Landscape of TPMT and NUDT15 Pharmacogenetic Variation in a Cohort of Canadian Pediatric Inflammatory Bowel Disease Patients.

BACKGROUND: Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression. We aimed to evaluate PGx variation in genes supported by clinical guidelines that inform dosing of thiopurines and characterize differences in the distribution of actionable PGx variation among diverse ancestral groups. METHODS: Pharmacogenetic variation in TPMT and NUDT15 was captured by genome-wide genotyping of 1083 pediatric IBD patients from a diverse Canadian cohort. Genetic ancestry was inferred using principal component analysis. The proportion of PGx variation and associated metabolizer status phenotypes was compared across 5 genetic ancestral groups within the cohort (Admixed American, African, East Asian, European, and South Asian) and to prior global estimates from corresponding populations. RESULTS: Collectively, 11% of the cohort was categorized as intermediate or poor metabolizers of thiopurines, which would warrant a significant dose reduction or selection of alternate therapy. Clinically actionable variation in TPMT was more prevalent in participants of European and Admixed American/Latino ancestry (8.7% and 7.5%, respectively), whereas variation in NUDT15 was more prevalent in participants of East Asian and Admixed American/Latino ancestry (16% and 15% respectively). CONCLUSIONS: These findings demonstrate the considerable interpopulation variability in PGx variation underlying thiopurine metabolism, which should be factored into testing diverse patient populations.

In a large, pediatric inflammatory bowel disease cohort comprised of 5 genetic ancestry groups, we evaluated the distribution of loss-of-function pharmacogenetic variants in TPMT and NUDT15 and predicted phenotypes (impact on thiopurine metabolism).

Outcomes Following Acute Severe Colitis at Initial Presentation: A Multi-centre, Prospective, Paediatric Cohort Study.

AIM: To assess contemporary outcomes in children with acute severe ulcerative colitis [ASUC] at initial presentation. METHODS: Between April 2014 and January 2019, children aged <17 years, with new onset ASUC (Paediatric Ulcerative Colitis Activity Index [PUCAI ≥65) were prospectively followed in a Canadian inception cohort study. 16S rRNA amplicon sequencing captured microbial composition of baseline faecal samples. Primary endpoint was corticosteroid-free clinical remission with intact colon at 1 year [PUCAI <10, no steroids ≥4 weeks]. RESULTS: Of 379 children with new onset UC/IBD-unclassified, 105 [28%] presented with ASUC (42% male; median [interquartile range; [IQR]) age 14 [11-16] years; extensive colitis in all). Compared with mild UC, gut microbiome of ASUC patients had lower α-diversity, decreased beneficial anaerobes, and increased aerobes; 54 [51%] children were steroid-refractory and given infliximab [87% intensified regimen]. Corticosteroid-free remission at 1 year was achieved by 62 [61%] ASUC cohort (by 34 [63%] steroid-refractory patients, all on biologics; by 28 [55%] steroid responders,13 [25%] on 5- aminosalicylic acid [5-ASA], 5 [10%] on thiopurines, 10 [20%] on biologics). By 1 year, 78 [74%] escalated to infliximab including 24 [47%] steroid-responders failed by 5-ASA and/or thiopurines. In multivariable analysis, clinical predictors for commencing infliximab included hypoalbuminaemia, greater PUCAI, higher age, and male sex. Over 18 months, repeat corticosteroid course[s] and repeat hospitalisation were less likely among steroid-refractory versus -responsive but -dependent patients (adjusted odds ratio [aOR] 0.71 [95% CI 0.57-0.89] and 0.54 [95% CI 0.45-0.66], respectively). CONCLUSION: The majority of children presenting with ASUC escalate therapy to biologics. Predictors of need for advanced therapy may guide selection of optimal maintenance therapy.

ADALIMUMAB VERSUS INFLIXIMAB IN LUMINAL PEDIATRIC CROHN'S DISEASE: COMPARABLE OUTCOMES IN A PROSPECTIVE MULTICENTER COHORT STUDY.

