Context mining and graph queries on giant biomedical knowledge graphs

Contextual information is widely considered for NLP and knowledge discovery in life sciences since it highly influences the exact meaning of natural language. The scientific challenge is not only to extract such context data, but also to store this data for further query and discovery approaches. Classical approaches use RDF triple stores, which have serious limitations. Here, we propose a multiple step knowledge graph approach using labeled property graphs based on polyglot persistence systems to utilize context data for context mining, graph queries, knowledge discovery and extraction. We introduce the graph-theoretic foundation for a general context concept within semantic networks and show a proof of concept based on biomedical literature and text mining. Our test system contains a knowledge graph derived from the entirety of PubMed and SCAIView data and is enriched with text mining data and domain-specific language data using Biological Expression Language. Here, context is a more general concept than annotations. This dense graph has more than 71M nodes and 850M relationships. We discuss the impact of this novel approach with 27 real-world use cases represented by graph queries. Storing and querying a giant knowledge graph as a labeled property graph is still a technological challenge. Here, we demonstrate how our data model is able to support the understanding and interpretation of biomedical data. We present several real-world use cases that utilize our massive, generated knowledge graph derived from PubMed data and enriched with additional contextual data. Finally, we show a working example in context of biologically relevant information using SCAIView.


Background
The amount of available and stored data is constantly increasing in many areas in the course of digitalization. The increasing amount of data represents a great challenge for storage and requires the development of new storage technologies. At the same time, with more available data and different storage technologies, new applications based on the data are of great interest. Large data collections are used for data mining and knowledge discovery to answer new and complex questions more efficiently. For this purpose, data is often stored in nonrelational databases, and while there are many types available, one of the more interesting and promising types is knowledge graphs. In this database structure, the entities of a domain are stored as nodes in a graph while connections between these entities are represented by edges. This allows for visualization and analysis of networks between the data in order to discover new applications.
Current systems use RDF (Resource Description Framework) Triple Stores, systems that inherently have some serious limitations especially when compared to a labeled property graph. For example, nodes and edges have no internal structure which does not allow complex queries like subgraph matchings or traversals and it is not possible to uniquely identify instances of relationships which have the same type, see [1]. Several approaches have been made to create RDF knowledge graphs, for example Bio2RDF (see [2] and [3], reviewed by [4] or [5]). For our generalized concept of context, we require labeled property graph structures.
Context is a widely discussed topic in text mining and knowledge extraction since it is an important factor in determining the correct semantic sense of unstructured text. In [6], Nenkova and McKeown discuss the influence of context on text summarization. Ambiguity is an issue for both common language words and those in scientific context. The challenge in this field is not only to extract such context data, but also to be able to store this data for further natural language processing (NLP), querying and discovery approaches. Here, we propose a multiple step knowledge graph-based approach to utilize context data for biological research and knowledge expression based on our results published in [7]. We present a proof of concept using biomedical literature and present an outlook on additional improvements which can be implemented in the next generation of knowledge extraction, e.g., training approaches from artificial intelligence and machine learning. Figure 1 depicts a real-world example subgraph induced by both automatically detected and manually curated context data which highlights the complexity and density of these graphs.
Knowledge graphs have been shown to play an important role in recent knowledge mining and discovery. A knowledge graph (sometimes also called a semantic network) is a systematic way to connect information and data to knowledge on a more abstract level compared to language graphs. This type of data structure has many advantages in terms of searching within biomedical data and serves as a vital tool capable of generating novel ideas. Another important attribute when generating knowledge is context and therefore connecting knowledge graphs using contextual information can further enhance data analysis and hypothesis generation.
