Abstract
Objective
The novel Eosinophilic Esophagitis Symptom Questionnaire (EoE-SQ) is a patient-reported outcome measure that assesses symptoms beyond dysphagia in adults and adolescents with eosinophilic esophagitis (EoE).
Methods
The EoE-SQ was administered in the phase 3 R668-EE-1774 trial (NCT03633617), which assessed the efficacy and safety of dupilumab in adults and adolescents with EoE. Baseline and follow-up data were used to estimate its psychometric properties and to determine meaningful score change.
Results
The sample included 239 patients (median [range] age, 24 [12-68] years). The EoE-SQ frequency/severity scores showed internal consistency and test–retest reliability. Construct validity was demonstrated through moderate-to-strong correlations between EoE-SQ frequency/severity and other EoE-specific patient-reported outcome measures at baseline (frequency, r = 0.49-0.84; severity, r = 0.46-0.84) and at week 24 (frequency, r = 0.55-0.83; severity, r = 0.46-0.83). In known-groups analyses, the EoE-SQ frequency/severity scores discriminated between patient groups at varying EoE severity levels (defined by the Patient Global Impression of Severity [PGIS]). The EoE-SQ had good responsiveness, with the highest reductions in EoE-SQ frequency/severity scores (indicating greater symptomatic improvement) observed for patients with improved global assessment scores; ANOVA tests were statistically significant for PGIS and Patient Global Impression of Change (P ≤ .0001). A minimum 3.7-point and 5.3-point reduction (representing symptom improvement) in EoE-SQ frequency and severity scores, respectively, were considered clinically meaningful by patients.
Conclusions
The EoE-SQ showed good reliability, construct validity, and responsiveness for the assessment of EoE symptoms beyond dysphagia and can be used in combination with existing patient-reported outcome questionnaires to evaluate the full breadth of symptoms experienced by adult and adolescent patients with EoE.
Key words: Eosinophilic esophagitis, patient-reported outcomes measure, symptoms, validation
Eosinophilic esophagitis (EoE) is a type 2 inflammatory, chronic, and progressive disease that is characterized by eosinophilic infiltration of the esophageal epithelium. While EoE can develop at any age, it is most common in individuals over 30 years of age.1,2 Recent prevalence estimates have reported approximately 142.5 cases per 100,000 people in the United States, a rate that has been steadily increasing.3 Patients with EoE present with symptoms related to esophageal dysfunction.4,5 The predominant symptom among adult and adolescent patients is dysphagia, which can lead to food impaction. Patients may also experience a range of additional symptoms, including abdominal pain, chest pain, heartburn, regurgitation, and vomiting. Among adult and adolescent patients, these symptoms are reported less frequently compared with dysphagia but still contribute to the overall EoE disease burden and negatively affect patients’ quality of life, substantially affecting patients’ productivity, emotional well-being, and social activity.1,4,6, 7, 8, 9, 10, 11, 12, 13 The chronic nature of EoE and the burden of symptoms on patients’ lives highlight the need to evaluate the full symptom experience of EoE.
The Dysphagia Symptom Questionnaire (DSQ) is a patient-reported outcome (PRO) measure that has been developed with patient input and validated in clinical trials for evaluating dysphagia and associated pain while swallowing in adult and adolescent patients with EoE.14 Although the DSQ assesses the predominant symptom of EoE, it omits the broad range of additional EoE symptoms that both adult and adolescent patients with EoE may experience. As such, there is a need for a valid and reliable complementary PRO questionnaire measuring the full breadth of symptoms.15,16
The Eosinophilic Esophagitis Endoscopic Reference Score (EoE-SQ) was developed to measure the frequency and severity of EoE symptoms, beyond dysphagia and pain while swallowing, that are experienced by adult and adolescent patients. Initial development of the EoE-SQ involved a literature review, advisory meetings with clinical experts, and patient interviews. After this, the EoE-SQ was subsequently administered in a randomized, placebo-controlled trial investigating the efficacy and safety of dupilumab for adult and adolescent patients with EoE (R668-EE-1774; NCT03633617). The analysis aimed to estimate the psychometric measurement properties of the EoE-SQ and to determine thresholds for meaningful score changes on the basis of data from R668-EE-1774.
Methods
Development and overview of EoE-SQ
Detailed information on the development of the EoE-SQ is presented in the Online Repository available at www.jaci-global.org. In brief, initial development of the EoE-SQ was informed by a literature review and advisory meetings with 3 EoE experts (physicians with expertise in research and care for patients with EoE). These activities identified key symptoms that were selected for inclusion in the EoE-SQ. After construction of the initial EoE-SQ, a set of cognitive debriefing (CD) interviews were conducted with adults and adolescents with EoE to confirm the relevance and comprehensiveness of the included concepts and patients’ ability to understand the questionnaire content. The draft EoE-SQ was tested in 11 in-depth CD interviews with 5 adult and 6 adolescent patients with EoE. An additional set of 12 high-level, confirmatory CD interviews were conducted to further test patient understanding of the EoE-SQ. The CD interview results showed that the instructions, items, response options, and recall period were easy to interpret and respond to.
