Text mining for identification of biological entities related to antibiotic resistant organisms

Introduction

Antibiotics are the most successful drugs of the last 100 years, responsible for saving countless lives and enabling modern medical procedures that would otherwise be unthinkable. However, all antibiotics derived from secondary or fully synthetic microbial metabolism products are subject to resistance (Wright, 2011).

Antimicrobial resistance (AMR) has been increasingly recognized as an important public health problem worldwide, considering that infections caused by multidrug-resistant organisms (MDR) result in a significant increase in mortality and cause a tremendous economic burden (Tran, Munita & Arias, 2015). In addition to the costs of rising hospital admission rates, it is estimated that by 2,050 there will be an economic loss of $100 trillion in global antibiotic production (Review on Antimicrobial Resistance, 2016).

In recent years, the scientific community has intensified efforts to combat this problem by making available a wide range of public databases specific to AMR, such as: National Database of Antibiotic Resistant Organisms (NDARO) (Annual Reports for NLM Program and Services, 2016), Comprehensive Antibiotic Resistance Database (CARD) (Alcock et al., 2020), Resfinder (Zankari et al., 2012), ResfinderFG (Munk et al., 2018), Resfams (Gibson, Forsberg & Dantas, 2015), Antibiotic Resistance Genes Database (ARDB) (Liu & Pop, 2009), MEGARes (Lakin et al., 2017), Antibiotic Resistance Gene Annotation (ARG-ANNOT) (Gupta et al., 2014), Mustard (Ruppe et al., 2019), Functional Antibiotic Resistance Metagenomic Element (FARME database) (Wallace et al., 2017), SARG (v2) (Yin et al., 2018), Lahey list of β-lactamases (Bush & Jacoby, 2010), β-Lactamase Database (BLDB) (Naas et al., 2017), Lactamase Engineering Database (LacED) (Thai, Bos & Pleiss, 2009; Thai & Pleiss, 2010), Comprehensive β-Lactamase Molecular Annotation Resource (CBMAR) (Srivastava et al., 2014), among others, which are frequently used as reference databases, with gene sequences related to antimicrobial resistance and metadata that enrich the characterization of sequences. Due to the increase in the volume of literature related to biological and health sciences, the curation process has become challenging for researchers and biocurators who use these databases as a source of research, mainly due to the time required to locate relevant information about biological entities related to antibiotic-resistant organisms. Even queries in specialized databases in biomedical literature such as PubMed (scientific and medical abstracts/citations), PubMed Central (full-text journal articles), NLM Catalog (index of NLM collections), Books (books and reports), and MeSH (ontology used for PubMed indexing) (Sayers et al., 2019), tends to make document selection difficult due to a large amount of retrieved items.

In this context, the adoption of text mining (TM) techniques are viable alternatives (Wei, Kao & Lu, 2013), as they can help in different stages of the standard biocuration workflow. According to (Hirschman et al., 2012), the steps are:

• Selection: search for articles relevant to the curation.

• Identification and standardization of bioentities: detection of mentions of bioentities relevant to the curatorship; for example, genes, proteins, or small molecules, linked to unique identifiers from databases such as UniProt, EntrezGene, or ChEBI.

• Detection of annotation events: identification and encoding of events, such as descriptions of protein-protein interactions, characterizations of gene products in terms of cellular location, molecular function, involvement in the biological process and phenotypic effect.

• Evidence qualifier association: association of experimental evidence that supports the annotation event performed due to biocuration efforts.

• Completion and verification of the database record.

TM technologies combine knowledge resources such as controlled vocabularies, taxonomies, and ontologies with linguistic analysis and machine learning to deal with language variations and extract not only terms from the text but also relationships between terms (Chaix et al., 2018).

