What Is Known
- Functional constipation is one of the most prevalent functional gastrointestinal disorders of childhood worldwide with a negative impact on health-related quality of life.
- Patient-reported outcomes are imperative to assess symptoms.
What Is New
- No prior study has investigated a broad gastrointestinal symptoms profile comparing functional constipation with healthy controls using a well-validated gastrointestinal-specific patient-reported outcome.
- Patients with functional constipation manifested a broad gastrointestinal symptom profile in comparison with healthy controls with large differences, highlighting the critical need for more efficacious interventions to achieve healthy functioning.
Functional constipation is one of the most prevalent functional gastrointestinal disorders (FGIDs) of childhood worldwide (1). Pediatric patients with functional constipation typically present with symptoms of infrequent bowel movements, straining or pain during bowel movements, episodes of fecal incontinence resulting from rectal fecal impaction, intermittent abdominal pain, and feelings of being full or bloated with no identifiable organic etiology (2). Functional constipation results in high use of health care resources, including ambulatory care visits, emergency room visits, and hospitalizations, with associated high health care costs (3). Treatment success can be elusive, with a significant subgroup of patients requiring long-term treatment (4).
Pediatric patient–reported outcomes (PROs) are necessary to measure the symptom profile of functional constipation from the patient's perspective. Pediatric patients with functional constipation report a negative impact on general overall health-related quality of life (HRQOL) (5–7). Nevertheless, a broad assessment of the gastrointestinal symptom profile of pediatric patients with functional constipation compared with age-, sex-, and race/ethnicity-matched healthy controls has not been documented with a reliable and valid multidimensional gastrointestinal symptom-specific PRO instrument with patient self-report and parent proxy report. Furthermore, in assessing the broad gastrointestinal symptom profile of functional constipation, it is instructive to compare these patients’ symptom profiles to another FGID known to manifest chronic constipation. Irritable bowel syndrome (IBS) provides an ideal comparison group with a known broad gastrointestinal symptom profile in which chronic constipation may be a salient symptom (8,9).
The primary study objectives were to address this significant gap in the literature by comparing a broad spectrum of gastrointestinal symptoms and gastrointestinal worry in pediatric patients with functional constipation to uniquely matched healthy controls using the recently developed Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales (10,11), to report on the internal consistency reliability of these new scales in patients with functional constipation, and to establish clinical interpretability of these scales in functional constipation through the identification of minimal important difference (MID) scores consistent with recommended standards for PRO instruments in patient-centered outcomes and comparative effectiveness research (12). We hypothesized that patients with functional constipation would report a broad profile of gastrointestinal symptoms and worry when compared with uniquely matched healthy controls. The secondary objective compared the symptom profile of patients with functional constipation with patients with IBS. Based on pediatric IBS subtypes (8), we expected that pediatric patients with functional constipation would report similar constipation scores to patients with IBS, but that patients with IBS would report a broader gastrointestinal symptom profile than patients with functional constipation given prior findings (9), with IBS-associated abdominal pain being the predominant differentiator (13–16).
METHODS
Pediatric Patients and Settings
Pediatric patients with physician-diagnosed functional constipation or IBS were recruited from 9 pediatric tertiary care gastroenterology clinical sites across the United States as part of a larger study for the PedsQL Gastrointestinal Symptoms Module field test (see Appendix) (10). Participants were identified through a medical chart review with International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes 564.0 (chronic constipation) or 564.1 (IBS) and met pediatric Rome III criteria for functional constipation or IBS (17). The present study reports unique statistical analyses of the data from the existing field test study database (5,9–11,18,19). The scale internal consistency reliability in functional constipation and the comparisons using an age-, sex-, and race-/ethnicity-matched healthy controls sample created uniquely for functional constipation, effect size differences between functional constipation with IBS, and MID scores specifically for functional constipation have not been reported. Written parental informed consent and child assent (when age appropriate) were obtained during the field test study (10). 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 (www.yougov.com, Palo Alto, CA), an Internet polling firm, as described (11). YouGov was contracted to select participants from among their panel that age, sex, and race/ethnicity matched the overall patient sample for the larger field test study (11). 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. 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 ≥6 months and interfered with the child's activities as used in PedsQL studies. Families in which parents self-reported that their child had a chronic health condition were not included in the matched healthy sample. From the total sample of 792 families who participated in the Internet survey, a sample of families with healthy children was derived for the present study to uniquely match the age, sex, and race/ethnicity of the functional constipation sample. Parental informed consent and child assent (when age appropriate) were obtained through the panel survey protocol (11). The research protocol for the healthy sample survey was approved by the institutional review board.
