IBD Biomarker Discovery and Validation Platform

Biomarker Discovery, Validation, and Multi-Omics Profiling for Disease Activity Assessment, Treatment Monitoring, and Risk Stratification in Inflammatory Bowel Disease: A Multicenter Prospective Biospecimen-Based Observational Cohort Study

The goal of this observational study is to establish a multicenter prospective clinical and biospecimen platform for biomarker discovery and validation in inflammatory bowel disease, including Crohn's disease and ulcerative colitis.

Researchers want to learn whether candidate biomarkers or combined biomarker models can help assess intestinal inflammation, monitor response to routine clinical treatment, predict treatment outcomes, and identify participants who may be at higher risk of disease progression.

The study may enroll participants with inflammatory bowel disease, unaffected first-degree relatives of participants with inflammatory bowel disease, unrelated healthy controls, and non-IBD disease controls when appropriate. Clinical information and biological samples, including blood, stool, and intestinal tissue, may be collected. Biomarkers measured in blood, stool, intestinal tissue, genetic data, immune profiles, microbiome data, and other multi-omics data may be evaluated.

The main questions this study aims to answer are:

Can candidate biomarkers or combined biomarker models identify endoscopic disease activity when compared with endoscopic assessment?

Can these biomarkers monitor or predict clinical response, clinical remission, endoscopic response, endoscopic remission, imaging response, or biomarker response during routine clinical care?

Can these biomarkers help predict treatment failure, disease progression, hospitalization, surgery, treatment escalation, or complex Crohn's disease phenotypes?

Participants will not be assigned to any treatment by the study. All treatments and clinical management decisions will be chosen by treating physicians as part of routine medical care.

This is a multicenter prospective observational cohort study designed to establish a clinical data and biospecimen-based platform for biomarker discovery, validation, and multi-omics research in inflammatory bowel disease. The study will enroll participants with inflammatory bowel disease, including Crohn's disease, ulcerative colitis, or IBD-unclassified when applicable, as well as unaffected first-degree relatives, unrelated healthy controls, and non-IBD disease controls when appropriate.

The study is not designed to assign or test any study-directed treatment. All medical treatments, including biologic therapies, targeted small-molecule therapies, nutritional therapy, endoscopy, imaging, surgery, and other clinical management decisions, will be determined by treating physicians according to routine clinical practice. The study will observe participants during routine care and collect standardized clinical data, biospecimens, endoscopic findings, histologic findings, laboratory results, imaging findings, treatment exposure information, and follow-up outcomes.

The overall purpose of this study is to evaluate whether candidate biomarkers or combined biomarker models can be used to assess disease activity, identify endoscopic and histologic inflammation, monitor response to routine clinical treatment, predict treatment outcomes, and support risk stratification for disease progression. Endoscopic assessment will serve as the primary reference standard for evaluating biomarker performance for objective intestinal inflammation.

The study is intended to function as an open biomarker discovery and validation platform. It will evaluate both pre-specified biomarkers and additional candidate biomarkers identified through genetic, pharmacogenetic, immune, microbiome, transcriptomic, proteomic, metabolomic, single-cell, tissue-based, spatial, or other multi-omics analyses. Pre-specified biomarker domains may include blood-based biomarkers, stool-based biomarkers, tissue-based biomarkers, genetic markers, immune-related markers, microbiome-derived markers, and multi-omics-derived candidate biomarkers. Examples may include leucine-rich alpha-2 glycoprotein, fecal calprotectin, C-reactive protein, oncostatin M, TL1A/TNFSF15-related markers, TNFSF15 genotype, selected HLA or other pharmacogenetic markers when available, and additional biomarkers selected from exploratory omics analyses.

The primary analysis will evaluate the diagnostic performance of candidate biomarkers or combined biomarker models for endoscopic disease activity. Reference measures may include SES-CD, standardized small-bowel endoscopic assessments, capsule endoscopy scores, Mayo endoscopic score, UCEIS, or other accepted endoscopic assessments when applicable. Performance measures may include area under the receiver operating characteristic curve, sensitivity, specificity, predictive values, and biomarker cut-off values. Cut-off values may be explored in discovery datasets and evaluated in internal and external validation cohorts.

A second core analysis will evaluate whether baseline biomarker profiles, longitudinal biomarker changes, or combined biomarker models can monitor or predict treatment response during routine clinical care. Treatment response outcomes may include clinical response, clinical remission, endoscopic response, endoscopic remission, imaging-defined response or remission, fecal calprotectin response, C-reactive protein response, treatment escalation, treatment failure, hospitalization, surgery, or relapse when available.

