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<article xmlns:xlink="http://www.w3.org/1999/xlink">
  <front>
    <journal-meta />
    <article-meta>
      <title-group>
        <article-title>Automatic extraction of semantic relations between medical entities: Application to the treatment relation</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <string-name>Asma Ben Abacha</string-name>
          <email>asma.benabacha@limsi.fr</email>
          <xref ref-type="aff" rid="aff0">0</xref>
        </contrib>
        <contrib contrib-type="author">
          <string-name>Pierre Zweigenbaum</string-name>
          <email>pz@limsi.fr</email>
          <xref ref-type="aff" rid="aff0">0</xref>
        </contrib>
        <aff id="aff0">
          <label>0</label>
          <institution>LIMSI-CNRS</institution>
          ,
          <addr-line>BP 133 - F-91403 Orsay Cedex</addr-line>
        </aff>
      </contrib-group>
      <abstract>
        <p>Information extraction is a complex task which is necessary to develop highprecision information retrieval tools. In this paper, we present MeTAE, a platform to extract medical entities and the medical relations linking them. The proposed approach relies on linguistic patterns and domain knowledge and consists in two steps: (i) recognition of medical entities and (ii) identification of the correct semantic relation between each pair of entities. The first step is achieved by an enhanced use of MetaMap which improves the precision obtained by MetaMap by 19.59% in our evaluation. The second step relies on linguistic patterns which are built semiautomatically from a corpus selected according to semantic criteria. We evaluate our system's ability to identify medical entities of 16 types. We also evaluate the extraction of treatment relations between a treatment (e.g., medication) and a problem (e.g., disease): we obtain 75.72% of precision and 60.46% of recall. We achieve encouraging results w.r.t similar research works in the literature.</p>
      </abstract>
    </article-meta>
  </front>
  <body>
    <sec id="sec-1">
      <title>1 Introduction</title>
      <p>Medical knowledge is growing significantly every
year. According to some studies, the volume of
this knowledge doubles every five years
(Engelbrecht, 1997), or even every two years (Hotvedt,
1996). With large-scale digitisation, several
medical search engines went on display, such as
PubMed1 for searching biomedical literature,
CISMeF2, catalog and index of french medical Web
sites or Health On the Net3, a public medical</p>
      <sec id="sec-1-1">
        <title>1http://www.pubmed.com 2http://www.chu-rouen.fr/cismef 3http://www.healthonnet.org</title>
        <p>search engine.</p>
        <p>But, while these search engines have a big
contribution in making large volumes of
medical knowledge accessible, their users have often
to deal with the burden of browsing and filtering
the numerous results of their queries in order to
find the precise information they were looking for.
This point is more crucial for practitioners who
may need an immediate answer to their queries
during their work.</p>
        <p>In this context, we need systems able to respond
to users queries with precise answers. Such tools
need deep analysis of biomedical documents in
order to extract relevant information. At the first
level of this information come the medical
entities (e.g. diseases, drugs, symptoms). At the
second, more complicated level comes the extraction
of semantic relationships between these entities.</p>
        <p>In this paper, we present our method to extract
semantic relations between medical entities, with
an empirical study on the “treatment” relation. We
first propose an enhanced use of MetaMap
(Aronson, 2001) to extract medical entities and
compare it with the simple application of MetaMap on
the same test corpora. To extract occurrences of
the target relations, we then design linguistic
patterns based on selected sentences from PubMed
Central articles. We present a method to
obtain such sentences by leveraging UMLS
Metathesaurus knowledge and MeSH indexing of PubMed
Central. We evaluate entity and relation extraction
on a distinct corpus of 580 sentences and obtain
promising results. We also present MeTAE, a
platform for automatic semantic annotation and
exploration of medical texts which incorporates these
information extraction components and lets a user
query the obtained information. We finally discuss
our results and conclude on further work.</p>
      </sec>
    </sec>
    <sec id="sec-2">
      <title>Background</title>
      <p>
        The reference tool for medical entity recognition
is MetaMap (Aronson, 2001), a system which
maps medical text to UMLS concepts. Using
MetaMap therefore provides a strong baseline to
start with. MetaMap is able to identify most
concepts in the titles of articles from MEDLINE
        <xref ref-type="bibr" rid="ref5">(Pratt
and Yetisgen-Yildiz, 2003)</xref>
        . (Meystre and Haug,
2005) obtained good precision and recall measures
(resp. 0.753 and 0.892) with an approach based on
MetaMap for extracting “medical problems”.