Measures
PedsQL Gastrointestinal Symptoms Scales
The PedsQL Gastrointestinal Symptoms Scales encompass 10 individual scales: Stomach Pain and Hurt Scale (6 items), Stomach Discomfort When Eating Scale (5 items), Food and Drink Limits Scale (6 items), Trouble Swallowing Scale (3 items), Heartburn and Reflux Scale (4 items), Nausea and Vomiting Scale (4 items), Gas and Bloating Scale (7 items), Constipation Scale (14 items), Blood in Poop Scale (2 items), and Diarrhea Scale (7 items). The scales comprise 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. The instructions ask how much of a problem each item has been during the last 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 = never a problem, 1 = almost never a problem, 2 = sometimes a problem, 3 = often a problem, and 4 = almost always a problem). To further increase the ease of use for the young child self-report (ages 5–7 years), the response scale is reworded and simplified to a 3-point scale (0 = not at all a problem, 2 = sometimes a problem, and 4 = a lot of a problem) and uses a faces scale. Items are reverse scored and linearly transformed to a 0 to 100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, and 4 = 0), so that lower scores demonstrate more (worse) gastrointestinal symptoms and hence lower (worse) gastrointestinal-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 >50% of the items in the scale are missing, the scale score is not computed (20). 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 and other well-established HRQOL measures (20,21). To create the 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 Gastrointestinal Symptoms Scales.
PedsQL Gastrointestinal Worry Scales
The PedsQL Gastrointestinal Worry Scales encompass 2 individual scales: Worry About Going Poop Scale (5 items) and Worry About Stomach Aches Scale (2 items). Lower scores demonstrate more (worse) gastrointestinal-specific worry and hence lower (worse) gastrointestinal-specific HRQOL. These scales are scored similarly to the Gastrointestinal Symptoms Scales.
PedsQL Family Information Form
Parents completed the Family Information Form, which contains demographic information including the child's date of birth, sex, race/ethnicity, and parental education information (22).
Statistical Analysis
Cronbach coefficient alpha was used to determine scale internal consistency reliability (23). Scales with internal consistency reliabilities of ≥0.70 are recommended for comparing patient groups, whereas an internal consistency reliability criterion of 0.90 is recommended for analyzing individual patient scores (24). Clinical interpretability using the known-groups validity method compares scale scores across groups known to differ in the health construct being investigated (12). In this study, Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales scores in groups differing in known health condition (healthy participants vs participants known to have functional constipation), and comparisons between patients with functional constipation versus patients with IBS, were computed using independent samples t tests (Bonferroni familywise correction for multiple comparisons = 0.05/13 for child self-report and parent proxy report). To determine the magnitude of the anticipated differences, effect sizes were calculated by taking the difference between the healthy sample means with the functional constipation sample means, and between the functional constipation sample means with the IBS sample means, divided by the pooled standard deviation (SD) for each separate calculation. Effect sizes for differences in means are designated as small (0.20), medium (0.50), and large (0.80) in magnitude (25). The MID was calculated using the standard error of measurement (SEM) derived by multiplying the SD by the square root of 1-alpha (Cronbach alpha reliability coefficient) (26). The SEM has been linked to the MID, in which 1 SEM has demonstrated a strong correspondence to anchor-based individual change thresholds (27). The MID is considered the smallest clinically meaningful change in a PRO scale that can be detected (28,29).