As a basis for this work, we generated a knowledge graph that initially contains publication metadata from PubMed (see https://www.ncbi.nlm.nih.gov/pubmed) which has more than 30 million documents at its disposal, including biomedical publications. In subsequent steps, the knowledge graph was expanded to include BEL (Biological Expression Language) relations and named entities obtained from text mining using JProMiner (see [8]) and stored in SCAIView (see https://www.scaiview.com/) as well as ontologies or terminologies like MeSH. This results in a large amount of data for the graph with a very high number of nodes Fig. 1 Here, we present an example subgraph of the knowledge graph that shows several molecular key players (like Amyloid-beta precursor protein (APP), and Calsyntenin-1 (CLSTN!)) and their interactions which are involved in processes that finally lead to acquiring Alzheimer's disease. We focus on the BEL statement act(p(HGNC:KLC1))->p(HGNC:MAPT). This BEL statement describes that the phosphorylation activity of the human (HGNC) "Kinesin light chain 1" (KLC1) protein leads to a phosphorylation of the "Microtubuleassociated protein tau" (MAPT) protein. Which is a key event. The Cypher-query found all relations and this graph was extended to the neighborhood of both nodes. Both HGNC terms have evidences in different documents (orange). Some context entities (pink nodes). Several entities can be found in this context, for example APP, CLSTN1 or SFAM MAPK JNK Family. Some other entities are automatically detected using text mining, others are manually curated like confidence value Low (bottom) or subgraph annotations like "Tau protein subgraph" or "Axonal transport subgraph" (top) (colour figure online) and edges. Saving and managing such a graph poses challenges due to the horizontal scalability of graph databases, therefore, it is to be expected that search queries on the graph have a long runtime. This paper presents a polyglot persistence approach to tackle this challenge using Neo4j, a graph database with a native graph storage.
Here, we use a general definition of context data assuming that each information entity can also be contextual information for other entities, for example a document can also serve as context for other documents (e.g., by citing or referring to the other publication). An author is both metainformation for a document, but also itself context (by other publications, affiliations, co-author networks, ...). Other data is more obviously purely context: named entities, topic maps, keywords, etc. extracted with text mining from documents. However, relations extracted from a text document may stand for themselves, occurring in multiple documents and still valuable without the original textual information.
To start, we begin with a simple document graph and, in the first step, we added context metainformation (see Fig. 2). This leads to an initial knowledge graph which can be used for preliminary context-based text mining approaches. In doing so, additional context data is added to the knowledge graph, such as entities or concepts from ontologies or relations extracted from the analyzed text. The resulting knowledge graph can be used as starting basis Proposed workflow to extend a knowledge graph. First starting with a document graph, the basic document metainformation like authors, keywords, etc. are added. This can be used as a basis for text mining which can be used to extend the graph again, for example named entity recognition (NER) may use normalized keywords as context. Topic detection may also benefit from already assigned keywords, journals or author information. The graph can also be extended by knowledge discovery processes, for example finding parameters of a clinical trial, progression within electronic health records, etc. In any case new context information are added to the initial graph and improve the input of further algorithms for more detailed text mining approaches which utilize the novel context data. These steps can be repeated several times to further enrich the graph.
In fact, using a graph structure to house data has several additional advantages for knowledge extraction: biological and medical researchers, for example, are interested in exploring the mechanisms of living organisms and gaining a better understanding of underlying fundamental biological processes of life. Systems biology approaches, such as integrative knowledge graphs, are important to decipher the mechanism of a disease by considering the system as a whole, which is also known as the holistic approach. To this end, disease modeling and pathway databases both play an important role. Knowledge graphs built using BEL are widely applied in biomedical domain to convert unstructured textual knowledge into a computable form. The BEL statements that form knowledge graphs are semantic triples that consist of concepts, functions and relationships [9]. In addition, several databases and ontologies can implicitly form a knowledge graph. For example Gene Ontology, see [10] or DrugBank, see [11] or [12] cover a large amount of relations and references to which reference other fields.
There are still several crucial issues to consider when converting literature to knowledge such as evaluating the quality and completeness of such networks. Here, we rely on existing data sets and present a novel approach on this data. We do not omit the question of quality control this as a task of the initial data. Furthermore, in order to generate new knowledge, context of concepts in a knowledge graph must be considered.
To start, we first present a preliminary overview about information theory and management. Afterward, we will introduce and discuss the novel approach of managing and mining contextual data of knowledge graphs. Finally, we will give a detailed list of issues that need to be addressed and show the results from evaluating real use cases.