      </p>
      <p>However, the use of MetaMap leads to some
residual problems at two levels: (i) in the
segmentation and the extraction of medical entities:
MetaMap considers some general words and some
verbs as medical entities (e.g. best, normal, take,
reduce) and (ii) in the categorization of medical
entities: MetaMap may propose several concepts
for the same term as well as several semantic types
for the same concept. We address these two issues
in our system by performing independent
segmentation of the text given to MetaMap, then
imposing constraints on the semantic types of concepts
it detects.</p>
      <p>
        Domain-independent relation extraction has
been studied by a wide range of approaches
which can be classified in four categories.
Statistical approaches based on term frequency and
co-occurrence of specific terms (Hindle, 1990),
machine learning techniques
        <xref ref-type="bibr" rid="ref7">(Zhu et al., 2009)</xref>
        ,
linguistic approaches (Hearst, 1992) (e.g. using
manually written extraction rules) and hybrid
approaches which combine two or more of the
preceding methods
        <xref ref-type="bibr" rid="ref6">(Suchanek et al., 2006)</xref>
        .
      </p>
      <p>
        In the medical domain, the same strategies
can be found but the specificities of the domain
led to specialised methods.
        <xref ref-type="bibr" rid="ref2">(Cimino and
Barnett, 1993)</xref>
        used linguistic patterns to extract
relations from titles of Medline articles. The
authors used MeSH headings and co-occurrence of
target terms in the title field of a given
article to construct relation extraction rules. (Khoo
et al., 2000) focused on extracting causal
relations from abstracts of biomedical articles by
aligning manually-constructed graph patterns with
syntactic dependency trees. (Lee et al., 2003)
used UMLS to identify semantic relations between
medical entities. Their first method could extract
68% of the semantic relations in their test
corpus but if many relations were possible between
the relation arguments no disambiguation was
performed. Their second method (Lee et al., 2004)
targeted the precise extraction of “treatment”
relations between drugs and diseases. Manually
written linguistic patterns were constructed from
medical abstracts talking about cancer. Their system
reached 84% recall but an overall 48.14%
precision.
        <xref ref-type="bibr" rid="ref3">(Embarek and Ferret, 2008)</xref>
        proposed an
approach to extract four kinds of relations (Detect,
Treat, Sign and Cure) between five kinds of
medical entities. The patterns used were constructed
automatically using an alignment algorithm wich
maps sentence parts using an edit distance (defined
between two sentences) and different word-level
clues.
      </p>
      <p>
        SemRep
        <xref ref-type="bibr" rid="ref4">(Rindflesch et al., 2000)</xref>
        , a natural
language processing application, targeted the
extraction of semantic relationships in biomedical text
through a rule-based approach. SemRep
        <xref ref-type="bibr" rid="ref1">(Fiszman
et al., 2007)</xref>
        obtained a 53% recall and 67%
precision in identifying risk factors and biomarkers
for diseases asserted in MEDLINE citations. An
enhanced version of SemRep
        <xref ref-type="bibr" rid="ref1">(Ahlers et al., 2007)</xref>
        was proposed to identify core assertions on
pharmacogenomics and obtained an overall 55% recall
and 73% precision.
      </p>
      <p>Domain-independent relation extraction
methods are not directly applicable to the medical
domain due to the lack of domain independent
markers that may help to recognise medical entities
(e.g. capital letters, regular grammatical structure)
and to the variety in the expression of domain
concepts (e.g. Amoxicillin = amoxycillin = AMOX).
To bypass these problems, medical relation
extraction approaches often rely on domain knowledge
such as the UMLS Metathesaurus and Semantic
Network. But the post-use of extracted relations
is not always taken into account in the extraction
procedure. For instance, if the extracted relations
are to be used in keyword querying systems, we
should either give priority to recall or give the
same priority for recall and precision, while, if the
final application is a question answering system
for practitioners, priority should be given to the
precision of extraction. Medical relation
extraction approaches sometimes also do not care about
extracting the arguments of a relation (e.g. (Lee et
al., 2004)), or evaluate their approaches by
counting relations extracted with only one argument as
correct (e.g. (Pustejovsky et al., 2002)),
considering that recall is the most important measure. In
our context we are interested in medical question
answering systems as back-end and give priority
to precision, considering the correct extraction of
arguments as mandatory to validate the identified
relations.</p>
      <p>Most relation extraction methods rely on a
corpus where example occurrences of the target
relations can be found. For instance, given pairs of
seed terms which are known to entertain the
target relation, semi-supervised methods such as that
introduced in (Hearst, 1992) collect occurrences
of these term pairs in the corpus and use them to
build relation patterns.</p>
      <p>The selection of a relevant corpus is a key point
here: for such a method to work, the corpus must
contain mentions of the target relationship
between these pairs of terms. We propose a method
to increase the chances that such mentions are
actually found in the selected texts.