RESULTS
Patient Characteristics
Table 1 contains the demographic characteristics of the functional constipation and IBS samples. A total of 189 families with children with functional constipation participated (116 children and 188 parents of children). There were 64 patients ages 2 to 4 years (34%) for the functional constipation sample: 43 patients ages 5 to 7 years (23%), 66 patients ages 8 to 12 years (35%), and 16 patients ages 13 to 18 years (8%). A total of 43 families with children with IBS participated (39 children and 43 parents of children).
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TABLE 1: Characteristics of pediatric patients with functional constipation, matched healthy controls, and pediatric patients with IBS
Characteristics of Healthy Controls
Table 1 contains the demographic characteristics of the healthy controls sample matched to the functional constipation sample. A total of 341 families (283 healthy children and 194 parents of healthy children) participated. There were no significant differences between the functional constipation sample and the healthy controls for age (t[528] = −0.068, P > 0.05), sex (χ2 [1] = 0.002, P > 0.05), or race/ethnicity (χ2 [4] = 0.058, P > 0.05). We also conducted a post hoc analysis of parental education. There were no significant differences between the functional constipation sample and the healthy controls for maternal education (χ2 [6] = 12.36, P > 0.05). There was a significantly higher education level, however, for paternal education for the healthy sample versus the functional constipation sample (χ2 [6] = 15.63, P < 0.05).
Internal Consistency Reliability
Cronbach alpha internal consistency reliability coefficients are shown in Table 2. All scales exceeded the minimum reliability standard of 0.70 required for group comparisons.
TABLE 2: Comparisons of PedsQL Gastrointestinal Symptoms Scales and Worry Scales Scores between pediatric patients with functional constipation and healthy controls for child self-report and parent proxy report
Comparisons With Healthy Controls
Table 2 demonstrates comparisons between pediatric patients with functional constipation with the healthy controls. For each of the Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales, pediatric patients with functional constipation demonstrated significantly more (worse) symptoms and worry (ie, lower scale scores) than the healthy controls (Bonferroni familywise correction for multiple comparisons, P = 0.0038), except for the Trouble Swallowing Scale for parent proxy report. The largest effect sizes were generally demonstrated for those scales most indicative of the expected symptom profile for patients with functional constipation in comparison with the healthy controls. Specifically, for patient self-report, patients with functional constipation demonstrated the largest effect sizes (>1.0) in comparison with the healthy controls in the following order beginning with the largest effect size: Worry About Going Poop Scale, Diarrhea Scale, Worry About Stomach Aches Scale, Constipation Scale, Stomach Pain and Hurt Scale, and Gas and Bloating Scale. For the parent proxy report, the following order was demonstrated beginning with the largest effect size: Constipation Scale, Worry About Going Poop Scale, Gas and Bloating Scale, Stomach Pain and Hurt Scale, Worry About Stomach Aches Scale, Diarrhea Scale, and Stomach Discomfort When Eating Scale. It should be noted that the Diarrhea Scale includes items such as “I have poop accidents in my underwear” that may reflect fecal incontinence for patients with functional constipation.
Comparisons With Patients With IBS
Table 3 presents the findings for the comparisons between pediatric patients with functional constipation and patients with IBS. Patients with functional constipation demonstrated no significant differences in the Constipation Scale in comparison with patients with IBS. After controlling for multiple comparisons, pediatric patients with functional constipation self-reported and their parents proxy reported significantly fewer symptoms than patients with IBS on the Stomach Pain and Hurt Scale, Stomach Discomfort When Eating Scale, and Worry About Stomach Aches Scale, with medium to large effect sizes.
