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Validation of gene expression biomarker analysis for biopsy-based clinical trials in Crohn's disease.

ABSTRACT: The ability to measure the expression of proinflammatory cytokines from intestinal biopsies in patients with Crohn's disease in an accurate and reproducible way is critical for proof-of-concept and mechanism-of-action trials; however, the number of biopsies from a segment of the ileum or colon required to yield reproducible results has not been rigorously evaluated. We examined intestinal biopsies from patients with Crohn's disease to validate methods for detecting changes in inflammatory gene expression.To evaluate the reproducibility of gene expression measurements, intestinal biopsies were obtained from designated segments from 6 healthy controls, 6 patients with active Crohn's disease, and 6 patients with inactive Crohn's disease. Disease activity was based on the simple endoscopic score for Crohn's disease. Expression of 7 proinflammatory genes was measured from each biopsy using quantitative polymerase chain reaction. Using a linear mixed effects model, the power to detect transcriptional changes corresponding to active and inactive Crohn's disease was calculated.Total simple endoscopic score for Crohn's disease score corresponds with expression of most inflammatory biomarkers. For most genes, 2 to 5 biopsies are needed to reduce sampling error to <25% for most genes. To measure changes in mRNA expression corresponding to active versus inactive Crohn's disease, 1 to 2 intestinal biopsies from 3 patients before and after treatment are needed to yield power of at least 80%.Measuring proinflammatory gene expression from mucosal biopsies from patients with Crohn's disease is practicable and provides objective biomarkers that can be used in proof-of-concept and mechanism-of-action trials to assess response to therapy.

SUBMITTER: Boland BS

PROVIDER: S-EPMC4404151 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Validation of gene expression biomarker analysis for biopsy-based clinical trials in Crohn's disease.

Boland Brigid S BS Boyle David L DL Sandborn William J WJ Firestein Gary S GS Levesque Barrett G BG Hillman Joshua J Zhang Bing B Proudfoot James J Eckmann Lars L Ernst Peter B PB Rivera-Nieves Jesus J Pola Suresh S Copur-Dahi Nedret N Zou Guangyong G Chang John T JT

Inflammatory bowel diseases 20150201 2

<h4>Background</h4>The ability to measure the expression of proinflammatory cytokines from intestinal biopsies in patients with Crohn's disease in an accurate and reproducible way is critical for proof-of-concept and mechanism-of-action trials; however, the number of biopsies from a segment of the ileum or colon required to yield reproducible results has not been rigorously evaluated. We examined intestinal biopsies from patients with Crohn's disease to validate methods for detecting changes in ...[more]

PMID: 25545378

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Project description:BACKGROUND:Environmental Enteropathy (EE), characterized by alterations in intestinal structure, function, and immune activation, is believed to be an important contributor to childhood undernutrition and its associated morbidities, including stunting. Half of all global deaths in children <?5?years are attributable to under-nutrition, making the study of EE an area of critical priority. METHODS:Community based intervention study, divided into two sub-studies, 1) Longitudinal analyses and 2) Biopsy studies for identification of EE features via omics analyses. Birth cohorts in Matiari, Pakistan established: moderately or severely malnourished (weight for height Z score (WHZ)?<?-?2) children, and well-nourished (WHZ?>?0) children. Blood, urine, and fecal samples, for evaluation of potential biomarkers, will be collected at various time points from all participants (longitudinal analyses). Participants will receive appropriate educational and nutritional interventions; non-responders will undergo further evaluation to determine eligibility for further workup, including upper gastrointestinal endoscopy. Histopathological changes in duodenal biopsies will be compared with duodenal biopsies obtained from USA controls who have celiac disease, Crohn's disease, or who were found to have normal histopathology. RNA-Seq will be employed to characterize mucosal gene expression across groups. Duodenal biopsies, luminal aspirates from the duodenum, and fecal samples will be analyzed to define microbial community composition (omic analyses). The relationship between histopathology, mucosal gene expression, and community configuration will be assessed using a variety of bioinformatic tools to gain better understanding of disease pathogenesis and to identify mechanism-based biomarkers. Ethical review committees at all collaborating institutions have approved this study. All results will be made available to the scientific community. DISCUSSION:Operational and ethical constraints for safely obtaining intestinal biopsies from children in resource-poor settings have led to a paucity of human tissue-based investigations to understand and reverse EE in vulnerable populations. Furthermore, EE biomarkers have rarely been correlated with gold standard histopathological confirmation. The Study of Environmental Enteropathy and Malnutrition (SEEM) is designed to better understand the pathophysiology, predictors, biomarkers, and potential management strategies of EE to inform strategies to eradicate this debilitating pathology and accelerate progress towards the 2030 Sustainable Development Goals. TRIAL REGISTRATION:Retrospectively registered; clinicaltrials.gov ID NCT03588013 .

Dataset Information

Validation of gene expression biomarker analysis for biopsy-based clinical trials in Crohn's disease.

Publications

Validation of gene expression biomarker analysis for biopsy-based clinical trials in Crohn's disease.

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