Preliminaries
Data and knowledge management, sometimes also called information management, is a core topic of data engineering and data mining. It is also an interdisciplinary field encompassing economics (how efficient and expensive is the solution?), psychology (do people use this solution in a way that was intended?) and, of course, informatics. One of the core concepts is DIKW (data, information, knowledge, wisdom, see [13]), an approach used to describe all of the important steps which are necessary to understand the ideas of data and knowledge management.
Knowledge is often seen as either explicit or implicit, while data is always presented as an explicit concept. It is important to note that implicit knowledge is not available for data mining as it is only available as personal knowledge or experience. In information theory, knowledge is obtained from data and information. Data are recorded, context-free facts such as measured values from devices (mass spectroscopy) or basic notes (weight of patients), but can also include images (e.g., computer tomography). If this data is enriched by context, which implies meaning and purpose we get information. This information leads to knowledge and wisdom if-once again-enriched by context.
The concept of DIKW hierarchy is crucial for the understanding of the work presented here. First proposed by [14] in 1987, it was developed by [15] in 1989 who also introduced the perspective of wisdom. At times, this hierarchy is depicted as a knowledge pyramid while other times it is a linear chain. We may combine both perspectives: The linear perspective of understanding and context with past and future and the pyramid's perspective describing the amount of data leading to a smaller amount of information, etc. More information about this topic can be found in the work of [13] or [16].
A knowledge graph is a systematic way to connect information and data to knowledge. It is thus a crucial concept on the way to generate knowledge and wisdom, to search within data, information and knowledge. The relations r ∈ R can be ontology relations, thus in general we can say every ontology E i which is part of the data model is a subgraph of G indicating E ⊆ G. In addition, we allow inter-ontology relations between two nodes e 1 , e 2 with e 1 ∈ E 1 , e 2 ∈ E 2 and E 1 = E 2 . In more general terms, we define R = {R 1 , ..., R n } as a list of either inter-ontology or innerontology relations. Both E as well as R are finite discrete spaces.
Every entity e ∈ E may have some additional metainformation which needs to be defined with respect to the application of the knowledge graph. For instance, there may be several node sets (some ontologies, some document spaces (patents, research data, ...), author sets, journal sets, ...) E 1 , ..., E n so that E i ⊂ E and E = ∪ i=1,...,n E i . The same holds for R when several context relations come together such as "is cited by," "has annotation," "has author," "is published in," etc. Definition 1.2 (Context) We define context C as a set with context subsets C = {c 1 , ..., c m }. This is a finite, discrete set. Every node v ∈ G and every edge r ∈ R may have one or more contexts c ∈ C denoted by con(v) ⊂ G or con(r ) ⊂ G.
It is also possible to set con(v) = ∅. Thus we have a mapping con : E ∪ R → P(C). If we use a quite general approach toward context, we may set C = E. Therefore, every interontology relation defines context of two entities, but also the relations within an ontology can be seen as context. With the neighborhood N (E i ) every node set E i ∈ {E 1 , ..., E n } induces a subgraph G[E i ] ⊂ G: we denote the extended context subgraph which also contains the neighbors of each node in G, which is context of that node.
For a graph drawing perspective, if G c [E i ] defines a proper surface, we can think about a graph embedding of another subgraph This concept was introduced in [17]. Here, semantic knowledge graph embeddings were displayed between different layers. Every layer (for example: molecular layer, document layer, mechanism layer) corresponds to another context defining new contexts on other layers.

Definition 1.4 (Context metagraph)
We can create the metagraph M = (C, R ) of these contexts. Each context is identified by a node in M. If there is a connection in G between two contexts, we add an edge (c 1 , Adding edges between the knowledge graph G or a subgraph G = (E , R ) ⊆ G = (E, R) and the metagraph M in G ∪ M will lead to a novel graph. This can be either seen as inverse mapping con −1 (G ) or as the hypergraph H(G ) = (X ,Ê) given by This graph can be seen as an extension of the original knowledge graph G where contexts connect not only to the initial nodes, but also every two nodes in G are connected by a hyperedge if they share the same context.
If C = E, this will lead to new edges in G thus enriching the original graph. This step should be performed after every additional extension of graph G.
We denote this hypergraph H on a knowledge graph G and a metagraph M with H G|M . We can add multiple metagraphs M 1 and M 2 which is denoted by H G|M 1 ,M 2 .
The resulting graph can thus be seen as an enrichment of the original knowledge graph G with contexts. It can be used to answer several research questions and to find graph-theoretic formulations of research questions.
If the mapping con is well defined for the domain set, then Graph H can be generated in polynomial time. Since this is generally not the case, this step usually contains data or text mining task to generate other contexts from free texts or knowledge graph entities. With respect to the notation described in [18] this problem p can be formulated as p = D|R|f : D → X|err |∅. Here, the domain set D is explicitly given by D = G or-if additional full-textsD supporting the knowledge graph G exist-D = {G,D}, which in our case is the domain subset R = D. Therefore, we need to find a description function f : D → X with a description set X = C which holds all contexts. To find relevant contexts, we also need to measure the error as defined by err : Several research questions must be considered. First, what metainformation can be used to generate context for a new metagraph? Several promising candidates include authors, citations, affiliation, journal, MeSH terms and other keywords since they are all available in most databases. We also need to discuss text mining results such as NER and relationship mining. Having more general data including study data, genomics, images, etc. we might also consider side effects; disease labels, population labels (male; female; age; social class; etc.). Figure 2 shows a proof of concept for a less complex text mining metadata approach which describes the process of starting with a simple document graph that can be extended with more context data derived from text mining. We discuss this in more detail in the next section.
The second research question addresses the application of this novel approach for both biomedical research as well as text classification and clustering, NLP and knowledge discovery, with a focus on Artificial Intelligence (AI). How can we use the context metagraph to answer biomedical questions? What can we learn from connections between contexts and how do they look like in the knowledge graph? How can we use efficient graph queries utilizing context? It may also be useful to filter paths in the knowledge graph according to a given context or to generate novel visualizations. A possible question might be to learn about mechanisms linked to comorbidities or mechanisms being contextualized by drug information. The metagraph may also contain information about cause-and-effect relationships in the knowledge graph that are "valid" in a biomedical sense under certain conditions as well as contextualization based on demographic information or polypharmacy information. We will discuss several use cases in the last section of this paper.

