A Comparison of Preference-Based, Generic and Disease-Specific Health-Related Quality of Life in Pediatric Inflammatory Bowel Disease.

Objective: Generic preference-based HRQOL assessments used expressly for economic evaluation have not been examined in pediatric Crohn's disease (CD) and ulcerative colitis (UC). The objective was to further assess the construct validity of preference-based HRQOL measures in pediatric IBD by comparing the Child Health Utility 9 Dimensions (CHU9D) and Health Utilities Index (HUI) to the disease-specific IMPACT-III and to the generic PedsQL in children with CD and with UC. Methods: The CHU9D, HUI, IMPACT-III and/or PedsQL were administered to Canadian children aged 6 to 18 years with CD and UC. CHU9D total and domain utilities were calculated using adult and youth tariffs. HUI total and attribute utilities were determined for the HUI2 and HUI3. Total scores for IMPACT-III and PedsQL were determined. Spearman correlations were calculated between generic preference-based utilities and the IMPACT-III and PedsQL scores. Results: The questionnaires were administered to 157 children with CD and 73 children with UC. Moderate to strong correlations were observed between the CHU9D, HUI2, HUI3 and the disease-specific IMPACT-III or generic PedsQL. As hypothesized, domains with similar constructs demonstrated stronger correlations, such as the Pain and Well-being domains. Conclusions: While all questionnaires were moderately correlated with the IMPACT-III and PedsQL questionnaires, the CHU9D using youth tariffs and the HUI3 were most strongly correlated and would be suitable choices to generate health utilities for children with CD or UC for the purpose of economic evaluation of treatments in pediatric IBD.

Targeted Assessment of Mucosal Immune Gene Expression Predicts Clinical Outcomes in Children with Ulcerative Colitis.

BACKGROUND AND AIMS: We aimed to determine whether a targeted gene expression panel could predict clinical outcomes in paediatric ulcerative colitis [UC] and investigated putative pathogenic roles of predictive genes. METHODS: In total, 313 rectal RNA samples from a cohort of newly diagnosed paediatric UC patients (PROTECT) were analysed by a real-time PCR microfluidic array for expression of type 1, 2 and 17 inflammation genes. Associations between expression and clinical outcomes were assessed by logistic regression. Identified prognostic markers were further analysed using existing RNA sequencing (RNA-seq) data sets and tissue immunostaining. RESULTS: IL13RA2 was associated with a lower likelihood of corticosteroid-free remission (CSFR) on mesalamine at week 52 (p = .002). A model including IL13RA2 and only baseline clinical parameters was as accurate as an established clinical model, which requires week 4 remission status. RORC was associated with a lower likelihood of colectomy by week 52. A model including RORC and PUCAI predicted colectomy by 52 weeks (area under the receiver operating characteristic curve 0.71). Bulk RNA-seq identified IL13RA2 and RORC as hub genes within UC outcome-associated expression networks related to extracellular matrix and innate immune response, and lipid metabolism and microvillus assembly, respectively. Adult UC single-cell RNA-seq data revealed IL13RA2 and RORC co-expressed genes were localized to inflammatory fibroblasts and undifferentiated epithelial cells, respectively, which was supported by protein immunostaining. CONCLUSION: Targeted assessment of rectal mucosal immune gene expression predicts 52-week CSFR in treatment-naïve paediatric UC patients. Further exploration of IL-13Rɑ2 as a therapeutic target in UC and future studies of the epithelial-specific role of RORC in UC pathogenesis are warranted.

Indirect and Out-of-Pocket Disease-associated Costs in Pediatric Inflammatory Bowel Disease: A Cross-sectional Analysis.

