ORIGINAL ARTICLE

PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales in Pediatric Patients with Inflammatory Bowel Disease in Comparison with Healthy Controls James W. Varni, PhD,1,2 James P. Franciosi, MD,3 Robert J. Shulman, MD,4 Shehzad Saeed, MD,3 Samuel Nurko, MD,5 Deborah A. Neigut, MD,6 Cristiane B. Bendo, PhD,7 Ashish S. Patel, MD,8 Mariella M. Self, PhD,9 Miguel Saps, MD,10 George M. Zacur, MD,3 Jolanda Denham, MD,11 Chelsea Vaughan Dark, PhD,12 and John F. Pohl, MD,13 for the Pediatric Quality of Life Inventory Gastrointestinal Symptoms Module Testing Study Consortium

Background: Patient-reported outcomes are essential in determining the broad impact of inflammatory bowel disease (IBD) and treatments from the patient’s perspective. The primary study objectives were to compare the gastrointestinal symptoms and worry of pediatric patients with IBD with matched healthy controls and to compare Crohn’s disease and ulcerative colitis with each other using the Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms and Gastrointestinal Worry Scales.

Methods: PedsQL Gastrointestinal Symptoms and Worry Scales were completed in a 9-site study by 256 pediatric patients with IBD and 259 parents of patients (263 families; Crohn’s disease [n ¼ 195], ulcerative colitis [n ¼ 68]). Ten Gastrointestinal Symptoms Scales measuring stomach pain, stomach discomfort when eating, food and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and bloating, constipation, blood in poop, and diarrhea were administered along with 2 Gastrointestinal Worry Scales. A matched group of 384 healthy children families completed the PedsQL in an Internet survey.

Results: PedsQL Gastrointestinal Symptoms and Worry Scales distinguished between pediatric patients with IBD in comparison with healthy controls (P , 0.001), with larger effect sizes for symptoms indicative of IBD, supporting known-groups validity and clinical interpretability including minimal important difference scores. Patients with Crohn’s disease or ulcerative colitis did not demonstrate significantly different gastrointestinal symptoms or worry in comparison with each other.

Conclusions: The PedsQL Gastrointestinal Symptoms and Worry Scales may be used as common metrics across pediatric patients with IBD, including Crohn’s disease and ulcerative colitis separately to measure gastrointestinal-specific symptoms in clinical research and practice. (Inflamm Bowel Dis 2015;21:1115–1124) Key Words: PedsQL, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, patient-reported outcomes

Received for publication January 5, 2015; Accepted January 22, 2015. From the 1Department of Pediatrics, College of Medicine, Texas A&M University, College Station, Texas; 2Department of Landscape Architecture and Urban Planning, College of Architecture, Texas A&M University, College Station, Texas; 3Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; 4Department of Pediatrics, Baylor College of Medicine, Children’s Nutrition Research Center, Texas Children’s Hospital, Houston, Texas; 5Center for Motility and Functional Gastrointestinal Disorders, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts; 6Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Colorado, Aurora, Colorado; 7Department of Pediatric Dentistry and Orthodontics, Faculty of Dentistry, Federal University of Minas Gerais, Belo Horizonte, Brazil; 8Division of Pediatric Gastroenterology, Children’s Medical Center of Dallas, University of Texas Southwestern Medical School, Dallas, Texas; 9Departments of Psychiatry and Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas; 10Division of Gastroenterology, Hepatology and Nutrition, Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois; 11Division of Pediatric Gastroenterology, Nationwide Children’s Hospital, Ohio State University School of Medicine, Columbus, Ohio; 12Department of Psychology, Texas A&M University, College Station, Texas; and 13Department of Pediatric Gastroenterology, Primary Children’s Hospital, University of Utah, Salt Lake City, Utah (Drs. Franciosi and Denham are now with the Division of Gastroenterology, Hepatology and Nutrition, Nemours Children’s Hospital, Orlando, Florida. Dr. Saps is now with the Division of Pediatric Gastroenterology, Nationwide Children’s Hospital, Ohio State University, Columbus, Ohio. Dr. Zacur is now with the Division of Pediatric Gastroenterology, C.S. Mott Children’s Hospital, University of Michigan, Ann Arbor, Michigan. Dr. Vaughan Dark is now with the Division of Pediatric Pulmonology, Children’s Medical Center, Dallas, Texas). No funding was specifically designated for the PedsQL Gastrointestinal Symptoms Module field test study data collection effort or manuscript preparation. Item development for the PedsQL Gastrointestinal Symptoms Module was previously supported by Takeda Pharmaceuticals North America, Inc. Data collection for the healthy controls sample was supported by intramural funding from the Texas A&M University Foundation. A list of the Pediatric Quality of Life Inventory Gastrointestinal Symptoms Module Testing Study Consortium sites is contained in the Appendix 1. The PedsQL is available at http://www.pedsql.org. Author disclosures are available in the Acknowledgments. Reprints: James W. Varni, PhD, College of Architecture, Texas A&M University, 3137 TAMU, College Station, TX 77843-3137 (e-mail: [email protected]). Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000351 Published online 19 March 2015.

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he inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, are characterized by chronic inflammation in the gastrointestinal (GI) tract.1,2 Approximately, 20% to 30% of IBD prevalence has been estimated to occur in pediatric patients,3 with recent estimates suggesting an increasing prevalence worldwide.1,4,5 In pediatric patients, a greater prevalence has been observed for Crohn’s disease relative to ulcerative colitis,4 with a greater rise in Crohn’s disease incidence relative to ulcerative colitis.3 Pediatric patients ages 10 to 14 years of age with IBD have demonstrated the highest age-related incidence rate (56%) in a recent childhood cohort, with 18% of patients diagnosed between 5 and 9 years of age, 8% before age 4% and 19% between ages 15 and 17 years.3 The most commonly presenting GI symptoms for both Crohn’s disease and ulcerative colitis are abdominal pain, diarrhea, and rectal bleeding.6 Recent initiatives to improve the quality of care of pediatric patients with IBD have been encouraging but have lacked a broad multidimensional assessment of GI symptoms from the patient’s perspective in the evaluation of health outcomes.7,8 Patient-reported outcomes (PROs) integrate the patient’s perspective into patient-centered outcomes and comparative effectiveness research.9,10 With the publication of the Food and Drug Administration guidelines to industry regarding PROs,11 there has been greater emphasis on the integration of PROs with clinical and biological data in the evaluation of treatment efficacy in gastroenterology clinical trials,12,13 including for patients with IBD.14 PROs are essential in determining the broad impact of IBD and its treatments from the perspective of pediatric patients.15–18 The Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales were developed to address a significant gap in the pediatric gastroenterology literature.19 There are no other reliable and valid multidimensional GI symptoms-specific PRO instruments for pediatric patients, which provide a common metric across both functional and organic GI diseases and which include both patient self-reports for ages 5 to 18 years and parent proxy-reports for ages 2 to 18 years.20 Although the IMPACT-III questionnaire is a well-developed IBD-specific HRQOL instrument,21–23 it lacks the broader profile assessment of GI symptoms and wider age range that are measured by the PedsQL Gastrointestinal Symptoms and Worry Scales, does not have a well-validated parent proxyreport version, and importantly does not include benchmarking with healthy controls. Furthermore, the most recent iteration of the 6 scales of the 35-item IMPACT-III only contains 7 items measuring diverse bowel symptoms, with other scales measuring systemic symptoms (3 items), emotional functioning (7 items), social functioning (12 items), body image (3 items), and treatment/interventions (3 items).24,25 The 7 items in the IMPACT-III bowel symptoms scale each measure a different symptom, with single items measuring stomach pain, bothered by diarrhea, eating restrictions, passing gas, afraid of having soiling accidents, feeling sick, and worry about blood in stool. In contrast, the 58 items contained in the 10 multi-item Gastrointestinal Symptoms Scales

