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Original Articles: Gastroenterology: Inflammatory Bowel Disease

Gastrointestinal Symptoms Predictors of Health-Related Quality of Life in Patients With Inflammatory Bowel Disease

Varni, James W.∗,†; Shulman, Robert J.; Self, Mariella M.§; Saeed, Shehzad A.||; Patel, Ashish S.; Nurko, Samuel#; Neigut, Deborah A.∗∗; Saps, Miguel††; Franciosi, James P.||; Denham, Jolanda M.‡‡; Zacur, George M.||; Dark, Chelsea V.§§; Bendo, Cristiane B.||||; Pohl, John F.¶¶; on behalf of the Pediatric Quality of Life Inventory Gastrointestinal Symptoms Module Testing Study Consortium

Author Information
Journal of Pediatric Gastroenterology and Nutrition: December 2016 - Volume 63 - Issue 6 - p e186-e192
doi: 10.1097/MPG.0000000000001428

Abstract

What Is Known

  • Past research has demonstrated that pediatric patients with inflammatory bowel disease report significantly impaired generic (general or nondisease-specific) health-related quality of life.

What Is New

  • No prior study has investigated the multidimensional gastrointestinal symptoms predictors of generic health-related quality of life in pediatric patients with inflammatory bowel disease from the perspectives of patients and parents.
  • Gastrointestinal symptoms accounted for 40% and 37% of the variability in health-related quality of life from the patient and parent perspectives, respectively, reflecting large effect sizes. Identifying disease-specific gastrointestinal symptoms that are the most important predictors from the patient and parent perspectives facilitates a family-centered approach to interventions designed to ameliorate impaired health-related quality of life.

Crohn disease and ulcerative colitis are the 2 most common inflammatory bowel diseases (IBDs) characterized by life-long chronic relapsing and remitting inflammation in the gastrointestinal tract (1,2). Recent estimates have indicated an increasing IBD prevalence worldwide (1,3,4), with approximately 25% of IBD prevalence estimated to occur in pediatric patients (5,6). The highest age-related incidence rate for the initial diagnosis of IBD in pediatric patients has been reported at 56% between 10 and 14 years of age, followed by 19% between ages 15 and 17 years, 18% between ages 5 and 9 years, and 8% before 4 years of age (5). A greater incidence and prevalence has been reported internationally for Crohn disease compared with ulcerative colitis in pediatric patients (3,5,6).

There has been a heightened awareness of the importance of incorporating patient-reported outcome data with clinical and biological data in determining treatment efficacy in clinical trials for patients with IBD (7). Past research has demonstrated the significant negative effect of pediatric IBD on generic (general or nondisease-specific) health-related quality of life (HRQOL), IBD-specific HRQOL as measured by the IMPACT questionnaire, and multidimensional fatigue from the patient's perspective (8–14). Generic HRQOL is a multidimensional construct, consisting at the minimum of the physical, psychological (including emotional and cognitive), and social health dimensions delineated by the World Health Organization (15,16).

Although the most commonly presenting gastrointestinal symptoms for both Crohn disease and ulcerative colitis are abdominal pain, diarrhea, and rectal bleeding (17), recent findings with the Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms Scales suggest a broader gastrointestinal symptoms profile for pediatric patients with IBD compared with healthy controls when assessed utilizing a validated multidimensional patient-reported outcome measurement instrument (18). The identification of specific patient-reported gastrointestinal symptoms predictors of generic HRQOL in pediatric patients with IBD derived from a standardized multidimensional gastrointestinal symptoms profile may facilitate interventions designed to ameliorate impaired overall HRQOL. Nevertheless, to our knowledge, there has been no prior research utilizing patient self-reported and parent proxy-reported multidimensional gastrointestinal symptoms as potential predictors of generic HRQOL in pediatric patients with IBD.

