PedsQL™ Eosinophilic Esophagitis Module: Feasibility, Reliability and Validity

Abstract

Objective

Eosinophilic esophagitis (EoE) is a chronic esophageal inflammatory condition with a paucity of information on health-related quality of life (HRQOL). The objective of the study was to report on the measurement properties of the PedsQL™ EoE Module.

Methods

The PedsQL™ EoE Module was completed in a multisite study by 196 pediatric EoE patients and 262 EoE parents.

Results

The PedsQL™ EoE Module scales evidenced excellent feasibility (0.6%–3.1% missing), excellent group comparison reliability across total scale scores (patient α = 0.93; parent proxy α = 0.94), good reliability for the seven individual scales (patient α = 0.75–0.87; parent proxy α = 0.81–0.92), excellent test-retest reliability (patient ICC = 0.88; parent ICC= 0.82), demonstrated no floor effects and low ceiling effects, and demonstrated a high percentage of scaling success for most scales. Intercorrelations with the PedsQL™ Generic Core Scales were in the medium (0.30) to large (0.50) range. PedsQL™ EoE Module scores were worse among patients with active histologic disease (> 5 eos/hpf) compared to those in remission (patient self-report: 63.3 vs. 69.9 [p<0.05]; parent proxy-report: 65.1 vs. 72.3 [p<0.01]), and those treated with dietary restrictions compared to those with no restrictions (patient self-report: 61.6 vs. 74.3 [p< 0.01]; parent proxy-report: 65.5 vs. 74.7 [p<0.01]).

Conclusions

The results demonstrate excellent measurement properties of the PedsQL™ EoE Module. Patients with active histologic disease and those treated with dietary restrictions demonstrated worse PedsQL™ scores. The PedsQL™ EoE Module may be utilized in evaluation of pediatric EoE disease-specific HRQOL in clinical research and practice.

Introduction

Eosinophilic esophagitis (EoE) is a chronic esophageal inflammatory condition with an increasing prevalence approaching 1 per 1000 in the U.S. pediatric population (1, 2). Food allergies are a common cause of EoE, and strict dietary antigen elimination is a common treatment (3, 4). Pediatric health outcomes in current EoE clinical practice typically focus primarily on histologic and symptomatic improvement (3), and patient health-related quality of life (HRQOL) is not routinely assessed with standardized instruments. However, as our understanding of pediatric EoE is rapidly evolving, so too does the recognition that there are many important components to this chronic condition beyond counting the number of esophageal eosinophils on mucosal biopsies.

Legislative changes over the last several years, including the Pediatric Exclusivity Provision of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA), have established voluntary and mandatory guidelines for drug studies in children which have resulted in a significant growth in clinical trials for pediatric patients (5). Despite these pediatric initiatives that have created the opportunity for children to be included in clinical trials, until relatively recently, pediatric patients have not been provided the opportunity to self-report on matters pertaining to their health and well-being in clinical trials (6). The emerging paradigm shift toward patient-reported outcomes (PROs), including recent guidelines from the U.S. Food and Drug Administration (FDA), has provided the opportunity to further emphasize the value and critical need for pediatric patient self-report measurement as efficacy outcomes in pediatric clinical trials (5, 7).

Although pediatric patients with EoE experience significant disease- and treatment-related sequelae, to our knowledge, there is no validated EoE-specific HRQOL instrument to document the impact of EoE on the daily lives of affected pediatric patients that includes pediatric patient self-report for ages 5–18 years and parent proxy-report for ages 2–18 years. Recently, we utilized the Pediatric Quality of Life Inventory™ (PedsQL™) 4.0 Generic Core Scales to investigate the generic HRQOL of patients with eosinophilic gastrointestinal (GI) disease (EGID, including EoE) in comparison with several other pediatric chronic conditions and healthy controls (8). Not only did patients with EGID and their parents report significantly lower generic HRQOL than healthy controls, but they reported generic HRQOL lower than pediatric patients with inflammatory bowel disease, epilepsy, type 1 diabetes, sickle cell disease, post-renal transplantation, cystic fibrosis, and obesity (8). In addition, we have identified that untreated pediatric EoE patients are at risk for adverse impact on their generic HRQOL an average of 15 years after their initial endoscopy (1).

Even though the PedsQL™ 4.0 Generic Core Scales (Physical, Emotional, Social, and School Functioning Scales) assess generic issues common across healthy and ill pediatric populations, as well as benchmarking with healthy populations, a disease-specific HRQOL instrument is essential to understanding the particular health issues most germane to pediatric EoE patients from their perspective (9). In addition, an EoE disease-specific HRQOL instrument would be expected to be more sensitive to detecting change in health status over time within a population of EoE children than a generic scale alone. To better understand differences in health status within the population of pediatric EoE patients and to enhance the ability to measure the impact of disease-modifying therapies, we developed items for a new EoE disease-specific HRQOL instrument. This new instrument is targeted to pediatric EoE utilizing qualitative methods to support content validity (9, 10), and is consistent with recent FDA guidelines on PRO measures in chronic diseases (5).

Given the lack of an empirically validated multidimensional pediatric EoE disease-specific HRQOL instrument in the extant literature, the objective of the present study was to address this significant gap in the EoE literature by describing the measurement properties for both pediatric patient self-report and parent proxy-report for the new PedsQL™ Eosinophilic Esophagitis Module. We present the initial feasibility, reliability, and validity of the new PedsQL™ EoE Module scales. Based on previous PedsQL™ 4.0 Generic Core Scales disease-specific findings, we hypothesized that pediatric patients with EoE would manifest lower PedsQL™ 4.0 Generic Core Scales scores in comparison to a matched healthy children sample, supporting discriminant validity (11–18). We further hypothesized that greater EoE-specific symptoms or problems would be significantly correlated with lower generic HRQOL as measured by the PedsQL™ 4.0 Generic Core Scales, with medium to large effect sizes, based on the conceptualization of disease-specific symptoms as causal indicators of generic HRQOL, supporting construct validity (19). In addition to analyzing these measurement properties, we also sought to test the hypotheses that PedsQL™ EoE Module scale scores would be lower (worse) in patients with (1) active histologic disease compared to those in remission, and in (2) patients treated with dietary elimination compared to those treated with no diet restrictions.

