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An ileal Crohn's disease gene signature based on whole human genome expression profiles of disease unaffected ileal mucosal biopsies.

Zhang T, Song B, Zhu W, Xu X, Gong QQ, Morando C, Dassopoulos T, Newberry RD, Hunt SR, Li E - PLoS ONE (2012)

Bottom Line: This gene is an established biomarker for prostate cancer, but has not previously been associated with Crohn's disease.Immunohistochemical staining confirmed increased expression of FOLH1 in the ileal epithelium.These results provide evidence for convergent molecular abnormalities in the macroscopically disease unaffected proximal margin of resected ileum from ileal CD subjects.

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, United States of America.

ABSTRACT
Previous genome-wide expression studies have highlighted distinct gene expression patterns in inflammatory bowel disease (IBD) compared to control samples, but the interpretation of these studies has been limited by sample heterogeneity with respect to disease phenotype, disease activity, and anatomic sites. To further improve molecular classification of inflammatory bowel disease phenotypes we focused on a single anatomic site, the disease unaffected proximal ileal margin of resected ileum, and three phenotypes that were unlikely to overlap: ileal Crohn's disease (ileal CD), ulcerative colitis (UC), and control patients without IBD. Whole human genome (Agilent) expression profiling was conducted on two independent sets of disease-unaffected ileal samples collected from the proximal margin of resected ileum. Set 1 (47 ileal CD, 27 UC, and 25 Control non-IBD patients) was used as the training set and Set 2 was subsequently collected as an independent test set (10 ileal CD, 10 UC, and 10 control non-IBD patients). We compared the 17 gene signatures selected by four different feature-selection methods to distinguish ileal CD phenotype with non-CD phenotype. The four methods yielded different but overlapping solutions that were highly discriminating. All four of these methods selected FOLH1 as a common feature. This gene is an established biomarker for prostate cancer, but has not previously been associated with Crohn's disease. Immunohistochemical staining confirmed increased expression of FOLH1 in the ileal epithelium. These results provide evidence for convergent molecular abnormalities in the macroscopically disease unaffected proximal margin of resected ileum from ileal CD subjects.

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Receiver operating characteristic (ROC) curve for different classification methods on the training set.
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pone-0037139-g001: Receiver operating characteristic (ROC) curve for different classification methods on the training set.

Mentions: Majority vote based on the median score of seven classifier tools (see Materials and Methods) was used to assess the accuracy associated with each feature subset for ileal CD phenotype in the training set via Jack-Knife (take-one-out) cross validation. The feature subset selected by the boosting method yielded the highest area under the curve (AUC) and overall accuracy (see Table 2). The smoothed receiver operating characteristic (ROC) curves for the seven classifiers as well as their majority vote based on the training data were comparable (see Figure 1). We then applied this 17 gene signature to an independent test set that was collected after the training set (see Figure 2, Table 3). As shown in Table S2, the polarity of the mean fold change for this 17 ileal gene signature was preserved in both the training and test set. Of note, errors in classification reflected misclassification of UC samples as ileal CD samples. The smoothed ROC curves are shown in Figure 2 in order to facilitate visual differentiation of the different classifiers. There was good agreement between the AUC for the empirical and smoothed ROC curves (see Table S3), indicating that the smoothed ROCs retained the key properties of the empirical ROCs.


An ileal Crohn's disease gene signature based on whole human genome expression profiles of disease unaffected ileal mucosal biopsies.

Zhang T, Song B, Zhu W, Xu X, Gong QQ, Morando C, Dassopoulos T, Newberry RD, Hunt SR, Li E - PLoS ONE (2012)

Receiver operating characteristic (ROC) curve for different classification methods on the training set.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351422&req=5

pone-0037139-g001: Receiver operating characteristic (ROC) curve for different classification methods on the training set.
Mentions: Majority vote based on the median score of seven classifier tools (see Materials and Methods) was used to assess the accuracy associated with each feature subset for ileal CD phenotype in the training set via Jack-Knife (take-one-out) cross validation. The feature subset selected by the boosting method yielded the highest area under the curve (AUC) and overall accuracy (see Table 2). The smoothed receiver operating characteristic (ROC) curves for the seven classifiers as well as their majority vote based on the training data were comparable (see Figure 1). We then applied this 17 gene signature to an independent test set that was collected after the training set (see Figure 2, Table 3). As shown in Table S2, the polarity of the mean fold change for this 17 ileal gene signature was preserved in both the training and test set. Of note, errors in classification reflected misclassification of UC samples as ileal CD samples. The smoothed ROC curves are shown in Figure 2 in order to facilitate visual differentiation of the different classifiers. There was good agreement between the AUC for the empirical and smoothed ROC curves (see Table S3), indicating that the smoothed ROCs retained the key properties of the empirical ROCs.

Bottom Line: This gene is an established biomarker for prostate cancer, but has not previously been associated with Crohn's disease.Immunohistochemical staining confirmed increased expression of FOLH1 in the ileal epithelium.These results provide evidence for convergent molecular abnormalities in the macroscopically disease unaffected proximal margin of resected ileum from ileal CD subjects.

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, United States of America.

ABSTRACT
Previous genome-wide expression studies have highlighted distinct gene expression patterns in inflammatory bowel disease (IBD) compared to control samples, but the interpretation of these studies has been limited by sample heterogeneity with respect to disease phenotype, disease activity, and anatomic sites. To further improve molecular classification of inflammatory bowel disease phenotypes we focused on a single anatomic site, the disease unaffected proximal ileal margin of resected ileum, and three phenotypes that were unlikely to overlap: ileal Crohn's disease (ileal CD), ulcerative colitis (UC), and control patients without IBD. Whole human genome (Agilent) expression profiling was conducted on two independent sets of disease-unaffected ileal samples collected from the proximal margin of resected ileum. Set 1 (47 ileal CD, 27 UC, and 25 Control non-IBD patients) was used as the training set and Set 2 was subsequently collected as an independent test set (10 ileal CD, 10 UC, and 10 control non-IBD patients). We compared the 17 gene signatures selected by four different feature-selection methods to distinguish ileal CD phenotype with non-CD phenotype. The four methods yielded different but overlapping solutions that were highly discriminating. All four of these methods selected FOLH1 as a common feature. This gene is an established biomarker for prostate cancer, but has not previously been associated with Crohn's disease. Immunohistochemical staining confirmed increased expression of FOLH1 in the ileal epithelium. These results provide evidence for convergent molecular abnormalities in the macroscopically disease unaffected proximal margin of resected ileum from ileal CD subjects.

Show MeSH
Related in: MedlinePlus