Published online 24 May 2023 Nucleic Acids Research, 2023, Vol.

51, Web Server issue W237–W242

https://doi.org/10.1093/nar/gkad445

GEPI: large-scale text mining, customized retrieval

and flexible filtering of gene/protein interactions
1 1 ,* 1 , 2 ,*
Erik Faessler , Udo Hahn and Sascha Schäuble
1
Jena University Language and Information Engineering (JULIE) Lab, Friedrich Schiller University Jena,
Fürstengraben 30, 07743 Jena, Germany and 2 Microbiome Dynamics, Leibniz Institute for Natural Product Research
and Infection Biology (Leibniz-HKI), 07745 Jena, Germany

Received March 18, 2023; Revised May 01, 2023; Editorial Decision May 09, 2023; Accepted May 11, 2023

Downloaded from https://academic.oup.com/nar/article/51/W1/W237/7177881 by guest on 04 February 2024

ABSTRACT GRAPHICAL ABSTRACT
We present GEPI, a novel Web server for large-scale
text mining of molecular interactions from the scien-
tific biomedical literature. GEPI leverages natural lan-
guage processing techniques to identify genes and
related entities, interactions between those entities
and biomolecular events involving them. GEPI sup-
ports rapid retrieval of interactions based on power-
ful search options to contextualize queries targeting
(lists of) genes of interest. Contextualization is en-
abled by full-text filters constraining the search for in-
teractions to either sentences or paragraphs, with or
without pre-defined gene lists. Our knowledge graph
is updated several times a week ensuring the most
recent information to be available at all times. The
result page provides an overview of the outcome of a
search, with accompanying interaction statistics and
visualizations. A table (downloadable in Excel for- INTRODUCTION
mat) gives direct access to the retrieved interaction The molecular interactions between genes or gene prod-
pairs, together with information about the molecular ucts (e.g. exemplifying gene binding or positive regulatory
entities, the factual certainty of the interactions (as events) are the subject of a large body of scientific research
verbatim expressed by the authors), and a text snip- that is rapidly growing and typically communicated in scien-
pet from the original document that verbalizes each tific papers. Manually curated interaction databases such as
interaction. In summary, our Web application offers HPRD (1), INTACT (2) and BIOGRID (3) contain millions
free, easy-to-use, and up-to-date monitoring of gene of interactions extracted from thousands of publications.
Such databases offer structured, high-quality, and detailed
and protein interaction information, in company with
interaction data enabling continuous scientific hypothesis
flexible query formulation and filtering options. GEPI testing and discovery. However, only a small fraction of
is available at https:// gepi.coling.uni-jena.de/ . the complete set of documents in PubMed (PM) (with over
35M citations) and PubMed Central (PMC) (with more
than 5.1M full texts in its Open Access (OA) subset, as of
March 2023) is covered by such databases through manual
curation efforts. Therefore, automatic means of harvesting
such information from the biomedical literature on a larger
scale became a focus of research in the recent years.
STRING (4–6), because of its long-term development
history dating back to the beginning of this millennium
(7), is one of the most popular tools in the biomolecular

* To
whom correspondence should be addressed. Tel: +49 3641 944 320; Email: udo.hahn@uni-jena.de
Correspondence may also be addressed to Sascha Schäuble. Tel: +49 3641 532 1152; Fax: +49 3641 532 2152; Email: sascha.schaeuble@leibniz-hki.de