Secondary analyses will evaluate biomarker performance against specific clinical and objective outcomes. These may include histologic disease activity and histologic remission; clinical remission rate and clinical response rate using disease-specific clinical definitions; concordance with fecal calprotectin as an established stool-based comparator biomarker; concordance with C-reactive protein as an established blood-based comparator biomarker; cross-sectional imaging-defined radiologic response and remission using MRE or CTE when available; intestinal ultrasound-defined response and remission or transmural healing; and disease progression or poor outcomes.

The study will also include family-based and exploratory analyses. The inclusion of unaffected first-degree relatives is intended to support analyses of genetic susceptibility, shared environmental exposure, immune profiles, microbiome features, and other biomarkers related to inflammatory bowel disease. Exploratory analyses may assess genetic or pharmacogenetic markers, multi-omics-derived biomarkers, and biomarker profiles associated with complex Crohn's disease phenotypes, including perianal fistula, stricturing disease, penetrating disease, surgery, treatment escalation, or treatment failure.

Previously collected biospecimens and clinical data from prior ethics-approved prospective studies may be included as discovery datasets when permitted by the original consent, ethics approval, and the current platform protocol. Later enrolled participants from the same research network may be used as an internal validation cohort. Participants from collaborating centers or external datasets may be used as an external validation cohort when available. This discovery and validation framework is intended to improve reproducibility, reduce overfitting, and evaluate the generalizability of candidate biomarkers and biomarker-based prediction models.

Statistical analyses may include descriptive statistics, group comparisons, correlation analyses, regression models, survival analyses, mixed-effects models for longitudinal data, receiver operating characteristic analyses, threshold exploration, model calibration, model discrimination, reclassification analyses, decision curve analyses, and internal or external validation. The long-term goal is to provide a standardized clinical and biospecimen platform to support objective disease monitoring, treatment prediction, risk stratification, and future precision medicine research in inflammatory bowel disease.

Eligibility Criteria:

Inclusion Criteria:

1. General inclusion criteria for all participants:

   • Age 14 years or older.
   • Able to provide written informed consent; for minors, consent from a legal guardian and assent from the participant will be obtained according to local ethics requirements.
   • Willing to provide clinical information and/or biospecimens, which may include blood, stool, intestinal tissue, or other available biological samples.
   • Able to participate in study-related data and sample collection according to the study protocol.

2. Participants with inflammatory bowel disease:

   • Diagnosed with inflammatory bowel disease, including Crohn's disease, ulcerative colitis, or IBD-unclassified when applicable, according to accepted national or international diagnostic criteria.
   • May be newly diagnosed, previously diagnosed, under routine follow-up, or receiving routine clinical treatment.
   • Clinical data, treatment exposure information, laboratory results, endoscopic findings, histologic findings, imaging findings, biospecimens, and follow-up outcomes may be available or collected.

3. Unaffected first-degree relatives of participants with inflammatory bowel disease:

   • Biological first-degree relatives of participants with inflammatory bowel disease, including parents, siblings, or offspring.
   • No prior diagnosis of inflammatory bowel disease at enrollment.
   • Willing to provide clinical information and/or biospecimens for family-based genetic, environmental, immune, microbiome, and multi-omics analyses.

4. Unrelated healthy controls:

   • Individuals without a diagnosis of inflammatory bowel disease.
   • No first-degree biological relationship to enrolled participants with inflammatory bowel disease.
   • No known active gastrointestinal inflammatory disease at enrollment.

5. Non-IBD disease controls:

   • Individuals with gastrointestinal symptoms or other non-IBD conditions who undergo clinical evaluation but are not diagnosed with inflammatory bowel disease.
   • Clinical information and/or biospecimens may be collected as disease controls when appropriate.

Exclusion Criteria:

• Refusal or inability to provide informed consent or required assent when applicable.
• Active severe infection or chronic infectious disease that may substantially affect biomarker interpretation, including active tuberculosis, active hepatitis B or C, HIV infection, or other clinically significant active infection.
• Pregnancy or lactation at the time of enrollment.
• Severe mental illness, cognitive impairment, or other condition that prevents cooperation with study procedures.
• Known primary extraintestinal autoimmune disease or systemic inflammatory disease that is considered the main disease and may substantially confound biomarker interpretation.
• Current or recent participation in another interventional clinical trial that may substantially affect the study biomarkers or outcome assessments, as judged by the investigator.
• History of malignant tumor or other severe comorbidity that may substantially affect study participation or biomarker interpretation, as judged by the investigator.
• Inadequate biospecimen quality, missing key clinical information, or inability to complete essential study assessments for the relevant analysis.