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and the 7 items contained in the 2 multi-item Gastrointestinal Worry Scales were designed as common metrics to broadly measure multidimensional GI symptoms and worry across pediatric populations, including benchmarking with healthy controls.20,26 In clinical research and practice, the clinical interpretability of PRO scores includes comparing scores in populations known to be healthy versus populations known to have a specific disease (known-groups validity), and the delineation of a minimal important difference (MID) in scores between groups and/or changes over time.9 The MID has been defined as “the smallest difference in score in the outcome of interest that informed patients or informed proxies perceive as important, either beneficial or harmful, and that would lead the patient or clinician to consider a change in the management”.27 In this definition, “informed proxies” are considered only if “informed patients” cannot or prefer not to make decisions about the management of their health condition.27 In the context of pediatric disease management, the perspectives of both pediatric patients and their parents are essential.28 Although there have been studies on the measurement properties of the PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales across multiple functional and organic GI diseases,20,26 there has been no previous investigation with these scales comparing GI symptoms and worry in pediatric patients with IBD as a group with an age, gender, and race-/ethnicity-matched healthy control samples uniquely matched specifically to the IBD sample nor have data been reported on the feasibility, internal consistency reliability, parent/child agreement, and MID scores specifically for pediatric patients with IBD. Consequently, the primary objectives of this study were to compare GI symptoms and worry in pediatric patients with IBD as a combined group with a matched sample of healthy controls and to compare Crohn’s disease and ulcerative colitis to each other using the PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales. We hypothesized that the PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales most indicative of IBD-specific symptoms would distinguish between pediatric patients with IBD as a group in comparison with healthy children, supporting construct validity using the known-groups method.29 Given the symptom profile of pediatric patients with IBD, we expected that the PedsQL Pain and Hurt Scale, Gas and Bloating Scale, Constipation Scale, Blood in Poop Scale, Diarrhea Scale, and Worry Scales to demonstrate the largest effect size differences in comparison with the matched healthy controls. We also expected that the PedsQL Food and Drink Limits Scale to demonstrate large effect sizes in comparison with the healthy controls given dietary restrictions in the management of IBD. Given the dearth of definitive empirical literature comparing pediatric patients with Crohn’s disease and ulcerative colitis to each other using PRO scales measuring a broad profile of GI symptoms,16,22 we conducted exploratory analyses between these 2 diagnostic groups using these new PedsQL scales.

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METHODS Pediatric Patients and Settings Pediatric patients with physician-diagnosed Crohn’s disease or ulcerative colitis using International Classification of Diseases, Ninth Revision, Clinical Modification Diagnosis Codes were recruited from 9 pediatric tertiary care GI clinical sites across the United States for the PedsQL Gastrointestinal Symptoms Module field test study.20 Data collection for the PedsQL Gastrointestinal Symptoms Module field test study took place between March 2011 and November 2013.20 Written parental informed consent and child assent (when age appropriate) were obtained for these data during the field test study.20 The research protocol for the field test study was approved by the institutional review board at each participating institution.

Healthy Controls’ Sample The PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales’ healthy controls’ comparison sample was derived from data collected by the Scientific Research group at YouGov (see www.yougov.com), an Internet polling firm as previously described.26 YouGov was contracted to select participants from among their panel that age, gender, and race/ethnicity matched the GI sample. In addition to completing the PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales, parents completed the PedsQL Family Information Form, which included a question on whether their child had a chronic health condition.30 Specifically, parents answered a question on the presence of a chronic health condition (“In the past 6 months, has your child had a chronic health condition?”) defined as a physical or mental health condition that had lasted or was expected to last at least 6 months and interfered with the child’s activities as previously used in PedsQL studies.30–32 Families in which parents self-reported that their child had a chronic health condition were not included in the matched healthy sample, consistent with previous PedsQL studies.33,34 From the total sample of 792 families who participated in the Internet survey, an age, gender, and race/ ethnicity sample of 384 families with healthy children was uniquely derived to match the age, gender, and race/ethnicity of the IBD group (combined sample of Crohn’s disease and ulcerative colitis). Parental informed consent and child assent (when age appropriate) were obtained through the panel survey protocol. The research protocol for the healthy sample survey was approved by the institutional review board.

Measures PedsQL Gastrointestinal Symptoms Module Development The PedsQL Gastrointestinal Symptoms Module items and scales were developed through a literature review of the relevant research, national consultation with pediatric gastroenterologists, as well as focus interviews, cognitive interviews, and pretesting

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protocols with pediatric patients and their parents, including patients with Crohn’s disease and ulcerative colitis.19 The PedsQL Gastrointestinal Symptoms Module includes 74 items incorporated into 14 individual scales.20 The PedsQL Gastrointestinal Symptoms Module consists of 10 Gastrointestinal Symptoms Scales, 2 Gastrointestinal Worry Scales, a Medicines Scale, and a Communication Scale. Only the PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales from the PedsQL Gastrointestinal Symptoms Module are included in this study because the Medicines and Communication Scales are not relevant to healthy populations.

