis of cognitive interviews. CONCLUSIONS: Forty-eight candidate items are ready for quantitative testing to select the best, smallest set of questions that, together with PEF, can efficiently identify patients in need of diagnostic evaluation for clinically significant COPD.

Facial affect perception in alcoholics.

Satisfactory interpersonal interaction involves understanding others' facial expressions. Alcoholic individuals often have severe interpersonal difficulties that may relate to poor and distorted perception of facial expressions. The importance of attention direction has been highlighted by the finding, in recent primate studies, of neurons responsible for the detection of attention direction. Studies on humans suggest that expression perception is modulated by attention direction (whether the expression is directed towards or away from the observer). Here, for the first time, the relationship between attention direction and perception of expression (anger, sadness, happiness and disgust) in alcoholic and control subjects is investigated. We used animated facial stimuli depicting different emotions to give measures of recognition accuracy and of perceptual sensitivity. Our study demonstrated that alcoholics made more errors than control subjects in recognising expressions generally and had a tendency to mis-label sad expressions directed towards them as being hostile (angry/disgusted). When asked to select the point when they started to see the expression, alcoholics, especially female alcoholics, chose higher expression intensities. This study highlights the importance of investigating the modulating effects of attention direction when studying the perception of expressions and provides an indication of how alcoholics' inappropriate social reactions may be triggered.