An example on evaluation of pathway pairwise similarity matrix using Kappa statistics.

<p>The relationships between proteins and associated pathways were represented as a binary matrix of size <i>M×n</i>, corresponding to <i>M</i> enriched pathways and <i>n</i> associated proteins. The absence and presence of a protein in a pathway were denoted as 0 and 1, respectively.</p

Integrative Computational and Experimental Approaches to Establish a Post-Myocardial Infarction Knowledge Map

<div><p>Vast research efforts have been devoted to providing clinical diagnostic markers of myocardial infarction (MI), leading to over one million abstracts associated with “MI” and “Cardiovascular Diseases” in PubMed. Accumulation of the research results imposed a challenge to integrate and interpret these results. To address this problem and better understand how the left ventricle (LV) remodels post-MI at both the molecular and cellular levels, we propose here an integrative framework that couples computational methods and experimental data. We selected an initial set of MI-related proteins from published human studies and constructed an MI-specific protein-protein-interaction network (MIPIN). Structural and functional analysis of the MIPIN showed that the post-MI LV exhibited increased representation of proteins involved in transcriptional activity, inflammatory response, and extracellular matrix (ECM) remodeling. Known plasma or serum expression changes of the MIPIN proteins in patients with MI were acquired by data mining of the PubMed and UniProt knowledgebase, and served as a training set to predict unlabeled MIPIN protein changes post-MI. The predictions were validated with published results in PubMed, suggesting prognosticative capability of the MIPIN. Further, we established the first knowledge map related to the post-MI response, providing a major step towards enhancing our understanding of molecular interactions specific to MI and linking the molecular interaction, cellular responses, and biological processes to quantify LV remodeling.</p></div

Localization of 613 MIPIN proteins.

<p>The complete set of MIPIN proteins (including interacting partners of seed proteins) are shown to be residing in 76 locations, with plasma membrane, extracellular region, and cytosol being the most preferred sites. The indentation represents the structural hierarchy of cellular component terms.</p

Specificity of GO biological process terms.

<p>(<b>Top left</b>) Histogram of number of ancestors. (<b>Bottom left</b>) Histogram of number of offspring. (<b>Top right</b>) Histogram of GO proportion. (<b>Bottom right</b>) Histogram of information content.</p

Specificity of the MIPIN.

<p>(<b>A</b>) Gaussian-like distribution of closeness centrality of MIPIN. (<b>B</b>) Closeness centrality vs. degree in MIPIN. Vertices having from 1 to 5 degrees displayed substantial differences in closeness centrality (red); on the other hand, as the degree of vertices increased, closeness centrality exhibited minor variation (green). These graphs demonstrate the clear differences between MIPIN and random networks (see also <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003472#pcbi.1003472.s001" target="_blank">Figure S1</a> and <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003472#pcbi.1003472.s002" target="_blank">S2</a>).</p

Interaction between labeled proteins with predicted proteins.

<p>Known down-regulated proteins are represented as hexagons. Known up-regulated proteins are represented as circles. Predicted up-regulated proteins are represented as rounded rectangles. Green nodes indicate seed proteins, and red nodes indicate extended interacting proteins.</p

Localization of 38 MIPIN seed proteins.

<p>Seed proteins are localized in 19 locations, more than half of which are in the extracellular matrix (ECM) region. The indentation represents the cellular component hierarchy from the most general to more specialized terms. A horizontal blue line is used to separate ECM from cellular components.</p

Structure of the MI-specific protein-protein interaction network (MIPIN).

<p>(<b>A</b>) Construction of the MIPIN from 38 seed proteins. Seed proteins are denoted as green circles while extended proteins (with interacting partners) are represented as red circles. Interactions are represented as blue edges. Seed proteins not localized in ECM were labeled with dark green background in the list. (<b>B</b>) Degree distribution of MIPIN. The histogram shows that the degree distribution of MIPIN followed a power law function, indicating that MIPIN is a scale-free network robust to disturbance. The degree ranged from 1 to 366, with polyubiquitin-C being an outlier with the highest degree and not included in the plot.</p

The most significant GO biology process terms based on four specificity measures (number of ancestors, offspring score, GO proportion, and information content).

<p>The most significant GO biology process terms based on four specificity measures (number of ancestors, offspring score, GO proportion, and information content).</p

Heat map of Kappa similarity matrix for enriched Biocarta pathways.

<p>The graph visualizes the similarity of different pathways using Kappa statistics (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003472#s4" target="_blank"><i>Methods</i></a> for details). At the cutoff value of 2.5, we identified 10 clusters. Checking protein functions in these pathways, we grouped these clusters into 7 components, including <b>K</b>inase <b>P</b>athways (<b>KP1–4</b> in chartreuse), <b>A</b>ngiogenesis (<b>A</b> in green), <b>A</b>cute <b>MI</b> (<b>AMI</b> in orange), <b>I</b>nflammatory <b>R</b>esponses (<b>IR1–2</b> in red), <b>H</b>ypoxia (<b>H</b> in magenta), <b>LV</b> remodeling (<b>LV</b> in dark red), and other <b>S</b>ignaling <b>P</b>athways (<b>SP</b> in dark green). Colors for the clustering boxes are matched for <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003472#pcbi-1003472-t003" target="_blank">Table 3</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003472#pcbi.1003472.s011" target="_blank">Table S8</a> and, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003472#pcbi.1003472.s003" target="_blank">Figure S3</a>.</p