Methods

Eosinophilic Esophagitis Sample

Families were invited to participate from six sites across the United States. A total of 263 families (196 children ages 5–18 years and 262 parents of children ages 2–18 years) completed the questionnaires. The sample consisted of children who had received a physician diagnosis of EoE. Specifically, all children had their diagnosis confirmed by an EoE subspecialty physician with an endoscopy with 15 or more eosinophils per high powered field (eos/hpf) in an endoscopic biopsy of the distal esophagus after being treated with 8 or more weeks with proton pump inhibitor therapy or having a negative pH probe test. Patients with eosinophilic gastrointestinal disorders beyond the esophagus were excluded. Among confirmed EoE patients, their most recent endoscopy results (range 3 days to 9.3 years) were also stratified into those with active disease (using both > 5 eos/hpf and >15 eos/hpf cut points) and those in histologic remission. In addition, parents of EoE patients who self-reported whether their child used dietary elimination therapy for EoE were dichotomized into those with no dietary restrictions and those with dietary restrictions. The average age of the 177 boys (67.3%) and 70 girls (26.6%) (Missing gender values = 16 [6.1%]) was 8.75 years (SD = 4.50; Missing age values = 2 [0.8%]). With respect to race/ethnicity, the sample contained 233 (88.6%) self-reported White non-Hispanic, 11 (4.2%) Hispanic, 5 (1.9%) Black non-Hispanic, 3 (1.1%) Asian/Pacific Islander, and 11 (4.1%) Other or Missing. With respect to parent education in the electronic questionnaire cohort (n=213), 1.4% of mothers and 2.4% of fathers did not complete high school; 4.7% of mothers and 11.3% of fathers had a high school degree; 24.4% of mothers and 20.7% of fathers completed some college; 35.7% of mothers and 30.0% of fathers had a college degree; and 30.0% of mothers and 28.6% of fathers had a graduate degree (missing: 3.8% mothers and 7.0% fathers).

Healthy Children Sample: PedsQL™ 4.0 Generic Core Scales

The age, gender, and race/ethnicity matched healthy children sample (n = 1164) was derived from the previously conducted PedsQL™ 4.0 Generic Core Scales initial field test (20) and a State’s Children’s Health Insurance Program (SCHIP) evaluation in California (21). Children were assessed either in physicians’ offices during well-child visits, by telephone, or via a statewide mailing. The average age of the 783 boys (67.3%) and 381 girls (32.7%) was 8.75 years (SD = 4.18). With respect to race/ethnicity, the sample contained 1068 (91.8%) White non-Hispanic, 57 (4.9%) Hispanic, 23 (2.0 %) Black non-Hispanic, and 16 (1.4%) Asian/Pacific Islander. Parental level of education was not available for the total sample, although the statewide SCHIP sample was representative of low-income families. The healthy sample was randomly matched to the EoE sample by age, gender, and race/ethnicity utilizing SPSS 19.0 (22).

Measures

PedsQL™ Eosinophilic Esophagitis Module

The PedsQL™ Eosinophilic Esophagitis Module was developed through a literature review of the relevant research, consultation with EoE health care professionals, focus interviews, cognitive interviews, and pre-testing protocols (9, 10). Development of the items for the PedsQL™ EoE Module began in 2008. The child self-report items are listed in Table 1.

Table 1.

PedsQL™ Eosinophilic Esophagitis Module Child Self-Report Item Content

Symptoms I

1. I have chest pain, ache, or hurt

2. I have burning in my chest, mouth, or throat (heartburn) 1

3. I have stomach aches or belly aches

4. I throw up (vomit)

5. I feel like I am going to throw up, but don’t (nausea) 1

6. When I am eating food comes back up my throat 1

Symptoms II2

1. I have trouble swallowing

2. I feel like food gets stuck in my throat or chest

3. I need to drink to help me swallow my food

4. I need more time to eat than other kids my age

Treatment

1. It is hard for me to remember to take my medicines 1

2. I do not want to take my medicines

3. I do not like going to the doctor

4. I do not like getting an endoscopy (scope, EGD)

5. I do not like getting allergy testing

Worry

1. I worry about having EoE 1

2. I worry about getting sick in front of other people

3. I worry about what other people think about me because of EoE 1

4. I worry about going to the doctor

5. I worry about getting an endoscopy (scope, EGD)

6. I worry about getting allergy testing

Communication3

1. I have trouble telling other people about EoE 1

2. I have trouble talking to my parents about how I feel

3. I have trouble talking to other adults about how I feel

4. I have trouble talking to my friends about how I feel

5. I have trouble talking to doctors or nurses about how I feel

Food and Eating

1. It is hard not being allowed to eat some foods

2. It is hard for me not to sneak foods that I am allergic to 4

3. It is hard for me not to eat the same things as my family

4. It is hard for me not to eat the same things as my friends

Food Feelings

1. I worry about eating foods I’m allergic to or not supposed to eat

2. I feel mad (get upset) about not eating foods I am allergic to or not supposed to eat

3. I feel sad about not eating foods I am allergic to or not supposed to eat

Feeding Tube5

1. It is hard for me to remember to use my feeding tube 1

2. It is hard for me to use my feeding tube

Note:

¹items not included in young child self-report (ages 5–7) and parent proxy-report for young child (ages 5–7) and toddlers (ages 2–4).

²for young child self-report (ages 5–7), scale only for clinical purposes.

³scale not included in parent proxy-report for toddlers (ages 2–4).

⁴item not included in parent proxy-report for toddlers (ages 2–4).