In the last decade, several applications in the biomedical area were developed (Fleuren et al., 2011; Fontelo, Liu & Ackerman, 2005; Perez-Iratxeta, Bork & Andrade, 2001; Lewis et al., 2006; Fontaine et al., 2009; States et al., 2009; Huang et al., 2013; Hokamp & Wolfe, 2004; Plikus, Zhang & Chuong, 2006; Becker et al., 2003; Douglas, Montelione & Gerstein, 2005; Brancotte et al., 2011; De et al., 2010; Smalheiser, Zhou & Torvik, 2008; Chen & Sharp, 2004; Li et al., 2013; Glynn, Kerin & Sweeney, 2010; Xuan et al., 2007; Giglia, 2011; Tsuruoka et al., 2011; Fernandez, Hoffmann & Valencia, 2007; Raja, Subramani & Natarajan, 2013; Pafilis et al., 2009; Rebholz-Schuhmann et al., 2008; Plake et al., 2006; Soldatos et al., 2010; Franceschini et al., 2013) using one or more of the following TM steps: (i) retrieving textual resources relevant to a particular subject of interest, a process known as information retrieval (IR), (ii) detect the occurrence of specific keywords of interest and the relationships between these keywords and (iii) infer new relationships based on known facts, and this step is called knowledge discovery (KD) (Fleuren & Alkema, 2015).

One of the most used machine learning techniques in knowledge discovery, especially in document screening, is text classification. However, supervised classification requires the prior labeling of a training set, a non-trivial task for human curators, as it requires a lot of time and effort.

In this sense, Suomela & Andrade (2005) propose a methodology for automatic (binary) classification of large volumes of data, adopting the word counting technique, known as the bag of words (BOW) (Manning, Raghavan & Schütze, 2008), a textual representation that composes the vector space model (Salton, Wong & Yang, 1975), where documents are converted into vectors of words. A weighting scheme is applied to each word, which can be a simple word count or a metric such as Term Frequency-Inverse Document Frequency (TF-IDF) (Manning, Raghavan & Schütze, 2008; Paik, 2013; Chen, 2017) and based on the arithmetic mean of the weights of these words, text summaries are classified as relevant or irrelevant.

This methodology was implemented from specific abstracts of an area of interest, extracted from Pubmed, and inspired the development of the MedlineRanker application (Fontaine et al., 2009) and served as a baseline for this study, which instead of the bag of words, adopts a representation approach based on neural networks (Bengio et al., 2006), called Paragraph Vector-Distributed Memory (PV-DM) (Le & Mikolov, 2014), capable of revealing semantic characteristics between documents, a property that makes this approach useful for many natural language processing (NLP) tasks and justifies its wide use in works involving natural language understanding (Collobert & Weston, 2008; Zhila et al., 2013), machine translation (Mikolov, Le & Sutskever, 2013; Zou et al., 2013), image comprehension (Frome et al., 2013) and relational extraction (Socher et al., 2013a).

The study of antimicrobial resistance genes is essential to public health. However, there is challenging to handle and extract the amount of available data of scientific and medical manuscripts from public databases without computational methods. Thus, this work proposes an unsupervised learning-based TM approach for ranking the relevance of articles on AMR context to generate a set of training, accurate enough to generalize new data, maximizing the efficiency of the supervised classifiers.

Materials and Methods

Labeling pipeline

Figure 1 shows the TM steps implemented in this work in order to label the data.

Information retrieval

An Application Programming Interface (API) was implemented to retrieve a collection of relevant articles in the Drug Resistance, and Microbial domain through the Pubmed Central (PMC) database, which contains free full-text files of the Library’s of Medicine and the US National Institutes of Health (NIH/NLM) biomedical literature are available. In the API, the E-Search and E-Fetch tools from the E-utilities package were used, which provide a structured interface for accessing the Entrez system, the NCBI database system, which currently includes 38 databases, covering a variety of biomedical data, including nucleotide and protein sequences, gene records, three-dimensional molecular structures, and biomedical literature (NCIBI Homepage, https://www.ncbi.nlm.nih.gov/books/NBK3827/). Table 1 presents the set of parameters incorporated into the search (E-Search).

Table 1:

Parameters E-Search PubMed central.

Parameters	Value
URL	https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi?db=pmc&term=%22drug%20resistance,%20microbial%22[MeSH%20Terms]%20OR%20(%22drug%22[All%20Fields]%20AND%20%22resistance%22[All%20Fields]%20AND%20%22microbial%22[All%20Fields])%20OR%20%22microbial%20drug%20resistance%22[All%20Fields]%20OR%20(%22drug%22[All%20Fields]%20AND%20%22resistance%22[All%20Fields]%20AND%20%22microbial%22[All%20Fields])%20OR%20%22drug%20resistance,%20microbial%22[All%20Fields])%20AND%20%22open%20access%22[filter]&retmax=10000
db	PMC (full text articles)
Term	(“drug resistance, microbial”[MeSH Terms] OR (“drug”[All Fields] AND “resistance”[All Fields] AND “microbial”[All Fields]) OR “microbial drug resistance”[All Fields] OR (“drug”[All Fields] AND “resistance”[All Fields] AND “microbial”[All Fields]) OR ”drug resistance, microbial”[All Fields])
Free text articles	Open access