3</p>
    </sec>
    <sec id="sec-3">
      <title>Annotation Method</title>
      <p>Our method is twofold. In a first step, we
extract medical entities from sentences and
determine their categories. In a second step, we extract
semantic relations between the extracted entities.
3.1</p>
      <sec id="sec-3-1">
        <title>Medical Entity Recognition</title>
        <p>By “medical entity”, we refer to an instance of a
medical concept such as Disease or Drug. Medical
entity recognition consists in: (i) identifying
medical entities in the text and (ii) determining their
categories. For instance, in the following sentence
“ACE inhibitors reduce major cardiovascular
disease outcomes in patients with diabetes.”, the
medical entity ACE inhibitors should be identified as
a treatment and the medical entity cardiovascular
disease outcomes should be identified as a
problem.</p>
        <p>One of the most important obstacles to
identifying medical entities is the high terminological
variation in the medical domain (e.g Swine
influenza = swine flu = pig flu). MetaMap
(Aronson, 2001) deals with this variation by using
morphological knowledge found in the UMLS
Specialist Lexicon and term variants present in the
UMLS Metathesaurus. However, as mentioned in
the Background section, some issues must still be
addressed. According to empirical observations,
the sentence and noun phrase segmentations
provided by MetaMap is not as performant as the
segmentation provided by other non-specialized tools
known in Natural Language Processing. Besides,
a disambiguation step is required on the obtained
concepts.</p>
        <p>To solve these problems, we propose an
approach in three points:
1. Split the biomedical texts into sentences and
extract noun phrases with non-specialized
tools. We use LingPipe4 and
treetaggerchunker which offer a better segmentation
according to empirical observations.
2. Determine medical entities as well as UMLS
concepts and semantic types with MetaMap.
3. Filter the obtained medical entities with (i) a
list of the most frequent/noticeable errors and
(ii) a restriction on the semantic types used
by MetaMap in order to keep only semantic
types which are sources or targets for the
targeted relations (cf. Table 1).</p>
      </sec>
      <sec id="sec-3-2">
        <title>Category</title>
      </sec>
      <sec id="sec-3-3">
        <title>Problem</title>
      </sec>
      <sec id="sec-3-4">
        <title>Treatment</title>
      </sec>
      <sec id="sec-3-5">
        <title>Test</title>
      </sec>
      <sec id="sec-3-6">
        <title>Example Semantic Types</title>
        <p>
          Anatomical Abnormality, Injury
or Poisoning, Disease or
Syndrome
Pharmacologic Substance,
Therapeutic or Preventive Procedure
Diagnostic Procedure,
Laboratory Procedure
Our approach is based on the use of linguistic
patterns. For every couple of medical entities, we
collect the possible relations between their
semantic types in the UMLS Semantic Network (e.g.
between the semantic types Therapeutic or
Preventive Procedure and Disease or Syndrome there are
five relations: treats, prevents, complicates, etc.).
We construct patterns for each relation type (cf.
Section 3.3) and match them with the sentences
in order to identify the correct relation. The
relation extraction process relies on two criteria: (i)
a degree of specialization associated to each
pattern and (ii) an empirically-fixed order associated
to each relation type which allows to order the
patterns to be matched. We target six relation types,
described in Figure 1.
Semantic relations are not always expressed with
explicit words such as treat or prevent. They
are also frequently expressed with combined and
complex expressions. Therefore, it is difficult to
build patterns which can cover all relevant
expressions. However, the use of patterns is one of the
most effective methods for automatic information
extraction from textual corpora if they are
efficiently designed
          <xref ref-type="bibr" rid="ref2 ref3">(Cimino and Barnett, 1993; Lee
et al., 2004; Embarek and Ferret, 2008)</xref>
          .
        </p>
        <p>To build patterns for a target relation R, we used
a corpus-based strategy akin to that of (Hearst,
1992) and followers. We illustrate it with the
treats relation. To apply this strategy we first
need seed terms corresponding to pairs of concepts
known to entertain the target relation R. To obtain
such pairs, we extracted from the UMLS
Metathesaurus all the couples of concepts connected by
the relation R. For instance, for the treats
Semantic Network relation, the Metathesaurus contains
45,145 treatment-problem pairs linked with the
“may treat” Metathesaurus relation (e.g.