The findings of these activities resulted in a 10-item questionnaire that assessed 5 key symptoms of EoE (excluding dysphagia, so as to not overlap with the DSQ), including chest pain, stomach pain, heartburn, regurgitation, and throwing up. These symptoms were included in the EoE-SQ because they are important and relevant from the perspective of adult and adolescent patients with EoE.
The finalized 10-item EoE-SQ measures the frequency (“During the past 7 days, how often did you experience [insert symptom] due to EoE?”) and severity (“During the past 7 days, how severe was your worst [insert symptom] due to EoE?”) of symptoms. Frequency of chest pain, stomach pain, heartburn (burning feeling in the chest), regurgitation (food or liquid coming back up into the throat), and throwing up is assessed seperately, with each symptom scored from 1 (low) to 5 (high) and with the total frequency score from all 5 symptoms ranging from 5 to 25. The severity of each of the 5 symptoms is scored from 0 (low) to 10 (high), with the exception of regurgitation and throwing up; during the interviews, participants found the severity of these symptoms difficult to describe, so both are excluded from the total severity score, which therefore ranges from 0 (low) to 30 (high).
More details on the development of the EoE-SQ are presented in the Online Repository available at www.jaci-global.org.
Ethics statement
Before recruiting patients, all study documents were submitted to and approved by the Copernicus institutional review board (approval COS1-18-259).
Analysis population
The EoE-SQ was implemented in the R668-EE-1774 (NCT03633617) clinical study as a secondary end point; data from this study were used to assess the psychometric properties of the questionnaire and to determine meaningful change scores. The R668-EE-1774 study was a phase 3, randomized, placebo-controlled clinical trial to investigate the efficacy and safety of dupilumab in adult and adolescent patients (aged ≥12 years) with EoE.17 Part A and part B of the study each comprised a 24-week double-blind treatment period, and part C comprised a 28-week extended active treatment period (in which patients remained unaware of their prior treatment). Part B comprised a larger sample size (n = 240) relative to part A (n = 81), so analysis results using part B data are presented here; results for part A were similar but are not presented. A subset of the full analysis set is used, the PRO population analysis set, which included patients who completed ≥1 PRO measures (DSQ, EoE Impact Questionnaire [EoE-IQ18], or EoE-SQ) at baseline. Participants were asked to complete the EoE-SQ electronically at baseline, week 12, and week 24. No imputation of missing responses was performed.
Psychometric validation
Score distribution
Descriptive statistics of item responses and computed average total scores at baseline and week 24 and the changes in EoE-SQ total scores from baseline to week 24 were reported. Floor (worst outcome) or ceiling (best outcome) effects, defined as >20% of patients with the worst score or the best score for EoE-SQ frequency or EoE-SQ severity, were assessed. Item–item and item–total score correlations were reported in order to evaluate redundancy and strength of the relationships of the items.
Reliability
Internal consistency reliability (the extent to which questionnaires measure the same concept) was assessed by the Cronbach alpha coefficient, with a score of ≥0.70 indicating internal consistency.19 Test–retest reliability (the reproducibility of scores over time among patients with stable disease under the same assessment conditions) was assessed between week 12 (test) and week 24 (retest) for EoE-SQ total scores by intraclass correlation coefficient (ICC; computed by the McGraw and Wong 2-way mixed-effect analysis of variance [ANOVA] model).20 The test–retest reliability of stable patient subsets (patients with the same Patient Global Impression of Severity [PGIS] or Patient Global Impression of Change [PGIC] score at test and retest) was assessed by the Cronbach alpha coefficient (scores ≥0.70 indicate test–retest reliability).19,21
Construct validity
Convergent and divergent validity (the relationships among multiple measures of similar constructs and the degree to which they follow predictable patterns) were assessed using correlations between the EoE-SQ total scores and scores on other EoE-related PRO (DSQ, EoE-IQ, PGIS) and clinical measures (the Eosinophilic Esophagitis Endoscopic Reference Score [EoE-EREFS] and histologic peak esophageal intraepithelial eosinophil count [PEIEC]) at baseline and week 24. The strength of correlation was interpreted using 2 frameworks: correlations of 0.10 to 0.29 are defined as small, 0.30 to 0.49 are medium, and ≥0.50 are large;22 or correlations of <0.3 are defined as weak, ≥0.3 to <0.7 moderate, ≥0.7 to <0.9 strong, and ≥0.9 very strong.23 Both frameworks imply increased correlation between 2 variables with increased correlation coefficients. Known-groups validity (comparing scores for hypothesized subgroups to assess the discriminating ability of the EoE-SQ) was assessed via ANOVA/t test to compare categories of PGIS at baseline and PEIEC at week 24.