PedsQL Gastrointestinal Symptoms Scales The PedsQL Gastrointestinal Symptoms Scales encompass 10 individual scales: (1) Stomach Pain and Hurt Scale (6 items), (2) Stomach Discomfort When Eating Scale (5 items), (3) Food and Drink Limits Scale (6 items), (4) Trouble Swallowing Scale (3 items), (5) Heartburn and Reflux Scale (4 items), (6) Nausea and Vomiting Scale (4 items), (7) Gas and Bloating Scale (7 items), (8) Constipation Scale (14 items), (9) Blood in Poop Scale (2 items), and (10) Diarrhea Scale (7 items). The format, instructions, Likert response scale, and scoring method for the PedsQL Gastrointestinal Symptoms Scales are identical to the PedsQL 4.0 Generic Core Scales,30 with higher scores indicating better HRQOL and hence lower symptoms.20 The scales comprised parallel child self-report and parent proxy-report formats for children ages 5 to 18 years and a parent proxy-report format for children ages 2 to 4 years. Child selfreport forms are specific for ages 5 to 7, 8 to 12, and 13 to 18 years. Parent proxy-report forms are specific for children ages 2 to 4 (toddler), 5 to 7 (young child), 8 to 12 (child), and 13 to 18 (adolescent), and assess parents’ perceptions of their child’s GIspecific symptoms. The items for each of the forms are essentially identical, differing in developmentally appropriate language, or the first or third person tense. The instructions ask how much of a problem each item has been during the past 1 month. A 5-point response scale is used across child and adolescent self-report for ages 8 to 18 years and parent proxy-report (0 ¼ never a problem; 1 ¼ almost never a problem; 2 ¼ sometimes a problem; 3 ¼ often a problem; 4 ¼ almost always a problem). 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 ¼ not at all a problem; 2 ¼ sometimes a problem; 4 ¼ a lot of a problem) and uses a faces scale adapted from the Pediatric Pain Questionnaire.35 Items are reverse-scored and linearly transformed to a 0 to 100 scale (0 ¼ 100, 1 ¼ 75, 2 ¼ 50, 3 ¼ 25, 4 ¼ 0), so that lower scores demonstrate more (worse) GI symptoms and hence lower (worse) GI-specific 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.36 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 www.ibdjournal.org |

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PedsQL peer-reviewed publications as well as other wellestablished HRQOL measures.28 To create the PedsQL Gastrointestinal Symptoms Scales Total Score (58 items), the mean is computed as the sum of the items divided by the number of items answered in the 10 PedsQL Gastrointestinal Symptoms Scales.

PedsQL Gastrointestinal Worry Scales The PedsQL Gastrointestinal Worry Scales encompass 2 individual scales: (1) Worry About Going Poop Scale (5 items) and (2) Worry About Stomach Aches Scale (2 items). The format, instructions, Likert response scale, and scoring method for the PedsQL Gastrointestinal Worry Scales are identical to the PedsQL 4.0 Generic Core Scales,30 with higher scores indicating better HRQOL and hence lower worry.20

detected.47,48 As articulated by Hilliard et al,48 “The SEM estimates the variation in scores due to the measurement precision in the scale and assumes that a change in scores smaller than the value of the SEM likely results from measurement error rather than a meaningful increase or decrease in the value of the construct being measured.” Intraclass correlation coefficients (ICCs) were used to determine agreement between patient self-report and parent proxy-report.49 The ICC provides an index of absolute agreement as it takes into account the ratio between subject variability and total variability.50 ICCs are designated as #0.40 poor to fair agreement, 0.41 to 0.60 moderate agreement, 0.61 to 0.80 good agreement, and 0.81 to 1.00 excellent agreement. Statistical analyses were conducted using SPSS.51

PedsQL Family Information Form Parents completed the PedsQL Family Information Form, which contains demographic information including the child’s date of birth, gender, race/ethnicity, and parental education information.30

Statistical Analysis Feasibility was determined from the percentage of missing values.37 Missing #2% of data in applied research settings is considered acceptable.38 Cronbach’s coefficient alpha was used to determine scale internal consistency reliability.39 Scales with internal consistency reliabilities of 0.70 or greater are recommended for comparing patient groups, whereas an internal consistency reliability criterion of 0.90 is recommended for analyzing individual patient scores.40 Construct validity was determined using the known-groups method.29 The known-groups validity method compares scale scores across groups known to differ in the health construct being investigated.41,42 In this study, PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales scores in groups differing in known health condition (healthy participants and participants known to have IBD) and comparisons between patients with Crohn’s disease and patients with ulcerative colitis were computed37,43 using independent samples t-tests (Bonferroni familywise correction for multiple comparisons ¼ 0.05/13 for child self-report and parent proxy-report, respectively). To determine the magnitude of the anticipated differences, effect sizes were calculated.44 Effect size as used in these analyses was calculated by taking the difference between the healthy sample means and the IBD sample means, and between the Crohn’s disease sample means and ulcerative colitis sample means, divided by the pooled SD. Effect sizes for differences in means are designated as small (0.20), medium (0.50), and large (0.80) in magnitude.44 The MID was calculated using the SEM.45 The SEM is derived by multiplying the SD by the square root of 1-alpha (Cronbach’s alpha reliability coefficient).45 The SEM has been linked to the MID, in which 1 SEM has demonstrated a strong correspondence to anchor-based individual change thresholds for a number of PRO measures.46 The MID is considered the smallest clinically meaningful change in a PRO instrument that can be

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RESULTS Patient Characteristics Table 1 contains the demographic characteristics of the IBD patient sample. A total of 263 families (256 children and 259 parents of children) participated and completed the PedsQL scales. Patients were diagnosed with either Crohn’s disease (n ¼ 195 families) or ulcerative colitis (n ¼ 68 families).

Healthy Controls Characteristics Table 1 contains the demographic characteristics of the healthy controls sample. A total of 384 families (384 children and 194 parents of children) participated and completed the PedsQL scales.

Feasibility: Missing Item Responses For the IBD sample, the percentage of missing item responses on the 58 items of the PedsQL Gastrointestinal Symptoms Scales was 1.47% and 1.72% for child self-reports and parent proxy-reports, respectively. For the IBD sample, the percentage of missing item responses on the 7 items of the PedsQL Gastrointestinal Worry Scales was 0.95% and 1.98% for child selfreports and parent proxy-reports, respectively.

Internal Consistency Reliability Cronbach’s alpha internal consistency reliability coefficients for the PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales are shown in Table 2 for the patients with IBD as a group, and in Table 3 for patients with Crohn’s disease and ulcerative colitis, separately. For patient self-report, all scales exceeded the minimum reliability standard of 0.70 required for group comparisons except for the Trouble Swallowing Scale and Heartburn and Reflux Scale. For parent proxyreport, all scales exceeded the minimum reliability standard for group comparison except for the Heartburn and Reflux Scale for ulcerative colitis. The Gastrointestinal Symptoms Scales Total Score for both patients’ self-reports and parent proxy-reports

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TABLE 1. Characteristics of Pediatric Patients with Inflammatory Bowel Disease and Healthy Controls Characteristics

Patient Families, n (%) or Mean (SD)

Healthy Families, n (%) or Mean (SD)

263 13.9 (3.1)

384 13.9 (2.8)

147 (55.9) 116 (44.1)

199 (51.8) 185 (48.2)

206 15 26 6

301 22 38 9

Total number Age Gender Male Female Race/ethnicity White non-Hispanic Hispanic Black non-Hispanic Asian/Pacific Islander Native American Other Parent education mothers Less than high school graduate High school graduate Some college or certification course College graduate Graduate or professional degree Missing Parent education fathers Less than high school graduate High school graduate Some college or certification course College graduate Graduate or professional degree Missing