Consequently, to address this significant gap in the pediatric IBD literature, the primary objective of the present study was to investigate the predictive effect of a multidimensional gastrointestinal symptoms profile on generic HRQOL from the perspectives of pediatric patients with IBD and their parents. Based on the conceptualization of disease-specific symptoms as causal indicators of generic HRQOL (19), and our previous findings which identified significant differences across a multidimensional gastrointestinal symptoms profile when comparing pediatric patients with IBD to matched healthy controls (18), we expected that individual scales measuring patient self-reported and parent proxy-reported gastrointestinal symptoms would be significantly associated with generic HRQOL at the bivariate level of analysis. Although we anticipated that stomach pain would be a significant predictor variable in the multivariate models (20), given the lack of definitive prior research on the effect of a multidimensional gastrointestinal symptoms profile on generic HRQOL utilizing multivariate statistical methods, a priori hypotheses were not generated regarding the relative significance of the other individual gastrointestinal symptoms in the multivariate predictive models tested. We also tested this predictive multivariate model in exploratory analyses separately for Crohn disease and ulcerative colitis.

METHODS

Pediatric Patients and Settings

Pediatric patients with physician-diagnosed Crohn disease or ulcerative colitis based on ICD-9-CM Diagnosis Codes were recruited from 9 pediatric tertiary care gastroenterology clinical sites across the United States for the PedsQL Gastrointestinal Symptoms Module field test study (See Supplemental Digital Content, Appendix, https://links.lww.com/MPG/A812) (21). Data collection for the PedsQL Gastrointestinal Symptoms Module field test study took place between March 2011 and November 2013 (21). The present study reports unique statistical analyses of the data from the existing field test study database (8,18, 21–25). Specifically, we have not previously reported on multivariate models predicting generic HRQOL utilizing the Gastrointestinal Symptoms Scales in IBD. Written parental informed consent and child assent (when age appropriate) were obtained during the field test study (21). The research protocol for the field test study was approved by the institutional review board at each participating institution.

Measures

Pediatric Quality of Life Inventory Gastrointestinal Symptoms Scales

The PedsQL Gastrointestinal Symptoms Scales encompass 10 individual multi-item 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 Stool Scale (2 items), and 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 (26), with higher scores indicating better HRQOL and hence lower symptoms (21). The scales are composed of 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 self-report 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 gastrointestinal-specific symptoms. For the purposes of the present study, only patients ages 5 to 18 years were included. The items for each of the forms are essentially identical, differing in developmentally appropriate language, or 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 = never a problem; 1 = almost never a problem; 2 = sometimes a problem; 3 = often a problem; 4 = 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 = not at all a problem; 2 = sometimes a problem; 4 = a lot of a problem), and uses a faces scale adapted from the Pediatric Pain Questionnaire (27).

Items are reverse scored and linearly transformed to a 0 to 100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 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 (28). This accounts in part 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 (29). Cronbach alpha internal consistency reliability coefficients for the current sample ranged from 0.87 to 0.94 for patient self-report and 0.93 to 0.95 for parent proxy-report.

Pediatric Quality of Life Inventory 4.0 Generic Core Scales

The 23-item PedsQL 4.0 Generic Core Scales encompass: Physical Functioning Scale (8 items), Emotional Functioning Scale (5 items), Social Functioning Scale (5 items), and School Functioning Scale (5 items) (26). To create the Total Scale Score, the mean is computed as the sum of the items divided by the number of items answered in the Physical, Emotional, Social, and School Functioning Scales. The Total Scale Score measures overall generic HRQOL (26). Higher scores indicate better HRQOL. Cronbach alpha internal consistency reliability coefficients for the current sample were 0.91 for patient self-report and 0.94 for parent proxy-report.

Pediatric Quality of Life Inventory Family Information Form

Parents completed the PedsQL Family Information Form which contains demographic information including the child's age, sex, and race/ethnicity information (26).

Statistical Analysis

PedsQL Gastrointestinal Scales were selected as potential predictors of generic HRQOL based on previous findings comparing pediatric patients with IBD to healthy controls (18). Specifically, we selected the 6 Gastrointestinal Symptoms Scales that demonstrated medium (0.50) to large (0.80) effect size differences between patients with IBD compared with healthy controls (18). We considered these clinically important differences based on previous evidence (30).