OBJECTIVES: Data on pediatric inflammatory bowel disease (IBD)-associated indirect and out-of-pocket (OOP) costs are limited. We aimed to estimate indirect (lost work hours and productivity) and OOP pediatric IBD-associated costs in Canada. METHODS: In a nation-wide cross-sectional analysis, caregivers of children with IBD were invited to complete a questionnaire on lost work hours and OOP costs related to IBD in the 4 weeks prior to the survey. Participants were reinvited to periodically answer the same questionnaire every 3-9 months for 2 years. Lost productivity was calculated using the Human Capital method. Costs were reported in 2018 inflation-adjusted Canadian dollars. Predictors of high cost users (top 25%) were examined using binary logistic regression. RESULTS: Consecutive 243 (82 incident cases) of 262 (92.7%) approached participants completed the first survey with a total of 450 surveys longitudinally completed over 2 years. The median annual indirect cost per patient was $5966 (IQR $1809-$12,676), with $5721 (IQR $1366-$11,545) for Crohn's disease (CD) and $7007 (IQR $2428-$14,057) for ulcerative colitis (UC) ( P = 0.11). The annual median per patient OOP costs were $4550 with $4550 for CD and $5038 for UC ( P = 0.53). Longer travel distance to clinic was associated with higher OOP costs (odds ratio = 4.55; P < 0.0001; 95% confidence interval: 1.99-10.40). CONCLUSIONS: Indirect and OOP IBD-associated costs are substantial and more likely to affect families living in remote communities.

Imputing missing patient-level data and propensity score matching in cost-effectiveness analysis in Crohn's disease.

OBJECTIVES: The effect of imputing missing data followed by propensity score analysis on the incremental cost-effectiveness ratio (ICER) in a cost-effectiveness analysis is unknown. The objective was to compare alternative approaches in grouping data following imputation and prior to calculating propensity scores for use in economic evaluation. METHODS: Patient-level data from an observational study of 573 children with Crohn's disease were used in a microsimulation model to determine the incremental cost of early anti-tumor necrosis factor-α treatment compared to standard care per remission week gained. Multiple imputation of a missing covariate followed by propensity score matching to create comparator groups was approached in two ways. The Within approach calculated propensity scores on each imputed dataset separately, while the Across method averaged propensity scores to create one matched population resulting in multiple sets of health state transition probabilities. RESULTS: The incremental cost per remission week gained ranged from CAD$2,236 to CAD$12,464 (mean CAD$4,266) with Within datasets and was CAD$4,679 per remission week gained with the Across dataset. CONCLUSION: Imputation of missing patient-level data and propensity score analysis increases methodological uncertainty in cost-effectiveness analysis. The present study indicated that the Across approach may be less cumbersome, and slightly reduce bias and variance.

An Assessment of the Validity and Reliability of the Pediatric Child Health Utility 9D in Children with Inflammatory Bowel Disease.

Health utilities relevant to children are lacking, compromising health funding and policy decisions for children. The Child Health Utility 9D (CHU9D) is a recently developed preference-based health utility instrument designed for use in children. The objective was to examine the validity of the CHU9D in a cohort of 285 Canadian children aged 6.5 to 18 years of age with Crohn's disease (CD) and ulcerative colitis (UC), (collectively inflammatory bowel disease (IBD)). The correlation and agreement between paired CHU9D and Health Utility Index (HUI) assessments were determined with Spearman coefficients and Bland-Altman levels of agreement. Total and domain utilities were calculated for the CHU9D using Australian adult and youth tariffs. Algorithms for HUI2 and HUI3 were used. Domain correlations were determined between domains with expected overlap between instruments. In CD and in UC, correlations between CHU9D, HUI2, and HUI3 utilities ranged between 0.62 to 0.67 and 0.67 to 0.69, respectively (p < 0.05). CHU9D utilities were lower using youth tariffs compared to adult tariffs. A large range in health utilities suggested a heterogeneous quality of life. The CHU9D is a good option for preference-based utility measurement in pediatric IBD. Additional research is required to derive pediatric tariffs to conduct economic evaluation in children.

Development and Validation of the Mucosal Inflammation Noninvasive Index For Pediatric Crohn's Disease.