⁵scale only for clinical purposes.

Reproduced with permission from J.W. Varni, Ph.D. Copyright © 1998. The PedsQL™ is available at http://www.pedsql.org.

The 33-item PedsQL™ EoE Module encompasses 7 Scales: 1) Symptoms I (6 items; chest/throat/stomach pain and nausea/vomiting), 2) Symptoms II (4 items; trouble swallowing), 3) Treatment (5 items; treatment barriers), 4) Worry (6 items; worries about treatment and disease), 5) Communication (5 items; communication with others about EoE), 6) Food and Eating (4 items; food and eating allergies and limitations), 7) Food Feelings (3 items; emotions associated with food allergies). A 1 to 2 item scale (depending on age) Feeding Tube Scale is included only for clinical purposes and is not included in the quantitative analyses. In addition to a PedsQL™ EoE Module Total Scale Score, a PedsQL™ EoE Module Total Symptom Scale Score was also developed. The format, instructions, Likert response scale, and scoring method for the PedsQL™ EoE Module are identical to the PedsQL™ 4.0 Generic Core Scales, with higher scores indicating better HRQOL and lower EoE symptoms and problems (20).

The Scales are comprised of parallel child self-report and parent proxy-report formats for children ages 5–18 years, and a parent proxy-report format for children ages 2–4 years. Child self-report forms are specific for ages 5–7, 8–12, and 13–18 years. Parent proxy-report forms are specific for children ages 2–4 (toddler), 5–7 (young child), 8–12 (child), and 13–18 (adolescent), and assess parents’ perceptions of their child’s HRQOL. The instructions ask how much of a problem each item has been during the past one month. The grammar and syntax of the new items were structurally equivalent to those in the existing PedsQL™ item bank. Instructions and response scales for the PedsQL™ EoE Module were created to be consistent with the instructions and response scales of the PedsQL™ 4.0 Generic Core Scales for ages 2–18 years and other PedsQL™ Disease-Specific Modules (11–18). The PedsQL™ 5-point Likert-type response scale has been widely utilized in published PedsQL™ studies (0 = never a problem; 1 = almost never a problem; 2 = sometimes a problem; 3 = often a problem; 4 = almost always a problem), and has also previously undergone extensive cognitive interviewing for a number of Pediatric Patient Reported Outcomes Measurement Information System (PROMIS) scales and were found acceptable and understood by both pediatric patients and parents (23–26). To further increase the ease of use for the young child self-report (ages 5–7), the response scale is reworded and simplified to a 3-point scale (0 = not at all a problem; 2 = sometimes a problem; 4 = a lot of a problem). This simplification to a 3-point scale for the young child self-report is consistent with the PedsQL™ 4.0 Generic Core Scales as well as with all of the PedsQL disease-specific modules (27). See Table 1 for several age differences across items and scales.

Items are reverse-scored and linearly transformed to a 0–100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL. Scale Scores are computed as the sum of the items divided by the number of items answered (this accounts for missing data). If more than 50% of the items in the scale are missing, the Scale Score is not computed (28). This accounts for the differences in sample sizes for scales reported in the Tables. Although there are other strategies for imputing missing values, this computation is consistent with the previous PedsQL™ peer-reviewed publications as well as other well-established HRQOL measures (20, 29, 30). To create the PedsQL™ EoE Module Total Scale Score (33 items), the mean is computed as the sum of the items divided by the number of items answered in the Symptoms I, Symptoms II, Treatment, Worry, Communication, Food and Eating, and Food Feelings Scales. To create the PedsQL™ EoE Module Symptoms Total Scale Score (10 items), the mean is computed as the sum of the items divided by the number of items answered in the Symptoms I and Symptom II Scales. The Feeding Tube Scale is not included in the Total Scale Score since this scale is typically completed only by a small subgroup of patients and parents.

The PedsQL™ 4.0 Generic Core Scales

The 23-item PedsQL™ 4.0 Generic Core Scales encompass: 1) Physical Functioning (8 items), 2) Emotional Functioning (5 items), 3) Social Functioning (5 items), and 4) School Functioning (5 items) (20, 31). The Physical Health Summary Score is the same as the Physical Functioning Scale. To create the Psychosocial Health Summary Score, the mean is computed as the sum of the items divided by the number of items answered in the Emotional, Social, and School Functioning Scales.

The PedsQL™ Family Information Form

Parents completed a modified PedsQL™ Family Information Form which contains demographic information including the child’s date of birth, gender, race/ethnicity, and parental education and occupation information (20).

Procedures

Data collection for the field test took place over a 13-month period between January 2011 and February 2012. Participants were children ages 5–18 years who had received a physician diagnosis of EoE and parents of children ages 2–18 years who had received a physician diagnosis of EoE at 6 clinical centers across the United States (Cincinnati Children’s Hospital Medical Center, Children’s Hospital of Philadelphia, Children’s Hospital Colorado, Riley Children’s Hospital, Texas Children’s Hospital, Nationwide Children’s Hospital). All eligible patients at each clinical site were invited to participate in the study. The human subject institutional review boards at each center approved the study.

Statistical Analysis

Feasibility was determined from the percentage of missing values (32). Cronbach’s coefficient alpha was utilized to determine scale internal consistency reliability (33). Scales with internal consistency reliabilities of 0.70 or greater are recommended for comparing patient groups, while an internal consistency reliability criterion of 0.90 is recommended for analyzing individual patient scores (34, 35). Test-retest reliability was calculated for a subset of the sample (n = 102) using Intraclass Correlation Coefficients (ICCs) (36). Patients and their parents were assessed on average 14 days after baseline. ICCs are designated as <0.40 poor to fair agreement, 0.41–0.60 moderate agreement, 0.61–0.80 good agreement, and 0.81–1.00 excellent agreement (36). Range of measurement was based on the percentage of scores at the extremes of the scaling range, that is, the maximum possible score (ceiling effect) and the minimum possible score (floor effect). Surveys with small floor or ceiling effects (1% to 15%) are considered to meet acceptable measurement standards, while surveys with moderate floor or ceiling effects (> 15%) are considered less precise in measuring latent constructs at the extremes of the scale (37). Multitrait scaling analyses were conducted to determine the extent to which individual items correlated with their hypothesized scale construct rather than with other scales (38). Multitrait scaling analyses were summarized via tests of individual item scaling success, defined as the percentage of items correlating equal to or higher with their hypothesized scale construct rather than with another scale using adjusted scale scores for scales in which the item was part of the score (32).