TABLE 3: Comparisons of PedsQL Gastrointestinal Symptoms Scales and Worry Scales scores between pediatric patients with functional constipation and IBS for child self-report and parent proxy report
Table 3 also shows the MID scores for pediatric patients with functional constipation. These MID values provide additional information on the clinical interpretability of these scales specifically for patients with functional constipation. For example, a patient self-reported score change ≥6.59 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 functional constipation on the 0 to 100 scale range. Similarly, a parent proxy reported score change ≥5.90 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 functional constipation from the parent's perspective. The other MID values in Table 3 can be similarly interpreted.
DISCUSSION
Pediatric patients with functional constipation reported a broad gastrointestinal symptom profile in comparison with uniquely matched healthy controls with large effect size differences. Given the prevalence of gastrointestinal symptoms in the general pediatric population (13,15,30,31), it is imperative to benchmark the gastrointestinal symptom profile of pediatric patients with functional constipation with age-, sex-, and race/ethnicity-matched healthy controls to more fully understand the magnitude of these differences from the gastrointestinal functioning of healthy children. Benchmarking to healthy controls provides a more precise target of gastrointestinal symptoms ideally attainable by interventions designed to normalize gastrointestinal symptoms within the range of healthy functioning. The large deviations from the gastrointestinal functioning of healthy children across multiple domains for patients with functional constipation highlights the critical need for more efficacious interventions for this patient group.
Patients with functional constipation self-reported similar scores on the Constipation Scale in comparison with patients with IBS. Patients with IBS self-reported a broader symptom profile than patients with functional constipation, with the largest scale score differences for the Stomach Pain and Hurt Scale, the Stomach Discomfort When Eating Scale, and the Worry About Stomach Aches Scale. These differences are consistent with the literature on IBS, with abdominal pain being the predominant differentiator (13–16). The comparisons between patients with functional constipation and those with IBS are instructive in demonstrating the broad symptom profile of pediatric patients with functional constipation in comparison with another FGID known to be a multisymptom disorder (8,9).
Our findings demonstrate the internal consistency reliability, known-groups validity, and MID scale scores for the PedsQL Gastrointestinal Symptoms Scales and Gastrointestinal Worry Scales specifically for pediatric patients with functional constipation. These data address the recommended minimum standards for clinical interpretability of PRO scale scores (12). The MID values in the tables denote the smallest clinically meaningful change in the individual scales that can be detected for pediatric patients with functional constipation and represent meaningful variation in the measured symptom construct that is likely not because of measurement error (29). These MID scale values may be used in estimating sample size requirements for a clinical trial by determining the a priori statistical power to detect a clinically meaningful change when using these PROs as endpoints. The MID values may also be used as reference tables for health outcome evaluations in clinical practice settings (29).
The present study has several strengths, including the relatively large overall sample size for the patients with chronic constipation and the matched healthy sample, and the nationwide representation of the participants. Limitations include the lack of information on families who chose not to participate, a significantly higher paternal education level for the healthy sample in comparison with the functional constipation sample, and the use of an existing database (10). Patients with IBS were not identified by subtype in the field test study, and the IBS sample size would preferably have been larger. The IBS sample consisted of a young adolescent age group and a greater percentage of girls. This higher prevalence of female patients with IBS is consistent with the literature for pediatric and adult patients (8,32). In contrast, the demographic characteristics of the functional constipation sample consisted of a younger age group with approximately equal sex prevalence, generally consistent with the literature (1). Future studies with a larger sample of pediatric patients with IBS should attempt a closer demographic match.