BACKGROUND & AIMS: Mucosal healing (MH) has become a goal of therapy for Crohn's disease (CD), but frequent endoscopies are not feasible. We aimed to develop and validate a non-invasive index to assess mucosal inflammation in children with CD. METHODS: We collected data from the multi-center prospective ImageKids study, in which children with CD underwent ileocolonoscopy with magnetic resonance enterography. We investigated the association of pediatric CD activity index (PCDAI) items and laboratory test results with the simple endoscopic score for CD (SESCD). We used these data in a blended mathematical judgmental clinimetric approach to develop a weighted categorized index to identify children with CD who have MH, which we called the MINI index. We validated the index using data from 3 independent patient cohorts. The derivation and validation cohorts included 154 and 168 children, respectively (age 14.1 ± 2.5 years and 14.2 ± 3.9 years), of whom 16% and 36% had MH (defined as SESCD<3). RESULTS: In multivariable models, the stooling item of the PCDAI, erythrocyte sedimentation rate, and level of fecal calprotectin were associated with SESCD (all P < .05). We added data on level of C-reactive protein to develop the MINI index. MINI scores below 8 identified children with MH with 88% sensitivity and 85% specificity in the derivation cohort and with 84% sensitivity and 87% specificity in the validation cohorts. Ninety percent of the patients in the validation cohort with scores of 8 or more had active mucosal inflammation, yet 78% of patients with scores below 8 had MH. Scores below 6 increase the positive predictive value to 86%. CONCLUSIONS: We developed an index to non-invasively assess mucosal inflammation in children with CD. This index, identifies children with MH with high sensitivity and specificity. The added benefit of MINI over measurement of fecal calprotectin was small but significant, especially for patients with concentrations of fecal calprotectin from 100 to 599 µg/g. ClinicalTrials.gov no: NCT01881490.

Cost-effectiveness and Clinical Outcomes of Early Anti-Tumor Necrosis Factor-α Intervention in Pediatric Crohn's Disease.

BACKGROUND: Anti-tumor necrosis factor-α (anti-TNF-α) treatments are increasingly used to treat pediatric Crohn's disease, even without a prior trial of immunomodulators, but the cost-effectiveness of such treatment algorithms has not been formally examined. Drug plan decision-makers require evidence of cost-effectiveness to inform funding decisions. The objective was to assess the incremental cost-effectiveness of early intervention with anti-TNF-α treatment vs a conventional step-up strategy per steroid-free remission-week gained from public health care and societal payer perspectives over 3 years. METHODS: A probabilistic microsimulation model was constructed for children with newly diagnosed moderate to severe Crohn's disease receiving anti-TNF-α treatment and concomitant treatments within the first 3 months of diagnosis compared with children receiving standard care consisting of steroids and/or immunomodulators with the possibility of anti-TNF-α treatment after 3 months of diagnosis. A North American multicenter observational study with 360 patients provided input into clinical outcomes and health care resource use. RESULTS: Early intervention with anti-TNF-α treatment was more costly, with an incremental cost of CAD$31,112 (95% confidence interval [CI], $2939-$91,715), and more effective, with 11.3 more weeks in steroid-free remission (95% CI, 10.6-11.6) compared with standard care, resulting in an incremental cost per steroid-free remission-week gained of CAD$2756 from an Ontario public health care perspective and CAD$2968 from a societal perspective. The incremental cost-effectiveness ratio was sensitive to the price of infliximab. CONCLUSIONS: The results suggest that although early anti-TNF-α was not cost-effective, it was clinically beneficial. These findings, along with other randomized controlled trial evidence, may inform formulary decision-making.

Toward enteral nutrition for the treatment of pediatric Crohn disease in Canada: a workshop to identify barriers and enablers.

The treatment armamentarium in pediatric Crohn disease (CD) is very similar to adult-onset CD with the notable exception of the use of exclusive enteral nutrition (EEN [the administration of a liquid formula diet while excluding normal diet]), which is used more frequently by pediatric gastroenterologists to induce remission. In pediatric CD, EEN is now recommended by the pediatric committee of the European Crohn's and Colitis Organisation and the European Society for Paediatric Gastroenterology Hepatology and Nutrition as a first-choice agent to induce remission, with remission rates in pediatric studies consistently >75%. To chart and address enablers and barriers of use of EEN in Canada, a workshop was held in September 2014 in Toronto (Ontario), inviting pediatric gastroenterologists, nurses and dietitians from most Canadian pediatric IBD centres as well as international faculty from the United States and Europe with particular research and clinical expertise in the dietary management of pediatric CD. Workshop participants ranked the exclusivity of enteral nutrition; the health care resources; and cost implications as the top three barriers to its use. Conversely, key enablers mentioned included: standardization and sharing of protocols for use of enteral nutrition; ensuring sufficient dietetic resources; and reducing the cost of EEN to the family (including advocacy for reimbursement by provincial ministries of health and private insurance companies). Herein, the authors report on the discussions during this workshop and list strategies to enhance the use of EEN as a treatment option in the treatment of pediatric CD in Canada.