Discriminant validity for the PedsQL™ 4.0 Generic Core Scales in EoE was determined utilizing the known-groups method (39). The known-groups method compares scale scores across groups known to differ in the health construct being investigated. Generic Core Scales scores in groups differing in known health condition (pediatric patients with EoE and healthy children) were computed using independent samples t-tests. We hypothesized that the Generic Core Scales would distinguish between healthy children and pediatric patients with EoE based on previous PedsQL™ findings in other pediatric chronic conditions (14, 16, 40) and pediatric patients with EGID (8). Effect sizes were calculated to determine the magnitude of the differences (41). Effect size as utilized in these analyses was calculated by taking the difference between the healthy sample mean and the EoE sample mean, divided by the pooled standard deviation. Effect sizes for differences in means are designated as small (0.20), medium (0.50), and large (0.80) in magnitude (42).

An analysis of the intercorrelations among the PedsQL™ 4.0 Generic Core Scales and Summary Scores with the EoE Module Scale Scores was used to examine construct validity for the PedsQL™ EoE Module. Computing the intercorrelations among scales provides initial information on the construct validity of an instrument (35). We hypothesized that greater disease-specific symptoms or problems would correlate with lower overall generic HRQOL as measured by the PedsQL™ 4.0 Generic Core Scales based on the conceptualization of disease-specific symptoms as causal indicators of generic HRQOL (43). Pearson Product Moment Correlation coefficients effect sizes are designated as small (0.10), medium (0.30), and large (0.50) (41).

To support additional construct validation for the PedsQL™ EoE Module scales and summary scores, we performed contrast analyses between patients treated with dietary restrictions versus those with no restrictions, and in patients with active histologic disease versus those in remission using independent samples t-tests.

Intraclass Correlation Coefficients (ICCs) were used to determine agreement between patient self-report and parent proxy-report (36). The ICC provides an index of absolute agreement as it takes into account the ratio between subject variability and total variability (36, 44). ICCs are designated as <0.40 poor to fair agreement, 0.41–0.60 moderate agreement, 0.61–0.80 good agreement, and 0.81–1.00 excellent agreement (45, 46). Statistical analyses were conducted using SPSS Version 19.0 for Windows (22).

Results

Feasibility: Missing Item Responses

The percentage of missing item responses on the PedsQL™ EoE Module was 0.8% and 0.6% for the first five scales for child self-reports 8–18 and 5–7 years of age, respectively. For parent proxy-report, the percentage of missing item responses was 1.0% (ages 8–18), 3.1% (ages 5–7) and 2.8% (ages 2–4) for the first five scales on the PedsQL™ EoE Module. The percentage of missing item responses were not computed for the last two scales since they consist of conditional items and individuals were asked to respond to them only if they were allergic to certain foods and cannot eat some foods. For child self-report and parent proxy-report on the PedsQL™ 4.0 Generic Core Scales, the percentage of missing item responses was 0.8% and 0.4%, respectively, for all scales except the parent proxy-report School Functioning Scale. The percentage of missing items for the proxy-report School Functioning Scale was 1.8% (ages 5–18) and 19.7% (ages 2–4). This large percentage for toddlers (ages 2–4) may exist since instructions on the PedsQL™ toddler form ask parents to complete the School Functioning Scale if their child attends school or daycare and many toddlers do not attend school or daycare.

Range of Measurement

Table 2 contains the percentage of scores at the extremes of the scaling range (floor and ceiling effects) for the PedsQL™ EoE Module scales and summary scores. For child self-report, there were no significant floor effects for any of the scales or summary scores, and only a ceiling effect for the Communication Scale. For parent proxy-report, there were no significant floor effects for any of the scales or summary scores, and marginal ceiling effects for the Symptoms II, Treatment, Worry and Communication Scales.

Table 2.

PedsQL™ Eosinophilic Esophagitis Module Scores, Reliability and Percent Floor and Ceiling Effects for Child Self-Report and Parent Proxy-Report

EoE Module Scales	Number of Items	n	α	Mean	SD	% Floor	% Ceiling
Child Self-Report
EoE Module Total Scale	33	196	0.93	65.2	19.1	0	0
Symptoms Total Score	10	139*	0.85*	69.8	19.0	0	1.5
Symptoms I	6	196	0.83	66.7	20.1	0.4	4.6
Symptoms II	4	139*	0.86*	70.9	24.3	0	10.6
Treatment	5	195	0.75	55.5	26.8	1.9	3.4
Worry	6	196	0.85	68.1	26.1	0.8	11.8
Communication	5	196	0.87	74.0	25.7	0.8	23.2
Food and Eating	4	171	0.87	60.3	32.4	4.9	12.9
Food Feelings	3	161	0.81	57.2	32.5	5.7	10.3
Parent Proxy-Report
EoE Module Total Scale	33	262	0.94	67.4	17.6	0	0.4
Symptoms Total Score	10	258	0.89	68.0	20.0	0	3.8
Symptoms I	6	258	0.88	67.8	20.9	0	6.8
Symptoms II	4	258	0.83	68.2	23.9	0.8	15.6
Treatment	5	261	0.81	72.5	22.8	0	18.3
Worry	6	254	0.87	72.1	23.5	0.4	16.3
Communication	5	196	0.92	67.1	27.2	1.5	16.7
Food and Eating	4	227	0.82	59.8	27.1	2.3	12.5
Food Feelings	3	216	0.84	55.6	28.0	3.4	10.6

Note: α = Cronbach’s alpha internal consistency reliability. SD = standard deviation.

