Integrative multi-platform meta-analysis of gene expression profiles in pancreatic ductal adenocarcinoma patients for identifying novel diagnostic biomarkers

Applying differentially expressed genes (DEGs) to identify feasible biomarkers in diseases can be a hard task when working with heterogeneous datasets. Expression data are strongly influenced by technology, sample preparation processes, and/or labeling methods. The proliferation of different microarray platforms for measuring gene expression increases the need to develop models able to compare their results, especially when different technologies can lead to signal values that vary greatly. Integrative meta-analysis can significantly improve the reliability and robustness of DEG detection. The objective of this work was to develop an integrative approach for identifying potential cancer biomarkers by integrating gene expression data from two different platforms. Pancreatic ductal adenocarcinoma (PDAC), where there is an urgent need to find new biomarkers due its late diagnosis, is an ideal candidate for testing this technology. Expression data from two different datasets, namely Affymetrix and Illumina (18 and 36 PDAC patients, respectively), as well as from 18 healthy controls, was used for this study. A meta-analysis based on an empirical Bayesian methodology (ComBat) was then proposed to integrate these datasets. DEGs were finally identified from the integrated data by using the statistical programming language R. After our integrative meta-analysis, 5 genes were commonly identified within the individual analyses of the independent datasets. Also, 28 novel genes that were not reported by the individual analyses (`gained' genes) were also discovered. Several of these gained genes have been already related to other gastroenterological tumors. The proposed integrative metaanalysis has revealed novel DEGs that may play an important role in PDAC and could be potential biomarkers for diagnosing the disease.This work was supported by the Instituto de Salud Carlos III (grant number DTS15/00201 to OC), Ministerio de Economía Competitividad (the Spanish Ministry of Economy and Competitiveness) (grant number TIN2015-71873-R to IR), Consejería de Salud, Junta de Andalucía (PIN-0474-2016 to JP), Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (P12-TIC-2082 to IR) and the University de Granada (grant number 15/13 to OC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

ROC Curves for the 5 genes commonly expressed: <i>FAMI3</i>, <i>IRAK3</i>, <i>DENND2D</i>, <i>PLBD1</i> and <i>AGPAT9</i>.

<p>Curves are provided for both Illumina and Affymetrix individual analyses as well as our integrative meta-analysis. The Area Under the Curve (AUC) metrics are also provided for each curve.</p

La Vigie marocaine

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Coincident genes in the three analyzes: Affymetrix, Illumina and integrated meta-analysis.

<p>Coincident genes in the three analyzes: Affymetrix, Illumina and integrated meta-analysis.</p

Characteristics of both Cohort 1 and Cohort 2 groups of PDAC patients.

<p>Characteristics of both Cohort 1 and Cohort 2 groups of PDAC patients.</p

Comparison of individual analysis by technology with integrated analysis.

<p><b>a</b> Coincident genes in the three analyzes: Affymetrix, Illumina and integrated meta-analysis (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194844#pone.0194844.t002" target="_blank">Table 2</a>). <b>b</b> Remaining differentially expressed genes in individual Illumina and the integrative meta-analysis (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194844#pone.0194844.s006" target="_blank">S1 Table</a>). <b>c</b> Remaining differentially expressed genes in individual Affymetrix and the integrative meta-analysis (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194844#pone.0194844.s007" target="_blank">S2 Table</a>). <b>d</b> Differentially expressed genes in the integrative meta-analysis but not in individual analysis (gained genes) (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194844#pone.0194844.s008" target="_blank">S3 Table</a>).</p