Responsiveness
The extent to which the EoE-SQ can detect change in patients reporting changes in other EoE assessments (PGIS/PGIC and categorized PEIEC at week 24) was evaluated after confirming sufficient correlations between the changes in the different measures from baseline to week 24. The ANOVAs for differences in score changes from baseline to week 24 by response groups were based on the PGIS (“Improved” ≥1-point improvement in severity; “No change” = 0-point change in severity; “Worsened” ≥1-point worsening in severity); PGIC (“Better” = “A little better,” “Moderately better,” and “Very much better”; “No change” = “No change”; “Worse” = “A little worse,” “Moderately worse,” and “Very much worse”); and PEIEC (Responder, ≤6 eosinophils per high-power field [eos/hpf]; Non-responder, >6 eos/hpf). Standardized effect size (SES) statistics for within and between-change groups (SES of 0.20 is defined as small, 0.50 as moderate, and 0.80 as large22) are also reported.
Interpretation of change
Anchor-based within-patient change (changes that patients perceive as meaningful improvement) was assessed by calculating the mean (standard deviation; 95% confidence interval [CI]) and median change in EoE-SQ scores from baseline to week 24 on the basis of change in PGIS and PGIC response at week 24. A correlation of r ≥ 0.37 was considered appropriate for a potential anchor measure. Disease of patients who reported a ≥1-point improvement on the PGIS or a response of at least “A little better” on the PGIC was considered improved. Empirical cumulative distribution function plots were derived for each score category of the PGIS or PGIC. Supportive distribution-based estimates of meaningful change were computed as 0.2 and 0.5 standard deviation of baseline scores, and standard error of measurement was computed using the test–retest ICC as a reliability estimate.
Results
Baseline characteristics
In part B of R668-EE-1774, 239 patients completed at least one PRO measure (any of DSQ, EoE-IQ, or EoE-SQ) at baseline. The median (range) age was 24 (12-68) years; most patients were White (90.4%), and over half were male (63.6%) (Table I).
Table I.
Patient demographic and disease characteristics at baseline (PRO population analysis set)
| Characteristic | Total (N = 239) | Adults (n = 160) | Adolescents (n = 79) |
|---|---|---|---|
| Age (years) | |||
| Mean (SD), median | 28.1 (13.1), 24.0 | 34.7 (11.3), 35.0 | 15.0 (1.6), 15.0 |
| Sex | |||
| Female | 87 (36.4) | 65 (40.6) | 22 (27.8) |
| Male | 152 (63.6) | 95 (59.4) | 57 (72.2) |
| Race | |||
| Asian | 5 (2.1) | 3 (1.9) | 2 (2.5) |
| Black or African American | 8 (3.3) | 1 (0.6) | 7 (8.9) |
| White | 216 (90.4) | 152 (95.0) | 64 (81.0) |
| Other | 7 (2.9) | 1 (0.6) | 6 (7.6) |
| Not reported | 3 (1.3) | 3 (1.9) | 0 |
| Ethnicity | |||
| Hispanic or Latino | 13 (5.4) | 10 (6.3) | 3 (3.8) |
| Not Hispanic or Latino | 225 (94.1) | 149 (93.1) | 76 (96.2) |
| Unknown | 1 (0.4) | 1 (0.6) | 0 |
| Comorbidity | |||
| Allergic rhinitis | 153 (64.0) | 96 (60.0) | 57 (72.2) |
| Asthma | 107 (44.8) | 62 (38.8) | 45 (57.0) |
| Atopic dermatitis | 62 (25.9) | 29 (18.1) | 33 (41.8) |
Data are presented as n (%) unless otherwise indicated. Adults are aged ≥18 years; adolescents, ≥12 to <18 years.
IQR, Interquartile range; Max, maximum; Min, minimum; Q, quartile; SD, standard deviation.
Score distribution
Among 239 patients, 228 completed the EoE-SQ at baseline and 212 completed the EoE-SQ at week 24 (Table II). Most EoE-SQ severity response options were used for each symptom, though “Chest pain,” “Stomach pain,” and “Heartburn” had fewer responses at each extreme (least or most severe response options) than for “Regurgitation” or “Throwing up” (Table III). Both the EoE-SQ frequency and severity total scores decreased from baseline to week 24, representing an improvement in the frequency and severity of symptoms. No floor effects were observed in either score, and there were minimal ceiling effects for the frequency total score at baseline and no ceiling effect for the severity total score, indicating the potential to show both improvement and worsening in both scores over time.
Table II.
Descriptive statistics for EoE-SQ frequency and severity total score at baseline and week 24
| Characteristic | Baseline (n = 239) | Week 24 (n = 227) | Change (n = 227) |
|---|---|---|---|
| EoE-SQ frequency total score | |||
| No. | 228 | 212 | 202 |
| Mean (SD) | 11.59 (4.161) | 8.45 (3.668) | −3.12 (3.456) |
| Median | 11.00 | 7.00 | −3.00 |
| IQR (Q1-Q3) | 8.00 to 14.00 | 5.00 to 10.00 | −5.00 to −1.00 |
| Min-max | 5.0 to 24.0 | 5.0 to 24.0 | −15.0 to 5.0 |
| Patients (%) with worst (highest) EoE-SQ total score∗ | 0 | 0 | —§ |
| Patients (%) with best (lowest) EoE-SQ total score† | 3.1% | 25.9% | —§ |
| Percentage missing¶ | 4.6% | 6.6% | 11.0% |
| EoE-SQ severity total score | |||
| Mean (SD) | 9.90 (6.697) | 5.34 (5.958) | −4.54 (5.749) |
| Median | 9.00 | 4.00 | −4.00 |
| Q1: Q3 | 5.00 : 14.50 | 0.00 : 9.00 | −8.00 : 0.00 |
| Min : max | 0.0 : 30.0 | 0.0 : 24.0 | −21.0 : 8.0 |
| Patients (%) with worst (highest) EoE-SQ total score∗ | 0.9% | 0% | —§ |
| Patients (%) with best (lowest) EoE-SQ total score† | 9.2% | 35.8% | —§ |
| Percentage missing¶ | 4.6% | 6.6% | 11.0% |
IQR, Interquartile range; SD, standard deviation.