(78.3) (5.7) (9.9) (2.3)

(78.4) (5.7) (9.9) (2.3)

1 (0.4) 9 (3.4)

1 (0.3) 13 (3.4)

12 (4.6)

26 (6.8)

29 (11.0)

58 (15.1)

65 (24.7)

85 (22.1)

101 (38.4) 45 (17.1)

150 (39.1) 65 (16.9)

11 (4.2)

0 (0)

15 (5.7)

23 (6.0)

40 (15.2)

63 (16.4)

55 (20.9)

93 (24.2)

68 (25.9) 58 (22.1)

122 (31.8) 83 (21.6)

27 (10.3)

0 (0)

exceeded the reliability criterion of 0.90 recommended for analyzing individual patient scores, as did a number of the individual scales.

familywise correction for multiple comparisons, P ¼ 0.0038), except for the Trouble Swallowing Scale. The largest effect sizes were generally demonstrated for those scales most indicative of the expected symptom profile for patients with IBD. Specifically, for both patient self-report and parent proxy-report, patients with IBD demonstrated the largest effect sizes (.0.50) for the Stomach Pain and Hurt Scale, Food and Drinks Limits Scale, Gas and Bloating Scale, Constipation Scale, Blood in Poop Scale, Diarrhea Scale, Worry About Going Poop Scale, and Worry About Stomach Aches Scale in comparison with the healthy controls. Additionally, for parent proxy-report, the Stomach Discomfort When Eating Scale demonstrated a .0.50 effect size in comparison with the healthy controls. Table 3 presents the findings for the comparisons between patients with Crohn’s disease and patients with ulcerative colitis. For both patient self-report and parent proxy-report, patients with Crohn’s disease and patients with ulcerative colitis did not demonstrate statistically significant differences in the PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales in comparison with each other. Patients with Crohn’s disease did demonstrate nonsignificantly more (worse) GI symptoms than patients with ulcerative colitis, except for blood in poop and diarrhea, with generally small effect sizes across scales.

MID Scores Table 2 shows the MID scores for pediatric patients with IBD as a group. Table 3 shows the MID scores for patients with Crohn’s disease or ulcerative colitis separately. These MID values provide additional information on the clinical interpretability of the scales specifically for pediatric patients as an IBD group, and individually for patients with either Crohn’s disease or ulcerative colitis. For example, in Table 2, a patient self-reported score change greater than or equal to 5.04 on the Constipation Scale is a numerical value indicating the smallest clinically meaningful change in this scale that can be detected specifically for patients with IBD as a group. The other MID values in Table 2 can be similarly interpreted. In Table 3, a patient self-reported score change greater than or equal to 6.33 on the Diarrhea Scale is a numerical value indicating the smallest clinically meaningful change in this scale that can be detected specifically for patients with Crohn’s disease. The other MID values in Table 3 can be similarly interpreted for patients with Crohn’s disease or ulcerative colitis.

Parent/Child Agreement

Known-Groups Validity

ICCs between child and parent report for the PedsQL scales are shown in Table 4. The majority of the ICCs are in the good agreement range.

Table 2 demonstrates comparisons between pediatric patients with IBD as a group in comparison with the matched healthy controls. For each of the PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales, pediatric patients with IBD demonstrated significantly greater symptoms and worry (i.e., lower scale scores) than the healthy controls (Bonferroni

The findings demonstrate the measurement properties of the PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales in pediatric patients with IBD as a group, and

DISCUSSION

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TABLE 2. PedsQL Gastrointestinal Symptoms Scales and Worry Scales Scores Comparisons Between Pediatric Patients with IBD and Healthy Controls for Child Self-Report and Parent Proxy-Report Inflammatory Bowel Disease GI Symptoms Scales and Worry Scales Child Self-Report Symptoms Total Scoreb Stomach Pain and Hurt Stomach Discomfort When Eating Food and Drink Limits Trouble Swallowing Heartburn and Reflux Nausea and Vomiting Gas and Bloating Constipation Blood in Poop Diarrhea Worry About Going Poop Worry About Stomach Aches Parent Proxy-Report Symptoms Total Scoreb Stomach Pain and Hurt Stomach Discomfort When Eating Food and Drink Limits Trouble Swallowing Heartburn and Reflux Nausea and Vomiting Gas and Bloating Constipation Blood in Poop Diarrhea Worry About Going Poop Worry About Stomach Aches

Items

58 6 5 6 3 4 4 7 14 2 7 5 2 58 6 5 6 3 4 4 7 14 2 7 5 2

a N ¼ 256 0.97 0.91 0.87 0.88 0.62 0.61 0.86 0.88 0.94 0.89 0.92 0.86 0.81 N ¼ 259 0.97 0.95 0.95 0.95 0.87 0.77 0.93 0.92 0.95 0.94 0.94 0.91 0.86

Healthy Controls a

Mean

SD

MID

77.3 69.1 81.5 71.5 95.5 84.6 87.7 68.2 75.5 81.0 79.7 81.7 69.2

15.0 20.7 20.2 23.9 9.8 15.3 17.1 21.3 20.6 25.3 22.5 22.0 29.1

2.60 6.21 7.28 8.28 6.04 9.55 6.40 7.38 5.04 8.39 6.36 8.23 12.68

75.5 64.5 72.7 70.0 95.5 85.6 84.3 68.9 76.4 77.6 76.1 78.9 67.2

16.4 23.8 24.7 27.5 10.6 16.6 20.3 22.9 20.2 27.3 23.3 23.3 28.8

2.84 5.32 5.52 6.15 3.82 7.96 5.37 6.48 4.52 6.69 5.71 6.99 10.80

a

Mean

N ¼ 384 0.98 88.0 0.93 80.1 0.92 88.6 0.94 88.9 0.91 95.0 0.83 89.5 0.92 90.9 0.94 82.1 0.96 86.9 0.88 96.0 0.94 93.7 0.90 94.1 0.83 89.8 N ¼ 194 0.98 88.9 0.95 79.5 0.95 86.7 0.93 89.6 0.95 96.6 0.78 92.3 0.94 90.8 0.95 85.0 0.97 88.5 0.95 95.9 0.92 94.6 0.91 95.0 0.82 91.0

SD

Differences (95% CI)

Effect Size

13.7 18.5 17.3 18.4 12.3 15.3 15.8 20.3 17.2 12.2 12.7 13.6 17.8

10.7 11.0 7.1 17.4 20.5 4.9 3.2 13.9 11.4 15.0 14.0 12.4 20.6

(8.4 to 12.9)c (7.9 to 14.0)c (4.2 to 10.1)c (14.2 to 20.7)c (22.3 to 1.3) (2.4 to 7.3)c (0.6 to 5.8)d (10.6 to 17.2)c (8.4 to 14.3)c (12.1 to 18.0)c (11.2 to 16.7)c (9.7 to 15.2)c (17.0 to 24.2)c