Technical setup
We illustrate the following methods with example runs on PubMed and PMC data. Both sources are already included in the SCAIView NLP-pipeline. PubMed contains 30 million abstracts from biomedical literature, while PMC houses nearly 4 million full-text articles. First and foremost, the knowledge graph must be stored and accessed by the software in an efficient manner. To this end, a software component was written to integrate the knowledge graph into our SCAIView microservice architecture, see [19]. This integration also ensures that the knowledge graph is constantly updated with preprocessed data. The software component also provides an API to execute several queries on the knowledge graph and is capable of returning the result in JSON Graph Format which can be easily displayed by many frontend frameworks.
Our software component was written in Java using Spring Boot and Spring Data to be able to access the database backend in an abstract way and ensure the exchangeability of the database technology. The database backend in our case is the graph database Neo4j. To this end, we designed a software component that exports the data derived from SCAIView as CSV files.
Storing a large knowledge graph from PubMed, such as the one presented here, in a single database is not a simple task, and we expected the execution of our graph queries to be very slow due to the size of the knowledge graph. To speed up the run times of the queries, we decided to implement an approach that divides the graph using polyglot persistence. Polyglot persistence is defined as combining heterogenous data storing technologies into a single application. Instead of storing all of the data in one database, we chose to store different parts of the data in different database technologies. The benefit of polyglot persistence is that each database technology has different strengths and the application can take advantage of them all.
In Neo4j, the graph structure is stored separately from the properties of nodes and edges. This organization structure makes traversing the knowledge graph easier, however, storing and accessing string attributes takes longer than integer attributes because of this property [20]. To take advantage of this characteristic of Neo4j, we designed a storing system that Fig. 3 Example of a stored document node in Neo4j. On the left side, a PubMed document is stored with all of its attributes. Using polyglot persistence we see on the right side the same document containing integer encodings for two original attributes in Neo4j. The encoding of the used attributes is stored in the key-value database Redis. An other attribute for content of the document like "Cost-effectiveness..." is still stored as its original string value encodes either some or all string (depending on the test scenario) attributes of the graph as integers using polyglot persistence. By encoding and storing these attributes in key-value databases, we reduced the data size of the knowledge graph and were able to speed up the property access of Neo4j. Figure 3 provides an illustration of the designed polyglot persistence system.
In two iterations, we selected suitable attributes of all node types thus leading to three systems: the original one using only Neo4j (called Full) and two polyglot persistence systems (called Poly1 and Poly2). Full stores all data directly in Neo4j. Poly1 stores only a few information in another redis database while Poly2 uses not a single redis database but rather combines multiple redis databases storing different information and the Neo4j graph database.
We implemented another software component to execute the data preprocessing step for Poly1 and Poly2. It uses the created CSV input files of Full to run the data encoding in keyvalue databases and generates CSV input files for the Neo4j graph databases of the polyglot persistence systems. The whole process is illustrated in Fig. 4.
To compare the execution runtime of queries on all three systems Full, Poly1 and Poly2, we collected 27 real-word graph queries using the given knowledge graph. The results of the query runtimes are discussed in Sect. 2.