Floor effect—that is, scores are so high that questionnaire will not be able to detect further worsening.
Ceiling effect—that is, scores are so low that questionnaire will not be able to detect further improvements.
Analysis not applicable.
Percentage based on number of patients in the Patient-Reported Outcome Population Analysis Set completing the corresponding clinic visits.
Table III.
EoE-SQ item-level distribution at baseline and week 24
| Characteristic | Mean (SD) | Frequency in past week (%) |
||||
|---|---|---|---|---|---|---|
| Never | 1 day | 2-6 days | Once daily | More than once daily | ||
| Baseline EoE-SQ frequency score | ||||||
| Chest pain | 2.5 (1.24) | 58 (25.4) | 52 (22.8) | 75 (32.9) | 21 (9.2) | 22 (9.6) |
| Stomach pain | 2.2 (1.26) | 102 (44.7) | 32 (14.0) | 63 (27.6) | 16 (7.0) | 15 (6.6) |
| Heartburn | 2.7 (1.34) | 58 (25.4) | 41 (18.0) | 70 (30.7) | 27 (11.8) | 32 (14.0) |
| Regurgitation | 2.7 (1.22) | 41 (18.0) | 64 (28.1) | 73 (32.0) | 23 (10.1) | 27 (11.8) |
| Throwing up | 1.5 (0.83) | 163 (71.5) | 28 (12.3) | 34 (14.9) | 1 (0.4) | 2 (0.9) |
| Week 24 EoE-SQ frequency score | ||||||
| Chest pain | 1.6 (0.95) | 129 (60.8) | 46 (21.7) | 26 (12.3) | 7 (3.3) | 4 (1.9) |
| Stomach pain | 1.7 (1.06) | 135 (63.7) | 30 (14.2) | 35 (16.5) | 4 (1.9) | 8 (3.8) |
| Heartburn | 1.8 (1.02) | 102 (48.1) | 60 (28.3) | 38 (17.9) | 5 (2.4) | 7 (3.3) |
| Regurgitation | 2.0 (1.23) | 96 (45.3) | 56 (26.4) | 33 (15.6) | 11 (5.2) | 16 (7.5) |
| Throwing up | 1.3 (0.69) | 181 (85.4) | 13 (6.1) | 15 (7.1) | 1 (0.5) | 2 (0.9) |
| Baseline EoE-SQ severity score | ||||||
| Chest pain | 3.5 (2.69) | 58 (25.4) | 2 (0.9) | 18 (7.9) | 39 (17.1) | 28 (12.3) |
| Stomach pain | 2.6 (2.78) | 103 (45.2) | 1 (0.4) | 13 (5.7) | 20 (8.8) | 24 (10.5) |
| Heartburn | 3.7 (2.83) | 58 (25.4) | 3 (1.3) | 15 (6.6) | 31 (13.6) | 26 (11.4) |
| Regurgitation | 4.0 (2.85) | 41 (18.0) | 9 (3.9) | 21 (9.2) | 31 (13.6) | 28 (12.3) |
| Throwing up | 1.6 (2.82) | 163 (71.5) | 0 (0.0) | 4 (1.8) | 4 (1.8) | 13 (5.7) |
| Week 24 EoE-SQ severity score | ||||||
| Chest pain | 1.6 (2.38) | 129 (60.8) | 4 (1.9) | 14 (6.6) | 18 (8.5) | 16 (7.5) |
| Stomach pain | 1.6 (2.46) | 135 (63.7) | 3 (1.4) | 13 (6.1) | 13 (6.1) | 13 (6.1) |
| Heartburn | 2.1 (2.45) | 102 (48.1) | 6 (2.8) | 25 (11.8) | 17 (8.0) | 18 (8.5) |
| Regurgitation | 2.4 (2.78) | 96 (45.3) | 8 (3.8) | 18 (8.5) | 26 (12.3) | 16 (7.5) |
| Throwing up | 0.7 (2.04) | 181 (85.4) | 3 (1.4) | 2 (0.9) | 4 (1.9) | 3 (1.4) |
For frequency, 1 day means the symptom occurred on 1 day in past week; once daily means the symptom occurred every day in past week. PRP, PRO population.
