The BBOP Study

Biologically Based Outcome Predictors in Juvenile Idiopathic Arthritis

Innovation

BBOP is a large-scale, Canada-wide study aims to generate new knowledge to better predict outcomes of Juvenile Idiopathic Arthritis (JIA), the most common childhood rheumatic disease (The word 'idiopathic' means the cause is unknown). BBOP applies innovative protocols and analytical frameworks to conduct a prospective, longitudinal study to comprehensively investigate how interactions of inherent biological factors (such as genetics and immune and inflammatory processes) with lifestyle factors (such as nutrition and physical activity) and environmental exposures (such as stress and sunlight), can help predict JIA outcomes and improve the precision with which children can be diagnosed.

The BBOP Study recruited 186 newly diagnosed JIA patients from 12 Canadian sites. Study participants were evaluated at the time of enrollment and 6, 12, 18, and 24 months later. The BBOP dataset comprises extensive information about the characteristics of the child's disease and information about family and social history, stress, physical, activity, and nutrition, as examples. In addition, the study collected information about the study participants' genetic make-up and how the genes are expressed, and tested for a wide array of inflammatory blood and urine markers.

Discovery

Even though the BBOP Study concluded the last participant follow-up visit in 2013, the vast dataset continues to be analyzed and new information discovered. To date, 17 manuscripts arising from the BBOP Study have been published. Research teams from across Canada continue to analyze BBOP data, prepare manuscripts, and develop plans to mobilize results into actions that benefit patients. Some of the key discoveries resulting from the BBOP Study include:

Ethics: The BBOP Study revealed opportunities for and demonstrated the feasibility of standardizing regulatory approvals for pediatric research ethics that could be applied efficiently across Canada. Read more.
Biologic Sample Protocols: Standardized operating procedures were rigorously developed and tested, including protocols for collecting, processing, transporting, and storing biologic samples. Read more.
Reconsidering the Classification of Childhood Arthritis: JIA comprises a heterogeneous group of conditions. There are seven different categories are recognized. Advanced computer-based machine learning was applied to clinical and biologic data to provide novel insight into explaining the biologic basis for the different ways childhood arthritis can present. Analysis of BBOP data revealed unique patterns demonstrating the value of applying advanced analytical frameworks for studying childhood rheumatic diseases. Read more. This observation was further considered in another BBOP analysis in which data mining analyses were applied to clinical and inflammatory biomarker data. Discrete clusters that intersect multiple JIA categories were discovered. The results of this project suggest that certain groups of patients within different JIA categories are more aligned pathobiologically than their separate clinical categorizations suggest. Read more. These two BBOP initiatives will contribute to developing biologically based refinements in JIA classification.
JIA Genetics:
- One type of JIA is systemic JIA, is characterized by arthritis and widespread inflammation resulting in features such as fever and rash. The BBOP Study contributed data to international collaborative initiatives aimed at discovering genetic factors that might influence the occurrence and course of systemic JIA. Two genetically determined factors, HLA-DRB1*11 and variants of the MHC Class II locus, were found to be strong risk factors for systemic JIA. Read more.
- The BBOP Study contributed data to a study that distinguished systemic JIA genetic profiles from other forms of JIA, an observation with important clinical and therapeutic implications. Read more.
- Only one JIA category, rheumatoid factor positive polyarthritis (RF+ polyarticular JIA), resembles adult rheumatoid arthritis. BBOP contributed data to an international study that showed that the genetic profile of RF+ polyarticular JIA resembles adult rheumatoid arthritis. This observation has important implications for guiding treatment and predicting disease courses and outcomes. Read more.
- BBOP gene expression data were analyzed using a novel analytical approach (ISOpure-S1). Using pre- and post-treatment gene expression profiles, the analysis found a gene expression signature that significantly correlated with clinical outcomes. Read more.
- The BBOP Study contributed to an international collaboration, which found that IL1RN (Interleukin 1 Receptor Antagonist) locus is a susceptibility locus for systemic JIA. The genetically encoded high expression of IL1RN and production of interleukin 1Ra (Interleukin 1 receptor antagonist protein) protects against the development of systemic JIA. The genetic variations of the IL1RN gene that are high expression alleles are associated with non-responsiveness to medication intended to block IL-1, a key cytokine that promotes inflammation in systemic JIA. Read more.
- The BBOP Study inspired additional publications relating to novel approaches for analyzing genetic datasets, including in the context of JIA. One report demonstrated that the choice of methods for analyzing genetic data can significantly alter results. Using BBOP genetic data, the research showed that even among clinically and biologically homogenous JIA subsets, gene analysis results can differ depending on the methods used. An additional study demonstrated that the choice of gene set database for a particular condition might profoundly affect the outcome of the analysis. Read more and more.
Predicting Outcomes in JIA: By applying data mining computational techniques, the BBOP Study data revealed that a select group of clinical and biomarker attributes could more effectively predict JIA outcomes than clinical features alone. Read more.
An Upstream Inflammatory Biomarker in JIA (sLRP1): The BBOP Study investigated an inflammatory biomarker, soluble low-density lipoprotein receptor-related protein 1 (sLRP1), for the first time in JIA. Results showed that sLRP1 levels correlate with clinical and biomarker indicators of short-term improvement in JIA disease activity, suggesting that sLRP1 might be a useful upstream biomarker for assessing JIA disease activity and outcome prediction. Read more.
Physical Activity in JIA: The BBOP Study found that Canadian children with JIA have lower levels of physical activity compared to healthy children. Furthermore, the study showed that levels of physical activity decline over time in children with JIA and that the decline is associated with more disease activity and higher levels of disease-specific stress. Read more.

Engagement

The BBOP Study was supported by funding from the Canadian Institutes for Health Research (Institute of Musculoskeletal Health and Arthritis and Institute of Infection and Immunity; FRN #82517); The Arthritis Society; The Canadian Arthritis Network (SRI-IJD-01); The University of Saskatchewan; The Manitoba Institute of Child Health; McGill University (Division of Pediatric Rheumatology); Memorial University; The University of British Columbia (Division of Pediatric Rheumatology); The Clinical Research Centre of the Centre Hospitalier Universitaire de Sherbrooke (CHUS); The Jim Pattison Children’s Hospital Foundation; The Haslam Fund (University of Saskatchewan), The Kleiman Fund (University of Saskatchewan), and the Weir Family Fund (University of Saskatchewan).
The BBOP Study team includes more than 50 Canadian investigators and consumer partners with lived experiences with JIA plus international collaborators.
The BBOP Study results have been published in scientific journals, presented at national and international meetings and in the media.
Five graduate students were engaged in the BBOP Study.

Action

The BBOP Study has helped establish foundational operating procedures and templates that have helped inform subsequent large scale, Canadian and international JIA research initiatives including the UCAN-Can-Du Study and the UCAN Cure Study, which aimed at discovering ways to better understand JIA and personalize the care of affected children, and the LEAP Study, aimed at understanding the role of physical activity in JIA.
Standard procedures developed for the BBOP Study for biologic sample handling are now entrenched in our research protocols.
New approaches to creating a more refined, evidenced-based approach for the classification of JIA are being informed by information generated from studies such as the BBOP Study.
National efforts are underway and are striving to standardize pediatric ethics approvals in Canada.
New ways to analyze complex datasets are being applied, and additional advanced analytical frameworks are being considered and developed.
The BBOP study has led to research investigating new biomarkers in JIA: the association of uveitis and JIA, the role of oral health in JIA, and the facilitators and barriers to digital health literacy in children and families affected by having JIA.
Additional consumer partners have been added to our team, and an enhanced electronic/digital knowledge mobilization strategy is being deployed.