C The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
W238 Nucleic Acids Research, 2023, Vol. 51, Web Server issue
community for gene and protein interaction retrieval and
features text mining as one of its data input channels. Re-
searchers mainly from the field of natural language process-
ing (NLP) approached the automatic analysis of biomedical
literature in a series of challenge competitions, where tools
for the extraction of molecular events were rigorously eval-
uated against shared benchmark datasets (for a survey, see
(8)). Some of the front-runner systems were subsequently
integrated into Web servers, such as BIOCONTEXT (9) or
EVEXDB (10).
We here introduce an alternative NLP-based system,
Gene and Protein Interactions (GEPI), for the quick and
versatile retrieval of up-to-date molecular interactions from
the biomedical literature contained in PM and the OA
subset of PMC. GEPI comes as a Web application with
a graphical user interface that allows easy access also to
non-programming end users. It can be queried with one or
two (unlimited) lists of gene/protein IDs and related entity
classes. Boolean full-text queries can be specified to filter for
the sentence or paragraph context in which interactions oc-
cur. Additional filter options for restricting search to docu-
ment titles and section headings provide further options to
constrain the retrieval of gene/protein associations. These
full-text filters can also be used without the necessity to pro-
vide input genes at all. An assessment of the degree of fac-
tuality (11,12) for each interaction or event is derived from
verbatim signals in the documents where authors express
their (un)certainty for an observed or stipulated interaction
(using hedging expressions such as ‘maybe’ or ‘[our data]
suggest that’). Such factuality tags may be used, e.g. to fil-
ter out negated or low-certainty interaction statements.
As a response to the often raised request for recency of
information, GEPI includes automated procedures for up-
dating the indexed literature from PubMed and PMC mul-
tiple times a week. The obtained results are shown in a
dashboard which includes base statistics and visualizations,
as well as a comprehensive downloadable table summariz-
ing all identified interactions and their associated literature
passages.
BACKGROUND
The retrieval of bio-molecular interactions from scientific
documents requires gene recognition (GR), where spans of
text that correspond to names or identifiers for gene enti-
ties are identified, e.g., Arp5 as a gene in the text passage
‘[...] the protein level of Arp5 was markedly reduced [...]’.
To uniquely identify gene mentions, database IDs are as-
signed to them in the gene normalization (GN) step. A num-
ber of tools handle both tasks, e.g., GNAT (13), GENO (14),
GNORMPLUS (15), the system proposed in (16) and oth-
ers. After gene and protein mentions have been recognized,
semantic relations between pairs of genes/proteins must be
identified––the correlate of factual assertions in documents.
Again, NLP community challenges were the drivers for a
number of powerful relation extractors, such as TEES (17),
JREX (18), BIOSEM (19), VERSE (20) or DEEPEVENTMINE
(21).
For the choice of GEPI components, we evaluated ex-
isting NLP solutions with focus on the following criteria:
open source availability, performance, integratability into
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Figure 1. GEPI components and their data flow dependencies.
our NLP infrastructure, execution speed, and currency of
the employed databases for GN. Considering the optimal
combination of these requirements, for gene recognition and
normalization, we equipped GEPI with GNORMPLUS, a
freely available tool that can be applied to arbitrary doc-
uments, both abstracts and full texts. It was already ap-
plied to and evaluated on the whole of PubMed and PMC
in PUBTATOR CENTRAL (22), demonstrating its large-scale
applicability. The tool has been continuously updated since
its first release, thus ensuring its currency. Using the same
assessment criteria from above, for event extraction, GEPI
runs BIOSEM. It showed competitive overall performance in
major Shared Tasks, with very high precision values, result-
ing in a high fraction of relevant events. Given the require-
ment of correctly identifying both gene occurrences and
their interactions, this ensures that GEPI generates mean-
ingful results, thus minimizing the number of false positives.
METHODS
Text analytics: extracting gene/protein interactions
Figure 1 depicts the components of the GEPI application
ecosystem. The input to the pipeline are XML documents
from PubMed and PMC. Mentions of genes, gene products,
families, protein complexes and molecular events between
those entities are extracted by an NLP pipeline (depicted
in Supplementary Figure S1) and indexed into an Elastic-
Search (ES) cluster. A Neo4j graph database stores struc-
tured gene information that includes relationships express-
ing orthology, family or group membership, protein com-
plexes and their subunits, and gene ontology annotations.
This information (taken from FamPlex, GO, NCBI Gene,