BACKGROUND: This study compared real-world effectiveness between adalimumab (ADA) and infliximab (IFX) in children with Crohn's disease (CD). METHODS: Children enrolled into the prospective Canadian Children Inflammatory Bowel Disease Network (CIDsCaNN) National Inception Cohort between 2014 and 2020 who commenced ADA or IFX as first anti-tumor necrosis factor (antiTNF) agent for luminal CD were included. Multivariate logistic regression modelled the propensity of commencing ADA; propensity score matching was used to match IFX-treated children to ADA-treated children. The primary outcome at one year was steroid-free clinical remission (SFCR). Secondary outcomes at one year were I) combined SFCR and c-reactive protein (CRP) remission; II) treatment intensification; and III) antiTNF durability. Odds ratios (aOR) and hazard ratio (aHR) adjusted for concomitant immunomodulator use with 95% confidence interval (CI) are reported. RESULTS: In the propensity score matched cohort of 147 ADA-treated and 147 IFX-treated children, 92 (63%) ADA- and 87 (59%) IFX-treated children achieved SFCR at one year (aOR: 1.4, 95% CI 0.9-2.4); 75 of 140 (54%) ADA- and 85 of 144 (59%) IFX-treated children achieved combined SFCR and CRP remission (aOR: 1.0, 95% CI 0.6-1.6). ADA-treated children less frequently underwent treatment intensification (21 [14%]) compared to IFX-treated children (69 [47%]) (P<0.0001). Discontinuation of antiTNF occurred in 18 (12%) ADA-treated and 15 (10%) IFX-treated children (aHR: 1.2, 95% CI 0.6-2.2). CONCLUSION: Children with Crohn's disease achieved favourable outcomes at one year with either ADA or IFX as first antiTNF agents. Those receiving IFX did not have significantly superior outcomes compared to clinically similar children receiving ADA.

Diagnostic Delay Is Associated With Complicated Disease and Growth Impairment in Paediatric Crohn's Disease.

BACKGROUND: Paediatric data on the association between diagnostic delay and inflammatory bowel disease [IBD] complications are lacking. We aimed to determine the effect of diagnostic delay on stricturing/fistulising complications, surgery, and growth impairment in a large paediatric cohort, and to identify predictors of diagnostic delay. METHODS: We conducted a national, prospective, multicentre IBD inception cohort study including 1399 children. Diagnostic delay was defined as time from symptom onset to diagnosis >75th percentile. Multivariable proportional hazards [PH] regression was used to examine the association between diagnostic delay and stricturing/fistulising complications and surgery, and multivariable linear regression to examine the association between diagnostic delay and growth. Predictors of diagnostic delay were identified using Cox PH regression. RESULTS: Overall (64% Crohn's disease [CD]; 36% ulcerative colitis/IBD unclassified [UC/IBD-U]; 57% male]), median time to diagnosis was 4.2 (interquartile range [IQR] 2.0-9.2) months. For the overall cohort, diagnostic delay was >9.2 months; in CD, >10.8 months and in UC/IBD-U, >6.6 months. In CD, diagnostic delay was associated with a 2.5-fold higher rate of strictures/internal fistulae (hazard ratio [HR] 2.53, 95% confidence interval [CI] 1.41-4.56). Every additional month of diagnostic delay was associated with a decrease in height-for-age z-score of 0.013 standard deviations [95% CI 0.005-0.021]. Associations persisted after adjusting for disease location and therapy. No independent association was observed between diagnostic delay and surgery in CD or UC/IBD-U. Diagnostic delay was more common in CD, particularly small bowel CD. Abdominal pain, including isolated abdominal pain in CD, was associated with diagnostic delay. CONCLUSIONS: Diagnostic delay represents a risk factor for stricturing/internal fistulising complications and growth impairment in paediatric CD. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

School nutrition: Support for providing healthy food and beverage choices in schools.

The implementation of nutrition policies and guidelines in Canadian schools has increased the availability and consumption of nutrient-rich foods while reducing access to and consumption of foods and beverages that are high in sugars, sodium, and saturated fats. Positive changes in health outcomes for children and youth, such as improved body mass indices, have been observed. However, observed impacts of school nutrition policies on academic performance have been mixed. This statement reviews key elements of school nutrition policies, with specific focus on nutrition standards. School nutrition policies should align with recommendations in Canada's Food Guide and promote nutrient-rich foods and beverages that are lower in saturated fat, sugar, and sodium.