Higher scores equal better HRQOL. For the calculation of the Cronbach’s alpha values for EoE Module Total Scale Score, the sample size was smaller because of listwise deletion based on all items completed (child = 157, parent = 146)

^*Because of the low Cronbach’s alpha value (0.39) for young child self-report (ages 5–7), this age group was not used to calculate the overall Symptoms II score and Symptoms Total Score. For ages 5–7, this scale is only used for clinical purposes, and is not included in the scale scores.

For child self-report (ages 5 to 7 years), Symptoms I Scale contains 3 items, Treatment Scale contains 4 items, Worry Scale contains 4 items, and Communication Scale contains 4 items.

For parent-report for toddlers (ages 2 to 4 years), there is no Communication Scale, and the Food and Eating Scale contains 3 items; For parent proxy-report for toddlers and young child (ages 2 to 4 and 5 to 7 years), Symptoms I Scale contains 3 items, Treatment Scale contains 4 items, and Worry Scale contains 4 items; For parent proxy-report for young child (ages 5 to 7 years), the Communication Scale contains 4 items. See Appendix 1 for the child self-report items for ages 8–18.

Internal Consistency Reliability

Internal consistency reliability coefficients for the PedsQL™ EoE Module summed across the age groups are shown in Table 3. All child self-report and parent proxy-report scales on the EoE Module exceed the minimum reliability standard of 0.70 required for group comparisons summed across the age groups. The Total Scale Scores for both child self-report and parent proxy-report exceed the reliability criterion of 0.90 recommended for analyzing individual patient scores. Table 3 contains the internal consistency reliability coefficients individually across the age groups. For child self-reports, except for the Symptoms II Scale for 5–7 age group, all other scales demonstrated higher values than the minimum reliability standard of 0.70. For parent proxy-report, all scales exceed 0.70 internal consistency reliability coefficients individually across the age groups.

Table 3.

PedsQL™ Eosinophilic Esophagitis Module Scales Cronbach’s Alpha Internal Consistency Reliability for Child Self-Report and Parent Proxy-Report by Age and Summary Score/Scale

EoE Module Scales	Age Group				Total Sample
	(2–4)	(5–7)	(8–12)	(13–18)
Child Self-Report	N = 0	N = 56	N = 78	N = 62	N = 196
EoE Module Total Scale Score	NA	0.89*	0.94	0.95	0.93
Symptoms Total Scale Score	NA	0.77*	0.85	0.86	0.85*
Symptoms I	NA	0.90	0.76	0.82	0.83
Symptoms II	NA	0.39*	0.83	0.88	0.86*
Treatment	NA	0.78	0.74	0.73	0.75
Worry	NA	0.82	0.81	0.88	0.85
Communication	NA	0.82	0.87	0.90	0.87
Food and Eating	NA	0.82	0.88	0.93	0.87
Food Feelings	NA	0.73	0.83	0.88	0.81
Parent Proxy-Report	N = 66	N = 56	N = 77	N = 63	N = 262
EoE Module Total Scale Score	0.93	0.94	0.95	0.92	0.94
Symptoms Total Scale Score	0.89	0.91	0.91	0.87	0.89
Symptoms I	0.87	0.94	0.89	0.83	0.88
Symptoms II	0.79	0.75	0.87	0.87	0.83
Treatment	0.83	0.88	0.78	0.82	0.81
Worry	0.89	0.92	0.88	0.84	0.87
Communication	NA	0.94	0.93	0.89	0.92
Food and Eating	0.80	0.82	0.85	0.81	0.82
Food Feelings	0.81	0.79	0.89	0.84	0.84

^*The Cronbach’s alpha value for young child self-report (5–7 years-old) was not used to calculate the overall Symptoms II and overall Symptoms Total Scale Score Cronbach’s alpha, because of its low value (0.39). For ages 5–7, this scale is only used for clinical purposes, and is not included in the scale scores.

NA = not applicable.

Online-only Appendix 1 (http://links.lww.com/MPG/A207) presents internal consistency reliability coefficients for the PedsQL™ 4.0 Generic Core Scales for the EoE sample. All child self-report and parent proxy-report scales on the Generic Core meet or exceed the minimum reliability standard of 0.70 required for group comparisons, except for child self-report Social Functioning (0.69). The Total Scale Scores for both child self-report and parent proxy-report exceed the reliability criterion of 0.90 recommended for analyzing individual patient scores.

Test-Retest Reliability

Table 4 presents Intraclass Correlation Coefficients (ICCs) for test-retest reliability. In a subsample (n =102), patients and their parents were readministered the PedsQL™ EoE Module on average 12.3 days (SD = 4.0) after baseline. All but one of the ICCs were in the good to excellent test-retest reliability range for both patients and parents.

Table 4.

PedsQL™ Eosinophilic Esophagitis Module Scales Interclass Correlation Coefficients (ICCs) for Test-Retest Reliability for Child Self-Report and Parent Proxy-Report

	Test-Retest Agreement Child ICCs n = 61	Test-Retest Agreement Parent ICCs n = 102
EoE Module Total Scale Score	0.88	0.82
Symptoms Total Scale Score	0.87a	0.82
Symptoms I	0.80	0.83
Symptoms II	0.85a	0.75
Treatment	0.71	0.62
Worry	0.77	0.60
Communication	0.67	0.77b
Food and Eating	0.84	0.79
Food Feelings	0.82	0.75

Note:

^an = 40

^bn = 69 (smaller sample sizes as a result of age differences across forms).

ICCs = Intraclass Correlation Coefficients.

ICCs are designated as ≤0.40 poor to fair agreement, 0.41–0.60 moderate agreement, 0.61–0.80 good agreement, and 0.81–1.00 excellent agreement.