etc.) is incorporated in the NLP pipeline for the resolu-
tion of ambiguous gene groups, families and protein com-
plexes. The events and interactions in ES are connected to
the entities in Neo4j via unique IDs. Together they form a
knowledge graph that feeds the GEPI Web application. To
ensure high result reliability, GEPI restricts molecular inter-
actions to occur in single sentences. Finally, the Web appli-
cation leverages the gene database in Neo4j (holding stable
terminological background knowledge) and the ES index
(holding the continuously harvested results of relation ex-
traction) to serve user requests. More detailed descriptions
of the NLP pipeline and our data model can be found in
 Nucleic Acids Research, 2023, Vol. 51, Web Server issue W239
Table 1. Current numbers of molecular interactions in GEPI. This in-
cludes events with one and two arguments
Interactions Unique interactions
PubMed 14 441 503 411 500
PubMed Central 52 144 387 1 032 377
PM+PMC 66 585 890 1 204 986
Supplementary Material S1. An evaluation report on the
gene interaction extraction components is provided in Sup-
plementary Material S2. Evaluation results are shown in
Supplementary Tables S1 and S2.
Gene/protein search: finding molecular information
Input to the GEPI interface is provided by a query form;
the results of query processing are based on all interactions
stored in the knowledge graph (its current size is depicted
in Table 1).
The query form provides two input panels for lists of
genes and related entities we refer to as A-list and B-list,
respectively. Further input fields allow the specification of
a diverse set of filters described below. Input to the A- and
B-lists may consist of NCBI GENE (23) IDs and symbols,
UNIPROT (24) IDs, FAMPLEX (25) protein family and com-
plex identifiers or names, HGNC (26) gene group names, or
Gene Ontology (GO) (27) terms. Family and group query
items will include their members in the result, whereas GO
term queries will include genes that have been annotated
with the respective terms. Specifying only A items will re-
sult in an open search. This mode retrieves gene and protein
interactions between the entries of A and any other interac-
tion partners from the interaction database. If a second set
of gene/protein identifiers is entered for the B-list, a closed
search is performed. This mode yields only interaction items
that have an element of A as one and an element of B as their
other argument.
Adding genes to A- and B-lists in a search query is op-
tional. If left out, the result of such a ‘full-text-only’ search
comprises all molecular events in the interaction database
that match the respective query filters. This query type can
be used to identify published molecular interactions associ-
ated with specific filter terms, such as a condition (e.g., ‘el-
derly’) or a disease (e.g., ‘obesity’) without restrictions on
the associated genes.
The query form offers two input fields to specify full-text
queries either on the sentence or paragraph level. They act
as context-sensitive query filters for interactions. Sentence-
level context can be used to specify filter terms occurring in
addition to an interaction in a sentence. The paragraph level
widens the textual window around the interaction statement
and allows to retrieve interactions based on relevant context
keywords beyond sentence boundaries. Both filter queries
can be connected by Boolean AND or OR operators. An-
other full-text filter is sensitive to document titles and sec-
tion headings and can be applied to restrict the gene/protein
interaction search to, e.g., ‘Results’ sections only, since ‘In-
troduction’ and ‘Background’ sections commonly refer to
established (and thus less interesting) prior knowledge. Fur-
ther filter options may restrict the search results to specific
organisms, interaction types or factuality levels.
After the retrieval process, GEPI results are presented
in a dashboard. This includes aggregated overview pan-
els and a table of complete primary data where each re-
trieved interaction is listed individually within its document
context. The aggregation panels summarize the publication
state with respect to the input and include frequency-sorted
pie and bar charts of interaction partners and Sankey dia-
grams revealing interaction frequencies. We distinguish two
types of Sankey diagrams. The first shows the most fre-
quent interactions in the retrieval result. The second sum-
marizes second-degree interactions, offering information
on interaction partners occurring in more complex inter-
actions than provided in the output table. Finally, the table
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panel provides a list of direct associations between genes or
proteins associated to the current query. It discloses detailed
information about the gene mentions in the text, the NCBI
GENE IDs and symbols they were mapped to, and the sen-
tence in which interactions occurs. Where applicable, the ta-
ble offers links to the source databases of the molecular en-
tity, e.g. NCBI GENE for genes or HGNC for gene groups to
quickly obtain full gene names, gene descriptions and fur-
ther resources.
The primary data table can be downloaded as an Excel
workbook, including query details and the resulting inter-
action data. It also lists the occurrence counts of the gene or
protein symbols that take part in the interactions and how
often each symbol was found in interaction with another
symbol. Thus, the Excel workbook documents the query,
the query result, and additional statistics enabling efficient
downstream analysis. It can also be used for the manual cu-
ration of results, e.g. further filtering or the removal of er-
roneous result items.
USE CASES INVOLVING GEPI
We prepared two use cases that feature GEPI’s search and
filtering facilities. The first one presents a search for interac-
tion information about specific marker genes in the context
of the devastating invasive pulmonary aspergillosis disease
caused by the fungal opportunistic pathogen Aspergillus fu-
migatus (see Supplementary Material S3) (28). The second
one describes the application of GEPI to investigate the Fer-
ritin H chain in the context of disease tolerance in sepsis (see
Supplementary Material S4) (29). A detailed walk-through
how to use data from these studies with GePI is provided in
Supplementary Materials S5 and S6. The description of the
second use case includes a verification step of GEPI results
leveraging STRING (see Supplementary Data S7 for the raw
protein pair confidence values given by STRING). We also
specify the inputs to and outputs from GEPI in both use
cases for reference in Supplementary Data S8.
DISCUSSION
Automated molecular event extraction from scientific liter-
ature is an area of active research to by-pass large cover-
age gaps in manually curated life science databases. STRING,
for instance, brings together a multitude of biological in-
frastructure resources, including curated interaction and
genome sequence databases. One of STRING’s seven infor-
mation channels is concerned with textual data accessed
W240 Nucleic Acids Research, 2023, Vol. 51, Web Server issue
from PM and the PMC OA subset. STRING’s text min-
ing facilities collect information for the interaction of pro-
tein pairs in two fundamental ways. Firstly, statistical meth-
ods are leveraged to find over-represented proteins in docu-
ments with respect to the user input. This is used to calculate
an aggregated measure of confidence that a unique pair of
proteins is associated in general, instead of identifying ex-
plicit association descriptions of a protein pair in individual
documents (5). This can be witnessed in STRING’s text min-
ing viewer where at least two input proteins are highlighted
in each citation but are not necessarily mentioned in any
interaction. Secondly, a modern NLP approach is used to
find protein pairs explicitly described to physically interact,
i.e., to build protein complexes (5). For such cases, the text
mining viewer shows explicit verbalizations of physical in-
teractions in PM abstracts.
Unlike STRING, GEPI is an exclusively NLP-driven
tool designed towards the identification of interacting
gene/protein pairs or events involving single genes/proteins
from biomedical documents. As a safe-guard mechanism,
GEPI supplies the text passage provided with each result
item. By design, GEPI cannot render interaction data po-
tentially (only) stored in structured tables, e.g. Supplemen-
tary data, external of the publication text. GEPI covers a
broader range of interaction types, including binding (cor-
responding to STRING’s physical interaction), regulation
and activation, thus substantially widening the scope of
high-quality interaction descriptions extracted from the lit-
erature. GEPI’s additional capabilities of searching for a
closed pair of gene lists and filtering by document context,
make GePI a complementary tool to STRING, which (un-
like GEPI) processes several types of structured resources
(databases and terminologies). While STRING calculates
confidence scores aggregated from a diverse set of resources
for unique protein pairs, GEPI’s focus lies on the high-
quality extraction of interactions explicitly described in
publications together with factuality ratings extracted from
the textual context of interaction descriptions in the form
of hedging expressions.
In this regard, GEPI is much closer in spirit to BIOCON-
TEXT and EVEXDB. However, BIOCONTEXT and EVEXDB
allow only single gene queries to identify their interaction
partners. Even worse, the BIOCONTEXT Web server became
offline in the meantime. EVEXDB allows for queries of sin-
gle genes or a pair of genes. It provides interaction informa-
tion including statistics and interaction members, as well as
text snippets of the identified interactions grouped by in-
teraction type (regulation, binding, etc.). To the best of our
knowledge, EVEXDB has not been updated since 2013 and
thus features mostly outdated knowledge. Neither tool of-
fers further context filtering, nor non-programmatic means
to search for more than two genes at once.
GEPI’s value for the scientific community is also evi-
denced by the usage of prior versions of its NLP pipeline
for a variety of experimental studies. For these studies,
we developed NLP modules (30) that allow us to extract
molecular event information from the whole of PM and
PMC (OA subset) at any given point of time. Previous
instances of our NLP pipeline were already successfully
applied to identify potential interaction partners of pro-
teins found in phosphoproteomics experiments including
the 5’ adenosine monophosphate-activated protein kinase
(AMPK) complex (31). By using full-text filter capabilities,
we identified interactions between members of the Akt fam-
ily and pyruvate dehydrogenase kinase 2 (PDK2) in the con-
text of cellular stress (32). We also used our NLP engine to
gain literature-based insight into the current state of poten-
tial interaction partners on kinases of the PI3K/Akt sig-
naling network based on quantitative phosphoproteomics
as input for our NLP service (33). We furthermore com-
bined results from our event extraction system with large-
scale gene expression analysis and multiple validation ex-
periments to generate a molecular signature of the activa-
tion of aryl hydrocarbon receptor (AHR) (34). Finally, our
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efforts supported the analysis of peripheral blood samples
of children to investigate childhood asthma (35).
The above mentioned usage scenarios demonstrate the
flexible applicability of our NLP engines and their potential
to complement life-science data set analysis and hypothesis
generation. Besides its core functionality, the recognition of
gene and protein interactions in huge literature repositories,
GEPI excels with flexible options for expressive query for-
mulation and a wide range of filtering functions to constrain
its result sets which can then be channeled to its end users by
simple-to-(re)use reporting devices (Excel sheets). Further-
more, GEPI operates on up-to-date textual data (based on
short-term update cycles in the range of few days from the
current date) and runs efficiently (as evidenced by its timely
responses).
Despite the added value offered by GEPI, there is also
room for improvement. On the preprocessing level, BIOSEM
was used for its superior specificity and processing perfor-
mance but has been equalized, in the meantime, by deep
learning-based approaches (DL) that might identify addi-
tional interaction events, e.g., DEEPEVENTMINE. However,
these DL approaches have a high demand for computa-
tional power, and frequent updates incorporating new liter-
ature can become prohibitive with updates consuming sig-
nificant resources and taking prolonged periods of time. De-
spite the focus on high precision of GEPI’s NLP compo-
nents, false positive results cannot be ruled out. For fur-
ther result verification we recommend to query curated
databases, e.g. BIOGRID, or comparison of GEPI results
with those of STRING, given the same query. Indeed, we see
a clear complementary relation between GEPI and STRING:
The interactions explicitly described in the literature found
by GEPI can be corroborated with STRING’s diverse set
of evidence channels to obtain a high-certainty list of in-
teractions for each of which exists a directly linked liter-
ature support. We also recommend to investigate specific
text portions provided by GEPI for interactions not found
by BIOGRID or STRING. If their relevance is confirmed,
these may feature interactions currently not included in the
other databases.
CONCLUSION
We introduced GEPI, a Web application for the fully au-
tomated extraction of molecular events from the biomed-
ical literature. The automatically populated and updated
knowledge graph includes interactions mined from the
whole of PubMed and PubMed Central OA subset with
 Nucleic Acids Research, 2023, Vol. 51, Web Server issue W241
regular updates to keep up with newest developments in
the literature. We presented powerful query and filtering
options for contextualized retrieval of interactions between
genes, proteins, families and protein complexes. The interac-
tion results can be downloaded as an Excel workbook that
contains all identified relation pairs and statistics about the
frequency of the interaction partners and the interactions
themselves. For each result interaction, its textual source
is provided for cross-checking. The NLP pipelines we pre-
sented here and their accessibility via a Web application
opens our NLP service to the broad life science community
to effectively foster new scientific discoveries.
DATA AVAILABILITY
GePI is freely available at https://gepi.coling.uni-jena.de/.
SUPPLEMENTARY DATA
Supplementary Data are available at NAR Online.
ACKNOWLEDGEMENTS
We thank all GlioPATH groups headed by Christiane
Opitz, Kathrin Thedieck and Saskia Trump and their teams
for fruitful discussions.
FUNDING
S.S. acknowledges support from the BMBF e:Med initia-
tive GlioPATH [01ZX1402]; institutional funding from the
Leibniz-HKI; E.F. and U.H. were supported by BMBF
within the SMITH project [01ZZ1803G]. Funding of the
open access charges was supported by IBM via three ‘Un-
structured Information Analytics Awards’ donated to U.H.
between 2000 and 2008.
Conflict of interest statement. None declared.
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