DOI: 10.7717/peerj.13351/table-1

The terms of the MeSH hierarchy were adopted for antimicrobial resistance, considering that the terms MeSH is a controlled vocabulary of biomedical terms whose elements are assigned to a document by indexers (specialists in biomedical subjects) based on its context. They contain high-density document-wide information that cannot be deduced from the title or abstract that PubMed returns using keywords (NLM: Medical Subject Headings (MeSH)).

Then, a list of PMCIDs (unique identifiers provided by PubMed Central to each document) is generated to be used to access the full texts of articles through the E-Fetch utility.

Named entity recognition and knowledge discovery

The entity recognition and knowledge discovery process consist of two steps: in the first step (Fig. 1C), the Doc2Vec unsupervised learning algorithm from the Gensim library was used, which implements the Paragraph Vector–Distributed Memory model, to obtain the embedding of the retrieved documents (dense representation of a sequence of words). Table 2 displays the parameters used in the algorithm.

Table 2:

Parameters Doc2Vec algorithm.

Parameters	Value	Description
vector_size (int, optional)	300	Dimensionality of the feature vectors
alpha(float, optional)	0.025	The initial learning rate
min_alpha(float, optional)	0.00025	Learning rate will linearly drop to min_alpha as training progresses
workers (int, optional)	18	Use these many worker threads to train the model (= faster training with multicore machines)
min_count (int, optional)	3	Ignores all words with total frequency lower than this
epochs (int, optional)	30	Number of iterations (epochs) over the corpus
dm ({1,0}, optional)	1	Defines the training algorithm. If dm = 1, ‘distributed memory’ (PV-DM) is used. Otherwise, distributed bag of words (PV-DBOW) is employed

DOI: 10.7717/peerj.13351/table-2

In the second step (Fig. 1D), the pre-trained model was used, capable of predicting whether a set of documents {Doc₁, Doc₂, Doc₃…Doc_n} belong to the context of a central document Doc₀, to infer the similarity of the documents to the AMR context, represented by 4,290 terms extracted from CARD and the Gene Ontology Database (Ashburner et al., 2000), calculating the cosine distance (Nguyen & Bai, 2011) between them. The resulting value varies in the range between −1 and 1 where the higher the number, the greater the similarity with the context.

Finally, each of the scientific articles was automatically labeled (Fig. 1E), considering the arithmetic average of the cosine similarity, values above the average were defined as relevant and below the mean as irrelevant.

Evaluation of the proposed method

To evaluate the classification performance of the proposed TM approach (Fig. 2A), the same dataset was labeled using the Bag of words text representation model (Fig. 2B), adopting the specific vocabulary for AMR as a vector of features, and the documents were classified as relevant or irrelevant through the arithmetic mean of the weights of the words, obtained with the TF-IDF weighting method, similar to the methodology proposed in Suomela & Andrade (2005). Finally, the two (automatically) labeled databases were compared with a test database labeled by experts (Fig. 2C), who independently labeled the articles as relevant or irrelevant. Only the samples where the three experts converged on the labels were included in the test dataset.

Predictions with automatically labeled data

To evaluate the efficiency of the proposed approach, which uses neural embeddings for labeling, the generated datasets (Fig. 3: Dataset_1 and Fig. 3: Dataset_2) were used as input to the supervised classifier SVM (Boser, Guyon & Vapnik, 1992; Drucker et al., 1997). The classification performance was evaluated through the analysis of the Precision, Recall, Accuracy, and F-Measure metrics (Grandini, Bagli & Visani, 2020), calculated from the test base labeled by experts and not used to train the SVM models (Fig. 3).

For the SVM classifier, the feature/attribute vector (AMR vocabulary with 4,290 words) was weighted using the TF-IDF technique, and cross-validation, with 5-folds (default value of the adopted algorithm), was applied to explore the combination of parameters for determining the best model, as the effectiveness of the SVM depends on the kernel selection, which is the function that will be used by the algorithm, in the margin parameter (C), which determines a balance between maximizing the margin and minimizing classification errors, and the Gamma parameter, when the chosen kernel is Gaussian (or RBF) (Syarif, Prugel-Bennett & Wills, 2016), adopted in this experiment.

