RISK Cohort Study in Crohn's Disease

RISK Study Description:

Inflammatory bowel disease (IBD) pathogenesis likely involves the interaction between host genetics and “pre-programmed” host immune responses to enteric flora, resulting in disease susceptibility, development, and eventual disease expression. Our preliminary data suggests that 15% of children with new diagnosis of Crohn’s disease (CD) progress to complicated disease (stricturing and internal perforating) from non-complicating (inflammatory phenotype) disease within the first three years after diagnosis. Under the auspices of CCFA’s PRO-KIIDS (Pediatric Resource Organization for Kids with Intestinal Inflammatory diseases), a ‘pediatric network’ was formed in 2008 to undertake its first project “Risk Stratification”. A total of 47 pediatric IBD centers across USA and Canada participate in PRO-KIIDS. We hypothesize that “preprogrammed” genetic, immune and microbial factors (and not treatment) determine the subset of rapidly progressing complicated disease in 15% of children with CD. We are testing our hypothesis prospectively in an inception cohort of 1300 children with an initial diagnosis of CD, who will be followed for a minimum of 3 years (clinical review updates occurring every 6 months). We based our sample size estimate on Monte Carlo simulation studies.  With n=1100 (assuming ~15% loss to follow-up from the 1300 originally recruited), we anticipate to build a prediction model whose accuracy and predictive power in terms of c-statistics and PPV/NPV are 0.799, 0.482, and 0.899 respectively, with 90% confidence intervals of 0.047, 0.162 and 0.025 respectively. A cohort of 550 index cases (1100 total) will allow the inclusion of up to 7~10 variables in the final model , assuming the incidence of complicated behavior within 36 month follow up is at least 14%. To date, from 28 active sites, we have recruited a little over 1000 children (16 years or younger) with CD with inflammatory phenotype at the time of diagnosis while collecting genomic DNA, plasma (for serology), stool and mucosal biopsies. In addition, annual genomic DNA and plasma collection is ongoing. The enrolment is expected to end in December of 2011. Over 1000 follow-up visits have been performed, 33% of CD subjects have been followed to at least 12 months post diagnosis, 15% to at least 18 months.  5% have been lost to follow-up, 8% of subjects with at least 12 months follow-up have developed complicated disease. The genetics, serology and mucosal gene expression data at enrolment is expected in all subjects by December of 2011. Initial screen for genetics will be performed with immunochip which will test over 200,000 SNPs (single nucleotide polymorphisms). The serum will be tested for immune markers including ASCA, ompC, CBir and ANCA.  Global mucosal gene expression is being measured by microaaray and RNA-seq. We have banked DNA & plasma (n=1398), stool (n=623) and mucosal biopsy (n=3846) samples for future ancillary studies. The ultimate goals are to further develop a set of tools for understanding disease mechanism, and prognostication.