Description

IBD is increasingly common in Canada, particularly among children, even those whose families have recently moved here from countries where IBD is rare. Genetic factors are known to make children susceptible to IBD, but the equally important environmental factors are unknown. This multi-center network brings together investigators across Canada to understand why IBD affects so many Canadian children. We will study all children at the time of IBD diagnosis, asking questions about environmental, including dietary, exposures; obtaining blood for assessment of genetic risk; and stool for assessment of microorganisms that might be important in the development of IBD. The best treatments for specific types of IBD will be determined.

The Network's success will be as much dependent on its ability to re-distribute data, as its ability to efficiently and accurately collect it. In order to achieve the Network's goals related to improving care and informing clinical practice, it is imperative that the Network's raw data set can be rapidly re-formatted and re-presented to first inform and then report on (patient focused) clinical and quality indicators at both site and network levels.

Samples may be stored indefinitely so that, as additional genes, biomarkers, and microbes are discovered, their role in intestinal disease can be assessed. The importance of these samples increase over time as outcomes of intestinal disease and treatment may be tracked. As required in future, research studies proposing to use biobank data and/or samples will be submitted to a study committee and the REB (Research Ethics Board) for approval.

Approximately 2400 participants will be recruited to the Networks Inception Cohort study. They will be followed from recruitment until transfer to adult care.

Participants will be advised during the consent process that, as with any research study, they may withdraw at any time by informing a study team member verbally or in writing. A withdrawal request may be for all stored samples to be withdrawn, or it may be a request for no additional samples to be collected (though already stored specimens may be retained).

Sample Size and Power Considerations

The study's sample size is arbitrarily fixed given the national incidence rate, duration of recruitment, and selection of participating sites. Based on reported inception case numbers, and likely engagement success, we anticipate recruiting approximately 400 to 500 patients per year. Thus 1,200 to 1,500 subjects will have at least 18 months of follow-up data within the 5 year grant period. By the end of year 4 we would anticipate between 800 and 1000 subjects have 18-month outcomes, reducing to 400 or 500 by the 3 year mark. The primary analysis, within each of the described strata will be a test of proportions, presented as a Relative Risk. Current figures would suggest 60% of the study cohort will have Crohn's disease (CD), and of those 20% L1, 20% L2, 50% L3, and 10% isolated L4b. Approximately 20% of CD patients are exposed to anti-TNF within 12 months. Information from ongoing studies suggest at least 60% of patients are in a sustained clinical remission by 12 months. The minimum RR (effect size) we will be able to demonstrate in any analysis based on the network cohort, and the confidence (power) we can have in that estimation, will depend on the number of exposed subjects (cases) within the strata of interest and the anticipated outcome frequency in the unexposed subjects.

Environmental Exposure Assessment

We are systematically assessing environmental factors that have previously been associated with Inflammatory Bowel Disease in the literature and factors that are hypothesized to be associated with Inflammatory Bowel Disease based on knowledge of pathophysiology. All patients will complete the comprehensive questionnaire at least once during the duration of follow-up. The questionnaires will be internet-based and completed by the patient with parental assistance either at home or in the clinic.

We will assess the effect of environmental exposures on the following outcomes: type, location and extent of disease at diagnosis (2); disease severity at diagnosis, and subsequent clinical disease course. Disease course will be followed and ultimately classified as 'severe', 'indolent', 'continuous sustained clinical remission'. Time to sentinel events (such as surgery, commencement of anti-TNF therapy (anti-tumour necrosis factor), development of complicating disease behaviour) will also be recorded. We will examine the univariate effect of the listed environmental exposures including breastfeeding, antibiotic use, and passive smoking exposure on both the baseline phenotype and the subsequent disease course strata. Logistic regression models will be constructed to evaluate the potential effect of ethnicity (eg. South Asian versus Caucasian) after adjusting for environmental exposures. CD (Crohn's Disease) and UC (Ulcerative Colitis) will be studied separately. Risk estimates will be expressed as odds ratios with 95% confidence intervals. For sentinel events within 18 months of diagnosis we will apply semiparametric and nonparametric methods of survival analysis, including Cox regression models, to assess firstly the effect of various environmental factors stratified by ethnicity, as well as the association of race/ancestry after adjusting for environmental risk factors. The potential effect modification of South Asian ancestry on Inflammatory Bowel Disease prognosis will be formally assessed. Finally, a paired comparison will be attempted examining the effect of a change in exposure status on Inflammatory Bowel Disease disease course.