Pearson product-moment correlation analyses were conducted to test the bivariate associations between the hypothesized predictor variables (PedsQL Gastrointestinal Symptoms Scales) with generic HRQOL as measured by the PedsQL 4.0 Generic Core Scales Total Scale Score. Bivariate correlation effect sizes are designated as small (0.10), medium (0.30), and large (0.50) in magnitude (31). Predictive analytics models utilizing multiple regression analyses were conducted to statistically predict the HRQOL criterion variable by the Gastrointestinal Symptoms Scales predictor variables after controlling for the demographic variables (32). Multiple regression analysis is a conservative statistical approach that isolates the effects of a predictor variable on a criterion variable by controlling for the influence of covariates (32). Hierarchical multiple regression analysis was the statistical procedure for testing the incremental variance accounted for by the set of Gastrointestinal Symptoms Scales predictors.

In the hierarchical multiple regression analyses predicting the HRQOL criterion variable, age (continuous variable), sex (coded male = 1, female = 2) and race/ethnicity (coded White non-Hispanic = 1, other race/ethnicity = 0) were entered in step 1 as demographic covariates (statistical control variables). The 6 Gastrointestinal Symptoms Scales previously identified as demonstrating clinically important differences between pediatric patients with IBD and healthy controls were entered in step 2. This sequence of hierarchical steps was intended to control for the age, sex, and race/ethnicity background variables in step 1, which may influence generic HRQOL, and to test the incremental variance accounted for (R2 change) by the selected gastrointestinal symptoms in step 2 in predicting generic HRQOL in the statistical models tested for both patient self-report and parent proxy-report. R2 is the explained variability divided by the total variability around the criterion variable mean. R2 change is the percentage of variability in the criterion variable (HRQOL mean) explained by the step. In this way, the covariance (shared variance) in the predictor variables and covariates were controlled, facilitating interpretation of incremental variance by the gastrointestinal symptoms predictor variables. Multiple regression effect sizes (R2) are designated as small (0.02), medium (0.13), and large (0.26) in magnitude (31). Statistical analyses were conducted using IBM SPSS (Armonk, NY).

RESULTS

Patient Characteristics

A total of 260 families of children with IBD ages 5 to 18 years participated. Patients were diagnosed with either Crohn disease (n = 193 families) or ulcerative colitis (n = 67 families). The average age of the 146 boys (56.2%) and 114 girls (43.8%) was 14.1 years (SD = 2.9). With respect to race/ethnicity, the sample contained 203 (78.1%) White non-Hispanic, 15 (5.8%) Hispanic, 26 (10.0%) Black non-Hispanic, 6 (2.3%) Asian/Pacific Islander, 1 Native American (0.4%), and 9 (3.5%) other.

Gastrointestinal Symptoms and Generic Core Scales Means and Standard Deviations

Table 1 contains the means and standard deviations of the 6 Gastrointestinal Symptoms Scales and Generic Core Total Scale Score for patient self-report and parent proxy-report in IBD.

T1
TABLE 1:
Pediatric Quality of Life Inventory Gastrointestinal Symptoms Scales and Generic Core Total Scale Scores with bivariate correlations in pediatric patients with inflammatory bowel disease

Bivariate Correlations Between Gastrointestinal Symptoms With Generic Health-Related Quality of Life

Table 1 demonstrates the bivariate correlations between the Gastrointestinal Symptoms Scales with the Generic Core Total Scale Score in IBD. The Gastrointestinal Symptoms Scales were significantly correlated with generic HRQOL (all P < 0.001), demonstrating medium to large effect sizes.

Hierarchical Multiple Regression Analyses Predicting Generic Health-Related Quality of Life in Inflammatory Bowel Disease

Table 2 presents the hierarchical multiple regression analyses predicting generic HRQOL in pediatric patients with IBD. After controlling for age, sex, and race/ethnicity in step 1, the gastrointestinal symptoms in step 2 significantly accounted for 40% of the variability in patient self-reported generic HRQOL (F [6, 239] = 28.37, P < 0.001), and 37% of the variability in parent proxy-reported patient generic HRQOL (F [6, 229] = 23.37, P < 0.001), representing large effect sizes. For patient self-report (N = 249 listwise), stomach pain (β = 0.28, P < 0.001), food and drink limits (β = 0.21, P < 0.001), and constipation (β = 0.21, P < 0.005) were significant individual predictor variables after controlling for the other gastrointestinal symptoms and the demographic variables. For parent proxy-report (N = 239 listwise), stomach pain (β = 0.31, P < 0.001) and food and drink limits (β = 0.20, P < 0.005) were significant individual predictor variables after controlling for the other gastrointestinal symptoms and the demographic variables.