Finally, given the similarities and differences in gastrointestinal symptom profiles between patients with functional constipation and IBS, future research using the Rome III diagnostic criteria should investigate whether the IBS-constipation (IBS-C) subtype is a distinct disorder from functional constipation in childhood. In adult patients, the similarities in symptom profiles between patients with functional constipation and the IBS-C subtype have called into question whether these 2 groups of patients are distinct disorders as identified by the Rome III criteria (33). This is a limitation of the present Rome III criteria in that they were not specifically designed to identify IBS subtypes. Furthermore, the exact relation between functional constipation and the IBS-C subtype in children is also not clear. There is some controversy whether these 2 disorders represent a continuum, or different entities separated by the presence of abdominal pain that persists even after the constipation is adequately treated in those patients with IBS-C (33). Even though we did not classify our patients into different IBS subtypes, recent evidence suggests that in pediatric patients, IBS with constipation is the most common subtype, representing 58.1% in a recent study, whereas 34.1% of the sample were diagnosed with unsubtyped IBS, 5.4% presented with IBS with diarrhea, and 2.3% had mixed IBS (constipation and diarrhea) (8). These recent data further suggest the possibility that children with functional constipation and those with IBS-C are mostly differentiated by the presence of abdominal pain, generally consistent with the results of the present study. Our findings additionally support the validity of the PedsQL Gastrointestinal Symptoms Scales as common metrics in pediatric patients with functional constipation or IBS given that the data are consistent with the a priori hypotheses based on the aforementioned extant literature. That is, it was expected that IBS-associated abdominal pain would be the predominant differentiator in comparing these 2 patient groups using the new PedsQL Gastrointestinal Symptoms Scales.
In conclusion, the study findings contribute to our understanding of the broad gastrointestinal symptom profile of pediatric patients with functional constipation in comparison with matched healthy controls. The lack of statistically significant differences across multiple gastrointestinal symptoms between pediatric patients with functional constipation and those with IBS highlights the importance of clinical assessment across a broad symptom profile in the management of functional constipation. As noted above, these findings further support the utility of the new PedsQL Gastrointestinal Symptoms and Worry Scales as common metrics in identifying similarities and differences in multidimensional gastrointestinal functioning across different pediatric patient groups and healthy populations. When combined with generic HRQOL instruments that measure physical, emotional, social, and school functioning (5–7), these gastrointestinal-specific scales may result in a more comprehensive and precise understanding of the health and well-being of pediatric patients with functional constipation.
Appendix
PedsQL Gastrointestinal Symptoms Module Testing Study Sites
The PedsQL Gastrointestinal Symptoms Module Testing Study 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 (primary investigator [PI]: James 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: Jolanda Denham, MD); Department of Pediatrics, Baylor College of Medicine, Children's Nutrition Research Center, Texas Children's Hospital, Houston, TX (PIs: Robert J. Shulman, MD and Mariella M. Self, PhD); Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, Aurora, CO (PI: Deborah A. Neigut, MD); Center for Motility and Functional Gastrointestinal Disorders, Boston Children's Hospital, Harvard Medical School, Boston, MA (PI: Samuel Nurko, MD); Division of Pediatric Gastroenterology, Children's Medical Center of Dallas, University of Texas Southwestern Medical School, Dallas, TX (PI: Ashish S. Patel, MD); Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (PIs: James P. Franciosi, MD, Shehzad Saeed, MD, and George M. Zacur, MD); Division of Gastroenterology, Hepatology and Nutrition, Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL (PI: Miguel 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: John F. Pohl, MD).
REFERENCES
1. van den Berg MM, Benninga MA, Di Lorenzo C. Epidemiology of childhood constipation: a systematic review.
Am J Gastroenterol 2006; 101:2401–2409.
2. Nurko S, Zimmerman LA. Evaluation and treatment of constipation in children and adolescents.
Am Fam Physician 2014; 90:82–90.
3. Chogle A, Saps M. Yield and cost of performing screening tests for constipation in children.
Can J of Gastroenterol 2013; 27:e35–e38.
4. Nurko S, Saps M. Treating constipation with prucalopride: one size does not fit all.
Gastroenterology 2014; 147:1214–1216.
5. 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.
6. Youssef NN, Langseder AL, Verga BJ, et al. Chronic childhood constipation is associated with impaired quality of life: a case-controlled study.
J Pediatr Gastroenterol Nutr 2005; 41:56–60.
7. Hartman EE, Pawaskar M, Williams V, et al. Psychometric properties of the
PedsQL Generic Core Scales for children with
functional constipation in the Netherlands.
J Pediatr Gastroenterol Nutr 2014; 59:739–747.