Diazoxide may treat Hypoglycemia).</p>
        <p>We then need a corpus of texts where
occurrences of both terms of each seed pair will be
looked for. We build this corpus by querying the
PubMed Central database5 (PMC) of biomedical
articles with focused queries. These queries try to
identify articles that have high chances of
containing the target relation between the two seed
concepts. We aimed to optimize precision, therefore
we applied the following principles.</p>
        <p>• Since PMC, like PubMed, is indexed with
MeSH headings, we restrict our set of seed
concepts to those which can be expressed by
a MeSH term.
• We impose a MeSH-based search mode to
PMC by adding the /MH qualifier to the
concepts.
• We also want these concepts to play an
important role in the article. One way to
specify this is to ask for them to be ‘major
topics’ of the paper they index ([MAJR] field
in PubMed or PMC; note that this implies
/MH).
• Finally, the target relation should be present
between the two concepts. MeSH and PMC
provide a way to approximate a relation:
some of the MeSH subheadings (e.g., therapy
or prevention and control) can be taken as
representing underspecified relations, where
only one of the concepts is provided. For
instance, Rhinitis, Vasomotor/TH can be seen
as describing a treats relation (/TH) between
some unspecified treatment and a rhinitis.
Unfortunately, MeSH indexing does not
allow the expression of full binary relations
(i.e., linking two concepts), so we had to keep
this approximation.</p>
        <p>Queries are thus designed according to the
following model: &lt;problem&gt;/TH[MAJR] and
&lt;treatment&gt;/MH.</p>
        <p>They are submitted to PMC to obtain full-text
articles on the required topics. This method should</p>
        <sec id="sec-3-6-1">
          <title>5http://www.ncbi.nlm.nih.gov/pmc/</title>
          <p>increase the chances of obtaining sentences where
one of the reference relations occurs, and provides
a large variety of expressions of the target relation.</p>
          <p>The resulting corpus contains a set of medical
articles in XML format. From each article we
construct a text file by extracting relevant fields such
as the title, the summary and the body (if they
are available). Then, we split every text into
sentences using the segmentation model of the
LingPipe project. We apply MetaMap on each sentence
and keep the sentences which contain at least one
couple of concepts (c1, c2) connected by the target
relation R according to the Metathesaurus.</p>
          <p>This semantic pre-analysis reduces the manual
effort required for subsequent pattern
construction, which allows us to enrich the patterns and
to increase their number. The patterns constructed
from these sentences consist in regular expressions
taking into account the occurrence of medical
entities at precise positions. Table 2 presents the
number of patterns constructed for each relation type
and some simplified examples of regular
expressions. A similar process was performed to extract
another different set of articles for our evaluation.
4</p>
        </sec>
      </sec>
    </sec>
    <sec id="sec-4">
      <title>Evaluation</title>
      <p>In this section, we present our evaluation method
and the obtained results for medical entity
recognition and the extraction of treatment relations.
4.1</p>
      <sec id="sec-4-1">
        <title>Evaluation Method</title>
        <p>To build an evaluation corpus, we queried
PubMedCentral with MeSH queries (e.g. Rhinitis,
Vasomotor/th[MAJR] AND (Phenylephrine OR
Scopolamine OR tetrahydrozoline OR Ipratropium
Bromide)). Then we chose a subset of 20 varied
articles (e.g. reviews, comparative studies). We
verified that no article of the evaluation corpus is used
in the pattern construction process. The last stage
of preparation was the manual annotation of
medical entities and treatment relations in these 20
articles (total = 580 sentences). Figure 2 shows an
example of an annotated sentence.</p>
        <p>We use the standard measures of recall,
precision and F-measure. The precision of named
entity recognition depends both on the textual
boundaries of the extracted entity and on the
correctness of its associated category (semantic type).
In our evaluation, boundary-only errors cost half a
point and the precision is calculated according to
the following formula:</p>
        <p>P recision = C + 0.5 × B + 0 × T</p>
        <p>N
• C: number of correct entities.
• B: number of entities with correct semantic
type but incorrect boundaries.
• T: number of entities with wrong semantic
types.
• N: total number of retrieved entities. (C + B
+ T = N)</p>
        <p>The recall of named entity rceognition was not
measured due to the difficulty of annotating
manually all the medical entities in our corpus. For the
relation extraction evaluation, recall is the number
of correct treatment relations found divided by the
total number of treatment relations. Precision is
the number of correct treatment relations found
divided by the number of treatment relations found.