Creating a document and context graph with basic context extraction
The first step in creating a document and context graph with basic context extraction is to define the entity sets E 1 , ..., E n and their relations. The articles and abstracts from PubMed and PMC already contain a lot of contextual data. Thus, the starting point for our data schema is straight forward: We define E Document as the document set containing nodes, with each one representing one document. Furthermore, we may add a set E Source = {PubMed, PMC} as the source of a document. Thus, each document can be interpreted as contextual data of a particular data source.
Since the original data set contains a lot of additional metadata, we need to add them as single data points: all metadata are stored in new node sets. E Author stores the set of authors and E A f f iliation stores their affiliation, which is again considered context for the authors. Another relevant piece of contextual information is the publisher, in our case E J ournal . PubMed has several classifications for E J ournal including: Books and Documents, Case  Other important context directly obtained from the initial document data is E Annotation which stores multiple types of annotations such as named entities or keywords, all of which come from the MeSH tree, see [21]. Therefore, E MeS H ⊂ E Annotation inherently contains a hierarchy and edges R MeS H . The value of MeSH terms and their hierarchy for knowledge extraction was shown in several recent studies [22]. Figure 5 depicts the knowledge graph of a single document; Table 1 shows a list of all node types and relations. All other relations can be added between the sets E i , for example R isCoAuthor , R has A f f iliation , etc. With this information, it is-from an algorithmic point of view-quite easy to combine all context relations such as R has Document , R is Author , R has Annotation and R hasCitation , though these edges should also store additional provenance information as shown in Fig. 6.

Extending the knowledge graph using NLP-technologies
The initial knowledge graph can be extended by NLP-technologies. Terminologies and Ontologies are a widely considered topic in research during the last years. They play an important role in data and text mining as well as knowledge representation in the semantic web. They have become increasingly more important once data providers began publishing their data in a semantic web formats, namely Resource Description Framework (RDF, see [23]) and Web Ontology Language (OWL, see [24]), to increase integratability. The term terminology refers to the Simple Knowledge Organization System metamodel (SKOS, see [25] which can be summarized as concepts, unit of thoughts which can be identified, labeled with lexical strings, assigned notations (lexical codes), documented with various types of note, linked to other concepts and organized into informal hierarchies and association networks, aggregated, grouped into labeled and/or ordered collections and mapped to concepts. Several complex models have been proposed in the literature and have been implemented in software, see [26]. Controlled Vocabularies contain lists of entities which may be completed to a Synonym Ring to control synonyms. Ontologies also present properties and can establish associative relationships which can also be done by Thesauri or Terminologies. See [27] and [28] for a complete list of all models.
Here, we define Terminologies similar to Thesauri as a set of concepts. They form a DAG with child and parent concepts. Additionally, we have an associative relation which identifies related concepts. Each concept has at least one label, one of which is used as the preferred identifier while all others are synonyms. To sum up, using ontologies or terminologies for NER has several advantages. In particular, it leads to a hierarchy within these ontologies and orders named entities according to these relations. Though, we must not only consider ontologies and terminologies, but also controlled vocabularies such as MeSH. Here, we have additional annotations with different provenances, one derived as keywords with the data and one obtained from NER. The relations itself can be determined by using the original data structure: Either they are related to a document and thus describe an annotation or they describe a relation between two entities and the relation is described with the original data set which we will describe later.
Another example of a terminology is the Alzheimer's Disease Ontology (ADO, see [29]) E ADO or the Neuro-Image Terminology (NIFT, see [30]) E N I FT coming with their hierarchy R ADO , R N I FT . The process of NER leads to another context relation R has Annotation . Since not all ontologies or terminologies are described using the RDF or OBO format, we have to add data using multiple external sources via a central tool capable of providing all the necessary ontology data. We use a semantic lookup platform containing Ontology Lookup Service (OLS) and Ontology Xref Service (OxO) (see [31]).
Additional context data useful for knowledge extraction are citations such as the edges R hasCitation between two nodes in E Document . Data from PMC already contains citation data with unique identifiers (PubMed IDs). Some data is available with WikiData, see [32] and Fig. 7 An illustration of biological knowledge within the context graph. The document node (purple) has several orange annotation nodes which come from different terminologies found with NER. The areas in the background indicate arbitrary context subgroups to highlight that the different nodes belong to different backgrounds. The relation extraction task found the relation "Levomilnacipran" inhibits "BACE1," "BACE1" improves "Neuroprotection" and "BACE1" improves "Memory." These relations are illustrated with red edges. Since the document describes a clinical trial, this is also context for the relations as well. All other context is illustrated by colored sets, defining subgraphs (colour figure online) [33]. Other sources are rare, but exist, see [34]. Especially for PubMed a lot of research is working on this difficult topic, see for example [35].
Furthermore, we can consider the relational information between entities. For example, BEL statements naturally form knowledge graphs by way of semantic triples that consist of concepts, functions and relationships [9]. To tackle such complex tasks they constantly gather and accumulate new knowledge by performing experiments, and also studying scientific literature that includes results of further experiments performed by researchers. Existing solutions are primarily based on the methods of biomedical text mining which consists of extracting key information from unstructured biomedical text (such as publications, patents and electronic health records). Several information systems have been introduced to support curators in generating these networks such as BELIEF, a workflow that builds BEL-like statements semi-automatically by retrieving publications from a relevant corpus generator system called SCAIView, see [36] and [37]. Figure 7 illustrates a few basic relations such as "Levomilnacipran" inhibits "BACE1," "BACE1" improves "Neuroprotection" and "BACE1" improves "Memory," all of which were found using relation extraction methods on named entities in a document. Here, the relations between entities are directly described as BEL relations. It is important to note that context for a document can also be context for the derived relations and vice versa. If an entity that forms part of a relation has synonyms, or is found within another document with a different context, this may lead to a deeper understanding about the statement. Due to the complexity, the resulting graph structures become difficult to manually parse and interpret thus requiring algorithmic approaches to properly analyze.
Because the general subgraph isomorphism problem is known to be NP-complete, we expect that some of our queries, such as finding the shortest paths in P, to require a wide range runtimes.