T2
TABLE 2:
Hierarchical multiple regression analyses predicting generic health-related quality of life by the gastrointestinal symptoms predictor variables controlling for demographic variables in pediatric patients with inflammatory bowel disease

Exploratory Hierarchical Multiple Regression Analyses Predicting Generic Health-Related Quality of Life in Crohn Disease

After controlling for age, sex, and race/ethnicity in step 1, the gastrointestinal symptoms in step 2 significantly accounted for 41% of the variability in patient self-reported generic HRQOL (F [6, 179] = 23.30, P < 0.001), and 45% of the variability in parent proxy-reported patient generic HRQOL (F [6, 165] = 23.03, P < 0.001), representing large effect sizes for patients with Crohn disease. For patient self-report (N = 189 listwise), stomach pain (β = 0.27, P < 0.001), food and drink limits (β = 0.27, P < 0.001), and constipation (β = 0.28, P < 0.001) were significant individual predictor variables after controlling for the other gastrointestinal symptoms and the demographic variables. For parent proxy-report (N = 175 listwise), stomach pain (β = 0.26, P < 0.005) and food and drink limits (β = 0.26, P < 0.001) were significant individual predictor variables after controlling for the other gastrointestinal symptoms and the demographic variables. In addition for parent proxy-report, constipation (β = 0.16, P = 0.056) and blood in stool (β = 0.14, P = 0.051) demonstrated a trend approaching statistical significance.

Exploratory Hierarchical Multiple Regression Analyses Predicting Generic Health-Related Quality of Life in Ulcerative Colitis

After controlling for age, sex, and race/ethnicity in step 1, the gastrointestinal symptoms in step 2 significantly accounted for 43% of the variability in patient self-reported generic HRQOL (F [6, 50] = 6.37, P < 0.001), and 28% of the variability in parent proxy-reported patient generic HRQOL (F [6, 54] = 3.63, P < 0.005), representing large effect sizes for patients with ulcerative colitis. For patient self-report (N = 60 listwise), stomach pain (β = 0.39, P < 0.05) and gas and bloating (β = 0.45, P < 0.01) were significant individual predictor variables after controlling for the other gastrointestinal symptoms and the demographic variables. For parent proxy-report (N = 64 listwise), stomach pain (β = 0.49, P < 0.01) was a significant individual predictor variables after controlling for the other gastrointestinal symptoms and the demographic variables.

DISCUSSION

Our findings demonstrate that pediatric patient self-reported gastrointestinal symptoms were significant predictors of generic HRQOL in IBD, accounting for 40% of the variance, indicating a large effect size. Parent proxy-report similarly demonstrated a large effect size in the prediction of generic HRQOL by gastrointestinal symptoms in pediatric patients with IBD.

Patient-reported gastrointestinal symptoms differentially predicted HRQOL. Patient self-reported stomach pain, food and drink limits, and constipation were significant individual predictor variables after controlling for the other gastrointestinal symptoms and age, sex, and race/ethnicity in pediatric patients with Crohn disease, whereas patient self-reported stomach pain and gas and bloating were significant individual predictors for pediatric patients with ulcerative colitis. These findings suggest that in developing interventions to ameliorate impaired overall HRQOL in these patients, identifying the specific patient-reported predictors from a standardized multidimensional gastrointestinal symptoms profile may be most advantageous in maximizing treatment effectiveness. The assessment of pediatric patient gastrointestinal symptoms utilizing a standardized multidimensional gastrointestinal symptoms measurement instrument identifies in a systematic way the gastrointestinal symptoms that are most strongly associated with impaired HRQOL from the patient's perspective. Utilizing multi-item scales to measure these symptom constructs is different than typical clinical practice, and provides a more reliable and valid approach than asking patients about their symptoms without a standardized measurement instrument.

