Pediatric RISK Stratification Study
The Pediatric RISK Stratification Study (RISK) is designed to identify the genetic, microbiological, and immunological factors in children that are predictive of more severe IBD. 1, 100 patients at 28 centers in the United States and Canada have been recruited and enrolled at disease onset, and are being prospectively followed for complications and response to therapies. RISK findings will translate into new protocols for individualized approaches to treating Crohn’s disease and ulcerative colitis in children, aged 10 and under, and enable physicians to predict and prevent progression to severe disease and its lifelong consequences.
If physicians were able to accurately predict how a child’s IBD will progress, he or she could prescribe the appropriate medications at the right time, and their young patient’s risk of future complicated disease and serious side effects could be reduced. Some children diagnosed with Crohn’s disease or ulcerative colitis manifest mild disease course, do well with basic medication, and suffer minimal side effects. Other children, however, experience a more severe disease course, including growth failure, pubertal delay, continued active gastrointestinal symptoms, and impaired quality of life. These children eventually develop complicated or severe IBD that may require surgery.
Medications are able to change the natural history of IBD, postpone, and even avoid the need for surgery, but due to possible side effects and related significant costs, these medications are not used early in all young patients who might need them. CCFA’s RISK is compiling a short list of biomarkers that can predict – at the time of diagnosis – those children with Crohn's disease who are more likely to have a severe, complicated disease course and could, therefore, benefit from more intensive treatment at the outset.
The RISK cohort is comprised of the largest group of pediatric patients in the history of IBD research. For each patient, investigators are collecting bio-samples (i.e., DNA/RNA, blood, stools and intestinal biopsies at the time of diagnosis), which are then used to perform genetic, microbiological and serological analysis. As of July 2016, all subjects reached their 4-year follow-up mark.
Principal Investigator: Subra Kugathasan, Emory Children's Center (Atlanta, GA)
- Lee Ted Denson, Cincinnati Children's Hospital Medical Center
- Marla Dubinsky, Mount Sinai Hospital
- Jeffrey Hyams, Connecticut Children's Medical Center
- Michael Stephens, Mayo Clinic
- James Markowitz, Cohen Children's Medical Center of New York
- Thomas Walters, Hospital of Sick Children (Toronto, Canada)
- Bruce Aronow, Cincinnati Children's Hospital Medical Center
- Robert Baldassano, Children's Hospital of Philadelphia
- Mi-Ok Kim, Cincinnati Children's Hospital Medical Center
Current Activities & Objectives
With the active involvement of leading IBD researchers with diverse expertise, the study is near its primary goal of designing an accurate model that can predict a newly diagnosed child’s risk of developing IBD disease complications based on clinical, genetic, microbial and serologic variables.
- A group at the Cincinnati Children's Hospital Medical Center has been working to generate the RISK prediction model.
- Gene expression profiling studies performed at the Cincinnati Children's Hospital Medical Center and Emory Children's Center have identified two molecular signatures that are able to stratify patients at diagnosis, who are at risk of developing stricturing (or penetrating) disease. Patients with the stricturing signature have been shown to not respond to biological treatment.
Publications based on RISK findings include a 2015 article in PLoS One, “Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping,” which stated that the genetic mutations responsible for early onset inflammatory bowel diseases are very similar to those associated with adult onset of the disease (PLoS One. 2015 Jun 22;10(6):e0128074).
The RISK Stratification Study has enormous implications for IBD research and other initiatives funded by CCFA and the National Institutes of Health (which are also utilizing RISK-generated data). Based on the study’s progress, we may be able to determine with accuracy at the time of diagnosis whether a pediatric patient will develop complicated disease within four to five years of diagnosis. This empowers doctors and parents to decide on the best therapeutic intervention from disease onset, and will result in better health and quality of life outcomes for children with IBD.
The wealth of data and findings gathered through RISK will be housed in CCFA's IBD Plexus, the largest and most innovative research and information exchange platform created to date. Using IBD Plexus’ powerful data management platform, RISK information can be studied in conjunction with data from other CCFA initiatives (i.e., Genetics and Microbiome Initiatives), promising an exponential increase in our avenues of investigation into the causes and cures for IBD.
RISK is focused on the following two Aims:
- Aim 1: Develop and validate a composite risk score to predict complicating CD.
After completing 60 months (five years) of follow-up for the RISK pediatric cohort, investigators will test and validate a model for disease complications for patients, age ≥ 10 at diagnosis, including: intestinal deep ulcers, candidate genetic variants, and cytokine and microbial serologies. Both Cox Proportional Hazard (Cox-PH) regression and propensity scoring approaches will be used to test whether early anti-TNF therapy is associated with complications or outcomes.
- Aim 2: Identify and validate intestinal gene expression panels associated with complicated disease behavior.
Diagnostic tissue biopsy host gene expression panels are now utilized for several clinical indications in oncology and other fields. The RISK team anticipates that development of ileal and rectal gene expression panels that predict risk for complicated disease behavior will have a similarly profound impact upon clinical practice in the IBD field.
RNA sequencing (RNASeq) of ileal and rectal samples obtained at diagnosis will identify host gene expression modules associated with progression from inflammatory to complicated (stricturing/penetrating disease) behavior. Class prediction analysis, using independent discovery and validation groups, will test the accuracy of these gene panels for predicting disease complications.
RISK’s success will be measured by the demonstration that early introduction of anti-TNF therapy results in a reduction in rates of disease complications in the study’s high-risk patient sub-groups, and that this is superior to late or no introduction of anti-TNF.
All these results together will inform the development and validation of a patient decision aid, which will help guide parents and care givers in determining the most appropriate course of treatment for children newly diagnosed with Crohn’s disease.
Please contact Andres Hurtado-Lorenzo with any questions or comments regarding CCFA’s Microbiome Initiative.