Storing the knowledge graph
Storing all of the data in one graph database without using Redis (Full) uses 58.9 GB of memory, while Poly1 only uses 50.82 GB (Neo4j) and 0.9 GB (Redis) of memory. The third system, Poly2, uses 50.74 + 10.2 GB (Neo4j) and 1.4 GB (Redis) memory.
The import data is about 50 GB and generates nearly 160M nodes with relations. These nodes are merged by Neo4j to unique nodes. In the end, we obtained 71M unique nodes and 860M relationships. Given the input data, we create ∼30M nodes describing documents from PubMed and PMC, about 17M dedicated to authors, 21M affiliations and around 5M entities. The graph contains 554M annotation relationships and in total 850M relationships. Figure 8 shows the runtime results of the 27 real-world queries described in Table 2.

Polyglot persistence systems
We see that execution of some queries required a large amount of time with the longest query taking more than one hour. Interestingly, the execution time for most of the queries improved when ran using either the Poly1 or Poly2 implementation. We experienced that seven out of the 27 queries did not terminate. This was mainly due to main memory issues, other reasons for endless runtime could not be examined but we assume time complexity and implementation issues for that.
For most queries, the polyglot persistence systems achieve better results, in the best case up to 43%. However, there are differences between the systems for a few of the queries tested in that Poly1 can sometimes have better results than Poly2 and vice versa. Contrary to expectations, Full was found to have the best query time in most cases. The advantage of Poly1 over Poly2 can be explained by the fact that the memory consumption of Poly2 increased significantly due to the process of converting from string to integer and therefore the execution of the queries is slowed down. For the queries in which Poly2 performed better, this can be explained by the fact that the queries take advantage of the optimized polyglot data schema despite the higher memory consumption of the database. This is significant for example in queries 8 and 17.  Assignment of the entities to cliques Fig. 8 Runtime results of 27 real-world queries. The queries are grouped in four diagrams with similar runtimes for a better overview. We see that the execution time of most queries is improved with Poly1 and Poly2. In the best case, the improvement is 43% The differences in the results become clearer when looking at the differences in runtimes in percent comparing them with each other. The differences in the observed running times become clearer when analyzing the percent change in the runtime when compared to Full as shown in Table 3. For both systems, the average percent decrease in runtimes is calculated for all queries, in order to compare both polyglot systems each other and with Full. It is important to notice that the speedup factor is significant especially for those queries depending on a lot of attribute data-which is the data stored in the redis database, see in particular queries 14, 11 and 2.
There is no information for queries 4, 6, 7, 9, 12, 24 and 25, for which no runtime could be determined on the systems as they did not go to completion. These queries are primarily graph algorithms categorized as local and global structures in the schema discussed earlier.
The results do not show a clear trend for any of the categories discussed. The RPQ class improves on average by 15.8% while the ECRPQ class by 10.5%. The classes CRPQ, Page Rank, Degree Centrality and Connected Components are in the single-digit percentage range. Since the speedup factor heavily depends on how many attributes of nodes and edges are considered, it is not easy to measure this impact. This explains why for other time-consuming queries, the improvement of efficiency is not significant. In general, the subcategories of local structures seem to benefit more from the polyglot persistence designs. In addition, there is a tendency for queries that only need to consider a few node and edge types (often entity and hasRelation) to experience a greater decrease in runtimes than queries with many node and edge types. The evaluation was done using the same queries