Gastrointestinal Endoscopy Competency Assessment Tool: reliability and validity evidence.

BACKGROUND: Rigorously developed and validated direct observational assessment tools are required to support competency-based colonoscopy training to facilitate skill acquisition, optimize learning, and ensure readiness for unsupervised practice. OBJECTIVE: To examine reliability and validity evidence of the Gastrointestinal Endoscopy Competency Assessment Tool (GiECAT) for colonoscopy for use within the clinical setting. DESIGN: Prospective, observational, multicenter validation study. Sixty-one endoscopists performing 116 colonoscopies were assessed using the GiECAT, which consists of a 7-item global rating scale (GRS) and 19-item checklist (CL). A second rater assessed procedures to determine interrater reliability by using intraclass correlation coefficients (ICCs). Endoscopists' first and second procedure scores were compared to determine test-retest reliability by using ICCs. Discriminative validity was examined by comparing novice, intermediate, and experienced endoscopists' scores. Concurrent validity was measured by correlating scores with colonoscopy experience, cecal and terminal ileal intubation rates, and physician global assessment. SETTING: A total of 116 colonoscopies performed by 33 novice (<50 previous procedures), 18 intermediate (50-500 previous procedures), and 10 experienced (>1000 previous procedures) endoscopists from 6 Canadian hospitals. MAIN OUTCOME MEASUREMENTS: Interrater and test-retest reliability, discriminative, and concurrent validity. RESULTS: Interrater reliability was high (total: ICC=0.85; GRS: ICC=0.85; CL: ICC=0.81). Test-retest reliability was excellent (total: ICC=0.91; GRS: ICC=0.93; CL: ICC=0.80). Significant differences in GiECAT scores among novice, intermediate, and experienced endoscopists were noted (P<.001). There was a significant positive correlation (P<.001) between scores and number of previous colonoscopies (total: ρ=0.78, GRS: ρ=0.80, CL: Spearman's ρ=0.71); cecal intubation rate (total: ρ=0.81, GRS: Spearman's ρ=0.82, CL: Spearman's ρ=0.75); ileal intubation rate (total: Spearman's ρ=0.82, GRS: Spearman's ρ=0.82, CL: Spearman's ρ=0.77); and physician global assessment (total: Spearman's ρ=0.90, GRS: Spearman's ρ=0.94, CL: Spearman's ρ=0.77). LIMITATIONS: Nonblinded assessments. CONCLUSION: This study provides evidence supporting the reliability and validity of the GiECAT for use in assessing the performance of live colonoscopies in the clinical setting.

The gastrointestinal endoscopy competency assessment tool for pediatric colonoscopy.