Dietary Exposure Assessment

We are using a combination of quantitative dietary assessment utilizing the food frequency questionnaire, FFQ (Food Frequency Questionnaire), (modified for the age of population studied) and a qualitative dietary assessment using the modified Canadian Healthy Eating Index (HEIC-2009). This approach allows us to test the hypothesis that high caloric intake from processed and prepared foods with low glycemic index and high fat content have a facilitative effect on the development of Inflammatory Bowel Disease. Moreover, it allows us to examine diet-diet interactions, diet-gene interactions, and diet-microbiome interactions.

FFQ (Food Frequency Questionnaire) content validity and reproducibility will be assessed using Pearson correlation coefficients for normally distributed data and Spearman rank correlation coefficients where the data are not normally distributed. Caloric intake, dietary quality and specific dietary components such as fats/specific fatty acids, sugars, vitamin D and antioxidants will be divided into age and gender-specific quartiles from the distribution across Inflammatory Bowel Disease cases, based on phenotype (Ulcerative Colitis and Crohn's Disease) and disease severity (Pediatric Ulcerative Colitis Activity Index (PUCAI) and Pediatric Crohn's Disease Activity Index (PCDAI).) Logistic regression models will be developed, adjusting for age at recruitment, gender, ethnicity and additional environmental exposures (mutually adjusted for in analyses but updated in accordance with the additional data obtained through review of environmental exposure e.g. smoking status, appendectomy, tonsillectomy, usage of oral contraceptives, antibiotic use). Risk estimates will be expressed as odds ratio (OR) with corresponding 95% confidence intervals (CI) for Crohn's Disease and Ulcerative Colitis separately, as well as for Inflammatory Bowel Disease combined.

The National Coordinating Centre Team and Organizational Structure

The Network's National Coordinating Centre is housed at The Hospital for Sick Children, University of Toronto. Information Technology infrastructure and support will be provided by the SickKids Research Institute's Research IT Department. Additional 'ad-hoc' resources related to IT development/support, legal counsel, bio-statistical assistance will be available to the centre as required via the resources of the SickKids Research Institute.

The National Coordinating Centre is responsible for data-integrity and completeness and ensures accountability by sites for full and timely data completeness. Support systems for collecting and recording data and encourages 'real-time' data abstraction and direct data entry. The Network is utilizing the REDCap (Research Electronic Data Capture) application as its primary data-collection platform. REDCap is a secure, web-based application designed to support data capture for research studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data download to common statistical packages; and 4) procedures for importing data from external sources. Within the data collection platform, numerous 'real-time' and 'post hoc' data check procedures will be implemented. Statistics concerning 'data-integrity' will be reported to the Executive Committee on a regular and frequent basis. The National Coordinating Centre will conduct site-specific staff training at the initiation of the study, when new staff are employed, and when any new tools or significant study procedures are added to the protocol.

ORGANIZATION and GOVERNANCE of NETWORK

Preamble: During the next 5-year period, the Network Executive will aim to provide both the opportunity and governance to foster development of new leaders in pediatric IBD in Canada; continue to lead in pediatric IBD research; and initiate a plan for sustainability in leadership and research productivity/funding. Diversity in the broadest sense, inclusiveness and engagement will be core values for performance. Taken together, the proposed Network governance has been changed in the following ways:

1. A plan for regular renewal of the 3-person Executive committee, which going forward will always consist of 2 co-chairs and a co-chair elect.
2. A Steering Committee (composed of committee leads or co-leads and with two additional early career representatives) will be formed in which each committee will be responsible for specific academic areas and will develop a process for renewal of its leadership. The Steering Committee will meet on a monthly basis and report to the Executive committee to update progress in their areas of responsibility and the two bodies together will drive Network activities and plans.
3. A more comprehensive, broader-ranging committee structure with clear responsibilities and deliverables.
   1. 3-person Executive committee The 3-person executive committee is responsible for the overall directions, operation, and decisions of the Network. In a Network that aims to be sustainable, it is mandatory that there be a mechanism for renewal and revitalization of such leadership.