4.2</p>
      </sec>
      <sec id="sec-4-2">
        <title>Results</title>
        <p>Table 3 shows the precision of medical entity
recognition obtained by our entity extraction
approach (text to sentences segmentation with
LingPipe, sentence to noun phrase segmentation with
treetagger-chunker and stoplist filtering), using
LTS+MetaMap, compared to the simple use of
MetaMap. Entity type errors are denoted by T ,
boundary-only errors are denoted by B and
precision is denoted by P .</p>
        <p>The LTS+MetaMap method led to a significant
increase in the precision of medical entities
recognized by MetaMap. Actually, LingPipe
outperformed MetaMap in sentence segmentation on
our test corpus. LingPipe found 580 correct
sentences where MetaMap found 743 sentences
containing boundary errors and some sentences were
even cut in the middle of medical entities (most
often due to abbreviations). A qualitative study
&lt;relation&gt;
&lt;name&gt;treat&lt;/name&gt;
&lt;sentence&gt;A subsequent study of patients with
cSSSI also found that daptomycin resulted
in faster clinical improvement&lt;/sentence&gt;
&lt;status&gt;established-known&lt;/status&gt;
&lt;source&gt;daptomycin&lt;/source&gt;
&lt;target&gt;cSSSI&lt;/target&gt;
&lt;/relation&gt;
of the noun phrases extracted by MetaMap and
Treetagger-chunker also shows that the latter
produces less boundary errors.</p>
        <p>
          For the extraction of treatment relations, we
obtained 60.46% recall, 75.72% precision and
67.23% F-measure. Other relevant approaches to
our work like (Lee et al., 2004) obtained 84%
recall, 48.14% precision and 61.20% F-measure
for the extraction of treatment relations. Semrep
          <xref ref-type="bibr" rid="ref1">(Ahlers et al., 2007)</xref>
          obtained 54% recall, 84%
precision and 68.21% F-measure on a set of
predications including the treatment relationship (i.e.
administrated to, manifestation of, treats).
However, given the differences in corpora and in the
nature of relations, these comparisons must be
considered with caution.
5
        </p>
      </sec>
    </sec>
    <sec id="sec-5">
      <title>Annotation and exploration platform:</title>
    </sec>
    <sec id="sec-6">
      <title>MeTAE</title>
      <p>We implemented our approach in the MeTAE6
platform which allows to annotate medical texts
or files and writes the annotations of medical
entities and relationships in RDF format in
external supports (cf. Figure 3). MeTAE allows also
to explore sematically the available annotations
through a form-based interface. User queries are
reformulated in SPARQL language according to a
domain ontology which defines the semantic types
associated to the medical entities and the
semantic relationships with their possible domains and
ranges. Answers consist in sentences whose
annotations conform to the user query and their
corresponding documents (cf. Figure 4).</p>
      <p>6An enhanced version of the platform MeTAE will be
available online very shortly at http://www.limsi.fr/
Individu/abacha/metae.html
Several semantic relation extraction approaches
only address relation detection (e.g. find that
a sentence contains the searched relation (Lee
et al., 2004)). In the context of medical
question-answering systems, we are not only
interested in relation detection but also in the
linked medical entities. We focus on
searching &lt;source,relation,target&gt; triples such that the
source and the target have known categories
(semantic types) and such that the relation is valid
w.r.t domain knowledge and w.r.t linguistic
considerations (i.e. the sentence really says that
the source treats the target). In this context,
the same sentence may contain several triples
&lt;source,relation,target&gt;.</p>
      <p>A first analysis of the false positives shows that
the main error causes are: (i) errors in the
extraction of medical entities (ii) patterns of the
treatment relation that cover also forms of expression
of other relations and (iii) sentences that contain
possible source and target entities without them
being connected with the treatment relation.</p>
      <p>We obtained good results in precision and
Fmeasure compared to other semantic relation
extraction approaches. This meets our initial
objective, which is to have a high precision in
relation extraction in order to build efficient
questionanswering systems.
7</p>
    </sec>
    <sec id="sec-7">
      <title>Conclusion</title>
      <p>In this paper, we presented a knowledge and
linguistic-based approach for the extraction of
medical entities and the semantic relations linking
them. This approach is based on two main steps:
(i) the recognition of medical entities with an
enhanced use of MetaMap and (ii) the exploitation of
linguistic patterns taking into account the semantic
types of medical entities. The results obtained on
a real test corpus show the effectiveness of our
approach and its advantages for question-answering
systems.</p>
      <p>In short-term perspectives, we intend to study
the false negatives in order to improve our
patterns. We also intend to design a method which
extracts automatically contextual information such
as the status of the relation (e.g.
hypothetical, established-known) and information about
patients (e.g. gender, age).</p>
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    </sec>
  </body>
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