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A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus.

ABSTRACT: The analysis of patient blood transcriptional profiles offers a means to investigate the immunological mechanisms relevant to human diseases on a genome-wide scale. In addition, such studies provide a basis for the discovery of clinically relevant biomarker signatures. We designed a strategy for microarray analysis that is based on the identification of transcriptional modules formed by genes coordinately expressed in multiple disease data sets. Mapping changes in gene expression at the module level generated disease-specific transcriptional fingerprints that provide a stable framework for the visualization and functional interpretation of microarray data. These transcriptional modules were used as a basis for the selection of biomarkers and the development of a multivariate transcriptional indicator of disease progression in patients with systemic lupus erythematosus. Thus, this work describes the implementation and application of a methodology designed to support systems-scale analysis of the human immune system in translational research settings.

SUBMITTER: Chaussabel D

PROVIDER: S-EPMC2727981 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus.

Chaussabel Damien D Quinn Charles C Shen Jing J Patel Pinakeen P Glaser Casey C Baldwin Nicole N Stichweh Dorothee D Blankenship Derek D Li Lei L Munagala Indira I Bennett Lynda L Allantaz Florence F Mejias Asuncion A Ardura Monica M Kaizer Ellen E Monnet Laurence L Allman Windy W Randall Henry H Johnson Diane D Lanier Aimee A Punaro Marilynn M Wittkowski Knut M KM White Perrin P Fay Joseph J Klintmalm Goran G Ramilo Octavio O Palucka A Karolina AK Banchereau Jacques J Pascual Virginia V

Immunity 20080701 1

The analysis of patient blood transcriptional profiles offers a means to investigate the immunological mechanisms relevant to human diseases on a genome-wide scale. In addition, such studies provide a basis for the discovery of clinically relevant biomarker signatures. We designed a strategy for microarray analysis that is based on the identification of transcriptional modules formed by genes coordinately expressed in multiple disease data sets. Mapping changes in gene expression at the module l ...[more]

PMID: 18631455

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Project description:We designed a strategy for microarray analysis that is based on the identification of transcriptional modules formed by genes coordinately expressed in multiple disease data sets. Mapping changes in gene expression at the module level generated disease-specific transcriptional fingerprints that provide a stable framework for the visualization and functional interpretation of microarray data. The first step of the module-construction process analyzes expression patterns of transcripts across samples for individual diseases: sets of coordinately expressed transcripts were identified with an unsupervised clustering algorithm; in this case, the GeneSpring Version 7.1 (Agilent) implementation of the K-Means algorithm (k = 30). All transcripts detected in at least one sample were used as input; no screening for differential expression was performed. The second step of the module-construction process analyzed the “clustering behavior” of transcripts across diseases, taking into account the possibility that genes may cocluster in some diseases but not in others. Also, in our example, the transcripts that clustered together across all eight diseases were grouped to form a set of modules (round 1 of selection), and the stringency of the analysis was then decreased gradually to identify transcripts that belong to a similar K-means cluster in only a subset of diseases (round 2: seven out of eight diseases; round 3: six out of eight diseases). It is important to note that the module-selection process is “data-driven” and does not involve manual selection of genes by the investigator. We implemented the module-construction strategy described above, using as input a total of 239 peripheral-blood mononuclear cell (PBMC) samples obtained from individuals with one of the following conditions: systemic juvenile idiopathic arthritis (n = 47), systemic lupus erythematosus (n = 40), type I diabetes (n = 20), metastatic melanoma (n = 39), acute infections (Escherichia coli [n = 22], Staphylococcus aureus [n = 18], Influenza A [n = 16]) or liver-transplant recipients undergoing immunosuppressive therapy (n = 37). Transcriptional profiles were generated with Affymetrix U133A and U133B GeneChips (> 44,000 probe sets). A total of 4742 transcripts, distributed among 28 sets, were selected after running of the module-construction algorithm described above. Each module is assigned a unique identifier indicating the round and order of selection (i.e., M3.1 is the first module identified in the third round of selection). The stringency of this algorithm was tested statistically by implementation of the same module-construction procedure after randomization of the original data set. This process was repeated 200 times, without a single module identified. Therefore, the analysis of gene-cluster membership across multiple diseases provided a stringent means to identify PBMC transcriptional modules.

Project description:Genome wide association studies (GWAS) have identified autoimmune disease‑associated loci, a number of which are involved in numerous disease‑associated pathways. However, much of the underlying genetic and pathophysiological mechanisms remain to be elucidated. Systemic lupus erythematosus (SLE) is a chronic, highly heterogeneous autoimmune disease, characterized by differences in autoantibody profile, serum cytokines and a multi‑system involvement. This study presents the Epione application, an integrated bioinformatics web‑toolkit, designed to assist medical experts and researchers in more accurately diagnosing SLE. The application aims to identify the most credible gene variants and single nucleotide polymorphisms (SNPs) associated with SLE susceptibility, by using patient's genomic data to aid the medical expert in SLE diagnosis. The application contains useful knowledge of >70,000 SLE‑related publications that have been analyzed, using data mining and semantic techniques, towards extracting the SLE‑related genes and the corresponding SNPs. Probable genes associated with the patient's genomic profile are visualized with several graphs, including chromosome ideograms, statistic bars and regulatory networks through data mining studies with relative publications, to obtain a representative number of the most credible candidate genes and biological pathways associated with the SLE. Furthermore, an evaluation study was performed on a patient diagnosed with SLE and is presented herein. Epione has also been expanded in family‑related candidate patients to evaluate its predictive power. All the recognized gene variants that were previously considered to be associated with SLE were accurately identified in the output profile of the patient, and by comparing the results, novel findings have emerged. The Epione application may assist and facilitate in early stage diagnosis by using the patients' genomic profile to compare against the list of the most predictable candidate gene variants related to SLE. Its diagnosis‑oriented output presents the user with a structured set of results on variant association, position in genome and links to specific bibliography and gene network associations. The overall aim of the present study was to provide a reliable tool for the most effective study of SLE. This novel and accessible webserver tool of SLE is available at http://geneticslab.aua.gr/epione/.

Dataset Information

A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus.

Publications

A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus.

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