Correlations for all item–item and item–total scores for EoE-SQ frequency and severity at baseline are below the accepted threshold of 0.70 (r = 0.31-0.62; see Table E1 in the Online Repository available at www.jaci-global.org), indicating that none of the included items is redundant. In contrast, all “like” items (those assessing the same symptom) of the EoE-SQ frequency compared with severity had correlations ≥0.70, with all other nonlike item correlations ranging from 0.33 to 0.49.
Reliability
Internal consistency
The EoE-SQ frequency overall score exceeded the threshold for reliability at baseline (0.74) and at week 24 (0.78), and the EoE-SQ severity overall score exceeded the threshold at baseline (0.73) and at week 24 (0.75).
Test–retest reliability
For EoE-SQ frequency, for the subsample of patients with stable disease according to PGIS (the same response to PGIS at weeks 12 and 24), the ICC was 0.74, and for patients with stable disease according to PGIC (the same response to PGIC at weeks 12 and 24), the ICC was 0.87. These ICC values are above the minimum value of 0.70 recommended to indicate acceptable reliability. Mean score differences indicated no significant score changes over the test–retest period (P > .05). For EoE-SQ severity, the ICC for stable patients was 0.73 (PGIS) and 0.84 (PGIC), with no significant scores changes over the test–retest period (P > .05).
Construct validity
Convergent and divergent validity
The association pattern across the different measures was consistent with expectations (Table IV, and see Fig E1 in the Online Repository available at www.jaci-global.org). For example, the correlations between EoE-SQ frequency and other EoE-specific PRO scores (DSQ, EoE-SQ severity, EoE IQ, PGIS) scores were medium to large/moderate to strong at baseline (r = 0.49-0.84), and large/moderate to strong at week 24 (r = 0.55-0.83). In comparison, the correlations of EoE-SQ frequency with the clinical measure EoE-EREFS were considered small/low (baseline, r = −0.11; week 24, r = 0.05), which may be due to the different concepts measured; the EoE-EREFS assesses 5 esophageal components (edema, rings, exudates, furrows, and strictures) rather than assessing symptoms. Similarly, the correlation with the histologic measure of intraepithelial eosinophil count was small/low at week 24 (r = 0.09; correlation at baseline could not be assessed because the study required patients to have ≥15 eos/hpf before entry, thereby limiting the dynamic range of scores). Similar findings were observed for EoE-SQ severity correlations at baseline (r = 0.46-0.84) and at week 24 (r = 0.46-0.83) for EoE-specific PRO measures (DSQ, EoE-SQ frequency, EoE-IQ, PGIS), and EoE-EREFS at baseline (r = −0.19) and at week 24 (r = 0.05) and at week 24 (r = −0.02-0.04) for histologic PEIEC measures. The highest degree of correlation was observed between EoE-SQ frequency total score and EoE-SQ severity total score at baseline (r = 0.84) and at week 24 (r = 0.83).
Table IV.
Summary of key measurement properties of the EoE-SQ at baseline and week 24
| Measurement property | Frequency total score |
Severity total score |
|||
|---|---|---|---|---|---|
| Baseline | Week 24 | Baseline | Week 24 | ||
| Construct validity: Convergent and divergent validity | |||||
| Pearson correlation coefficient (no.) | DSQ | 0.55 (228) | 0.62 (174) | 0.46 (228) | 0.55 (174) |
| EoE-SQ (frequency or severity) | 0.84 (228) | 0.83 (213) | 0.84 (228) | 0.83 (213) | |
| EoE-IQ | 0.56 (224) | 0.72 (212) | 0.54 (224) | 0.61 (212) | |
| PGIS | 0.49 (228) | 0.55 (212) | 0.52 (228) | 0.46 (212) | |
| EoE-EREFS | −0.11 (237) | 0.05 (207) | −0.19 (228) | 0.05 (207) | |
| PEIEC | —∗ | 0.09 (208) | —∗ | 0.04 (208) | |
| Categorized PEIEC† | —∗ | 0.01 (208) | —∗ | −0.02 (208) | |
| Construct validity: Known-groups validity | |||||
| Mean (SD) score per known group (no.) | PGIS | None: 7.00 (—), 1 | None: 6.24 (2.076), 66 | None: 2.00 (—), 1 | None: 2.11 (4.418), 66 |
| Mild: 9.64 (3.017),100 | Mild: 8.33 (2.824), 106 | Mild: 6.49 (4.783),100 | Mild: 5.45 (5.495), 106 | ||
| Moderate: 12.56 (3.967), 107 | Moderate: 12.21 (4.628), 33 | Moderate: 11.78 (6.182), 107 | Moderate: 10.09 (6.535), 33 | ||
| Severe: 16.40 (4.570), 20 | Severe: 12.86 (4.488), 7 | Severe: 17.35 (7.795), 20 | Severe: 11.14 (5.640), 7 | ||
| P < .0001 | P < .0001 | P < .0001 | P < .0001 | ||
| Categorized PEIEC | ≤6 eos/hpf: not conducted† | ≤6 eos/hpf: 8.36 (3.683), 97 | ≤6 eos/hpf: not conducted† | ≤6 eos/hpf: 5.39 (6.286), 97 | |