Graph queries
Here, we present results of some of those 27 queries introduced. Query 1 returns a subgraph: Which author was the first to state that {Entity1} has an enhancing effect on {Entity2}?
A result graph can be found in Fig. 9. On the left, the isAuthor relation with the most recent author can be found. On the left the limit parameter was changed to 10 and thus the result graph shows the most recent 10 publications and authors. Query 2 returns a subgraph: Which genes {Entity1} play a role in two diseases {Entity2}? One example output graph can be found in Fig. 10 (left). Due to the limitation of our model to Alzheimer's disease, it is not surprising to find only one gene-APP. If we remove the limitation to two distinct diseases, the database returns a larger graph, see Fig. 10 (right). Here, we see, that we may need to utilize inherent ontology information to filter those nodes, that cover diseases. But we also see a second gene-TNF-with other diseases like Diabetes.

Discussion
Here, we introduce the graph-theoretic foundation for a general context concept within semantic networks and show a proof of concept based on biomedical literature and text mining. Our test system contains a knowledge graph derived from PubMed data which is then enriched with text mining data and domain-specific language data coming from BEL. This dense graph has more than 71M nodes and 850M relationships. We discuss the impact of this novel approach using 27 real-world use cases and graph queries.
This proof of concept of a biomedical knowledge graph combines several sources of data by relating their contextual data to one another. We processed data from PubMed and PMC which generated more than 30M document and metadata nodes. This initial knowledge graph was extended using results from text mining and NLR-tools already included in our software as well as with named entities from ontologies also stored in SCAIView. In addition, we added data generated by domain-specific languages such as BEL. Thus, we were able to assess both small data sets as well as large collections of data.
First we discuss the missing data and data integration problems, as well as the technical issues which need to be solved. Afterward, we give an outlook on NLP based on context information and the impact on answering semantic questions which is highly related to the FAIRification of research data. Finally, we discuss the integration of these methods with personalized medicine.

Missing data and quality control
There were several issues with data integration and missing data. Initially, we tried to integrate publication data from several external sources, but some publishers used OCR technologies to convert PDF documents in XML structures. These proved problematic to process as some fields were either missing or incorrectly filled out.
We have not yet solved the issue of author and affiliation disambiguation which remains a widely discussed topic, see [40]. An interesting novel approach-also based on Neo4j database technology-was introduced in [41]. Franzoni used topological and semantic structures within the graph for author disambiguation. Taking this into consideration, we plan to integrate such state-of-the-art technologies into our software in the future.
In addition, we did not consider the problem of quality control since the focus of our work was different. Our approach merged existing data sets and thus we rely on the quality control of these data sets. But merging data might lead to more quality problems as the issues with missing data have shown. Thus further research has to be carried out here. In addition, we presented some subgraphs received as output of the queries. However, we could not present and discuss a quantitative evaluation of these solutions. Since the output heavily depends on the data stored in the knowledge graph, this is another issue that needs to be considered helping to understand the quality of the results.

Performance
Furthermore, performance for some semantic queries remains a major problem due to the massive latency for request. Although the software is integrating in our microservice architecture, see [19], some queries did not run to completion. Here, we attempt to improve our initial setup by establishing a polyglot persistence architecture in the database backend [7]. The detailed analysis in Table 3 raises new questions: Is it possible to determine queries which are optimal for one particular architecture? The results generated through this modification are very encouraging and we will discuss additional topics for further research.