OBJECTIVES: Validated assessment tools are required to support competency-based education. We aimed to assess the reliability and validity of the Gastrointestinal Endoscopy Competency Assessment Tool for Pediatric Colonoscopy (GiECATKIDS), an instrument developed by 41 North American experts using Delphi methodology. METHODS: GiECATKIDS consists of a 7-item global rating scale (GRS) and an 18-item checklist (CL). An attending physician assessed 104 colonoscopies performed at 3 North American hospitals by 56 endoscopists, including 25 novices (<50 previous procedures), 21 intermediates (50-250), and 10 advanced endoscopists (>500). Another observer rated procedures to assess interrater reliability using intraclass correlation coefficient (ICC). Test-retest reliability was measured with ICC comparing endoscopists' first and second procedure scores. Discriminative validity was examined by comparing experience level with scores. Concurrent validity was assessed by correlating scores with colonoscopy experience, cecal and terminal ileal intubation rates, and physician global assessment. RESULTS: Interrater reliability of the GiECATKIDS was high (total: ICC = 0.88; GRS: ICC = 0.79; CL: ICC = 0.89). Test-retest reliability was excellent (total: ICC = 0.94; GRS: ICC = 0.94; CL: ICC = 0.84). GiECATKIDS total, GRS, and CL scores differed significantly among novice, intermediate, and advanced endoscopists (P < 0.001). There was a significant positive correlation (P < 0.001) between scores and number of previous colonoscopies (total: ρ = 0.91, GRS: ρ = 0.92, CL: ρ = 0.84), cecal intubation rate (total: ρ = 0.82, GRS: ρ = 0.85, CL: ρ = 0.77), ileal intubation rate (total: ρ = 0.82, GRS: ρ = 0.82, CL: ρ = 0.80), and physician global assessment (total: ρ = 0.95, GRS: ρ = 0.94, CL: ρ = 0.89). CONCLUSIONS: The GiECATKIDS demonstrates strong reliability and validity as a measure of performance of pediatric colonoscopy that can be used to support training and assessment.

Development of the gastrointestinal endoscopy competency assessment tool for pediatric colonoscopy (GiECAT KIDS).

OBJECTIVES: Many aspects of pediatric colonoscopy differ from adult practice. To date, there is no validated measure of endoscopic competence for use in pediatrics. Using Delphi methodology, we aimed to determine expert consensus regarding items required on a checklist and global rating scale designed to assess the competence of clinicians performing colonoscopy on pediatric patients. METHODS: A total of 41 North American pediatric endoscopy experts rated potential checklist and global rating items for their importance as indicators of the competence of trainees learning to perform pediatric colonoscopy. Responses were analyzed and re-sent to the panel for further ratings until consensus was reached. Items that ≥ 80% of experts rated as ≥ 4 out of 5 were included in the final instrument. Consensus items were compared with those items deemed by adult endoscopy experts as fundamental to assessing the performance of adult colonoscopy. RESULTS: Five rounds of surveys were completed with response rates ranging from 76% to 100%. Seventy-five checklist and 38 global rating items were reduced to 18 checklist and 7 global rating items that reached consensus. Three pediatric checklist items differed from those considered to be critical adult indicators, whereas 4 items on the latter did not reach consensus among pediatric experts. CONCLUSIONS: Delphi methodology allowed for achievement of expert consensus regarding essential items to be included in the Gastrointestinal Endoscopy Competency Assessment Tool for Pediatric Colonoscopy (GiECATKIDS), a measure of endoscopic competence specific to performing pediatric colonoscopy. Key differences in the checklist items, compared with items reaching consensus during a separate adult Delphi process using the same indicators, emphasize the need for a pediatric-specific tool.

Gastrointestinal Endoscopy Competency Assessment Tool: development of a procedure-specific assessment tool for colonoscopy.

BACKGROUND: Ensuring competence remains a seminal objective of endoscopy training programs, professional organizations, and accreditation bodies; however, no widely accepted measure of endoscopic competence currently exists. OBJECTIVE: By using Delphi methodology, we aimed to develop and establish the content validity of the Gastrointestinal Endoscopy Competency Assessment Tool for colonoscopy. DESIGN: An international panel of endoscopy experts rated potential checklist and global rating items for their importance as indicators of the competence of trainees learning to perform colonoscopy. After each round, responses were analyzed and sent back to the experts for further ratings until consensus was reached. MAIN OUTCOME MEASUREMENTS: Consensus was defined a priori as ≥80% of experts, in a given round, scoring ≥4 of 5 on all remaining items. RESULTS: Fifty-five experts agreed to be part of the Delphi panel: 43 gastroenterologists, 10 surgeons, and 2 endoscopy managers. Seventy-three checklist and 34 global rating items were generated through a systematic literature review and survey of committee members. An additional 2 checklist and 4 global rating items were added by Delphi panelists. Five rounds of surveys were completed before consensus was achieved, with response rates ranging from 67% to 100%. Seven global ratings and 19 checklist items reached consensus as good indicators of the competence of clinicians performing colonoscopy. LIMITATIONS: Further validation required. CONCLUSION: Delphi methodology allowed for the rigorous development and content validation of a new measure of endoscopic competence, reflective of practice across institutions. Although further evaluation is required, it is a promising step toward the objective assessment of competency for use in colonoscopy training, practice, and research.