| >6 to <15 eos/hpf: not conducted† | >6 to <15 eos/hpf: 7.77 (3.461), 30 | > 6 to <15 eos/hpf: not conducted† | >6 to <15 eos/hpf: 4.37 (5.353), 30 | ||
| ≥15 eos/hpf: not conducted† | ≥15 eos/hpf: 8.47 (3.366), 81 | ≥15 eos/hpf: not conducted† | ≥15 eos/hpf: 5.15 (5.329), 81 | ||
| P = not conducted† | P = .6401‡ | P = not conducted† | P = .6996‡ | ||
| Ability to detect change: Responsiveness and interpretation of change | |||||
| EoE-SQ change by PGIS change between baseline and week 24 | Change score, mean (SD), no. | NA | Improved: −4.1 (3.32), 122 | NA | Improved: −6.1 (5.84), 122 |
| NA | No change: −1.5 (3.10), 68 | NA | No change: −2.3 (4.82), 68 | ||
| NA | Worsened: −1.6 (2.94), 12 | NA | Worsened: −1.4 (3.94), 12 | ||
| NA | P < .0001‡ | NA | P < .0001‡ | ||
| EoE-SQ change by PGIC at week 24 | Change score, mean (SD), no. | NA | Better: −3.7 (3.34), 163 | NA | Better: −5.1 (5.69), 163 |
| NA | No change: −0.7 (2.42), 29 | NA | No change: −2.1 (5.95), 29 | ||
| NA | Worse: 0.1 (3.14), 10 | NA | Worse: −2.1 (3.28), 10 | ||
| NA | P < .0001‡ | NA | P = .0117‡ | ||
| PEIEC at week 24 | Change, mean (SD), no. | NA | Responder: (≤6 eos/hpf): −3.2 (3.30), 92 |
NA | Responder: −4.3 (5.45), 92 |
| NA | Non-responder: (>6 eos/hpf): −3.2 (3.51), 107 | NA | Non-responder: −4.9 (6.00), 107 | ||
| NA | P = .9985§ | NA | P = .4815§ | ||
| Pearson correlation of change coefficient (no.) at week 24 | DSQ | NA | 0.45 (165) | NA | 0.39 (165) |
| EoE-SQ (frequency or severity) | NA | 0.70 (203) | NA | 0.70 (203) | |
| EoE-IQ | NA | 0.53 (198) | NA | 0.42 (198) | |
| PGIS | NA | 0.41 (202) | NA | 0.39 (202) | |
| PGIC¶ | NA | 0.40 (202) | NA | 0.25 (202) | |
| EoE-EREFS | NA | 0.07 (198) | NA | −0.01 (198) | |
| PEIEC | NA | 0.11 (199) | NA | 0.04 (199) | |
| Categorized PEIEC†¶ | NA | 0.04 (199) | NA | −0.02 (199) | |
NA, Not applicable; SD, standard deviation.
Analysis not conducted because study inclusion criteria required patients to have ≥15 eos/hpf at baseline, thereby limiting the dynamic range of scores.
PEIEC was categorized as follows: ≤6 eos/hpf; >6 to <15 eos/hpf; and ≥15 eos/hpf.
ANOVA.
T-test.
PGIC and categorized PEIEC (eos/hpf) are observed values at week 24.
Known-groups validity
Higher mean EoE-SQ frequency total scores (ie, reflecting greater symptom frequency) were associated with more severe disease as measured by PGIS at baseline and at week 24 (Table IV). The ANOVA test by categories of PGIS was statistically significant at baseline and week 24 (P < .0001). No trend in mean EoE-SQ frequency total scores and PEIEC at week 24 was observed, and the t test result for differences between the groups was not statistically significant. The findings for EoE-SQ severity were consistent with those observed for EoE-SQ frequency (Table IV).
Responsiveness
The ability of the EoE-SQ frequency total score to show change in patients whose disease improved according to PGIS, PGIC, and PEIEC assessments was demonstrated by the pattern of change scores across the change and response groups as assessed via ANOVA. The highest reductions in EoE-SQ frequency total score (indicating greater symptomatic improvement) were observed for patients who had improved global assessment scores (Table IV). The ANOVA tests were statistically significant for both PGIS and PGIC (P ≤ .0001). Pairwise comparisons of mean changes in EoE-SQ frequency between patients whose disease had improved and those without change were statistically significant by either PGIS or PGIC (P ≤ .0001). The within-group change effect sizes were large for both the “improved” (PGIS; SES, −1.25) and “better” (PGIC; SES, −1.12) response groups; the change effect sizes were also large between the response groups (improved/better; no change; worsened/worse) defined by PGIS and PGIC (SES, −1.16 to 0.01) (Table E2). For PEIEC, no trend in mean EoE-SQ frequency total scores was evident between “Responders” (≤6 eos/hpf) and “Non-responders” (>6 eos/hpf); group comparisons were not statistically significant (Table IV). Similar findings were observed for EoE-SQ severity (Table IV and Table E2).
EoE-SQ total change scores for both EoE-SQ frequency and severity showed larger correlations with change scores from baseline to week 24 on other EoE-specific PRO measures (DSQ, EoE-IQ, PGIS, and PGIC) and smaller correlations with changes in the endoscopic and histologic measures (EoE-EREFS and PEIEC; Table IV).