Context-based NLP
This novel system was designed to extend our knowledge base by utilizing contextual data. Context serves as a very important foundation for text mining [6]. Context-based NER was discussed by [42] and there is still ongoing research such as the content-aware attributed entity embedding (CAAEE), see [43]. The key strength of our approach is that in every step of text mining and NLP, all contextual data is readily available and new data is continuously added. Therefore, this system can be used for both building and validating Machine Learning (ML) and AI approaches.
Of course, novel context data is not only suitable for NER, but also for relation extraction. Prajapati proposed a novel approach to context-based relation extraction [44]. Although our example is based on a small data set, the findings suggest that a lot of existing data can be utilized as context data such as entities annotated by NER or manually curated BEL statements.
Importantly, this research has several practical applications. First, it can be used to validate data sets for ML and AI approaches in context of text mining, however, further investigation is required as to how this data can be used systematically. And second, this approach generalizes the idea of context so that it can be used for semantic questions.

Answering semantic questions and FAIRification of data
Semantic questions can be formulated as subgraph structures of the initial knowledge graphs. For example we may ask: "Which articles have been authored by Pacheco?". This leads to a subgraph with two nodes v 1 , v 2 where v 1 =Pacheco and an edge (v 1 , v 2 ) =isAuthor, though this is a relatively simple query, much more complex examples can also be used.
In general, these semantic subgraph queries (or: graph queries) have an input Q = (V , E) ⊂ G and output all subgraphs H ⊂ G with H Q. Therefore, the problem of answering semantic questions is a generalization of the subgraph isomorphism problem. Here, we presented a more detailed classification of queries, of which many can be solved in polynomial time and as shown by their performance (Fig. 8).
We know that the most general case, subgraph isomorphism, is NP-hard, see [45]. It would be interesting to find a formulation of the generalization or restrictions that can be applied to these problems. Because Cypher already provides us with the possibility to query graph substructure, further research should be directed toward exploring the runtime, finding a better categorization of queries and discovering novel heuristics to solve this deficiency.
While this work did not consider the impact of novel ontologies and terminologies, it did substantiate the impact of them on context data. This is an interesting and important step toward the FAIRification of data. Wilkinson introduced his FAIR guiding principles in [46] referring to the findability, accessibility, interoperability and reusability of data, especially in regards to research data. A consequent application of context idea leads to metadata as context on data which can afterward be used to make metadata searchable even if the data itself is protected due to data protection rules. Thus, the inclusion of context in an information system such as SCAIView will allow the data to be both findable and accessible. Furthermore, if interoperable ontologies are available then this data will also be interoperable hence showing that our proposed system already satisfies the three out of four issues addressed by FAIR data.
However, the generalizability of these ideas is subject to certain limitations. For instance, the question of interoperable ontologies or ontologies covering the issues of interoperability of data is still not addressed and there is still no FAIR-data information system yet available.

Perspectives for personalized medicine
Hypothesis generation and knowledge discovery in biomedical data are widely sought after in medical research and digital health. Researchers often desire and utilize these tools when diagnosing patients, searching for genomic or molecular patterns, or build longitudinal models. In addition, the massive amount of data available can be harnessed to construct a multitude of predictive and personalized medicine using ML and AI approaches. One reasonable approach to tackle reproducible research in predictive medicine would be to use a standardized and FAIR context graph for biomedical research data. However, it would be necessary to annotate not only biomedical literature, but also research data such as molecular data, imaging data, genomics and electronical health records (EHR) with contextual information in order to ensure the most accurate results.
Once implemented, this type of information system can be used to retrieve information by way contextual data (cohort size, settings, demographics, ..) as well as by content (imaging data, genomic or molecular measurements, ...) and would be able to answer questions such as "Give me a clinical trial to reproduce my results or to apply my model" or "Give me literature for phenotype A, disease B age between C and D and a CT-scan with characteristic E." Here, we presented a novel approach capable of annotating research data with contextual information. The resulting structure is a knowledge graph representation of data, the context graph, which contains computable statement representation (e.g., RDF or BEL). This graph allows one to compare research data records from different sources as well as the selection of relevant data sets using graph-theoretical algorithms.

Conclusion
Storing and querying a giant knowledge graph as a labeled property graph is still a technological challenge. Here, we demonstrate how our data model is able to support the understanding and interpretation of biomedical data. We present several real-world use cases that utilize our massive, generated knowledge graph derived from PubMed data and enriched with additional contextual data. Finally, we show a working example in context of biologically relevant information using SCAIView.
Availability of data and materials Not applicable. The knowledge graph is available on request; the fundamental data is available using SCAIView.

Competing interests
The authors declare that they have no competing interests. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.