Construct Validity

Online-only Appendix 1 presents the differences between the pediatric patients with EoE and the healthy children sample. For each PedsQL™ 4.0 Generic Core Scales and Summary Scores, pediatric patients with EoE and their parents report statistically significant lower generic HRQOL than healthy children. The majority of effect sizes are in the medium range, supporting discriminant validity. The largest effect sizes for individual scales were demonstrated for the Physical Functioning (0.65), Emotional Functioning (0.65) and School Functioning (0.83) Scales for child self-report, and for the Emotional Functioning (0.87) and School Functioning (0.75) Scales for parent proxy-report.

Online-only Appendix 2 (http://links.lww.com/MPG/A208) presents the intercorrelations between the PedsQL™ EoE Module Scales and Total Scale Score, and the Generic Core Scales and summary scores. The majority of intercorrelations are in the medium to large range effect size range, supporting construct validity of the EoE Module Scales for child self-report and parent proxy-report. Smaller effect sizes were observed with the Food and Eating and Food Feelings Scales.

Item Scaling Tests

For the PedsQL™ EoE Module patient self-report scales, multitrait scaling analyses for item scaling success for the Symptoms Total Scale Score (ages 8–18), Symptoms I Scale, Symptoms II Scale (ages 8–18), Food and Eating Scale and Food Feelings Scale was 100.0%; for the Treatment Scale it was 20.0%; for the Worry Scale it was 50.0%; and for the Communication Scale it was 80.0%. For the parent proxy-report scales, scaling success was 100.0% for the Symptoms Total Scale Score, Symptoms I Scale, Symptoms II Scale, Treatment Scale, Worry Scale and Communication Scale; it was 75.0% for the Food and Eating Scale, and 66.7% for the Food Feelings Scale.

Parent/Child Agreement

ICCs between child and parent report are shown in Table 5. The majority of the ICCs are in the moderate to good agreement range for the PedsQL™ Scales.

Table 5.

Intraclass Correlations (ICCs) between Child Self-Report and Parent Proxy-Report on the PedsQL™ 4.0 Generic Core Scales and PedsQL™ Eosinophilic Esophagitis Module for Pediatric Patients with Eosinophilic Esophagitis Sample

PedsQL™ Scales	Parent-Child Agreement ICCs
Generic Core Scales
Generic Core Total	0.67
Physical Health	0.66
Psychosocial Health	0.62
Emotional Functioning	0.54
Social Functioning	0.50
School Functioning	0.70
Eosinophilic Esophagitis Module
EoE Module Total Scale Score	0.57
Symptoms Total Scale Score	0.58
Symptoms I	0.63
Symptoms II	0.55
Treatment	0.30
Worry	0.45
Communication	0.30
Food and Eating	0.52
Food Feelings	0.54

ICCs = Intraclass Correlation Coefficients.

ICCs are designated as ≤0.40 poor to fair agreement, 0.41–0.60 moderate agreement, 0.61–0.80 good agreement, and 0.81–1.00 excellent agreement.

Dietary Restrictions and Active Disease

To support additional construct validation for the PedsQL™ EoE Module Total Scale Scores, we performed contrast analyses between patients treated with dietary restrictions versus those with no restrictions, and in patients with active histologic disease versus those in remission. As shown in Figure 1, for children with no dietary restrictions the PedsQL™ EoE Module Total Scale Scores were better (higher) versus those with dietary restrictions (patient self-report: 74.3 [n=51] vs. 61.6 [n=143], respectively, [p<0.01, effect size = 0.71]; parent proxy-report: 74.7 [n=54] vs. 65.5 [n=207], respectively, [p<0.01, effect size = 0.53]). Figure 1 also contains the contrasts across the individual scales.

Figure 1.

PedsQL™ EoE Module Total Scale Scores, Total Symptom Scores and individual Scale Scores among EoE patients as child self-report (A.) and parent proxy-report (B.) comparing those with no dietary restrictions and those with strict dietary antigen elimination.

In addition, PedsQL™ EoE Module Total Scale Scores were better (higher) among patients in remission compared to those patients with active histologic disease when active disease was defined as peak distal eosinophil counts per high powered field (eos/hpf) of either < 5 eos/hpf versus > 5 eos/hpf (patient self-report: 69.9 [n=57] vs. 63.3 [n=139], respectively, [p<0.05, effect size = 0.36]; parent proxy-report: 72.3 [n=79] vs. 65.1 [n=182], respectively, [p<0.01, effect size = 0.43]), or <15 eos/hpf versus > 15 eos/hpf (patient self-report: 68.4 [n=85] vs. 62.7 [n=111], respectively, [p<0.05, effect size = 0.30]; parent proxy-report: 70.4 [n=120] vs. 64.7 [n=141], respectively, [p<0.01, effect size = 0.33]). PedsQL™ EoE Module Symptoms Total Scale Scores were also lower (worse) with active disease that was defined as peak distal eosinophil counts per high powered field (eos/hpf) of either < 5 eos/hpf versus > 5 eos/hpf (patient self-report: 71.9 [n=41] vs. 69.0 [n=98], respectively, [p=0.41, effect size = 0.16]; parent proxy-report: 73.3 [n=79] vs. 65.7 [n=178], respectively, [p<0.01, effect size = 0.39]), or <15 eos/hpf versus > 15 eos/hpf ((patient self-report: 72.5 [n=62] vs. 67.7 [n=77], respectively, [p=0.13, effect size = 0.26]; parent proxy-report: 70.9 [n=120] vs. 65.6 [n=137], respectively, [p<0.05, effect size = 0.27]). In this cross-sectional study, the time from the last endoscopy to assess histologic disease activity and completion of the questionnaires ranged from 3 days to 9.3 years. Therefore, an exploratory post-hoc analysis with regard to histologic disease activity and their relation to symptoms was conducted among a subgroup of patients who had their endoscopy within 30 days of completing study questionnaires. PedsQL™ EoE Module Symptoms Total Scale Scores for child self-report (ages 8–18) were lower (worse) with active disease that was defined as peak distal eosinophil counts per high powered field (eos/hpf) of either < 5 eos/hpf (75.0; n=3) versus >5 eos/hpf (57.3; n=4; p=0.34, effect size = 0.87); or < 15 eos/hpf (78.4; n=4) versus > 15 eos/hpf (46.9; n=3; p< 0.05, effect size = 1.94).