0.75 0.57 0.38 0.84 0.04 0.32 0.20 0.67 0.88 0.81 0.81 0.71 1.12

13.8 20.1 19.6 16.6 11.6 13.4 17.0 20.2 17.4 13.7 11.5 12.7 18.2

13.4 15.0 14.0 19.6 1.1 6.7 6.5 16.1 12.1 18.3 18.5 16.1 23.8

(10.6 to 16.3)c (10.8 to 19.1)c (9.8 to 18.2)c (15.2 to 24.0)c (21.0 to 3.2) (3.8 to 9.5)c (3.0 to 10.0)c (11.9 to 20.1)c (8.6 to 15.7)c (14.1 to 22.6)c (14.9 to 22.1)c (12.4 to 19.7)c (19.1 to 28.4)c

0.88 0.67 0.62 0.84 0.10 0.44 0.42 0.74 0.64 0.89 0.97 0.83 0.96

Effect sizes are designated as small (0.20), medium (0.50), and large (0.80). Lower scores demonstrate more (worse) GI symptoms and hence lower (worse) GI-specific HRQOL. a The SEM was derived by multiplying the SD by the square root of 1-alpha. PedsQL scores in the column represent the transformed value of 1 SEM. For example, a 2.60 change in the Gastrointestinal Symptoms Total Score for patient self-report on the 0 to 100 scale represents a MID. b Summary Score of the 10 Gastrointestinal Symptoms Scales scores. c P , 0.001, based on independent samples t-tests (Bonferroni familywise correction for multiple comparisons, P ¼ 0.0038). d P , 0.05. CI, confidence interval.

Crohn’s disease and ulcerative colitis separately. When comparing patients with Crohn’s disease to patients with ulcerative colitis, there were no statistically significant differences in the PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales, supporting the use of these scales as common metrics across pediatric patients with either Crohn’s disease or ulcerative colitis, or as a combined IBD group. The clinical interpretability of the PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales was

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demonstrated through known-groups validity comparisons with healthy controls and by providing MID values for each of the scale scores. The MID values in the tables represent the smallest clinically meaningful change in the individual scales that can be detected and represent meaningful variation in the measured construct (latent variable) that is likely not due to measurement error.48 The MID represents a value for each scale, separately for patient self-report and parent proxy-report, which indicates the magnitude of change in scale scores that is detectable by the

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TABLE 3. PedsQL Gastrointestinal Symptoms Scales and Worry Scales Scores Comparisons Between Pediatric Patients with Crohn’s Disease and Ulcerative Colitis for Child Self-Report and Parent Proxy-Report Crohn’s Disease GI Symptoms Scales and Worry Scales Child Self-Report Symptoms Total Scoreb Stomach Pain and Hurt Stomach Discomfort When Eating Food and Drink Limits Trouble Swallowing Heartburn and Reflux Nausea and Vomiting Gas and Bloating Constipation Blood in Poop Diarrhea Worry About Going Poop Worry About Stomach Aches Parent Proxy-Report Symptoms Total Scoreb Stomach Pain and Hurt Stomach Discomfort When Eating Food and Drink Limits Trouble Swallowing Heartburn and Reflux Nausea and Vomiting Gas and Bloating Constipation Blood in Poop Diarrhea Worry About Going Poop Worry About Stomach Aches

Items

58 6 5 6 3 4 4 7 14 2 7 5 2 58 6 5 6 3 4 4 7 14 2 7 5 2

a

Mean

N ¼ 192 0.97 76.5 0.90 68.2 0.87 80.4 0.88 70.4 0.60 95.1 0.62 84.0 0.87 86.8 0.88 66.8 0.94 74.3 0.86 82.5 0.92 80.2 0.84 81.4 0.81 67.5 N ¼ 192 0.98 74.5 0.95 63.8 0.95 71.4 0.94 69.1 0.88 94.7 0.79 84.5 0.93 82.8 0.92 66.9 0.95 74.9 0.93 79.6 0.94 76.5 0.91 79.0 0.85 66.6

Ulcerative Colitis a

SD

MID

15.0 20.5 20.9 24.4 10.2 15.6 17.8 21.2 21.0 23.3 22.4 21.2 29.8

2.60 6.48 7.54 8.45 6.45 9.62 6.42 7.34 5.14 8.72 6.33 8.48 12.99

16.7 24.4 25.0 27.4 11.6 17.6 21.1 22.4 20.8 25.8 23.2 23.5 28.5

2.36 5.46 5.59 6.71 3.98 8.07 5.58 6.33 4.65 6.80 5.68 7.05 11.04

a

Mean

N ¼ 65 0.97 79.7 0.92 71.9 0.85 84.7 0.88 74.6 0.72 96.5 0.60 86.5 0.81 90.4 0.88 72.5 0.92 79.3 0.96 76.4 0.92 78.4 0.90 82.7 0.80 74.2 N ¼ 67 0.97 78.4 0.95 66.5 0.95 76.7 0.95 72.7 0.83 97.8 0.65 88.7 0.90 88.4 0.93 75.1 0.94 80.5 0.97 72.0 0.94 75.2 0.92 78.6 0.90 68.8

SD

MIDa

14.8 21.0 17.9 22.3 8.4 14.7 14.8 21.4 18.8 30.2 23.1 24.2 26.5

2.56 5.94 6.93 7.72 4.45 9.30 6.45 7.41 5.32 6.04 6.53 7.65 11.85

23.2 23.7 24.3 24.2 21.4 22.5 23.6 25.7 25.0 6.1 1.8 21.3 26.7

(27.5 to 1.0) (29.6 to 2.1) (210.0 to 1.4) (211.0 to 2.6) (24.1 to 1.4) (26.9 to 1.8) (28.5 to 1.2) (211.7 to 0.4) (210.9 to 0.9) (21.1 to 13.4) (24.8 to 8.2) (27.6 to 4.9) (214.9 to 1.6)

0.21 0.18 0.21 0.18 0.14 0.16 0.21 0.31 0.28 0.24 0.08 0.06 0.23

15.4 22.1 23.7 27.6 6.6 13.1 17.1 23.4 18.0 31.1 23.8 22.9 29.6

2.68 4.94 5.30 6.15 2.72 7.75 5.41 6.19 4.41 5.39 5.83 6.48 9.36

23.9 22.7 25.3 23.6 23.1 24.2 25.6 28.2 25.6 7.6 1.3 0.4 22.2

(28.4 to 0.7) (29.4 to 4.0) (212.3 to 1.5) (211.3 to 4.0) (26.0 to 20.2)c (28.8 to 0.5) (211.2 to 0.04) (214.7 to 21.9)c (211.2 to 0.05) (20.08 to 15.2) (25.3 to 7.8) (26.1 to 7.0) (210.3 to 5.9)