For the sake of continuity, heading into phase 2, the previous Chair (Griffiths) and one Co-chair (Mack) of the former Network Management Committee (NMC) will remain on the Executive Committee as Co-chairs. A nomination committee, consisting of Drs. David Mack, Anthony Otley, and Sally Lawrence, geographically representing respectively Central, Eastern and Western Canada, will establish a slate of candidates for the Co-chair elect position to be voted on by the Network membership in the context of the late fall annual meeting. Process for voting to be established at late August steering committee meeting.

In general, as the Network continues in the future, an elected incoming Co-chair elect, will serve on the Executive committee for 3 years (one year as co-chair Elect; two years as Co-chair), long enough to allow success in leadership, but short enough so that the opportunity for such leadership is open to the many qualified individuals within the Network, which will enrich the reach and impact of the Network efforts. As a new Chair-elect joins the 3-person executive committee, the longest serving Co-chair moves off, having in general served for 3 years.

The first co-chair Elect will join Drs Griffiths and Mack on the Executive committee in the late fall of 2021. Given the crucial period of the upcoming two years, this Executive committee will exceptionally remain in place until fall of 2023 (rather than 2022, as would happen in general). The delayed movement of Dr. Griffiths off the Executive committee and correspondingly delayed second election of a new member will mean that the 2021 co-chair elect will exceptionally serve in leadership for 4 years instead of the customary three years.

2) Steering committee Members of the Steering Committee are either committee Leads or (for larger committees) Co-Leads, with the exception that two positions are reserved for early career representatives (one representing Basic Research; one representing Clinical and Translational research). These are all named in Figure. The early career representatives, chosen based on their abilities, accomplishments and contributions to the Network to date, are affiliated with committees, but are not being given administrative responsibilities for committee leadership. It is anticipated that they will contribute meaningfully to Steering committee discussions in these roles, which have been developed as part of the Network's commitment to Training and Mentoring of the next generation of leaders.

At monthly joint meetings of the Steering and Executive committees, the expectations are 1) that committee leads will report on their activities and 2) all members together will discuss and make decisions about Network initiatives.

This change in governance structure is being made for four main reasons: 1) to allow more regular and more productive interactions between leaders with clinical investigative expertise and those with basic research expertise, given the phase 2 mandate to ensure optimal utilization of collected biospecimens, 2) to allow delegation of responsibilities with accountability, thereby aiming to increase transparency and productivity 3) to allow for greater engagement of Canadian pediatric IBD sub-specialists to find solutions for pediatric IBD, to further standardize care and 4) to foster development of new and emerging leaders.

3) Broader committee structure As shown in the Figure, the scope of committee involvement has increased from the time of Network initiation to now include Clinical care and research; Education; Patient engagement and advocacy; Training and Mentorship in addition to the prior (but somewhat renamed and refocused) Basic and Translational Research; Data management and integration; Health services research. Committees with larger portfolios will have co-leads, with shared responsibilities.

Basic and Translational research committee (BTRC): Co-Leads: Bruce Vallance and Eytan Wine Clinical care and research committee (CCRC): Co-leads, Hien Huynh and Wael El-Matary Data Management and Integration: Lead,: Thomas Walters Health Services Research: Lead, Eric Benchimol Training and Mentorship: Lead, Kevan Jacobson Education: Co-leads, Colette Deslandres and Sally Lawrence Patient engagement and advocacy: Lead, Anthony Otley The major goals and areas of responsibility of individual committees are summarized as an Appendix.

The Network remains primarily a Network for research aimed at enhancing clinical outcomes, be it development of disease prevention strategies or superior treatment paradigms. It is committed to encouraging individuals to drive specific questions using the infrastructure provided and drawing on a larger patient base than is available in individual centres. A robust data management platform with feedback of data to sites will support collection and utilization of biospecimens for basic research. Consent for linkage of data/samples to administrative health data will facilitate long-term follow-up. An important improvement in Governance structure is the planned crosstalk between committees (e.g., ensuring mutual input between BTRC and CCRC projects), which will be achieved through the steering committee meetings as well as via co-membership in lead committees.

The addition of network-wide virtual educational initiatives over the past year has demonstrated that this is an effective way of engaging more physicians, researchers, and allied healthcare professionals in the Network. We anticipate that such interactive educational sessions will in turn 1) encourage greater engagement in prospective research and 2) provide a forum wherein data generated within the Network's studies will be shared, thereby stimulating further research and benefiting the clinical care of other patients nationally.

We anticipate that the Patient engagement and advocacy committee will have similar impact within the network.