Results and Discussion

Classification

The two labeled datasets were submitted to the supervised SVM classifier, excluding the test dataset labeled by experts from training.

Figure 4 presents the confusion matrix of the SVM_1 classifier, trained with data from dataset 1 (Fig. 3: Dataset_1). There is a high degree of precision both in terms of true positives (relevant articles classified as relevant) and true negatives (non-relevant articles classified as non-relevant).

Only one article was incorrectly classified as relevant (false positive), and five articles were incorrectly classified as irrelevant (false negative).

Figure 5 presents the confusion matrix of SVM_2, trained with data from dataset 2 (Fig. 3: Dataset_2), where a lower degree of precision is observed for both true positives and true negatives in relation to SVM_1. With this classifier, however, there was an increase in the number of incorrect classifications, with 33 articles incorrectly classified as relevant (false positives) and six articles incorrectly classified as irrelevant (false negatives).

Table 3 presents the results of the evaluation metrics: precision, recall, accuracy and the f-measure, obtained based on the results of the confusion matrix of the two classifiers. The results of the SVM_1 classifier were superior to the SVM_2 classifier in all evaluated metrics.

Table 3:

Classifier performance assessment.

	Class	Precision	Recall	F1-score	Support	Accuracy
SVM_1 (Doc2Vec+Mean)	0	0.74	0.93	0.82	15	0.90
	1	0.98	0.89	0.93	47
SVM_2 (TF-IDF+Mean)	0	0.21	0.60	0.32	15	0.37
	1	0.70	0.30	0.42	47

DOI: 10.7717/peerj.13351/table-3

Accuracy, a metric that represents the overall performance of a model, reached 90% of accuracy and the f-measure, which is a harmonic average between the precision and recall metrics and that can be used as a single measure to represent the quality in the text mining (Rodriguez-Esteban, 2009) reached 82% success rate for the positive class and 93% for the negative class.

The results show that the best performance was obtained with the database labeled by the PV-DM model.

Table 4 presents the percentage of correct predictions, both in the labeling and in the classification stage, in comparison with the data labeled by experts and validates the hypothesis that the use of Paragraph Vector, Distributed Representations of Sentences and Documents associated with similarity with a specific context is able not only to perform the binary classification of large volumes of data but also to optimize the percentage of hits of supervised classifiers. The SVM_2 classifier showed a reduction in the number of hits compared to the Labeling step, although we adopted the same attribute vector and the same representation in both experiments (bag of words, weighted with TF-IDF).

Table 4:

Results of labeling and classification steps vs experts.

	Relevant (%)	Irrelevant (%)
Labeling
Dataset_1	80	68
Dataset_2	66	34
Classification
SVM_1	93	89
SVM_2	60	29

DOI: 10.7717/peerj.13351/table-4

Conclusions

The proposed TM approach proved capable of identifying and prioritizing documents in the AMR context, as well as predicting the relevance of new documents in the same context. For this, we used the TM steps summarized in Fleuren & Alkema (2015), plus some specifics of the proposal such as (1) use of the MeSH hierarchy; (2) use of full text; (3) use of domain-specific dictionaries (CARD and Gene Ontology), fundamental in this process, as it facilitated the detection of similarity of articles to the AMR context and (4) adoption of unsupervised learning for better representation of texts. Additionally, we submitted the labeled bases to the SVM classifier to evaluate their performance in comparison to the test base labeled by human experts.

The proposed approach efficiently identifies scientific articles relevant to the AMR context. Therefore, it is a valuable tool to automate information capture processes from robust bibliographic reference databases such as Pubmed Central, as well as to accelerate the screening of documents with biocuration potential, facilitating the other stages of the biocuration process.

This work presents a new set of pre-trained document embeddings in the AMR domain and a base labeled for relevance according to similarity to CARD and Gene Ontology, which, in future work, can be used as input to other algorithms of supervised learning and for biocuration tools aimed at the identification and normalization of bioentities, detection of annotation events and filling out specific databases for AMR. This proposal is limited to the previous existence of an accurate database representing the main terms related to the target.

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