0.23 0.11 0.21 0.13 0.30 0.25 0.28 0.36 0.28 0.28 0.06 0.02 0.08

Differences (95% CI)

Effect Size

Negative values indicate that patients with Crohn’s disease demonstrate more GI symptoms than patients with ulcerative colitis. Effect sizes are designated as small (0.20), medium (0.50), and large (0.80). Lower scores demonstrate more (worse) GI symptoms and hence lower (worse) GI-specific HRQOL. a The SEM was derived by multiplying the SD by the square root of 1-alpha. PedsQL scores in the column represent the transformed value of 1 SEM. For example, a patient self-reported 5.14 change in the Constipation Scale for patients with Crohn’s disease on the 0 to 100 scale represents a MID. b Summary Score of the 10 GI Symptoms Scales scores. c P , 0.05, based on independent samples t-tests (Bonferroni familywise correction for multiple comparisons, P ¼ 0.0038). CI, confidence interval.

patient and parent as a clinically meaningful difference in the construct being measured by the individual scale, and provide an important reference point that can be used in clinical research and practice.48 It should be noted that the MID values as calculated using the SEM represent theoretically stable measurement properties of a PRO instrument.52 This measurement stability is a function of the fact that “whereas the SD and the reliability of a measure are sample dependent, their relationship (and hence the SEM) remains relatively constant across samples”.47 The PedsQL

MID scale values presented in the tables may be used in estimating sample size requirements by determining the apriori statistical power to detect a clinically meaningful change for a planned clinical trial using these PROs as endpoints. The PedsQL Gastrointestinal Scales and PedsQL Gastrointestinal Worry Scales can each be used individually given the symptom profile for patients with IBD as a group or separately for patients with Crohn’s disease or ulcerative colitis. Identifying individual scales that are most relevant given the objectives and www.ibdjournal.org |

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TABLE 4. ICCs Between Patient Self-Report and Parent Proxy-Report on the PedsQL Gastrointestinal Symptoms Scales and Worry Scales PedsQL Gastrointestinal Symptoms and Worry Scales Symptoms Total Scoreb Stomach Pain and Hurt Stomach Discomfort When Eating Food and Drink Limits Trouble Swallowing Heartburn and Reflux Nausea and Vomiting Gas and Bloating Constipation Blood in Poop Diarrhea Worry About Going Poop Worry About Stomach Aches

Parent–Child Agreement ICCsa 0.75 0.71 0.58 0.67 0.35 0.54 0.62 0.58 0.66 0.73 0.75 0.70 0.65

ICCs are designated as #0.40 poor to fair agreement, 0.41 to 0.60 moderate agreement, 0.61 to 0.80 good agreement, and 0.81 to 1.00 excellent agreement. a P , 0.001 for all ICCs. b Summary Score of the 10 GI Symptoms Scales scores.

hypotheses of a planned clinical trial addresses the recommended standards for “acceptable patient and investigator burden,”9 and the Consolidated Standards of Reporting Trials (CONSORT) PRO extension.10 In determining which scales to use in a planned clinical trial, the MID values for the individual scales and the effect size differences between the patient groups and the healthy controls for each scale, in combination with the hypothesized mechanism of the pharmaceutical or behavioral treatment, will facilitate the decision-making process in scale selection. For instance, based on effect sizes between patients in Table 3 and healthy controls in Table 2, a symptoms profile may be selected that represents the largest effect sizes for individual scale scores, with accompanying MID values for each scale to facilitate apriori statistical power calculations for a planned clinical trial and sample size requirements. Patients with Crohn’s disease did report nonsignificantly more GI symptoms than patients with ulcerative colitis, except for diarrhea and blood in poop. These findings most likely represent the inherent differences in these 2 diseases. Although Crohn’s disease and ulcerative colitis are both chronic diseases characterized by inflammation of the intestines that share common symptom profiles, there are some symptom, clinical, and immune profile differences.21,53,54 Nevertheless, given the variability in disease severity within each disease, there are few clinical features that consistency differentiate between the 2 groups,54 which is supported in part by the nonsignificant differences in symptoms shown in this study.

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The majority of the scales demonstrated good agreement between patient self-report and parent proxy-report. This good informant agreement between children and their parents as demonstrated by the ICC values is reflected in the similar symptom profile effects sizes between patients and healthy controls for both patient self-report and parent proxy-report. Specifically, for both patient self-report and parent proxy-report, patients with IBD demonstrated the largest effect sizes (.0.50) for the Stomach Pain and Hurt Scale, Food and Drinks Limits Scale, Gas and Bloating Scale, Constipation Scale, Blood in Poop Scale, Diarrhea Scale, Worry About Going Poop Scale, and Worry About Stomach Aches Scale in comparison with the healthy controls. Patients and parents similarly agreed on the symptom profiles between Crohn’s disease and ulcerative colitis. These findings suggest that pediatric patients and their parents perceive the child’s symptom profiles similarly and support the general recommendation to include both pediatric patient and parent reports in clinical research and practice.55 This study included a relatively large overall sample size for patients with IBD and the matched healthy controls, with a nationwide representation. The healthy controls sample for this study was specifically matched to the age, gender, and race/ ethnicity of the IBD sample. Previously, we matched the healthy controls sample to the patient characteristics of the combined group of patients with functional and organic diseases.26 As a result, the age of the matched healthy controls sample for the previous field test study was 11.4 years, whereas the gender match was 46.2% boys and 53.8% girls. The matched healthy controls sample in this study reflects the older age of pediatric patients with IBD (13.9 yr) and the higher percentage of boys in the IBD sample (51.8% boys and 48.2% girls) in comparison with the previous study. Uniquely matching the healthy controls sample to the specific patient age, gender, and race/ethnicity characteristics provides a more precise determination of known-groups validity by essentially controlling for these background demographic characteristics in the comparisons of scale scores. Limitations of this study include the lack of information on families who chose not to participate, and the ulcerative colitis patient group sample size would have ideally been larger. We did not screen for pain-related GI symptoms in the Internet survey, which may have attenuated the differences between the patient and healthy controls groups. We were limited by the available database, which did not include disease activity indices such as the Pediatric Crohn’s Disease Activity Index56 and the Pediatric Ulcerative Colitis Activity Index57 in the validation process. Future research will need to include these indices in the validation of these new scales. Future research with these new scales will also benefit from direct comparisons with the IMPACT-III in the validation process, as was done in the validation of the PedsQL 4.0 Generic Core Scales and the PedsQL Multidimensional Fatigue Scale in pediatric patients with IBD.18 The PedsQL Gastrointestinal Symptoms Scales can make a significant contribution to the research and clinical literature by measuring changes in a broad spectrum of GI symptoms over time

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in pediatric patients with IBD. The PedsQL Gastrointestinal Symptoms and Worry Scales, in combination with the PedsQL 4.0 Generic Core Scales (physical, emotional, social, and school functioning),15–18,58 and when indicated the PedsQL Multidimensional Fatigue Scale (general fatigue, sleep/rest fatigue, cognitive fatigue),18 have the potential to provide a more comprehensive understanding of the health and well-being of children with IBD, leading to greater insight into new areas for future interventions to enhance symptom management and overall health-related quality of life.