Assessment of knowledge in adolescents with inflammatory bowel disease using a novel transition tool.

BACKGROUND: In the transition from pediatric to adult care, patients are expected to increase their level of self-care. Knowledge of disease characteristics, medications, and resources is crucial. This study evaluated the knowledge of adolescents with inflammatory bowel disease (IBD) and their parents in four major domains: disease characteristics, treatments, medical history, and health services resources. METHODS: Patients age 14-18 years and their parents completed MyHealth Passport for IBD as a cross-sectional assessment of knowledge. Responses were evaluated for accuracy using medical records. The proportion of correct responses between patients/parents were compared. RESULTS: In all, 78 patients (age 16.2 ± 1.2 years, IBD duration 3.6 ± 2.5 years), and 64 parents participated. Patients and parents were equally likely to answer questions correctly regarding disease characteristics and treatment, but not health services resources. Most patients accurately identified IBD classification and listed medications. Neither patients nor parents accurately identified disease location or previous investigation results. Parents more likely correctly named insurance provider (odds ratio [OR] 6.33, 95% confidence intervals [CI] 2.68-15.0), and pharmacy location (OR 18.5, 95% CI 4.6-76.8). Multivariate regression revealed that patients with IBD type unclassified were more likely to be aware of their diagnostic classification (OR 17.2, 95% CI 2.81-105.4 compared with Crohn's disease patients). Older patients were less likely to recall if they had a small bowel x-ray (OR 0.59, 95% CI 0.35-0.996). CONCLUSIONS: Future educational interventions should target areas of weakness in adolescent knowledge, particularly health services resources. The MyHealth Passport for IBD (available freely online) could educate and instill independence in the transitioning adolescent.

Functional assessment of skeletal muscle regeneration utilizing homologous extracellular matrix as scaffolding.

The loss of a portion of skeletal muscle poses a unique challenge for the normal regeneration of muscle tissue. A transection injury with tissue loss will not heal due to the gap between muscle segments. A damage model was developed by removing a portion of the lateral gastrocnemius (GAS) of Sprague-Dawley rats. Maximal isometric, tetanic tension (P(o)) was measured after the removal of either a small defect (0.5 x 1.0 cm) or a large defect (1.0 x 1.0 cm) piece of the GAS. In situ P(o) immediately after creation of the defect was 88.3 +/- 2.0% of the nonoperated contralateral GAS force for small defect and 76.9 +/- 3.2% of control for large defect. No functional recovery occurred in either group over the course of 28 days. To enhance recovery, a homologous, decellularized, muscle extracellular matrix (ECM) was implanted into the 1 x 1 cm defect of the lateral GAS of Lewis rats. After 42 days, growth of blood vessels and myofibers into the ECM was apparent, but no restoration of P(o) occurred. These data demonstrate the ability of the ECM to support muscle and blood vessel regeneration, but full recovery of function does not occur after 42 days.

Pulse oximetry knowledge and its effects on clinical practice.

AIM: to explore literature pertaining to registered nurses' and/or doctors' knowledge in relation to the pulse oximetry in clinical practice. BACKGROUND: pulse oximeters provide non-invasive readings of both pulse rate and peripheral oxygen saturation, leading to quick identification of potential/actual problems. Because of this, clinicians, like nurses, may become too dependent on it, neglecting other aspects of the holistic assessment process. METHODS: a literature search was carried out between 1980 and 2006, with much of the data skewed towards 1994-2006. As the central focus was to be on pulse oximetry knowledge of nurses and/or doctors, articles included had to contain a central theme addressing this. Other criteria for inclusion were links between pulse oximetry and knowledge in clinical practice, nurses and/or doctors as participants in studies addressing this, as well as the clinical competency in relation to the device. CONCLUSION: improving knowledge may not necessarily be the answer in improving clinical competency. Future research will need to be carried out to measure the connection between knowledge and competency and to use that as a basis for education and training.