# A Linked Data Application for Harmonizing Heterogeneous Biomedical Information
## 3 Initial Model and New Information Sources
### The Initial Integration Model  
The former model already integrates several existing biomedical ontologies and databases that describe diseases, genes, gene products, biological processes, molecular functions, and the gene-disease and disease-disease associations. The entire list of the integrated data sources is reported in Table 1. A single knowledge model has been built by extracting and linking relevant information for research on NENs.  
Our model relies on the formalism of _multilayer networks_ to address the heterogeneity of interconnected information; this allows us to represent complexity by generalizing a graph structure where the nodes and edges are distributed on different layers, each representing an \"aspect\" of the domain [23].  
We define a multilayer network as a triple \(M=(V,E,L)\) where the sets \(V\) and \(E\) represent, respectively, the nodes and edges of the network, whereas \(L=\{L_{1},\ldots,L_{d}\}\) is the set of network layers [24]. In turn, each \(L_{i}\in L\) is a subgraph \(L_{i}=(V_{i},\ E_{i})\) composed by the nodes \(V_{i}\) and the edges \(E_{i}\) such that \(V=\cup_{i=1}^{d}V_{i}\) and \(E=\cup_{i=1}^{d}E_{i}\).  
\begin{table}
\begin{tabular}{l l l} \hline \hline
**Information Source** & **Format** & **Website** \\ \hline National Cancer Institute Thesaurus (NCIT) & OWL, OBO & ncthesaurus.nci.nih.gov \\ Orphanet Rare Disease Ontology (ORDO) & OWL & www.ebi.ac.uk/ols/ontologies/ordo \\ Disease Ontology (DO) & OWL, OBO & disease-ontology.org \\ Mondo Disease Ontology (MONDO) & OWL, OBO & mondo.monarchinitiative.org \\ Gene Ontology (GO) & OWL, OBO, CSV & geneontology.org \\ MedGen database & CSV & www.ncbi.nlm.nih.gov/medgen \\ DisGeNet database & RDF, CSV & www.disgenet.org \\ \hline \hline \end{tabular}
\end{table}
Table 1: List of the biomedical information sources integrated with the former model.  
In Figure 1 a sketch of the former model is depicted. The three interconnected layers represent information on diseases, affected genes, and their functions. We define specific concepts as shared nodes that realize bridges between layers. Layer 1 collects information about NENs as available in NCIT, ORDO, and DO ontologies. The _disease_ class (and its subclasses) acts as a bridge from layer 1 to layer 2 to highlight the variations in the human genome (available in the DisGeNet database) that lead to the NENs described at the first level as well as disease-disease associations based on their molecular causes.  
Then, the _gene_ class (and its subclasses) acts as a bridge from layer 2 to layer 3 to highlight additional information on genes and gene products responsible for the onset of NENs (available in the _Gene Ontology_). This also includes genes' molecular functions (i.e., the elementary activities of a gene product at the molecular level, such as binding or catalysis) and biological processes (i.e., the operations or sets of events relevant to the operation of living units: cells, tissues, organs, and organisms).  
We implement interlayer relations with the _equivalent-class_ OWL statement. In the same way, newly defined ontologies are linked with the original ontological sources. We developed a client-server application to access, browse, and query the defined model.