Instructions on "Food-Disease Associations"

The “Food-Disease Associations” section of NutriChem-2.0 accepts three types of queries. The first is to query the database using a plant-based food name, which we refer to as a food-query. The second is to query the database using a disease name, which we call a disease-query. The third is to query the database using a compound name (or structure), which we refer to as a compound-query. At the Home page, the text-input fields have cached the hundred most frequent used terms for each query. The dropdown box that appears when typing a name will show the hundred most frequent terms. However, querying a name not shown in the suggestion box is still possible.

The output window has two frames:

• The left-frame is a CytoscapeWeb Network (CWN). A blue edge indicates a preventive association (food associated with disease prevention or amelioration) and a red edge indicates a promoting association (food associated with disease progress).
• The right-frame is a simple list (LS). In LS, the user can access the relevant references in PubMed supporting the association by clicking on the respective PMID, together with other relevant supporting evidence.

The user has the option to vary (a) the minimum support, i.e. the minimum number of references, required for an edge (i.e. one food-compound or food-disease pair) and (b) the number of edges allowed to a query node in CWN. By default, we use a minimum of one reference for an edge (can range from 1 to 10) and a maximum of 15 edges for a node (can range from 5 to All edges). The reference limit applies to both the CWN and LS, while the limit on number of edges applies only to the CWN. It is, not recommended to show all edges in the CWN because this will consume system resources, when massive amounts of data returned. The full output list of the search is available from the LS.

The full LS is downloadable using the "Export table" button from the lower-right side and opens in Excel. The CWN is downloadable using the "Export network" button at the lower-left side. The file can be stored locally and can be opened using Cytoscape.

At the top of the interface, there are three action buttons. The first button "Home" returns the user to the search page. Other two buttons enable the user to switch between the compound and disease result sections.
In the CWN, the user has three special action buttons:

• "Get compound protein activities": If we select a node and click "Get compound protein activities", a list of proteins is returned showing compounds with measured binding activities to proteins (data from ChEMBL). From this list, the user has the option to click on either "bioassay", "compound" or "protein" for further information.
• "Get compound activities to disease proteins": If we select a node and click on "Get compound activities to disease proteins", a list of proteins is shown with a filter only for compounds targeting therapeutic proteins (proteins annotated to a disease in the Therapeutic Target Database).
• "Get predicted compound activities": If we select a node and click on "Get predicted compound activities", a list is returned with predicted compound-disease associations from the system-wide Fisher's exact test. The results are in three categories; corresponding to the experimental evidence that supports each prediction. The first category "Disease with protein targeted by compound" includes predicted disease associations, with experimental data for the compound and the targeted disease-related protein. The second category "Disease with protein targeted by similar compound" includes predicted disease associations, where there is experimental data for a similar compound (TC > 0.85) targeting a disease-related protein. The third category "Disease with no target information" includes predicted disease associations with no experimental data for the compound and no data for a similar compound targeting a disease-related protein. The user has access to further information on the respective ChEMBL compound data or the targeted protein, by clicking in the items in the list.

Food as query

(A) A search with "pomegranate" as the query and “Food-Disease Associations” selected. (B) By default, NutriChem shows the plant-compound section. By using the top buttons, the user can switch to the plant-disease section or go back to the Home page and submit a new query. The CWN at the left-hand side shows, by default, 15 compound associations while the LS shows the full list of associations. (C) If we select the compound "Quercetin", clicking on "Get compound protein activities" lists targeted proteins with experimental data. (D) "Get compound activities to disease proteins" filters the above results for therapeutic proteins only (proteins annotated to a disease in TTD and shows the disease-associated network for "Quercetin". (E) "Get predicted compound activities" lists predicted disease associations for "Quercetin" from the systems-wide Fisher's exact test. (F) The disease network of the query "pomegranate" returns by default 15 diseases in which pomegranate is known to have an effect. Blue edge: "preventive" association, red edge: "promoting" association. On the right-hand side the user can directly access all relevant references in PubMed in support of the pomegranate-disease associations, by clicking on the respective PMID.

Disease as query

(A) A search with "Diabetes" as the query and “Food-Disease Associations” selected. (B) The result section shows, by default, 15 plant-foods associations in the CWN and the full list of results at the LS. Clicking on any of the plant-food names in the network, enables the action buttons "Get compound activities to disease proteins" and "Get predicted compound activities", as described above. (C) Selecting "Ginger" and performing the action "Get compound activities to disease proteins" returns 9 compounds targeting diabetes-related targets with experimental data (from ChEMBL). (D) The "Get predicted compound activities" produces a corresponding list of predicted bioactivities, as described above.

Compound as query

(A) The user has the option to query a compound by name, SMILES, or do a search using the chemical structure of the compound by drawing it in the JSME molecular editor at the right-hand side. (B) TThe result section shows, by default 15 plant-foods associations in the CWN and the full list of results at the LS. Clicking on the compound node at the center of the network enables the three action buttons "Get compound protein activities", "Get compound activities to disease proteins", "Get predicted compound activities", as described above.