Interpretation of change
The adequacy of the PGIS and PGIC as anchor measures for the interpretation of the EoE-SQ frequency score was confirmed by correlations of change coefficients of 0.41 and 0.40, respectively (Table IV), both of which exceeded the recommended minimum of 0.37.24 For EoE-SQ severity, only PGIS can be considered an acceptable anchor measure (coefficient, 0.39) as the correlation coefficient for PGIC was below the recommended minimum (coefficient, 0.25; Table IV).
The mean and median changes in EoE-SQ frequency total score across the categories of each anchor measure demonstrated that lower EoE-SQ frequency total scores (ie, fewer symptoms) were associated with greater levels of improvement on the PGIS and PGIC. The empirical cumulative distribution function plots showed adequate separation of the response groups for PGIS and to a lesser extent for PGIC (see Figs E2 and E3 in the Online Repository available at www.jaci-global.org). Changes in EoE-SQ severity total score also exhibited this trend across PGIS categories—that is, greater reductions in EoE-SQ severity are observed with greater PGIS improvement. The empirical cumulative distribution function plots showed adequate separation of the categories for PGIS and less clear separation for PGIC (see Figs E4 and E5 in the Online Repository).
Mean changes in EoE-SQ frequency scores were −3.7 (n = 93; median, −4.0) for a 1-point improvement and −5.2 (n = 26; median, −4.0) for a 2-point improvement on the PGIS (Table V). The lower 95% CI bound for patients reporting “No change” on the PGIS was −2.3. The mean change value for patients who selected “A little better” on the PGIC was −2.4 (n = 45; median, −2.0) and −4.5 (n = 53; median, −4.0) for “Moderately better,” with a lower 95% CI bound for no change of −1.6.
Table V.
Change from baseline in EoE-SQ frequency and severity total score at week 24 using PGIS and PGIC anchor measures
| Characteristic | No. | Mean (SD) | 95% CI | Median |
|---|---|---|---|---|
| EoE-SQ frequency total change score from baseline to week 24 | ||||
| PGIS | ||||
| Worsening (≥ 1-point worsening) | 12 | −1.6 (2.94) | −3.45 to 0.28 | −2.0 |
| 0-point change | 68 | −1.5 (3.10) | −2.30 to −0.79 | −2.0 |
| 1-point improvement | 93 | −3.7 (2.91) | −4.29 to −3.09 | −4.0 |
| 2-point improvement | 26 | −5.2 (4.05) | −6.87 to −3.59 | −4.0 |
| 3-point improvement | 3 | −9.0 (3.61) | −17.96 to −0.04 | −8.0 |
| PGIC | ||||
| Worsening (a little, moderately, very much) | 10 | 0.1 (3.14) | −2.15 to 2.35 | 0.0 |
| No change | 29 | −0.7 (2.42) | −1.61 to 0.23 | −1.0 |
| A little better | 45 | −2.4 (2.98) | −3.27 to −1.48 | −2.0 |
| Moderately better | 53 | −4.5 (3.58) | −5.46 to −3.49 | −4.0 |
| Very much better | 65 | −4.1 (3.14) | −4.89 to −3.33 | −4.0 |
| EoE-SQ severity total change score from baseline to week 24 | ||||
| PGIS | ||||
| Worsening (≥1-point worsening) | 12 | −1.4 (3.94) | −3.92 to 1.09 | −1.0 |
| 0-point change | 68 | −2.3 (4.82) | −3.45 to −1.11 | −2.0 |
| 1-point improvement | 93 | −5.3 (5.39) | −6.38 to −4.16 | −5.0 |
| 2-point improvement | 26 | −8.9 (5.98) | −11.34 to −6.51 | −8.5 |
| 3-point improvement | 3 | −8.3 (11.72) | −37.44 to −20.78 | −13.0 |
EoE-SQ frequency and severity total scores range from 5 to 25 and 0 to 30, respectively; higher scores indicate greater symptom burden. SD, Standard deviation.
The mean changes in EoE-SQ severity total change scores were −5.3 (n = 93; median, −5.0) for a 1-point improvement and −8.9 (n = 26; median, −8.5) for a 2-point improvement on the PGIS (Table V). The lower 95% CI bound for patients reporting “No change” on the PGIS was −3.5.
The distribution-based estimates ranged from 0.832 to 2.117 for the EoE-SQ frequency score and 1.339 to 3.459 for the EoE-SQ severity score.
Discussion
This analysis assessed the psychometric validity of the EoE-SQ, a novel EoE-specific measure for the evaluation of EoE symptoms in adults and adolescents, by using data from a randomized phase 3 trial. Previous and ongoing clinical trials use dysphagia-focused symptom measures as their co–primary end points; however, given the broad range of symptoms experienced by patients with EoE, it is important to understand how new treatment options can alleviate the full spectrum of symptoms experienced by patients.25,26 The EoE-SQ was designed to complement existing questionnaires (eg, DSQ) to ensure that the full symptom experience of patients with EoE is captured.
