Title: Prognostic biomarkers to identify patients with severe Crohn’s disease: Systematic review, meta-analysis and prognostic model with external validation.
Funder: Department of Health and Social Care

Abstract: DESIGN: Systematic review (SR) & meta-analysis, model development/tuning & external validation via individual patient data (IPD). REVIEW STRATEGY: The SR will be lead by a clinical researcher with Crohns content expertise, helped by a statistician RA, both closely supervised by senior team members. SR will adhere to Preferred Reporting Items for Systematic Reviews & Meta-Analyses (PRISMA), using risk of bias tool for prediction studies PROBAST (to which we have pre-publication access). UCL MetaLib will search multiple databases simultaneously, 1980-present. We will use ExaCT information extraction system & also hand-search; see 2013 Scoping Review in detailed project description (DPD). TARGET POPULATION: Patients with established Crohns disease & biomarker data, with focus on new & severe diagnoses as specified by the brief (but not restricted to these as doing so would result in excessive discarded data; see scoping review DPD). HEALTH TECHNOLOGIES: We will search multiple biomarkers as specified in our DPD: Clinical/symptomatic, endoscopic, imaging, serological (inc. simple/genetic/antibody), faecal, histological, urinary, including those not perceived as “novel” since such established markers work well. OUTCOMES: We will use CHARMS to frame the SR question & extract data (as per our previous work). Extraction will include study design, methods, participants, interventions, outcomes, setting/context, disease severity & location/burden, biomarker, sample size, 2x2 tables, modelling methods, performance & prediction (if models identified). We will collect costs if possible. Outcomes will include disease severity & activity, which we expect to vary between studies; we will note specific definitions & perform sensitivity analyses. We will use PPI/experts to identify all important outcomes. ANALYSIS: We will meta-analyse univariable estimates via multilevel subject-specific (conditional) analysis, fitted by adaptive Gaussian quadrature. We will use stratified one-stage models, ensuring correct clustering of patients within studies via separate intercepts for each study. Subgroups examined as specified in our DPD. MODEL DEVELOPMENT & VALIDATION: We will combine promising biomarkers identified from unvariable analysis in a predictive model using multivariable analysis (see DPD). For external validation of model prediction of disease severity, we have IPD from two unpublished Crohns biomarker studies, METRIC (HTA11/23/01, MR Enterography or ulTRasound In Crohns) & PANTS (Personalised Anti-TNF Therapy in CrohnS), with >1050 highly-characterised patients recruited presently & >1850 by end 2015. Via our contacts, we will also seek other datasets. We will express validation results in terms of calibration, discrimination, sensitivity & specificity, & will recalibrate where applicable. We will provide an overall synthesis of evidence from the SR, univariable analysis, & our validated model, & will interpret clinical utility in conjunction with METRIC/PANTS panels & provide recommendations. Finally, we will propose a model & trial design for subsequent HTA external validation. TIMETABLE: 18 months total: initial 12 for SR/MA & latter 12 for model development/validation, overlapped by 6 months. EXPERTISE: We combine strong content expertise of Crohns biomarkers with deep statistical knowledge of SR, meta-analysis & prognostic model development, & access to IPD; METRIC/PANTS PIs are applicants/2 NIHR senior investigators.

Lay abstract: Crohn’s disease causes inflammation of the intestines. Traditional treatment uses drugs such as steroids and immunosuppression to reduce inflammation but relatively new drugs called “biologicals” are highly effective. The best known is infliximab. Biologicals reduce autoimmunity, which plays a large factor in Crohn’s disease. For many years treatment of severe Crohn’s disease has started by using low doses of steroids first, then gradually adding in stronger drugs, finally adding biologicals if inflammation is still present. However, recent research suggests that treating new patients with severe disease with biologicals straight away can stop the disease in its tracks. The aim is to prevent disease with “stronger” drugs first, rather than waiting. However, it is not sensible to treat all patients with biologicals first, because these drugs have side-effects and are very expensive. Our research therefore aims to identify which patients newly presenting with Crohn’s are destined to develop severe disease, thereby selecting those who need early biological treatment. We can do this using “biomarkers”, which are measurements made on patients that indicate present and future disease severity. There are many different biomarkers, including symptoms, features on endoscopy, measurements of chemicals in blood and stool, and some genes. For example, patients with severe Crohn’s disease have high levels of “CRP” protein in their blood. It is likely that measuring a combination of different biomarkers will best indicate which patients are destined to develop severe disease. In order to identify the best biomarkers, we will search all available medical research in this field using “systematic review” methods. This means the search is both comprehensive and unbiased. We will then select high-quality studies of Crohn’s patients (preferably those newly presenting with severe disease) that have used a biomarker(s) to measure disease severity. Then we can determine the volume and quality of research available for each individual biomarker. If sufficient good-quality studies are available, we can mathematically combine the results from individual studies to appear as if they came from one “big” study, a process known as “meta-analysis”. This allows us to estimate with more certainty which biomarkers best predict disease. After this, we will know which biomarkers have been well-studied and which can predict future disease severity. We will combine these biomarkers in a “model”, which will predict better than single biomarkers. We then need to see if the model “works” – i.e. does it predict patients’ disease accurately? We will do this using individual patient data from at least two large studies of Crohn’s disease that are currently unpublished; the researchers are co-applicants. Finally, we will adjust the model and give it to the funders of this research along with a proposal for a future clinical trial to test it. Ultimately, we aim to develop a model that physicians use to predict future disease severity in their patients, thereby guiding biological treatment. To perform this research we have brought together recognised experts in Crohn’s disease, biomarker assessment, systematic review, prognosis statistics, and we have patient representatives from Crohns & Colitis UK to keep the focus patient-centric. The research will take 18-months. We will then give our results to the HTA and present them in medical journals and conferences.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL