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\begin{document}

\title{Advancing the allergenicity assessment of new proteins using a text
mining resource}



\author[1]{F. Javier Moreno}%
\author[2]{Jorge Novoa}%
\author[3]{Antonio Fernández-Dumont}%
\author[4]{E.N. Clare Mills}%
\author[2]{Florencio Pazos}%
\affil[1]{Instituto de Investigacion en Ciencias de la Alimentacion}%
\affil[2]{Centro Nacional de Biotecnologia}%
\affil[3]{European Food Safety Authority}%
\affil[4]{University of Surrey School of Biosciences and Medicine}%


\vspace{-1em}



  
  \date{March 17, 2025}


\begingroup
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\selectlanguage{english}
\begin{abstract}
BACKGROUND: With a society increasingly demanding alternative protein
food sources, new strategies for evaluating protein safety issues, such
as their allergenic potential, are needed. Large-scale and systemic
studies on allergenic proteins are hindered by the limited and
non-harmonized clinical information available for these substances in
dedicated databases. A clearly missing key information is that
representing the symptomatology of the allergens, especially given in
terms of standard vocabularies, that would allow connecting with other
biomedical resources to carry out different studies related to human
health. In this work, we have generated the first resource with a
comprehensive annotation of allergens' symptomatology, using a
text-mining approach that extracts significant co-mentions between these
entities from the scientific literature. METHODS: The main resource of
biomedical literature (PubMed, \textasciitilde{}36 million abstracts)
was mined to automatically extract relationships between allergens and
clinical symptoms. The annotations are given in terms of standard
vocabularies in widely used biomedical databases. The method identifies
statistically significant co-mentions between the textual descriptions
of the two types of entities in the literature as indication of
relationship. RESULTS: 1,180 clinical signs extracted from the Human
Phenotype Ontology (HPO), the Medical Subject Heading (MeSH) terms of
PubMed together with other allergen-specific symptoms, were linked to
1,036 unique allergens annotated in the two main allergen-related public
databases via 14,009 relationships. CONCLUSIONS: This resource could
serve as a starting point for a future manually curated compilation of
allergen symptomatology. The annotations are publicly available through
an interactive web interface at
{[}https://csbg.cnb.csic.es/CoMent\_allergen/{]}(https://csbg.cnb.csic.es/CoMent\_allergen/).%
\end{abstract}%



\sloppy


\textbf{Advancing the allergenicity assessment of new proteins using a
text mining resource}

Jorge Novoa\textsuperscript{1}, Antonio
Fernandez-Dumont\textsuperscript{2}, E.N. Clare
Mills\textsuperscript{3}, F. Javier Moreno\textsuperscript{4}* and
Florencio Pazos\textsuperscript{5}*

\textsuperscript{1} Computational Systems Biology Group, National Centre
for Biotechnology (CNB-CSIC), 28049 Madrid, Spain.

\textsuperscript{2} European Food Safety Authority (EFSA), 43126 Parma,
Italy.

\textsuperscript{3} School of Biosciences and Medicine, The University
of Surrey, Guildford GU2 7XH, UK

\textsuperscript{4} Instituto de Investigaci\selectlanguage{ngerman}ón en Ciencias de la
Alimentación (CIAL), CSIC-UAM, CEI (UAM+CSIC), 28049 Madrid, Spain

CONTACT INFORMATION:

* Correspondence to:\emph{javier.moreno@csic.es}
;\emph{pazos@cnb.csic.es}

ORCID ID:

Clare Mills:\emph{https://orcid.org/0000-0001-7433-1740}; F. Javier
Moreno: \emph{https://orcid.org/0000-0002-7637-9542;}Florencio
Pazos:\emph{\url{https://orcid.org/0000-0002-2646-6226}}

\emph{PUBLISHED MANUSCRIPT:
\url{https://doi.org/10.1016/j.fct.2024.114638}~}

\textbf{Abstract}

BACKGROUND: With a society increasingly demanding alternative protein
food sources, new strategies for evaluating protein safety issues, such
as their allergenic potential, are needed. Large-scale and systemic
studies on allergenic proteins are hindered by the limited and
non-harmonized clinical information available for these substances in
dedicated databases. A clearly missing key information is that
representing the symptomatology of the allergens, especially given in
terms of standard vocabularies, that would allow connecting with other
biomedical resources to carry out different studies related to human
health. In this work, we have generated the first resource with a
comprehensive annotation of allergens' symptomatology, using a
text-mining approach that extracts significant co-mentions between these
entities from the scientific literature.

METHODS: The main resource of biomedical literature (PubMed,
\textasciitilde{}36 million abstracts) was mined to automatically
extract relationships between allergens and clinical symptoms. The
annotations are given in terms of standard vocabularies in widely used
biomedical databases. The method identifies statistically significant
co-mentions between the textual descriptions of the two types of
entities in the literature as indication of relationship.

RESULTS: 1,180 clinical signs extracted from the Human Phenotype
Ontology (HPO), the Medical Subject Heading (MeSH) terms of PubMed
together with other allergen-specific symptoms, were linked to 1,036
unique allergens annotated in the two main allergen-related public
databases via 14,009 relationships.

CONCLUSIONS: This resource could serve as a starting point for a future
manually curated compilation of allergen symptomatology. The annotations
are publicly available through an interactive web interface
at\emph{https://csbg.cnb.csic.es/CoMent\_allergen/}.

\textbf{Keywords:} allergen databases; allergen symptomatology; clinical
relevance; risk assessment; text mining

\textbf{Introduction}

Society currently demands for healthier food and more sustainable food
systems -- aiming at reducing global warming potential and making a more
effective use of water and land. Moreover, there is a need to securing
our food supply since the global population is expected to reach nearly
10 billion by 2,050\textsuperscript{{[}1{]}}. Therefore, the increasing
demand of protein in an overgrowing world is a global food system
challenge\textsuperscript{{[}2{]}}. Alternative proteins and innovative
foods are proposed as an answer, receiving extensive attention
worldwide\textsuperscript{{[}3{]}}. Before any innovative food can be
introduced into the market, a pre-market safety assessment is undertaken
ensuring the wholesomeness of the product. The allergenicity evaluation
of new food proteins is a key step in the risk assessment (RA) process.
Food proteins can cause life-threatening conditions
(\emph{e.g.,}anaphylactic reaction) and chronic pathologies
(\emph{e.g.,} celiac disease), although it is remaining to fully
understand what makes a protein an allergen. Food allergy shows a
substantial geographical variation in prevalence and causative foods in
both children and adults\textsuperscript{{[}4,5{]}}, and represents a
major public human health problem for which no effective cure
exists\textsuperscript{{[}6{]}}. According to recent epidemiological
data, food allergy prevalence is rising, the severity of allergic
reaction symptoms is high, and there are significant unmet needs for
those living with food allergies\textsuperscript{{[}7{]}}.

Allergenicity prediction is challenging because an allergic reaction to
a protein depends on a complex interplay between an individual's immune
system, the protein, as well as other environmental and life-style
factors (microbiome, environmental pollutants, diet, etc.). Current
strategies and tools used for the RA and management of food allergies
are considered rudimentary\textsuperscript{{[}8{]}} and present
limitations\textsuperscript{{[}9{]}}. Bioinformatic analysis is a
cornerstone in the allergenicity assessment, where the amino acid
sequence of the new protein is compared with those of known allergens
available in public databases. While these databases contain relevant
information of thousands of allergens, the inclusion criteria used are
often different and they lack systematic information on their associated
symptomatology\textsuperscript{{[}10,11{]}}. Such information is crucial
for interpreting the potential risk associated to a new protein, as
allergens are very diverse in terms of prevalence, potency and severity
of clinical symptoms, ranging from very mild clinical manifestations
(\emph{e.g.,} hives) to severe and even fatal
(\emph{e.g.,}anaphylaxis)\textsuperscript{{[}12,13{]}}.

Information on clinical symptoms caused by allergens is dispersed in the
scientific literature, expressed textually and not linked to the
structured biomedical databases via standard identifiers and
vocabularies. This hinders simple tasks such as the automatic assessment
of the symptomatology/severity of a new allergen by sequence matching
against others, as well as large scale studies aimed at getting insight
into this phenomenon.

In this work, we mined the main resource of biomedical literature
(PubMed, \textasciitilde{}36 million abstracts) to automatically extract
relationships between allergens and clinical symptoms. The method
identifies statistically significant co-mentions between the textual
descriptions of the two types of entities in the literature as
indication of relationship. With this approach, we generated the first
comprehensive structured database that associates allergens with
symptoms, expressed in terms of standard vocabularies. These
associations are available to the community through an interactive web
interface.

\textbf{Materials and Methods}

\textbf{Allergen datasets}

Two resources with information on allergenic substances,
WHO/IUIS\textsuperscript{{[}14,15{]}} and AllergenOnline
databases\textsuperscript{{[}16{]}}, were used. From WHO/IUIS, we
extracted the allergen exposure route, source (species scientific and
common names), and different fields used later as synonyms for the
literature searches: allergen name, GenBank nucleotide ID and Uniprot
ID. Following these two last IDs we obtained additional ``synonyms''
from the corresponding protein databases, including ``Title'' and
``Extra'' fields of GeneBank nucleotide and ``description'' and ``gene
name'' fields of Uniprot. From AllergenOnline, we retrieved the route
(``type'' field), allergen source (scientific and common names),
allergen name and its GenBank ID, used to extract additional synonyms as
in the previous case.

This process led to 2,967 allergens for which we have different synonyms
(including gene/protein names) as well as the entry/exposition route and
source species. Note that at this point this list is redundant as the
same allergen can be annotated in both databases, eventually with
different sets of synonyms.

\textbf{Literature searches}

For each allergen, we query NCBI's Entrez API to retrieve the list of
articles (PubMed entries) mentioning it. Thus, we construct a search
string with allergen's synonyms (combined with OR operators) and species
name(s) (with AND). For example, for an allergen with 3 synonyms, coming
from a species with common name ``scpC'' and scientific name ``spcS''
the search string is:

(``syn1''OR``syn2''OR``syn3'') AND (``spcC''OR``spcS'')

At this point, we make the list of allergens non redundant joining two
entries from the two databases when they share the same allergen
identifier based on the WHO/IUIS Allergen Nomenclature
system\textsuperscript{{[}17{]}}. As the list of retrieved articles
could be slightly different for the same allergen in each database due
to the different synonyms, for the unified entry we join all articles of
the original two entries. This led to a final list of 2,179 unique
allergens.

From the HPO\textsuperscript{{[}18{]}} we retrieved all terms under
``phenotypic abnormality'' (HP:0000118) in the HPO hierarchy, to avoid
HPO terms not related to phenotypes or clinical signs. This led to a
final list of 16,481 clinical signs and symptoms associated to human
pathologies, which includes different synonyms used for naming them. We
retrieved the list of PubMed entries mentioning a given HPO term by
querying the Entrez API with the term's synonyms combined with ``OR''.

As an additional vocabulary related to pathology, we included a list of
4,791 MeSH terms\textsuperscript{{[}19{]}} labelled with MeSH ``semantic
types'' related to diseases and symptoms (T046, T047, T048, T049, T184,
T019, T020, T190 and T191). We retrieved the lists of PubMed entries
associated to these terms by querying the Entrez API for articles
annotated with these terms in their MeSH fields.

Finally, as these two vocabularies are generic and might not have the
optimal level of detail for describing allergy-related symptomatology,
we retrieved an additional list of 108 clinical signs associated to
allergy\textsuperscript{{[}13{]}}, and followed a similar procedure for
obtaining the PubMed entries mentioning them.

\textbf{Detection of allergen-symptoms relationships}

For detecting significant literature co-mentions between allergens and
pathological terms, we followed a procedure similar to that
described\textsuperscript{{[}20{]}}. Being \emph{n\textsubscript{a}} the
number of articles mentioning a given allergen,\emph{n\textsubscript{s}}
number of articles mentioning a given clinical sign, \emph{b} those
mentioning both together (the intersection between the two sets of
articles) and \emph{P} the whole size of the PubMed database
(\textasciitilde{}36 million entries), we calculated the fraction of
papers mentioning the term of lowest frequency that mentions both:

\emph{s=b/MIN(n\textsubscript{a},n\textsubscript{s})}

The p-value of the null-hypothesis that the co-mention of both terms
occurs by chance due to their frequencies is calculated with the
hypergeometric distribution:

(eq 1)

\textbf{Large scale evaluation using entry/exposition routes}

With the procedure described above we obtain the pathological terms
significantly co-mentioned with a given allergen, which are expected to
reflect its symptomatology. As this set of annotations is the first of
its kind, there are no curated resources or gold standards to evaluate
its global quality. A way to evaluate the quality of these relationships
at large scale with the gathered data is to assess whether the symptoms
caused by the allergens with a given exposure route are scientifically
sound (\emph{e.g.,} allergens with ``dermal/skin'' exposure are expected
to be related to skin-related symptoms such as ``urticaria'').

To detect ``enriched'' symptoms in the allergens with a given exposure
route we used the same statistical test as above. From the list of
significant allergen-symptom co-mention relationships generated with the
procedure above, being \emph{n\textsubscript{a}} the number of
relationships involving allergens with a given exposure
route,\emph{n\textsubscript{s}} number of relationships involving a
given clinical sign, \emph{b} those relationships involving the clinical
sign and the entry way, and \emph{P} the total number of relationships,
we applied eq. 1 above. This returns the p-value of the null hypothesis
that allergens with that exposure route are associated to that symptom
by chance. Consequently, low p-values indicate significant relationships
between symptoms and exposure routes in the previously generated set of
allergen-HPO relationships. For this approach, we considered four
allergens exposure routes, obtained from the original allergen databases
as explained above: ``Airway'', ``Dermal-skin'', ``Ingestion'' and
``Injection''.

\textbf{Results}

2,179 unique allergen entries were collected from WHO/IUIS and
AllergenOnline databases and subjected to the analysis of significant
literature co-mentions with 21,380 pathological terms. Remarkably, 1,143
of these allergens (52.45\%) were not significantly correlated with any
pathological term (p-val\selectlanguage{english}[?]1E-2), suggesting that these allergens could
have a weak or inexistent clinical relevance based on the lack of
significant information on their biological activity found in the
literature. Indeed, a large fraction of those allergens without any
significant correlation with symptoms is never mentioned in PubMed
according with our searches, i.e., 1,064 out of 1,143 allergens
(93.1\%), being 760 of them retrieved from AllergenOnline and 304 from
WHO/IUIS database. In almost half of the remaining 79 allergens with
retrieved articles but no significant co-mentions with symptoms (38) had
only one article gathered from PubMed, whereas other 38 were quoted only
between 2 and 7 times. These observations indicate that most allergens
not statistically associated to any type of clinical symptoms were due
to the insufficient number of scientific articles available for them in
PubMed. Regarding the 3 allergens with no associated symptoms but
reported in 9 or more articles retrieved from PubMed, they belong to
uncommon food sources (\emph{i.e.,} fungi allergens Asp o 13, Asp o 21
and Pen ch 35). The rest of annotated allergen entries (1,036) were
associated with a great variety of clinical signs and symptoms (i.e.,
1,180) via 14,009 relationships.

\textbf{Figure 1A} shows the distribution of number of symptoms for the
allergens associated to 50 or more. The allergen associated to the
largest number of symptoms is \emph{Can f 3} (serum albumin of domestic
dog), associated to 313 terms. Some of these relationships for \emph{Can
f 3} could be artifacts due to the use of that protein and/or the
animal\emph{per se} in biomedical studies.

Overall, the symptomatology associated to allergens makes sense
considering the knowledge we have on them. For example, well-known food
allergens such as peanut Ara h 1 or birch pollen allergen Bet v 1 were
associated to a large variety of well-described clinical symptoms,
whereas gluten proteins were correlated to celiac disease, and
infections like anisakiasis and aspergillosis were exclusively
associated to parasites from \emph{Anisakis simplex} (and related worm
parasites) and fungi allergens, respectively. Likewise, aeroallergens
were predominantly correlated to symptoms involving the respiratory
system (\emph{e.g.,} rhinitis, asthma, wheezing, sneezing,
conjunctivitis, bronchial disorders). There are also trivial
associations with general terms such as ``allergy'' or
``hypersensitivity'', as well as some ``artifacts'' such as the
relationship between ``decrease circulating IgE'' and several allergens.
This association was inferred from articles describing structural
modifications of allergens in their native form, through processing or
chemical/enzymatic approaches, to reduce their allergenic potential.

\textbf{Figure 1B} shows the distribution of number of allergens
associated to the symptoms with 50 or more. As expected, the generic
term ``allergy'' is associated to almost all allergens (824 out of
1,036).

\textbf{Figure 2} shows, as an example, the symptomatology retrieved by
our system for \emph{Bet v 1} (major birch pollen allergen). The terms
include the very general \emph{allergy} , as well as the
typical\emph{rhinitis, conjunctivitis, pruritus/itching} , and the
rarer\emph{anaphylactic shock} . That list of terms nicely recapitulates
those manually compiled for this allergen in dedicated resources and
provide a clear picture of the symptomatology of this pollen allergen.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Figure 1.} A) Distribution of number of symptoms for the
allergens associated to 50 or more. B) Distribution of number of
allergens for the symptoms associated to 50 or more. Note that the same
term in different resources could lead to slightly different results due
to the different synonyms annotated in each resource, which affects the
bibliographic searches (e.g. ``hypersensitivity'' in HPO (HP:0041092)
and in MeSH (D006967).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Figure 2.} Screenshots of the web interface when used for
retrieving the symptoms associated to the major birch pollen allergen
(\emph{Bet v 1} ). The left panel shows the query form where the user
can enter the allergen or symptoms to search for (in this case the name
of the allergen) and the type of relationships. The right panel shows
the results of the query, in this case the list of symptoms for
\emph{Bet v 1} .

To identify those allergens potentially causing life-threatening, we
selected a series of severe symptoms which are disclosed in decreasing
order of frequency:

\begin{enumerate}
\tightlist
\item
  anaphylactic shock (HP:0100845) or anaphylaxis (D000707) associated to
  210 individual allergens;
\item
  exercise induced anaphylaxis (HP:0410139) associated to 34 individual
  allergens;
\item
  food-induced anaphylaxis (HP:0500095) associated to 27 individual
  allergens;
\item
  dyspnea (HP:0002094) associated to 10 individual allergens;
\item
  idiopathic anaphylaxis (HP:0410148) associated to 6 individual
  allergens;
\item
  loss of consciousness (HP:0007185) associated to 5 individual
  allergens;
\item
  hypotension (HP:0002615) associated to 4 individual allergens;
\item
  Collapse associated to 3 individual allergens;
\end{enumerate}

Overall, 222 allergens could be significantly correlated with
life-threatening severe allergic reaction symptoms (Supplementary Table
1), whereas 814 allergens were statistically correlated to a wide range
of less severe symptoms.

Regarding the main exposure route of those allergens correlated with
life-threatening severe allergic reaction symptoms, 121 allergens were
related to ingestion, 51 to insect venom allergies, 44 were classified
as aeroallergens (23 of them being derived from plants, 10 to cats,
dogs, horses or guinea pigs, 9 derived from dust mites, 2 corresponding
to american cockroach) and 6 related to dermal contact (mostly to latex
allergens) (Supplementary Table 1).

This list of 222 allergens was further manually refined based on the
following prioritization criteria:

i) consideration of ingestion, contact and airway exposure routes of
allergens related to food sources. This criterium served to disregard,
mainly, insect venom allergens, and some aeroallergens from sources
without any food relevance;

ii) consideration of allergens belonging to sources recognised as the
most common causing food allergies and intolerances based on European
Regulation\textsuperscript{{[}21{]}} and the reviewed Codex priority
allergen list by an \emph{ad hoc} Joint FAO/WHO Expert Consultation
Committee\textsuperscript{{[}22{]}}.

iii) consideration of allergens belonging to well-known allergen protein
families or subfamilies (\emph{e.g} ., tropomyosins, parvalbumins,
non-specific lipid-transfer proteins, 2S albumins, vicilins, legumins)
regardless of the food relevance of the source; or

iv) consideration of allergens not included in any of the above criteria
but unequivocally associated to life-threatening severe allergic
symptoms. This last criterium served to disregard a few allergens
included in the initial list as they could not be directly linked to
severe symptoms. This was due to several reasons, such as:

- some of the significant co-mentions retrieved in certain articles were
based on the correlation of anaphylaxis with the whole food source
instead of specific allergens,

- some articles compared allergens associated with a wide range of
symptoms and the text-mining approach could not automatically
differentiate among those allergens associated to severe symptoms and
those related to mild symptoms,

- some articles dealt with allergens and/or derived peptides used for
immunotherapy but these proteins were not identified as responsible for
triggering severe symptoms.

Overall, a refined list containing 137 food allergens resulted from
applying above criteria (\textbf{Table 1} ). This set of allergens could
be further considered for a more target allergenicity RA of novel
proteins as will be discussed below.

\textbf{Relationship with the exposure route}

As a large-scale valuation of the overall quality of these
allergen-symptom relationships obtained, we evaluated whether allergens
with a particular exposure route are preferentially linked to symptoms
intuitively associated to that entry way. If the allergen-symptom
relationships were globally wrong, very generic or totally random, these
exposure route--symptom relationships obtained from them neither would
present significant p-values nor have biological sense.

The whole list of significant exposure route--symptom relationships
(down to a p-value of 0.01) is available as Supplementary Table 2 and
represented in \textbf{Figure 3} .\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image7/image7}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image8/image8}

\end{center}
\end{figure}

\textbf{Figure 3.} Network representation of the associations between
allergens' entry way and symptomatology. The node labelled as ``--''
represents the allergens without annotated entry way, that correspond
mainly to allergens of nematode origin.

There are many relationships with good p-values and they make sense from
a biological/clinical point of view. Moreover, the symptomatology
associated to a given exposure route tends to be specific to it, with
only a few symptoms shared between routes (\textbf{Figure 3)} . As
mentioned above and now quantified, allergens with the ``Airway''
exposure route are clearly associated to symptoms and pathological terms
intuitively related to the respiratory system, such as ``asthma'',
``lung disease'' or ``rhinitis''. Similarly, ``Dermal-skin'' is
associated with latex-related allergy, eczema, dermatitis, etc. We also
find relationships between ``Dermal-skin'' and spina bifida related
pathological terms, due to the relationships between latex allergens and
this pathology. This relationship has been repeatedly reported in the
literature: patients with spina bifida have a higher incidence of latex
allergy, probably due to the exposure to latex in surgical procedures
and implants\textsuperscript{{[}23{]}}. So, this relationship is correct
but in the opposite direction to the others we try to detect: it is not
latex allergy what causes spina bifida but the other way around. The
``Food'' entry way is related to the trivial ``Food allergy''
(HP:0500093), ``food-induced anaphylaxis'', nut-related
hypersensitivity, celiac disease, body weight problems, etc. Finally,
the ``Injection'' entry way is related to ``poisoning'',
``chemically-induced disorders'', ``hemolysis'', ``insect allergy'', etc
(\textbf{Figure 3} ).

\textbf{Browsing the relationships}

All detected relationships between allergens and symptoms/pathological
terms can be interactively browsed and retrieved
at\emph{https://csbg.cnb.csic.es/CoMent\_allergen/}\textbf{.}The system
allows searching for a given allergen or symptom, retrieve the
relationships, sort/filter them according with different parameters,
access the set of articles co-mentioning them, etc. \textbf{Figure
2}shows screenshots of the web interface. The interface includes a
help/tutorial page describing in detail all its features.

\textbf{Discussion}

The consideration of the clinical relevance of individual food allergens
is a relevant factor for developing new strategies and tools for
improving the allergenicity RA of novel
proteins\textsuperscript{{[}24,25{]}}. However, this is challenging
because there is a lack of consensus lists of clinically relevant
allergens with demonstrable potency in eliciting an allergic
reaction\textsuperscript{{[}9{]}}. Here, we have generated the first
resource with a comprehensive annotation of allergens' symptomatology
using a text-mining approach that extracts significant co-mentions
between allergens and clinical symptoms from scientific literature. The
annotations are given in terms of standard vocabularies in widely used
biomedical databases, which allows connecting information on allergens
with a plethora of other resources.

An obvious drawback of this approach is that it detects generic
relationships non-informative about the underlying cause, the
''direction'' or their positive/negative nature. This is illustrated by
the relationship between latex allergy and spina bifida previously
commented. Another example is the relationship found between many
allergens and ``decreased IgE levels'' since reducing the levels of that
immunoglobulin is a treatment for some allergies (not a symptom of
them). Some wrong associations are also due to recurrent co-mentions
with terms mentioned in a general ``introductory'' context. This is, for
example, the case for the appreciable number of wrong linkages with
``anaphylaxis'' discussed in the Results. Despite these examples, in the
case of allergens, most of the co-mentions with symptoms and
pathological terms are expected to be correct and due to the
cause-effect relationships we are interested in. Even if it is not
possible to carry out an exhaustive evaluation of all the relationships,
as there are not curated resources to check against, the indirect
evaluation using the exposure route show that our results are globally
correct (\textbf{Figure 3} ). Future improvements of the system as well
as eventual manual curation of these allergen-symptom relationships
could lead to a fully curated resource.

Our approach could be a valid and starting point for the future grading
of allergens based on clinical symptoms and contribute to the refinement
of the current and over simplistic RA view where proteins are
categorized as allergens or non-allergens\textsuperscript{{[}9,21{]}}.
In this work, we mainly focus on identifying allergens causing
life-threatening symptoms and an initial list of 222 allergens is
provided with significant co-mentions (Supplementary Table 1). The main
routes of allergen exposure are considered, being ingestion (foods) the
most common one (54.5\%), followed distantly by injection (insect bites)
(23.0\%), inhalation (19.8\%), and skin (2.7\%). This list has been
further manually refined to a selection of 137 allergens of potential
food relevance for RA purposes (\textbf{Table 1} ). Remarkably, this
refined list could serve as a starting point to propose a selection of
the most relevant allergens as a potential set of reference proteins to
validate predictive models of allergenicity, which today does not exist.
In this context, a potential match of a novel protein with any of these
allergens, based on criteria like their similarity of amino acid
sequence and physicochemical properties, and/or secondary structure
motifs and 3D-structure, could indicate a high risk of allergenicity.
Moreover, a potential match with allergens statistically co-mentioned
with less severe symptoms (814 allergens are classified in this
category) or with none of them (1,143) could suggest a medium or low
risk of IgE allergenicity, respectively. This type of information
linking the allergen hit with the clinical symptomatology is crucial to
develop targeted and proportionate follow-up RA steps depending on the
risk level and accompanying uncertainties\textsuperscript{{[}25{]}}.

This resource, available to the community through a free web interface,
will allow connecting the, until now, isolated data on allergenic
substances with other biomedical databases (on genes, diseases,
molecular processes, etc.). For example, as HPO (symptom) profiles for
diseases are available, it would be possible to compare them with those
for allergens so that to inform practitioners of possible
allergy-disease misdiagnostics. In general, this massive information
would pave the way for systemic studies on the complex phenomena of
allergenicity. Systemic and network-based studies are widely used now in
biomedicine\textsuperscript{{[}26{]}} but they need massive amounts of
interconnected data, which are right now scarce for the particular case
of allergens.

This resource can also be useful for the similarity-based prediction of
allergenic proteins in new food sources, as a matching against a known
allergen can now be enriched with a profile of possible symptoms and,
eventually, a severity inference, as commented above. This
straightforward information will be of great utility for the
allergenicity RA process.

In a next step, this approach could also allow to perform data-mining
studies aimed at getting new insights into the molecular basis of other
hazardous properties (\emph{e.g.,} adjuvanticity, toxicity) advancing
the overall protein safety assessment.

\textbf{Funding}

This research was funded by the European Food Safety Authority (grant
number GP/EFSA/ENCO/2020/02-1).

\textbf{Disclaimer statement}

The conclusions, findings, and opinions expressed in this scientific
paper reflect only the view of the authors and are not the official
position of EFSA.

\textbf{Ethics declarations - Competing interests}

The authors declare no competing interests.

\textbf{Table 1.} Refined list of potential life-threatening allergens
and their associated symptomatology\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\textbf{Allergen ID} & \textbf{Species} & \textbf{Protein} &
\textbf{Source / Exposure route} & \textbf{HPO ID} & \textbf{HPO term
name} & \textbf{Co-mention p-value}\tabularnewline
\midrule
\endhead
Act\_d\_2\_c & actinidia deliciosa & thaumatin-like protein & {[}Food,
Food Plant{]} & HP:0100845 & anaphylactic shock &
0,000183\tabularnewline
Act\_d\_9\_c & actinidia deliciosa & profilin & {[}Food, Food Plant{]} &
HP:0100845 & anaphylactic shock & 0,000202\tabularnewline
Ana\_o\_2\_c & anacardium occidentale & 11s globulin seed storage
protein ana o 2.0101 small subunit & {[}Food, Food Plant{]} & HP:0100845
& anaphylactic shock & 0,000221\tabularnewline
Ana\_o\_3\_c & anacardium occidentale & ana o 3 gene & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 1,71E-05\tabularnewline
Ani\_s\_1\_c & anisakis simplex & excretory gland allergen ans1 &
{[}Food, Food Animal{]} & HP:0100845 & anaphylactic shock &
4,00E-03\tabularnewline
Ani\_s\_12\_c & anisakis simplex & ani s 12 allergen precursor &
{[}Food, Food Animal{]} & HP:0007185 & loss of consciousness &
0,000804\tabularnewline
Ani\_s\_2\_c & anisakis simplex & paramyosin & {[}Food, Food Animal{]} &
HP:0007185 & loss of consciousness & 0,001407\tabularnewline
Ani\_s\_4\_c & anisakis simplex & ani s 4 allergen; cystatin & {[}Food,
Food Animal{]} & HP:0100845 & anaphylactic shock &
1,09E-01\tabularnewline
Ani\_s\_5\_c & anisakis simplex & sxp/ral-2 family protein ani s 5 &
{[}Food, Food Animal{]} & HP:0100845 & anaphylactic shock &
0,007498\tabularnewline
Ani\_s\_9\_c & anisakis simplex & ani s 9 allergen precursor & {[}Food,
Food Animal{]} & HP:0100845 & anaphylactic shock &
0,005629\tabularnewline
Api\_g\_1\_c & apium graveolens & major allergen api g 1, isoallergen 2
& {[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
0,000778\tabularnewline
Api\_g\_2\_c & apium graveolens & stalk non-specific lipid-transfer
protein 1 & {[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
0,003756\tabularnewline
Api\_g\_4\_c & apium graveolens & minor pollen allergen api g 4 &
{[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
0,000486\tabularnewline
Ara\_h\_1\_c & arachis hypogaea & allergen ara h 1, clone p41b &
{[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
0\tabularnewline
Ara\_h\_10\_c & arachis hypogaea & oleosin ara h 10.0102 & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 0,006564\tabularnewline
Ara\_h\_11\_c & arachis hypogaea & oleosin ara h 11.0102 & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 0,004693\tabularnewline
Ara\_h\_15\_c & arachis hypogaea & oleosin ara h 15.0101 & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 0,003756\tabularnewline
Ara\_h\_2\_c & arachis hypogaea & seed storage protein ssp2 & {[}Food,
Food Plant{]} & HP:0100845 & anaphylactic shock & 0\tabularnewline
Ara\_h\_3\_c & arachis hypogaea & arah4 gene & {[}Food, Food Plant{]} &
HP:0100845 & anaphylactic shock & 0\tabularnewline
Ara\_h\_4\_c & arachis hypogaea & ara h 4 & {[}Food{]} & HP:0100845 &
anaphylactic shock & 0,007498\tabularnewline
Ara\_h\_5\_c & arachis hypogaea & profilin & {[}Food, Food Plant{]} &
HP:0100845 & anaphylactic shock & 1,67E-10\tabularnewline
Ara\_h\_6\_c & arachis hypogaea & allergen arah6 & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 0\tabularnewline
Ara\_h\_8\_c & arachis hypogaea & ara h 8 allergen isoform & {[}Food,
Food Plant{]} & HP:0100845 & anaphylactic shock &
0,00E+00\tabularnewline
Ara\_h\_9\_c & arachis hypogaea & non-specific lipid-transfer protein &
{[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
0\tabularnewline
Art\_v\_1\_c & artemisia vulgaris & major pollen allergen art v 1
precursor & {[}Airway, Aero Plant{]} & HP:0500095 & food-induced
anaphylaxis & 0,000546\tabularnewline
Art\_v\_3\_c & artemisia vulgaris & non-specific lipid-transfer protein
& {[}Airway, Aero Plant{]} & HP:0100845 & anaphylactic shock &
2,68E-02\tabularnewline
Ber\_e\_1\_c & bertholletia excelsa & 2s sulfur-rich seed storage
protein large chain 1b & {[}Food, Food Plant{]} & HP:0100845 &
anaphylactic shock & 0,000202\tabularnewline
Bet\_v\_1\_c & betula verrucosa & major pollen allergen bet v 1-f/i &
{[}Airway, Aero Plant{]} & HP:0100845 & anaphylactic shock &
0,001559\tabularnewline
Bomb\_m\_4\_c & bombyx mori & bomb m 4 & {[}Food{]} & HP:0100845 &
anaphylactic shock & 0,00094\tabularnewline
Bos\_d\_5\_c & bos domesticus & beta-lactoglobulin & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 1,11E-11\tabularnewline
Bos\_d\_6\_c & bos domesticus & bsa protein & {[}Food, Food Animal{]} &
HP:0100845 & anaphylactic shock & 0\tabularnewline
Can\_f\_1\_c & canis familiaris & major allergen can f 1 & {[}Airway,
Aero Animal{]} & HP:0100845 & anaphylactic shock &
0,000517\tabularnewline
Can\_f\_3\_c & canis familiaris & serum albumin & {[}Airway, Aero
Animal{]} & HP:0100845 & anaphylactic shock & 2,53E-03\tabularnewline
Can\_f\_5\_c & canis familiaris & arginine esterase & {[}Airway, Aero
Animal{]} & HP:0100845 & anaphylactic shock & 1,71E-05\tabularnewline
Can\_s\_3\_c & cannabis sativa & non-specific lipid-transfer protein &
{[}Airway, Aero Plant{]} & HP:0100845 & anaphylactic shock &
0,007498\tabularnewline
Cari\_p\_2\_c & carica papaya & papaya proteinase ii & {[}Food{]} &
HP:0100845 & anaphylactic shock & 0,001715\tabularnewline
Cha\_f\_1\_c & charybdis feriatus & heat stable allergen tropomyosin &
{[}Food, Food Animal{]} & HP:0100845 & anaphylactic shock &
7,29E-04\tabularnewline
Cit\_s\_1\_c & citrus sinensis & germin-like protein & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 0,003756\tabularnewline
Cit\_s\_2\_c & citrus sinensis & profilin & {[}Food, Food Plant{]} &
HP:0100845 & anaphylactic shock & 8,83E-01\tabularnewline
Cit\_s\_3\_c & citrus sinensis & non-specific lipid-transfer protein &
{[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
0,003756\tabularnewline
Cor\_a\_1\_c & corylus avellana & major pollen allergen cor a 1 isoforms
5, 6, 11 and 16 & {[}Airway, Food Plant{]} & HP:0100845 & anaphylactic
shock & 0\tabularnewline
Cor\_a\_11\_c & corylus avellana & 7s vicilin-like protein cor a 11 &
{[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
2,47E+00\tabularnewline
Cor\_a\_14\_c & corylus avellana & 2s albumin & {[}Food, Food Plant{]} &
HP:0100845 & anaphylactic shock & 4,09E-07\tabularnewline
Cor\_a\_2\_c & corylus avellana & minor allergen hazelnut profilin &
{[}Food, Aero Plant{]} & HP:0100845 & anaphylactic shock &
5,83E-06\tabularnewline
Cor\_a\_8\_c & corylus avellana & non-specific lipid-transfer protein
cor a 8.0101 & {[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock
& 1,86E-07\tabularnewline
Cor\_a\_9\_c & corylus avellana & 11s globulin-like protein & {[}Food{]}
& HP:0100845 & anaphylactic shock & 0,004693\tabularnewline
Cra\_c\_1\_c & crangon crangon & tropomyosin & {[}Food, Food Animal{]} &
HP:0100845 & anaphylactic shock & 0\tabularnewline
Cra\_c\_2\_c & crangon crangon & arginine kinase & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 1,23E-01\tabularnewline
Cra\_c\_4\_c & crangon crangon & sarcoplasmic calcium-binding protein &
{[}Food, Food Animal{]} & HP:0100845 & anaphylactic shock &
0,000283\tabularnewline
Cra\_c\_5\_c & crangon crangon & myosin light chain & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 2,37E-04\tabularnewline
Cra\_c\_6\_c & crangon crangon & troponin c & {[}Food, Food Animal{]} &
HP:0100845 & anaphylactic shock & 8,83E-01\tabularnewline
Cra\_c\_8\_c & crangon crangon & triosephosphate isomerase & {[}Food,
Food Animal{]} & HP:0100845 & anaphylactic shock &
0,006564\tabularnewline
Cry\_j\_1\_c & cryptomeria japonica & major allergen cry j 1 &
{[}Airway, Aero Plant{]} & HP:0100845 & anaphylactic shock &
1,11E-03\tabularnewline
Cyp\_c\_1\_c & cyprinus carpio & cyp c 1.02 gene & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 0,005221\tabularnewline
Der\_f\_1\_c & dermatophagoides farinae & major mite fecal allergen der
f 1 & {[}Airway, Aero Mite{]} & HP:0100845 & anaphylactic shock &
0,0001\tabularnewline
Der\_f\_2\_c & dermatophagoides farinae & mite allergen der f ii
precursor & {[}Airway, Aero Mite{]} & HP:0100845 & anaphylactic shock &
0,000145\tabularnewline
Der\_p\_1\_c & dermatophagoides pteronyssinus & major mite fecal
allergen der p 1 & {[}Airway, Aero Mite{]} & HP:0100845 & anaphylactic
shock & 4,48E-01\tabularnewline
Der\_p\_10\_c & dermatophagoides pteronyssinus & tropomyosin &
{[}Airway, Aero Mite{]} & HP:0100845 & anaphylactic shock &
2,08E-04\tabularnewline
Der\_p\_11\_c & dermatophagoides pteronyssinus & hdm allergen &
{[}Airway, Aero Mite{]} & HP:0100845 & anaphylactic shock &
2,91E-02\tabularnewline
Fag\_e\_2\_c & fagopyrum esculentum & 2s seed storage albumin protein &
{[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
1,82E-02\tabularnewline
Fag\_e\_3\_c & fagopyrum esculentum & vicilin-like protein & {[}Food,
Food Plant{]} & HP:0100845 & anaphylactic shock &
4,44E-10\tabularnewline
Fag\_e\_5\_c & fagopyrum esculentum & vicilin-like protein & {[}Food{]}
& HP:0100845 & anaphylactic shock & 0,00094\tabularnewline
Fel\_d\_1\_c & felis domesticus & major allergen i & {[}Airway, Aero
Animal{]} & HP:0100845 & anaphylactic shock & 0\tabularnewline
Fel\_d\_2\_c & felis domesticus & albumin precursor & {[}Airway, Aero
Animal{]} & HP:0410139 & exercise induced anaphylaxis &
0,000732\tabularnewline
Gal\_d\_1\_c & gallus domesticus & allergen gal d i & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 7,84E-01\tabularnewline
Gal\_d\_2\_c & gallus domesticus & unnamed protein product & {[}Food,
Food Animal{]} & HP:0100845 & anaphylactic shock & 0\tabularnewline
Gal\_d\_3\_c & gallus domesticus & allergen gal d iii & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 0,000858\tabularnewline
Gal\_d\_5\_c & gallus domesticus & preproalbumin serum albumin &
{[}Food, Food Animal{]} & HP:0100845 & anaphylactic shock &
0\tabularnewline
Gal\_d\_7\_c & gallus domesticus & myosin light chain 1, skeletal muscle
isoform & {[}Food{]} & HP:0100845 & anaphylactic shock &
0,002818\tabularnewline
Gal\_d\_8\_c & gallus domesticus & parvalbumin & {[}Food, Food Animal{]}
& HP:0100845 & anaphylactic shock & 4,16E-01\tabularnewline
Gly\_m\_3\_c & glycine max & profilin-2 & {[}Food, Food Plant{]} &
HP:0100845 & anaphylactic shock & 0,007498\tabularnewline
Gly\_m\_4\_c & glycine max & starvation-associated message 22 & {[}Food,
Food Plant{]} & HP:0100845 & anaphylactic shock & 0\tabularnewline
Gly\_m\_5\_c & glycine max & alpha' subunit of beta-conglycinin &
{[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
1,57E-03\tabularnewline
Gly\_m\_6\_c & glycine max & glycinin a-1a-b-x subunit & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 7,93E-06\tabularnewline
Gly\_m\_8\_c & glycine max & 2s seed storage albumin protein & {[}Food,
Food Plant{]} & HP:0100845 & anaphylactic shock &
0,008332\tabularnewline
Hev\_b\_1\_c & hevea brasiliensis & rubber elongation factor protein &
{[}Contact{]} & HP:0100845 & anaphylactic shock &
7.48E-01\tabularnewline
Hev\_b\_5\_c & hevea brasiliensis & major latex allergen hev b 5 &
{[}Contact{]} & HP:0100845 & anaphylactic shock &
7.97E-02\tabularnewline
Hev\_b\_6\_c & hevea brasiliensis & hevein hev1 precursor &
{[}Contact{]} & HP:0100845 & anaphylactic shock &
7.22E-02\tabularnewline
Hor\_v\_20\_c & hordeum vulgare & gamma-hordein-3 & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 1,85E+00\tabularnewline
Jug\_r\_1\_c & juglans regia & 2s albumin seed storage protein large
subunit & {[}Food, Food Plant{]} & HP:0410139 & exercise induced
anaphylaxis & 0,000176\tabularnewline
Lac\_s\_1\_c & lactuca sativa & non-specific lipid-transfer protein lac
s 1 & {[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
0,00188\tabularnewline
Lat\_c\_1\_c & lates calcarifer & parvalbumin beta-1 & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 0,006564\tabularnewline
Lin\_u\_1\_c & linum usitatissimum & cnl2 gene & {[}Food{]} & HP:0100845
& anaphylactic shock & 0,002818\tabularnewline
Lit\_c\_1\_c & litchi chinensis & minor allergen lit c 1 & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 2,65E-01\tabularnewline
Mal\_d\_1\_c & malus domestica & ribonuclease-like pr-10c & {[}Food,
Food Plant{]} & HP:0100845 & anaphylactic shock &
0,006055\tabularnewline
Mal\_d\_4\_c & malus domestica & pollen allergen mal d 4.0301 & {[}Food,
Food Plant{]} & HP:0100845 & anaphylactic shock &
1,39E+00\tabularnewline
Man\_i\_1\_c & mangifera indica & man i 1 & {[}Food{]} & HP:0100845 &
anaphylactic shock & 0,00094\tabularnewline
Met\_e\_1\_c & metapenaeus ensis & allergen met e i & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 0\tabularnewline
Mor\_n\_3\_c & morus nigra & non-specific lipid-transfer protein 1 &
{[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
0,00094\tabularnewline
NA\_0177\_AO & balanus rostratus & balanus r tropomyosin & {[}Food
Animal{]} & HP:0100845 & anaphylactic shock & 2,22E-11\tabularnewline
NA\_0278\_AO & bos taurus & alpha-lactalbumin & {[}Food Animal{]} &
HP:0100845 & anaphylactic shock & 0,004002\tabularnewline
NA\_0497\_AO & fagopyrum esculentum & 13s globulin seed storage protein
3 acidic chain & {[}Food Plant{]} & HP:0100845 & anaphylactic shock &
2,90E-03\tabularnewline
NA\_0522\_AO & fulvia mutica & fulvia tropomyosin & {[}Food Animal{]} &
D000707 & Anaphylaxis & 0,007953\tabularnewline
NA\_0571\_AO & haliotis diversicolor & haliotis hal m 1 tropomyosin &
{[}Food Animal{]} & HP:0100845 & anaphylactic shock &
0,008431\tabularnewline
NA\_0572\_AO & helianthus annuus & methionine-rich 2s protein & {[}Food
Plant{]} & SYMPT0012 & collapse & 0,006381\tabularnewline
NA\_0680\_AO & manilkara zapota & manilkara thaumatin like protein 1 &
{[}Food Plant{]} & HP:0100845 & anaphylactic shock &
0,002818\tabularnewline
NA\_0716\_AO & octopus vulgaris & octopus tropomyosin & {[}Food
Animal{]} & HP:0100845 & anaphylactic shock & 0,005629\tabularnewline
NA\_0909\_AO & portunus sanguinolentus & portunus por s and t
tropomyosin & {[}Food Animal{]} & HP:0100845 & anaphylactic shock &
0,007498\tabularnewline
NA\_0910\_AO & portunus trituberculatus & portunus por s and t
tropomyosin & {[}Food Animal{]} & HP:0100845 & anaphylactic shock &
7,29E-04\tabularnewline
NA\_0938\_AO & pseudocardium sachalinensis & pseudocardium tropomyosin &
{[}Food Animal{]} & D000707 & Anaphylaxis & 0,007953\tabularnewline
NA\_1087\_AO & triticum aestivum & triticum tri a 26 & {[}Food Plant{]}
& HP:0100845 & anaphylactic shock & 0\tabularnewline
NA\_1089\_AO & triticum aestivum & high molecular weight glutenin
subunit & {[}Gliadin{]} & HP:0100845 & anaphylactic shock &
5,89E-01\tabularnewline
NA\_1113\_AO & triticum urartu & triticum alpha/beta gliadin &
{[}Gliadin{]} & HP:0100845 & anaphylactic shock & 0\tabularnewline
Ole\_e\_2\_c & olea europaea & pollen allergen ole e 2 & {[}Airway, Aero
Plant{]} & HP:0100845 & anaphylactic shock & 0,000134\tabularnewline
Ole\_e\_3\_c & olea europaea & calcium-binding pollen allergen ole e 3 &
{[}Airway, Aero Plant{]} & D000707 & Anaphylaxis &
0,009171\tabularnewline
Ole\_e\_6\_c & olea europaea & major pollen allergen ole e 6 &
{[}Airway, Aero Plant{]} & HP:0100845 & anaphylactic shock &
0,001509\tabularnewline
Ole\_e\_7\_c & olea europaea & pollen allergen ole e 7 & {[}Airway, Aero
Plant{]} & HP:0100845 & anaphylactic shock & 2,36E-02\tabularnewline
Onc\_k\_5\_c & oncorhynchus keta & vitellogenin & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 0,005629\tabularnewline
Pen\_m\_1\_c & penaeus monodon & tropomyosin & {[}Food, Food Animal{]} &
HP:0100845 & anaphylactic shock & 1,13E-06\tabularnewline
Pen\_m\_2\_c & penaeus monodon & arginine kinase & {[}Food, Food
Animal{]} & HP:0500095 & food-induced anaphylaxis &
8,71E+00\tabularnewline
Pen\_m\_3\_c & penaeus monodon & myosin light chain & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 0,004693\tabularnewline
Pis\_s\_1\_c & pisum sativum & vicilin & {[}Food, Food Plant{]} &
HP:0100845 & anaphylactic shock & 1,98E-02\tabularnewline
Por\_p\_1\_c & portunus pelagicus & tropomyosin & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 8,83E-01\tabularnewline
Pru\_ar\_5\_c & prunus armeniaca & putative allergen protein & {[}Food,
Food Plant{]} & HP:0100845 & anaphylactic shock & 0,00094\tabularnewline
Pru\_av\_3\_c & prunus avium & non-specific lipid-transfer protein &
{[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
0,007498\tabularnewline
Pru\_p\_3\_c & prunus persica & non-specific lipid-transfer protein 1 &
{[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
0\tabularnewline
Pru\_p\_4\_c & prunus persica & profilin & {[}Food, Food Plant{]} &
HP:0100845 & anaphylactic shock & 0\tabularnewline
Pru\_p\_7\_c & prunus persica & peamaclein & {[}Food, Food Plant{]} &
HP:0100845 & anaphylactic shock & 0\tabularnewline
Ran\_e\_1\_c & rana esculenta & parvalbumin alpha & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 1,85E+00\tabularnewline
Ran\_e\_2\_c & rana esculenta & parvalbumin beta protein & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 1,85E+00\tabularnewline
Ras\_k\_1\_c & rastrelliger kanagurta & parvalbumin & {[}Food, Food
Animal{]} & HP:0100845 & anaphylactic shock & 0,00094\tabularnewline
Scy\_p\_1\_c & scylla paramamosain & tropomyosin & {[}Food, Food
Animal{]} & HP:0500095 & food-induced anaphylaxis &
0,000119\tabularnewline
Ses\_i\_1\_c & sesamum indicum & 2s albumin & {[}Food, Food Plant{]} &
HP:0100845 & anaphylactic shock & 0,000202\tabularnewline
Ses\_i\_2\_c & sesamum indicum & 2s seed storage protein 1 large subunit
& {[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
0,000166\tabularnewline
Ses\_i\_3\_c & sesamum indicum & 7s globulin & {[}Food, Food Plant{]} &
HP:0100845 & anaphylactic shock & 0,004693\tabularnewline
Sin\_a\_2\_c & sinapis alba & 11s globulin precursor & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 0,003756\tabularnewline
Sola\_l\_3\_c & solanum lycopersicum & non-specific lipid-transfer
protein 2 & {[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
0,005629\tabularnewline
Sola\_l\_7\_c & solanum lycopersicum & non-specific lipid-transfer
protein precursor & {[}Food, Food Plant{]} & HP:0100845 & anaphylactic
shock & 0,002818\tabularnewline
Sus\_s\_1\_c & sus scrofa & alb gene & {[}Food, Aero Animal{]} &
HP:0100845 & anaphylactic shock & 0\tabularnewline
Tri\_a\_12\_c & triticum aestivum & profilin-3 & {[}Food, Food Plant{]}
& D000707 & Anaphylaxis & 0,007343\tabularnewline
Tri\_a\_14\_c & triticum aestivum & non-specific lipid-transfer protein
& {[}Food{]} & HP:0500095 & food-induced anaphylaxis &
0,000166\tabularnewline
Tri\_a\_19\_c & triticum aestivum & omega-5 gliadin & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 0\tabularnewline
Tri\_a\_20\_c & triticum aestivum & gamma-gliadin & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 0\tabularnewline
Tri\_a\_21\_c & triticum aestivum & alpha/beta gliadin precursor &
{[}Airway, Food Plant{]} & HP:0410139 & exercise induced anaphylaxis &
0,000234\tabularnewline
Tri\_a\_34\_c & triticum aestivum & glyceraldehyde-3-phosphate
dehydrogenase & {[}Airway, Aero Plant{]} & HP:0100845 & anaphylactic
shock & 0,002163\tabularnewline
Tri\_a\_36\_c & triticum aestivum & low molecular weight glutenin
subunit & {[}Food, Food Plant{]} & HP:0100845 & anaphylactic shock &
8,99E-07\tabularnewline
Tri\_a\_37\_c & triticum aestivum & alpha purothionin & {[}Food, Food
Plant{]} & HP:0100845 & anaphylactic shock & 0,005629\tabularnewline
\bottomrule
\end{longtable}

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