8. Self MM, Czyzewski DI, Chumpitazi BP, et al. Subtypes of
irritable bowel syndrome in children and adolescents.
Clin Gastroenterol Hepatol 2014; 12:1468–1473.
9. Varni JW, Shulman RJ, Self MM, et al. Pediatric Quality of Life Inventory Gastrointestinal
Symptoms Module Testing Study Consortium. Symptom profiles in patients with
irritable bowel syndrome or functional abdominal pain compared to healthy controls.
J Pediatr Gastroenterol Nutr 2015; 61:323–329.
10. Varni JW, Bendo CB, Denham J, et al.
PedsQL™ Gastrointestinal
Symptoms Module: feasibility, reliability, and validity.
J Pediatr Gastroenterol Nutr 2014; 59:347–355.
11. 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.
12. 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.
13. Hyams JS, Burke G, Davis PM, et al. Abdominal pain and
irritable bowel syndrome in adolescents: a community-based study.
J Pediatr 1996; 129:220–226.
14. Mohammad S, Di Lorenzo C, Youssef NN, et al. Assessment of abdominal pain through global outcomes and recent FDA recommendations in children: are we ready for change?
J Pediatr Gastroenterol Nutr 2014; 58:46–50.
15. Chiou E, Nurko S. Functional abdominal pain and
irritable bowel syndrome in children and adolescents.
Therapy 2011; 8:315–331.
16. Czyzewski DI, Lane MM, Weidler EM, et al. The interpretation of Rome III criteria and method of assessment affect the
irritable bowel syndrome classification of children.
Aliment Pharmacol and Ther 2011; 33:403–411.
17. Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders: child/adolescent.
Gastroenterol 2006; 130:1527–1537.
18. Varni JW, Bendo CB, Shulman RJ, et al. Interpretability of the
PedsQL™ Gastrointestinal
Symptoms Scales and Gastrointestinal Worry Scales in pediatric patients with functional and organic gastrointestinal diseases.
J Pediatr Psychol 2015; 40:591–601.
19. Varni JW, Franciosi JP, Shulman RJ, et al.
PedsQL™ Gastrointestinal
Symptoms Scales and Gastrointestinal Worry Scales in pediatric patients with inflammatory bowel disease in comparison to healthy controls.
Inflamm Bowel Dis 2015; 21:1115–1124.
20. Fairclough DL. Design and Analysis of Quality of Life Studies in Clinical Trials: Interdisciplinary Statistics. New York: Chapman & Hall/CRC; 2002.
21. 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.
22. 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.
23. Cronbach LJ. Coefficient alpha and the internal structure of tests.
Psychometrika 1951; 16:297–334.
24. Nunnally JC, Bernstein IR. Psychometric Theory. New York, NY: McGraw-Hill; 1994.
25. Cohen J. Statistical Power Analysis for the Behavioral Sciences. Hillsdale, NJ: Erlbaum; 1988.
26. 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.
27. 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.
28. Crosby RD, Kolotkin RL, Williams GR. Defining clinically meaningful change in health-related quality of life.
J Clin Epidemiol 2003; 56:395–407.
29. 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.
30. Chitkara DK, Rawat DJ, Talley NJ. The epidemiology of childhood recurrent abdominal pain in Western countries: a systematic review.
Am J Gastroenterol 2005; 100:1868–1875.
31. Saps M, Sesphadri R, Sztainberg M, et al. A prospective school-based study of abdominal pain and other common somatic complaints in children.
J Pediatr 2009; 154:322–326.
32. Engsbro AL, Simren M, Bytzer P. Short-term stability of subtypes in the
irritable bowel syndrome: prospective evaluation using the Rome III classification.
Alimen Pharmacol Ther 2012; 35:350–359.
33. Wong RK, Palsson OS, Turner MJ, et al. Inability of the Rome III criteria to distinguish
functional constipation from constipation-subtype
irritable bowel syndrome.
Am J Gastroenterol 2010; 105:2228–2234.