Although a recent study investigated the effect of abdominal pain on generic HRQOL in pediatric patients with IBD using a single-item pain measure (20), the present study is the first to our knowledge to test a multivariate predictive model of generic HRQOL utilizing patient self-reported and parent proxy-reported validated multi-item gastrointestinal symptoms scales in pediatric patients with IBD. Utilizing a standardized multidimensional gastrointestinal symptoms measurement instrument resulted in the identification of not only stomach pain, but also food and drink limits and constipation in pediatric patients with Crohn disease, and gas and bloating in pediatric patients with ulcerative colitis as additional predictors, expanding the number of factors for interventions designed to enhance overall HRQOL.

The present study included a relatively large sample size for patients with IBD, with a nationwide representation. Limitations of the present study include the lack of information on families who chose not to participate; the sample size for ulcerative colitis would ideally have been larger; the lack of information on the therapies that the patients were being administered; the lack of information on disease extent, duration, presence or absence of complications, and the adverse effects from therapy; and the cross-sectional design, which limits assumptions of directionality in statistical prediction. Longitudinal research will be necessary to test the directionality of the variables tested. The available database did not include disease activity indices such as the Pediatric Crohn's Disease Activity Index (33) and the Pediatric Ulcerative Colitis Activity Index (34). Future research will need to include disease activity indices in the statistical models tested.

Disease activity, which may have an effect on HRQOL (9,35,36), when systematically measured has often been found to indicate that the majority of established patients with IBD in tertiary care gastroenterology clinical sites have either quiescent or mild disease severity (10). Thus, in tertiary care gastroenterology clinical sites such as represented in the present study, it may be expected that the majority of patients may have well-controlled disease, and hence may be manifesting gastrointestinal symptoms associated with comorbid conditions. For example, common abdominal pain predominant functional gastrointestinal disorders, such as irritable bowel syndrome (IBS) and functional abdominal pain (FAP), are known comorbid conditions occurring in patients with IBD (37,38), including in patients experiencing IBD remission (39–41). Thus, in addition to abdominal pain, patients with IBD may report gastrointestinal symptoms common to IBS and FAP as found in the present study (24). Further research will be needed to elucidate the co-occurrence of these comorbid conditions in pediatric patients with IBD, and the accompanying gastrointestinal symptoms that may impair overall HRQOL.

As demonstrated previously (18), pediatric patients with IBD manifest a broad multidimensional gastrointestinal symptoms profile compared with age, sex, and race/ethnicity-matched healthy controls even when treated in tertiary care gastroenterology clinics focused on patient disease and symptom management. Given that the gastrointestinal symptoms identified in the present study as the strongest predictors of impaired generic HRQOL share some similarities to the gastrointestinal symptoms of pediatric patients with IBS and FAP (24), then empirically derived cognitive-behavioral treatment strategies for these disorders may be clinically relevant in IBD comprehensive interdisciplinary care. These techniques include coping skills training, cognitive distraction, cognitive reappraisal, including managing catastrophizing cognitions regarding pain-related symptoms, and progressive relaxation (42–44). In addition, given the prevalence of depressive symptoms in pediatric patients with IBD (45), cognitive-behavioral treatment strategies for depression may also be effective in symptom management with the goal of improving overall generic HRQOL (46).

In conclusion, the findings identified specific gastrointestinal symptoms from the patient and parent perspectives that were most strongly associated with generic HRQOL and that may be important predictors of overall HRQOL in pediatric patients with IBD, and hence may facilitate interventions that serve to enhance the health and well-being of these patients. Given previous findings that lower overall HRQOL as measured by the PedsQL 4.0 Generic Core Scales was prospectively predictive of increased healthcare utilization in pediatric patients with IBD over a subsequent 12-month period (10), including the number of IBD-related hospital admissions, gastroenterology clinic visits, emergency department visits, psychology clinic visits, telephone contacts, and pain management referrals, then interventions that address patient-reported gastrointestinal symptoms predictors of generic HRQOL derived from a standardized multidimensional gastrointestinal symptoms profile may have a positive effect on healthcare utilization patterns in these patients through better case management (10), including initiatives to improve the quality of care of pediatric patients with IBD (47,48).

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Keywords:

Crohn disease; gastrointestinal symptoms; inflammatory bowel disease; patient-reported outcomes; PedsQL; ulcerative colitis

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