Discussion

These analyses support the feasibility, reliability and validity of the PedsQL™ EoE Module scales for pediatric patient self-report for ages 5–18 and parent proxy-report for ages 2–18. Moreover, the findings provide further support for the measurement properties of the PedsQL™ 4.0 Generic Core Scales in pediatric patients with EoE. The PedsQL™ EoE Module scales make a significant contribution to the empirical literature by creating a multidimensional EoE-specific instrument that can be integrated with the PedsQL™ 4.0 Generic Core Scales to provide a comprehensive assessment of patient generic and disease-specific HRQOL.

The PedsQL™ EoE Module had minimal missing responses, supporting feasibility, suggesting that pediatric patients and their parents were willing and able to provide good quality data regarding the child’s HRQOL. The PedsQL™ EoE Module scales internal consistency reliabilities exceeded the recommended minimum alpha coefficient standard of 0.70 for group comparisons, except for the Symptoms II Scale for child self-report ages 5–7. This specific scale for 5–7 age group was not used to calculate the overall Symptoms II and the overall Symptoms Total Scale Score alpha coefficients or scaling success, and should only be used for clinical or descriptive purposes. The PedsQL™ EoE Module individual scales may be utilized to examine specific domains of EoE-specific HRQOL given the requirements of a particular clinical trial, as well as subgroup differences across scales. The PedsQL™ EoE Module Total Scale and the Symptoms Total Scale scores both exceed the reliability criterion of 0.90 recommended for analyzing individual patient scores, except for child self-report ages 5–7 (α=0.89), which does not include the Symptoms II Scale items for the Total Scale Score calculation. Therefore, with regard to EoE symptom outcome assessments, we suggest that the child self-report PedsQL™ EoE Module Symptom I, Symptom II and Symptom Total Scale scores only be used for children ages 8–18 years of age, and that parent proxy-reports be utilized for children ages 2–7 years of age.

The PedsQL™ 4.0 Generic Core Scales differentiated generic HRQOL in pediatric patients with EoE and a matched healthy children sample as hypothesized with medium to large effect sizes. Pediatric patients with EoE reported lower HRQOL than did healthy children, with physical, emotional and school functioning showing the greatest differences between pediatric patient with EoE and healthy children. Differences in school functioning may be related to missing days of school for clinic or lab visits, hospitalizations, or other illnesses. The difficulties in school functioning reported by patient and parents suggests that clinicians should attend to the child’s academic functioning and should encourage families to advocate for their child’s academic support.

Pediatric patients with EoE and their parents showed moderate to good agreement across the scale scores of the PedsQL™ 4.0 Generic Core and EoE Module Scales, except for the Treatment and Communication Scales on the EoE Module that demonstrated poor to fair agreement. Agreement between child and parent reports on the PedsQL™ EoE Module Total Scale Score was moderate. These findings are in accordance with the results of the scaling item success. For parent proxy-report, all of the first five scales of the EoE Module achieved a 100% scaling item success, while for child self-report the Treatment, Worry and Communication Scales demonstrated a lower scaling success. The lower percentage of scaling item success on the Treatment and Worry Scales for child self-report suggests that the items of these specific scales are also highly correlated with other EoE scales. These finding are logical since the treatment of EoE is highly related to different EoE disease-specific symptoms and worrying is related to one’s symptoms and communications with others about symptoms and problems.

Although the primary focus of the current study was to demonstrate the feasibility, reliability and validity of the newly developed PedsQL™ EoE Module, we also explored several hypotheses as further evidence of construct validity. It is notable that the PedsQL™ EoE Module total scale scores were worse among patients with active histologic disease compared to those in histologic remission using both esophageal histologic disease activity cut points of 5 and 15 eos/hpf. This provides strong initial evidence that EoE specific-HRQOL may be impacted by treatment. It is notable that recent clinical trials have not shown improvements in assessments of HRQOL compared with placebo even though the treatment intervention (e.g., anti-IL-5) lowered esophageal eosinophil counts (47). We speculate that the usage of a properly validated EoE-specific HRQOL instrument, such as the PedsQL™ EoE Module, would improve the ability to identify potential beneficial effects. Further, although in-depth analyses of symptoms at the time of an endoscopy to assess histologic disease activity was beyond the scope of our current study, among the patient subgroup who completed the PedsQL™ EoE Module within 30 days of their last endoscopy, an exploratory post-hoc analysis demonstrated significant trends in the Symptoms I, Symptoms II and Symptoms Total Scale scores. In particular, the effect sizes of the 30-day subgroup for the PedsQL™ EoE Symptoms Total Scale Scores for patient self-report scores (ages 8–18) comparing patients with active disease (either defined at > 5 eos/hpf, or > 15 eos/hpf) to those in histologic remission were in the large effect size range with the latter reaching statistical significance despite a small sample size (< 15 eos/hpf (78.4; n=4) versus > 15 eos/hpf (46.9; n=3; p< 0.05, effect size = 1.94). However, it is important to emphasize that a detailed analysis of EoE Symptom assessments and their relation to histologic disease status was beyond the scope of the present construct validation study. Future research will seek to answer the important clinical question of not only whether the PedsQL™ EoE Module Total Scale Score, but also the individual PedsQL™ EoE Module Symptom Scales are worse among EoE patients at the time of their most recent endoscopy, and whether those patients with active symptoms and active histologic disease who respond histologically to EoE therapies also have symptomatic response utilizing the PedsQL™ Symptoms Scales. Given that it is widely recognized that EoE symptoms and histologic disease are not a perfect correlation, it is likely that both endpoints will need to be utilized for clinical trials. The recent Food and Drug Administration Gastroenterology Regulatory and Therapeutic Endpoints (GREAT) workshop (48) has continued to emphasize that all therapies need to be assessed in the context of their clinical benefit (e.g., survival, symptoms). Beyond FDA regulatory goals, it is important to emphasize that a patient’s global health needs to be the focus for treating disease. The World Health Organization has specifically defined health as, “A state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity”(49).