Nutrition for healthy term infants, six to 24 months: An overview.

Nutrition for Healthy Term Infants is a joint statement by Health Canada, the Canadian Paediatric Society, Dietitians of Canada and the Breastfeeding Committee for Canada. It was republished in September 2012, with recommendations on infant feeding from birth to six months of age. The statement was most recently updated in April 2014, with recommendations for feeding older infants and young children from six to 24 months of age. The present practice point outlines the statement development process and principles of feeding, with specific recommendations for clinicians. Health professionals who counsel families on nutrition in infants and young children are advised to read the statement in its entirety because discussion in the longer document expands on and clarifies advice summarized in the principles and recommendations given here. The complete statement is available on Health Canada's website: www.hc-sc.gc.ca/fn-an/nutrition/infant-nourisson/index-eng.php.

La nutrition du nourrisson né à terme et en santé est un document conjoint de Santé Canada, de la Société canadienne de pédiatrie, des Diététistes du Canada et du Comité canadien pour l'allaitement. Publié de nouveau en septembre 2012, il contenait des recommandations sur l'alimentation du nourrisson de la naissance à six mois. Il a été mis à jour en avril 2014 pour y incorporer des recommandations sur l'alimentation des nourrissons plus âgés et des jeunes enfants de six à 24 mois. Le présent point de pratique expose le processus d'élaboration du document et les principes d'alimentation, ainsi que des recommandations à l'intention des cliniciens. Les professionnels de la santé qui conseillent les familles en matière de nutrition du nourrisson et du jeune enfant sont invités à lire le document intégral, parce que les exposés approfondissent et clarifient les conseils résumés dans les principes et les recommandations du présent point de pratique. Le document intégral peut être consulté dans le site Web de Santé Canada (www.hc-sc.gc.ca/fn-an/nutrition/infant-nourisson/recom/recom-6-24-months-6-24-mois-fra.php).

Nutrition for healthy term infants, birth to six months: An overview.

Nutrition for healthy term infants is a joint statement by Health Canada, the Canadian Paediatric Society, Dietitians of Canada and the Breastfeeding Committee for Canada that was most recently updated in September 2012 with recommendations from birth to six months of age. This practice point outlines the development process, principles of infant feeding, and recommendations for clinicians. Health professionals involved in counselling families about infant nutrition are advised to read the statement in its entirety, because the underlying discussions expand upon and clarify the advice summarized in the principles and recommendations. The complete statement is available on Health Canada's website (www.hc-sc.gc.ca/fn-an/nutrition/infant-nourisson/recom/index-eng.php).

La nutrition du nourrisson né à terme et en santé est un document conjoint de Santé Canada, de la Société canadienne de pédiatrie, des Diététistes du Canada et du Comité canadien pour l'allaitement mis à jour en septembre 2012 qui contient des recommandations de la naissance à six mois. Le présent point de pratique expose le processus d'élaboration du document, les principes d'alimentation du nourrisson et des recommandations à l'intention des cliniciens. Les professionnels de la santé qui conseillent les familles en matière de nutrition du nourrisson sont invités à lire le document intégral, parce que les exposés approfondissent et clarifient les conseils résumés dans les principes et recommandations. Ce document est accessible dans le site Web de Santé Canada (www.hc-sc.gc.ca/fn-an/nutrition/infant-nourisson/recom/index-fra.php).

The minimal detectable change cannot reliably replace the minimal important difference.

