# A Linked Data Application for Harmonizing Heterogeneous Biomedical Information
## 4 The Integration and Harmonization Process
### Layer 4: Human Tissues  
This layer enhances the model with information, inherent to NENs, on the human tissues associated with the genes that cause these diseases. This information is retrieved from the _Human Tissues_ section of the HPA (see Section 3.2) which defines the distribution of gene products in the main tissues and organs of the human body. The collection and analysis of information relating to normal tissues are important and allow us to compare a pathological state with normality. On the other hand, inter-individual variations in the norm (e.g., age-related) can present a challenge in distinguishing a physiological condition from a pathological one. The Human Tissues section of the HPA describes the level of expression of gene products in 44 different non-diseased tissues. These gene products and related genes play an important role in organ physiology and provide the basis for organ-specific research. By correlating genes and tissues it is possible to highlight genes that are simultaneously present in groups of tissues, compared to all other human tissues. Such information helps to find similar characteristics between different organs and allows us to elucidate the function of the genes associated with NENs. Table 4 shows the main fields of the _HPA Normal Tissue Data Archive_. It is a tabular TSV file where each row represents the association between a gene and a human tissue. We filtered this extensive dataset to consider only the associations with a _medium_ or _high_ level of protein expression (_level_ field), only for the subset of genes already included in layer 2 of the integrated model (therefore related to NENs). Then the value of the _reliability_ field was considered. This value indicates the level of reliability of the analyzed protein expression pattern based on knowledge-based evaluation of available RNA-seq data, protein/gene characterization data, and immunohistochemical data from one or several antibodies designed toward non-overlapping sequences of the same gene. In our case, only the associations that are considered as _enhanced_, _supported_, or _approved_ were retained whereas _uncertain_ associations were discarded. \begin{table}
\begin{tabular}{l l l} \hline \hline
**Class** & **Sub classes** & **Description** \\ \hline \multirow{4}{*}{_Frequency Association_} & _Obligate_ & The phenotypic abnormality is always present, and the \\  & _Obligate_ & diagnosis cannot be confirmed if it is absent \\  & _Very Frequent_ & The phenotypic abnormality is present in 80\% to 99\% of cases \\  & _Frequent_ & The phenotypic abnormality is present in 30\% to 79\% of cases \\  & _Rare_ & The phenotypic abnormality is present in 5\% to 29\% of cases \\  & _Very Rare_ & The phenotypic abnormality is present in 1\% to 4\% of cases \\ \hline \multirow{4}{*}{_Diagnostic Criteria_} & _Criterion_ & The phenotypic anomaly is used consensually to establish the \\  & _Exclusion_ & The phenotypic anomaly allows to exclude the diagnosis \\  & _Pathognomatic_ & The phenotypic anomaly is sufficient to undoubtedly establish \\ \cline{1-1}  & & the diagnosis \\ \hline \multirow{2}{*}{_Provenance_} & \multirow{2}{*}{...} & Each subclass represents a set of scientific articles or expert \\ \cline{1-1}  & & advice qualifying the association \\ \hline \hline \end{tabular}
\end{table} 
Table 3: The _HOOM_ sub-classes qualifying a disease–phenotype association. To harmonize the filtered information with the multi-layered knowledge model, an ontological representation of gene-tissue association is created as represented in Figure 4 where gray classes and bold relationships are introduced by the scheme of this layer except for the dotted classes which are projected from the previous layers. In particular, the classes _Tissues_ and _Cell-Types_ were introduced whose instances are taken from the _HPA-controlled_ vocabularies. A _Gene-Tissue Association_ class was also introduced whose instances are dynamically generated from the filtered version of the HPA Normal Tissue Data Archive.