The Symptoms I, Symptoms II, and Symptom Total Score Scales achieved 100% scaling success across both pediatric patients self-report and parent proxy-report. The Symptoms I, Symptoms II and Symptom Total Score Scales may be indicated for clinical trials targeting symptom reduction in pediatric patients with EoE. The Symptom II Scale is particularly of interest as this scale captures the concepts of dysphagia from the patients’ perspective. Clinically, it is well recognized that patients may not realize that they have trouble swallowing, but they do need to drink liquids to help swallow food or take more time to eat food than other children. Our findings support the internal consistency and scaling success of the Symptom II Scale items, that is, that they are associated with one another, represent a unique scale, and that these items are not answered the same by all patients. Therefore, it is important to include all of these items to comprehensively evaluate EoE symptoms.

In addition to histologic disease activity status, we were also able to demonstrate that the PedsQL™ EoE Module Total Scale Scores were predictably worse among patients with more severe dietary restrictions. Although an in-depth analysis of the adverse psychological impact that severe dietary restrictions may have on patients and their families alike was beyond the scope of our present study, it is clear that this is a major area of concern and warrants further investigation. This also further supports the urgent need for novel EoE therapies that keep a focus on patient health that includes quality of life assessments and goes beyond esophageal eosinophil counting and only measures of disease status.

In addition to assessment of symptoms relative to histologic disease activity and degree of dietary restriction therapy, medication adherence is often an issue with chronic diseases that require long term therapy. It is interesting to note that the lowest score was for the child self-reported Treatment Scale when compared with other self-reported Module scales and when compared with the parent proxy-reported Treatment Scale score. In particular, this scale asks about medication adherence and difficulties with medications, clinic visits and diagnostic testing. Given that EoE is a chronic disease that requires long term treatment, issues of adherence to treatment become highly salient, and it is essential that the treatment is acceptable to the patients. This potentially emphasizes the need for behavioral health adherence interventions, and also additional treatment options since current treatments are a problem for the patients from their perspective. It also suggests that the EoE Module scales will be useful as new treatments are introduced to determine whether adherence is improved.

The present study has several strengths, including the rigorous methods used to construct the measure, the relatively large sample size, the broad age-range of participants, and the nation-wide representation of the participants (six clinical sites from across the country). Limitations include the lack of information on families who chose not to participate in the study, and the small sample sizes for the exploratory post-hoc analyses. Feasibility in the present study was assessed solely by the percentage of missing values; future investigations should also evaluate the feasibility of these measures with regard to completion time and non-response rate. The only measure used to assess construct validity was the PedsQL™ Generic Core Scales. Other measures assessing such constructs as depression, anxiety, family communication, and adherence to medical regimens were not collected for this study (to reduce participant burden), and future comparisons among these measures may add important information regarding the construct validity of the PedsQL™ EoE Module scales. The use of historical controls for the PedsQL™ 4.0 Generic Core Scales comparisons is another potential limitation. It should be noted, however, that the lower socioeconomic (SES) status of the healthy children comparison sample in the present study most likely under estimated the true differences between the EoE sample and healthy children given previous findings on the negative impact of lower SES on children’s HRQOL (50). Future studies with the PedsQL™ 4.0 Generic Core Scales should prospectively recruit an age, gender, race/ethnicity, and SES matched healthy cohort sample. Last, although the data of the present study provides some initial support towards the use of the PedsQL™ EoE Module scales and summary scores in clinical trials, prospective longitudinal studies are urgently needed.

The recall period for the PedsQL™ EoE Module utilized in the present study was the PedsQL™ standard “past one month” recall version. Although there are PedsQL™ Modules that also offer the acute “past 7 days” recall period option, we have found that the data from both recall periods are quite similar (14). The test-retest reliability data presented in present study demonstrated that the PedsQL™ EoE Module scales and summary scores did not change to a significant degree over an average interval of ~12 days between instrument administrations in pediatric patients with stable disease. In the adult dysphagia literature, the Mayo Dysphagia Questionnaire (MDQ) was found to be not responsive in a 14 day recall period, but rather performed better over a one month recall period (51). Additionally, there have been a number of responsiveness analyses with the PedsQL™ 4.0 Generic Core Scales in which the one month recall period was demonstrated to be sensitive to intervention effects (27). Future research studies may explore utilizing the PedsQL™ acute 7 day recall with the EoE Module to compare the acute and standard recall period versions. These analyses may help determine whether the PedsQL™ EoE Module responsiveness is improved by utilizing the 7 day recall period compared to the standard one month recall period.

In order to assess the clinical utility of this newly developed multidimensional EoE-specific HRQOL instrument, future studies using the measure in clinical trials would facilitate a more thorough understanding of the multidimensional nature of both the patient’s experience and the parent’s perceptions of their child’s experiences regarding the impact of EoE on generic and disease-specific HRQOL and facilitate medical decision-making for these patients. The development of the PedsQL™ EoE Module should help clinicians identify children at different levels of morbidity, identify the differential impact of various treatment regimens, identify those children at risk for emotional difficulties and school issues, and identify emerging problems over time for individual patients and patient groups.

Abbreviations

PedsQL™

Pediatric Quality of Life Inventory™

FDA

U.S. Food and Drug Administration

HRQOL

health-related quality of life

EoE

Eosinophilic Esophagitis