OBJECTIVE: We compared the minimal important difference (MID) with the minimal detectable change (MDC) generated by distribution-based methods. STUDY DESIGN: Studies of two quality-of-life instruments (Chronic Respiratory Questionnaire [CRQ] and Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ]) and two physician-rated disease-activity indices (Pediatric Ulcerative Colitis Activity Index [PUCAI] and Pediatric Crohn's Disease Activity Index [PCDAI]) provided longitudinal data. The MID values were calculated from global ratings of change (small change for CRQ and RQLQ; moderate for PUCAI and PCDAI) using receiver-operating characteristic (ROC) curve and mean change. Results were compared with five distribution-based strategies. RESULTS: Of the methods used to calculate the MDC, the 95% limits of agreement and the reliable change index yielded the largest estimates. In the patient-rated psychometric instruments, 0.5 SD was always greater than 1 standard error of measurements (SEM), and both fell between the mean change and the ROC estimates, on two of four occasions. The reliable change index came closest to MID of moderate change. CONCLUSION: For patient-rated psychometric instruments, 0.5 SD and 1 SEM provide values closest to the anchor-based estimates of MID derived from small change, and the reliable change index for physician-rated clinimetric indices based on moderate change. Lack of consistency across measures suggests that distribution-based approaches should act only as temporary substitutes, pending availability of empirically established anchor-based MID values.

Using the entire cohort in the receiver operating characteristic analysis maximizes precision of the minimal important difference.

OBJECTIVE: We compared the minimal important difference (MID) values obtained by the receiver operating characteristics (ROC) curve approach using different strategies on four outcome measures to guide the optimal use of ROC curve. STUDY DESIGN AND SETTING: Studies of two psychometric scales (Rhinoconjunctivitis Quality-of-Life Questionnaire [RQLQ] and Chronic Respiratory Questionnaire [CRQ]) and two clinimetric indices (Pediatric Ulcerative Colitis Activity Index [PUCAI] and Pediatric Crohn's Disease Activity Index [PCDAI]) instruments provided prospective longitudinal data. The MID was calculated from 7- and 15-point global ratings of change dichotomized in multiple ways, using the ROC curve method. Analysis was performed twice: first, using only the two groups adjacent to the dichotomization point (e.g., including only patients who had a small vs. moderate change); and second, using the entire cohort split at the same cutoff (e.g., including both unchanged subjects with those with small change vs. those who experienced moderate or large change combined). RESULTS: Using the entire cohort, rather than just those with ratings adjacent to the dichotomization point, yielded more precise and sensible MID estimates. With one exception, high precision was obtained when using the ROC curve method for any cutoff on the rating scale. CONCLUSION: When calculating the MID using the ROC curve method, the use of the entire cohort maximizes precision.

Canadian Helicobacter Study Group Consensus Conference: Update on the approach to Helicobacter pylori infection in children and adolescents--an evidence-based evaluation.

As an update to previously published recommendations for the management of Helicobacter pylori infection, an evidence-based appraisal of 14 topics was undertaken in a consensus conference sponsored by the Canadian Helicobacter Study Group. The goal was to update guidelines based on the best available evidence using an established and uniform methodology to address and formulate recommendations for each topic. The degree of consensus for each recommendation is also presented. The clinical issues addressed and recommendations made were: population-based screening for H. pylori in asymptomatic children to prevent gastric cancer is not warranted; testing for H. pylori in children should be considered if there is a family history of gastric cancer; the goal of diagnostic interventions should be to determine the cause of presenting gastrointestinal symptoms and not the presence of H. pylori infection; recurrent abdominal pain of childhood is not an indication to test for H. pylori infection; H. pylori testing is not required in patients with newly diagnosed gastroesophageal reflux disease; H. pylori testing may be considered before the use of long-term proton pump inhibitor therapy; testing for H. pylori infection should be considered in children with refractory iron deficiency anemia when no other cause has been found; when investigation of pediatric patients with persistent or severe upper abdominal symptoms is indicated, upper endoscopy with biopsy is the investigation of choice; the 13C-urea breath test is currently the best noninvasive diagnostic test for H. pylori infection in children; there is currently insufficient evidence to recommend stool antigen tests as acceptable diagnostic tools for H. pylori infection; serological antibody tests are not recommended as diagnostic tools for H. pylori infection in children; first-line therapy for H. pylori infection in children is a twice-daily, triple-drug regimen comprised of a proton pump inhibitor plus two antibiotics (clarithromycin plus amoxicillin or metronidazole); the optimal treatment period for H. pylori infection in children is 14 days; and H. pylori culture and antibiotic sensitivity testing should be made available to monitor population antibiotic resistance and manage treatment failures.