The EoE-SQ was developed and validated on the basis of best practice criteria.27, 28, 29 It was shown that EoE-SQ frequency and severity scores have acceptable distributional properties, reliability (internal consistency and test–retest reliability), construct validity (convergent and divergent, known groups), and responsiveness (ability to detect change). These findings support that the EoE-SQ is a valid and reliable measure that comprehensively assesses patient-reported symptoms of EoE beyond dysphagia, complementing evidence of the content validity of the measure obtained during development, which included qualitative input from adult and adolescent patients with EoE. No floor effects were observed, and there were minimal ceiling effects at baseline, which is expected because patients were required to have a DSQ score of ≥10 (range of 0 to 84, with lower scores indicating less frequent/severe dysphagia) at baseline, so patients likely had other nondysphagia symptoms at study entry as well. This implies that the instrument is capable of measuring changes in symptom frequency and severity over time. The high test–retest reliability showed that the EoE-SQ produces similar results over time for patients deemed similar on other measures. The EoE-SQ was shown to correlate with other EoE-related PRO instruments (PGIS, PGIC, EoE-IQ, and DSQ), as expected, given the relatedness of the concepts being assessed. Both the EoE-SQ frequency and severity scores were able to detect change in patients whose symptoms improved (based on PGIS or PGIC). When considering EoE-SQ change scores for patients with no change or with improvement on the PGIS anchor measure, the threshold range for score reduction (improvement) of 2.3 to 3.7 (or greater) in the frequency total score could be considered a clinically meaningful within-patient change. For EoE-SQ severity, an improvement of 3.5 to 5.3 (or greater) would constitute a clinically meaningful change.
An additional strength of the EoE-SQ is the inclusion of both adult and adolescent patients with EoE during the questionnaire development and validation analyses. This differentiates the EoE-SQ from existing PRO measures specifically for assessing EoE symptoms, which were designed for either adult or pediatric populations in isolation.30, 31, 32 Thus, the EoE-SQ allows for an accurate evaluation of the symptom experience of both adults and adolescents simultaneously, which is not possible with existing measures such as the DSQ.14,33
Limitations
A potential limitation are the few expert interviews conducted during questionnaire development; however, responses were consistent among the interviewed experts and compared with the symptom concepts identified through the literature review, suggesting that additional interviews would have not been informative. The number of comprehensive CD interviews with patients was also limited; however, the findings across the comprehensive CD and confirmatory, high-level CD interviews were consistent. Issues reported in both the comprehensive CD and the confirmatory CD interviews were minimal, and patients did not report any major issues with interpretation of the questionnaire. Further research may be needed to assess the usefulness of the questionnaire in settings outside the United States. Last, the EoE-SQ was not designed for or tested in patients <12 years old; alternative PRO tools for symptom assessment in this patient population have been developed.34
Conclusion
The results of these psychometric analyses showed that the EoE-SQ is a valid and reliable measure to assess the frequency and severity of patient-reported symptoms of EoE among adult and adolescent patients with EoE in a clinical trial setting. Therefore, the EoE-SQ is fit for purpose to assess the symptoms of EoE other than dysphagia and can be used in a complementary manner to existing PRO questionnaires. As opposed to previous dysphagia-focused questionnaires, the novel EoE-SQ instrument allows for an assessment of a comprehensive spectrum of symptomatic burden experienced by both adult and adolescent patients with EoE when used in conjunction with existing dysphagia-focused questionnaires.
Clinical implication.
The novel EoE-SQ allows for a comprehensive assessment of the whole symptomatic burden experienced by both adult and adolescent patients with EoE when used in conjunction with existing dysphagia-focused questionnaires.
Disclosure statement
Sponsored by Regeneron Pharmaceuticals Inc and Sanofi. Adelphi Values conducted the concept-focused literature review, expert advice meetings, and questionnaire development research, sponsored by Regeneron/Sanofi.
Data availability statement: Qualified researchers may request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, and statistical analysis plan) that support the methods and findings reported here. Individual anonymized participant data will be considered for sharing once the indication has been approved by a regulatory body, if there is legal authority to share the data and there is not a reasonable likelihood of participant reidentification. Requests should be submitted to to vivli.org.
Disclosure of potential conflict of interest: S. Kamat, X. Sun, and E. McCann are employees of Regeneron Pharmaceuticals Inc. A. Yaworsky is an employee of Adelphi Values. S. T. Tilton is an employee of Sanofi. M. Chehade has received consultant fees from Regeneron, Allakos, Adare/Ellodi, Shire/Takeda, AstraZeneca, Sanofi, Bristol Myers Squibb, Recludix Pharma, Phathom, and Uniquity Bio; and has received research funding from Regeneron, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, Celgene, and Danone. J. M. Spergel provided expert clinical advice during all research steps related to questionnaire development.
Acknowledgments
Medical writing support was provided by Vanessa Gross, of Value & Access (a division of Envision Pharma Group), United Kingdom, funded by Sanofi and Regeneron Pharmaceuticals according to Good Publication Practice guidelines.
Supplementary data
References
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