High dimensional integrative analysis of clinical and molecular factors to predict mucosal healing in Inflammatory Bowel Disease: Analysis of >1000 IBD patient multi-omics data of MUSIC/GIDAMPs Scotland study

Inflammatory Bowel Diseases (IBD), Crohn’s disease (CD) and Ulcerative Colitis (UC) are chronic immune-mediated conditions that affect 10 million people worldwide. IBD is characterized by persistent non-resolving gut inflammation. Despite advances of in immunotherapy, >50% of patients do not achieve mucosal healing in response to drug therapy¹. The MUSIC/GIDAMPs IBD study (www.musicstudy.uk) is an ongoing prospective cohort study in Scotland incorporating clinical and multiomic data of >1000 IBD (recruited between 2020-2023 in Scotland) patients to study their roles in what drives the mucosal healing process in IBD. This PhD project will focus on undertaking high dimensional analysis to build an integrative approach using current data to predict IBD patients that respond to medical therapy and undergo mucosal healing of the gut (full return from ulceration and inflammatory lesions to normal gut appearances). This project will include analysis of microbiome, genetics, proteomics, patient reported outcomes, clinical parameters of disease activity in a unique cohort of IBD patients that have been prospectively collected over 12 months with paired data to both endoscopic and histological gut follow-up to provide the essential information of ‘who undergoes full healing of the gut’. Modelling of predictive approaches will be applied to ongoing collaborative multicentre IBD studies in Scotland (FATE-CD [fibrosis]; BIOPIC [diet in CD]; miniMUSIC [paediatric IBD] and validation cohort of MUSIC from 2022-2025) in a further 500 IBD patients. 

1. Ho GT, Cartwright JA, Thompson EJ, Bain CC, Rossi AG. Resolution of Inflammation and Gut Repair in IBD: Translational Steps Towards Complete Mucosal Healing. Inflamm Bowel Dis 2020 Jul 17;26(8):1131-1143. doi: 10.1093/ibd/izaa045.

Background

Both UC and CD are characterized by gut inflammation (ulcerations, bleeding, swelling and narrowing as seen endoscopically OR infiltration of inflammatory and immune cells into the gut mucosa as seen histologically). Our ongoing MUSIC/GIDAMPs (2020-present) show that only 30% of IBD achieve complete mucosal healing – total return to normal gut appearances and function, both endoscopically and histologically. This is despite the availability of potent immune-therapies such as biologics and new small-molecules in IBD. Complete mucosal healing is the most important treatment goal as it is linked to the best long-term prognosis.

We do not understand why certain patients do not achieve mucosal healing.  

Hence the MUSIC/GIDAMPs study is an in-depth human prospective and cross-sectional study of >1000 IBD patients, incorporating >100 clinical and imaging data points and molecular –omics (genetics, microbiome [oral, gut and stool], blood proteomics with subset data on blood immunometabolism, gut and blood single-cell data; and drug response data to provide the platform for dedicated mechanistic studies (currently 10 different projects funded by MRC, ERC, Wellcome and CSO) to provide Precision Medicine approaches to indentify new tests and targets for IBD.

Aims

1. Develop a high dimensional computational analysis approach to predict complete mucosal healing in IBD.
2. To understand the interaction between clinical and molecular factors that can be predictive of clinical outcomes in a complex immune-mediated condition such as IBD.
3. To develop and refine biological endophenotype data in the core patients that do not undergo mucosal healing in IBD and potential biological pathways that can be targeted with future functional studies.

Training Outcomes

1. Clinical and molecular data integration, analysis and management towards meaningful clinical application in IBD.
2. Develop bioinformatics and computational biology expertise including AI-enabled tools (Random Forrest and unsupervised machine learning methods) to build predictive tools for IBD subtype, mucosal healing and disease activity.
3. Work with data management and clinical team to improve classification of mucosal healing and how this relates to molecular endophenotyping based on more complex contribution of microbiome and genetics.