ACKNOWLEDGMENTS Dr. J. W. Varni holds the copyright and the trademark for the PedsQL and receives financial compensation from the Mapi Research Trust, which is a nonprofit research institute that charges distribution fees to for-profit companies that use the Pediatric Quality of Life Inventory. Dr. J. W. Varni received investigatorinitiated funding from Takeda Pharmaceuticals North America, Inc. (Deerfield, Illinois) for the previous item generation qualitative methods study. Dr. J. F. Pohl received investigator-initiated funding from Takeda Pharmaceuticals North America, Inc. (Deerfield, Illinois) for the previous item generation qualitative methods study. Drs. J. W. Varni and J. F. Pohl did not receive funding from Takeda Pharmaceuticals North America, Inc., for the current quantitative methods field test study. Dr. J. F. Pohl has received the following funding: INSPPIRE to Study Acute Recurrent and Chronic Pancreatitis in Children, Grant# 10987759, National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases. Dr. J. F. Pohl is on the speaker’s bureau for Medical Education Resources, Inc. Dr. S. Nurko is supported by NIH grant K24DK082792A. Dr. R. J. Shulman is supported by NIH grants R01 NR013497, R34 AT006986, and T32 DK007664. Dr. S. Saeed has a consulting and speaker role for Abbvie, Inc. These grants are not related to this study. The remaining authors have no conflicts of interest to disclose.

REFERENCES 1. Kappelman MD, Moore KR, Allen JK, et al. Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population. Dig Dis Sci. 2013;58:519–525. 2. Ruel J, Ruane D, Mehandru S, et al. IBD across the age spectrum—is it the same disease? Nat Rev Gastroenterol Hepatol. 2014;11:88–98. 3. Malaty HM, Fan X, Opekun AR, et al. Rising incidence of inflammatory bowel disease among children: a 12-year study. J Pediatr Gastroenterol Nutr. 2010;50:27–31. 4. Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol. 2007;5:1424–1429. 5. Gasparetto M, Guariso G. Highlights in IBD epidemiology and its natural history in the paediatric age. Gastroenterol Res Pract. 2013;2013:1–12. 6. Mamula P, Markowitz JE, Baldassano RN. Inflammatory bowel disease in early childhood and adolescence: special considerations. Gastroenterol Clin North Am. 2003;32:967–995. 7. Crandall WV, Margolis PA, Kappelman MD, et al. Improved outcomes in a quality improvement collaborative for pediatric inflammatory bowel disease. Pediatrics. 2012;129:e1030–e1041. 8. Samson CM, Morgan P, Williams E, et al. Improved outcomes with quality improvement interventions in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2012;55:679–688.

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9. Reeve BB, Wyrwich KW, Wu AW, et al. ISOQOL recommends minimum standards for patient-reported outcome measures used in patient-centered outcomes and comparative effectiveness research. Qual Life Res. 2013;22: 1889–1905. 10. Calvert M, Blazeby J, Altman DG, et al. Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA. 2013;309:814–822. 11. FDA. Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Rockville, MD: Food and Drug Administration, U.S. Department of Health and Human Services; 2009. 12. FDA. Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics (GREAT Workshop). College Park, MD: Center for Drug Evaluation and Research, Food and Drug Administration; 2012. 13. FDA. Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics (GREAT II Workshop). College Park, MD: Center for Drug Evaluation and Research, Food and Drug Administration; 2013. 14. Williet N, Sandborn WJ, Peyrin–Biroulet L. Patient-reported outcomes as primary end points in clinical trials of inflammatory bowel disease. Clin Gastroenterol Hepatol. 2014;12:1246–1256. 15. Kunz JH, Hommel KA, Greenley RN. Health-related quality of life of youth with inflammatory bowel disease: a comparison with published data using the PedsQL 4.0 Generic Core Scales. Inflamm Bowel Dis. 2010;16: 939–946. 16. Perrin JM, Kuhlthau K, Chughtai A, et al. Measuring quality of life in pediatric patients with inflammatory bowel disease: psychometric and clinical characteristics. J Pediatr Gastroenterol Nutr. 2008;46:164–171. 17. Ryan JL, Mellon MW, Junger KW, et al. The clinical utility of healthrelated quality of life screening in a pediatric inflammatory bowel disease clinic. Inflamm Bowel Dis. 2013;19:2666–2672. 18. Marcus SB, Strople JA, Neighbors K, et al. Fatigue and health-related quality of life in pediatric inflammatory bowel disease. Clin Gastroenterol Hepatol. 2009;7:554–561. 19. Varni JW, Kay MT, Limbers CA, et al. PedsQL Gastrointestinal Symptoms Module item development: qualitative methods. J Pediatr Gastroenterol Nutr. 2012;54:664–671. 20. Varni JW, Bendo CB, Denham J, et al. PedsQL Gastrointestinal Symptoms Module: feasibility, reliability, and validity. J Pediatr Gastroenterol Nutr. 2014;59:347–355. 21. Griffiths AM, Nicholas D, Smith C, et al. Development of a quality-of-life index for pediatric inflammatory bowel disease: dealing with differences related to age and IBD type. J Pediatr Gastroenterol Nutr. 1999;28: S46–S52. 22. Otley A, Smith C, Nicholas D, et al. The IMPACT questionnaire: a valid measure of health-related quality of life in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2002;35:557–563. 23. Gallo J, Grant A, Otley AR, et al. Do parents and children agree? Qualityof-life assessment of children with inflammatory bowel disease and their parents. J Pediatr Gastroenterol Nutr. 2014;58:481–485. 24. Wernera H, Landolt MA, Buehrb P, et al. Validation of the IMPACT-III quality of life questionnaire in Swiss children with inflammatory bowel disease. J Crohns Colitis. 2014;8:641–648. 25. Abdovic S, Pavic AM, Milosevic M, et al. The IMPACT-III (HR) questionnaire: a valid measure of health-related quality of life in Croatian children with inflammatory bowel disease. J Crohns Colitis. 2013;7: 908–915. 26. Varni JW, Bendo CB, Denham J, et al. PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales in pediatric patients with functional and organic gastrointestinal diseases in comparison to healthy controls. Qual Life Res. 2015;24:363–378. 27. Schünemann HJ, Akl EA, Guyatt GH. Interpreting the results of patient reported outcome measures in clinical trials: the clinician’s perspective. Health Qual Life Outcomes. 2006;4:62. 28. Varni JW, Limbers CA. The Pediatric Quality of Life Inventory: measuring pediatric health-related quality of life from the perspective of children and their parents. Pediatr Clin North Am. 2009;56:843–863. 29. Hattie J, Cooksey RW. Procedures for assessing the validities of tests using the “known-groups” method. Appl Psychol Meas. 1984;8:295–305. 30. Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 Generic Core Scales in healthy and patient populations. Med Care. 2001;39:800–812. www.ibdjournal.org |

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31. Varni JW, Burwinkle TM, Seid M, et al. The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity. Ambul Pediatr. 2003;3:329–341. 32. Varni JW, Burwinkle TM, Seid M. The PedsQL 4.0 as a school population health measure: feasibility, reliability, and validity. Qual Life Res. 2006;15:203–215. 33. Alonso EM, Limbers CA, Neighbors K, et al. Cross-sectional analysis of health-related quality of life in pediatric liver transplant recipients. J Pediatr. 2010;156:270–276. 34. Pohl JF, Limbers CA, Kay MT, et al. Health-related quality of life in pediatric patients with long-standing pancreatitis. J Pediatr Gastroenterol Nutr. 2012;54:657–663. 35. Varni JW, Thompson KL, Hanson V. The Varni/Thompson Pediatric Pain Questionnaire: I. Chronic musculoskeletal pain in juvenile rheumatoid arthritis. Pain. 1987;28:27–38. 36. Fairclough DL. Design and Analysis of Quality of Life Studies in Clinical Trials: Interdisciplinary Statistics. New York, NY: Chapman & Hall/ CRC; 2002. 37. McHorney CA, Ware JE, Lu JFR, et al. 36-item short-form health survey (SF-36): III. Tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care. 1994;32:40–66. 38. Roth PL. Missing data: a conceptual review for applied psychologists. Personnel Psychol. 1994;47:537–570. 39. Cronbach LJ. Coefficient alpha and the internal structure of tests. Psychometrika. 1951;16:297–334. 40. Nunnally JC, Bernstein IR. Psychometric Theory. 3rd ed. New York, NY: McGraw-Hill; 1994. 41. McHorney CA, Ware JE, Rogers W, et al. The validity and relative precision of MOS short- and long-form health status scales and Dartmouth COOP charts: results from the Medical Outcomes Study. Med Care. 1992; 30:MS253–MS65. 42. Fayers PM, Machin D. Quality of Life: Assessment, Analysis, and Interpretation. New York, NY: Wiley; 2000. 43. McHorney CA, Ware JE, Raczek AE. The MOS 36-item short-form health survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care. 1993;31: 247–263. 44. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Erlbaum; 1988. 45. Wyrwich KW, Tierney WM, Wolinsky FD. Further evidence supporting an SEM-based criterion for identifying meaningful intra-individual changes in health-related quality of life. J Clin Epidemiol. 1999;52: 861–873. 46. Wyrwich KW, Norquist JM, Lenderking WR, et al. Methods for interpreting change over time in patient-reported outcome measures. Qual Life Res. 2013;22:475–483. 47. Crosby RD, Kolotkin RL, Williams GR. Defining clinically meaningful change in health-related quality of life. J Clin Epidemiol. 2003;56: 395–407. 48. Hilliard ME, Lawrence JM, Modi AC, et al. Identification of minimal clinically important difference scores of the Pediatric Quality of Life Inventory in children, adolescents, and young adults with type 1 and type 2 diabetes. Diabetes Care. 2013;36:1891–1897. 49. McGraw KO, Wong SP. Forming inferences about some intraclass correlation coefficients. Psychol Methods. 1996;1:30–46. 50. Bartko JJ. The intraclass correlation coefficient as a measure of reliability. Psychol Rep. 1966;19:3–11. 51. SPSS. SPSS 19.0 for Windows. Chicago, IL: SPSS, Inc.; 2010. 52. King MT. A point of minimal important difference (MID): a critique of terminology and methods. Expert Rev Pharmacoecon Outcomes Res. 2011;11:171–184.

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53. Kim SC, Ferry GD. Inflammatory bowel diseases in pediatric and adolescent patients: clinical, therapeutic, and psychosocial considerations. Gastroenterology. 2004;126:1550–1560. 54. Baldassano RN, Piccoli DA. Inflammatory bowel disease in pediatric and adolescent patients. Gastroenterol Clin North Am. 1999;28:445–458. 55. Eiser C, Varni JW. Health related quality of life and symptom reporting: similarities and differences between children and their parents. Eur J Pediatr. 2013;172:1299–1304. 56. Hyams J, Markowitz J, Otley A, et al. Evaluation of the pediatric crohn disease activity index: a prospective multicenter experience. J Pediatr Gastroenterol Nutr. 2005;41:416–421. 57. Turner D, Otley AR, Macks D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology. 2007;133:423–432. 58. Varni JW, Bendo CB, Nurko S, et al. Health-related quality of life in pediatric patients with functional and organic gastrointestinal diseases. J Pediatr. 2015;166:85–90.

APPENDIX 1: The PedsQL Gastrointestinal Symptoms Module Testing Study Consortium The Pediatric Quality of Life Inventory Gastrointestinal Symptoms Module Testing Study Consortium sites include a Network and Statistical Center at the Center for Health Systems & Design, Colleges of Architecture and Medicine, Texas A&M University, College Station, TX (PI: J. W. Varni, PhD), and 9 primary research data collection sites: Division of Pediatric Gastroenterology, Nationwide Children’s Hospital, Ohio State University School of Medicine, Columbus, OH (PI: J. Denham, MD); Department of Pediatrics, Baylor College of Medicine, Children’s Nutrition Research Center, Texas Children’s Hospital, Houston, TX (PIs: R. J. Shulman, MD and M. M. Self, PhD); Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Colorado, Aurora, CO (PI: D. A. Neigut, MD); Center for Motility and Functional Gastrointestinal Disorders, Boston Children’s Hospital, Harvard Medical School, Boston, MA (PI: S. Nurko, MD); Division of Pediatric Gastroenterology, Children’s Medical Center of Dallas, University of Texas Southwestern Medical School, Dallas, TX (PI: A. S. Patel, MD); Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH (PIs: J. P. Franciosi, MD, S. Saeed, MD, and G. M. Zacur, MD); Division of Gastroenterology, Hepatology and Nutrition, Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL (PI: M. Saps, MD); Division of Pediatric Gastroenterology, Hepatology and Nutrition, Goryeb Children’s Hospital, Morristown Medical Center, Morristown, NJ (PI: Barbara Verga, MD); Department of Pediatric Gastroenterology, Primary Children’s Hospital, University of Utah, Salt Lake City, UT (PI: J. F. Pohl, MD).