In a biological system there are entities of different types such as diseases and drugs performing important biological activities. The action of an entity can mediate or interfere with the action of other entities developing a complex network of interactions. Frequently entities perform more than one activity in the system, some which are known and integrate the current knowledge in life sciences. Other activities are not so well documented or remain unknown for long periods of time and are generally discovered by chance. Drugs, for instance, have a primary pharmacological activity and secondary activities responsible for side effects. However, drug side effects can be explored as new uses for the treatment of different diseases. A remarkable example is the impotence drug sildenafil citrate (Viagra®) that was originally designed for the treatment of angina and hypertension. Viagra® clinical trials revealed, nevertheless, the drug ability of increasing erectile function as its side effect [1].

On the other hand, research achievements in the post genomic age have promoted an enormous and continuous increasing on biological knowledge. These achievements often describe biological entity activities and have been published around the world aiming to assist, increase and speed up the number of discoveries in life sciences. A similar process has occurred since the inception of the World Wide Web and the rise of digital libraries. Web pages have been continuously and rapidly published given rise to a enormous amount of interlinked information. This allowed the conduction of many studies about methods for extracting and analysing the information published in this ocean of information. In many of these studies the vector space model (VSM) [2–4] has been recognized as an important tool to extract the most relevant information in a given context.

In this work we have developed an inference model based on the VSM in order to predict new interactions between biological entities of distinct categories such as ecosystems, organisms, organs, tissues, cells, organelles, genes, proteins, diseases and drugs. Our model constructs a network of known entity interactions from a textual collection. The documents in this collection describe the current knowledge in life sciences. Known entity interactions represent entity co-occurrences in at least one document of the textual collection. After finding all known interactions, our model traverses and analyzes the network predicting new entity interactions. Our objective is to use the known interactions to infer new (unknown) ones and to rank all found interactions. The ranking of interactions allows researchers to focus in the most promising activities, thus promoting further advances in life sciences.

The prediction of new interactions is performed using the VSM along with a transitive closure similar to that used in literature-based discovery [5]. The transitive closure relies on the fact that “IF an entity x interacts with entities y and w AND another entity z also interacts with entity y, THEN z probably also interacts with entity w”. Different from previous work, in our model we adapt this transitive closure in order to exploit the primary and secondary activities performed by entities of distinct biological categories. In the context of our model, x and z are entities of the same biological category, y and w are also entities of the same biological category. However, the category of entities x and z is different of that of entities y and w.

We have implemented a system called BioSearch [6] as a proof of concept of our model. The system deals with 4 types of distinct entities: diseases, drugs, genes, and targets. The textual collection used in the system encompasses a sample of 17,830 patent claims gathered from the United State Patent and Trade Mark Office (USPTO) [7]. We have used the patent claim because it is an important section in patent specifications, presenting the invention and defining the scope of patent protection [7, 8]. From 266,528 possible interactions between entities in our network, the system has found 1,027 known interactions in the patent claim collection and has inferred 3,195 new interactions. Thus, based on our model, the system has constructed a network with 4,222 interactions that can be further analyzed in order to promote new advances in science and technology.

To validate our results we have conducted an experiment over the patent issue dates. We have reconstructed the interaction network in a range of 30 years. We have observed that new interactions found in a given past year were confirmed by patents issued in a more recent date. For instance, we have 1 patent claim issued in 2005 specifying the interaction between the disease heart attack and the gene ppar-gama. When we removed this patent claim from the textual collection, 61 patent claims indicated this interaction as a possible new interaction in 2004. We have also found scientific papers that confirm some of the new inferred interactions. For instance, the best result found in our model specifies a new interaction between the adrenaline neurotransmitter and the androgen receptor gene in the 2-dimensional subnetwork gene × target. No patent claim in our collection indicates this interaction. However, Sastry et al. [9] reported in 2007 that the antiapoptotic effect of adrenaline partially depends on androgen receptor.

Entities in a biological system interact with each other forming an interaction network. We can classify these entities into categories such as diseases, drugs, genes, and targets. In this work we have combined these categories in order to construct a network composed of n-dimensional subnetworks. We have extracted all entity interactions of a subnetwork from a textual collection using the VSM. Given, for instance, the subnetwork with dimensional space drug × disease, consider that our model indicates we have documents reporting the use of drug m₁ in the treatment of diseases d₁ and d₂ (Figure 1 (a) ). Moreover, suppose the model also indicates we have documents which report the use of drug m₂ in the treatment of disease d₁. Then, drugs m₁ and m₂ possibly share some common characteristic responsible for the efficacy of these drugs in the treatment of both diseases d₁ and d₂. Thus, the model infers a new connection in the subnetwork drug × disease linking drug m₂ and disease d₂. The new connection represents a new use of drug m₂. Then, in this example, m₁ → d₁, m₁ → d₂, and m₂ → d₁ are known interactions found in the literature. On the other hand, m₂ → d₂ is a new interaction inferred from the previous three known interactions.

We have represented each subnetwork as a weighted graph whose weights measure the interaction level of the entities based on the textual collection. In this graph, nodes are entities of categories forming the subnetwork dimensional space, edges represent interactions between entities of distinct categories, and the interaction level is a value in the range [0, 1]. We determine the interaction level based on the VSM when we look for the entity co-occurrences throughout the textual collection. In a subnetwork with dimensional space drug × disease, for instance, suppose that drug m₁ treats diseases d₁ with interaction level A and d₂ with interaction level B (Figure 1 (b)). In addition, suppose drug m₂ treats disease d₁ with interaction level C. Then, the model assigns an interaction level to the new connection linking drug m₂ and disease d₂ whose value is determined based on A, B e C.

The graph in our model is represented by a matrix that receives biological entities of the subnetwork dimensions in its lines and columns (Figure 1 (c)). We have defined that three interactions in the matrix are in transitive closure when they satisfy the condition (x, y) and (x, w) and (z, y) → (z, w) that means ”IF entity x interacts with entities y and w AND entity z interacts with entity y THEN z may also interact with w”. Then, the model infers a new interaction in the matrix whenever it finds three interactions satisfying this transitive closure.

All cells in the matrix initially receive the value 0 indicating no entity interactions (Figure 2 (a)). We use the entities of a cell in order to form a query. This query represents a conjunction of entities of distinct categories. The conjunction is important because it ensures that documents in which the entities occur are not orthogonal, i.e., they must have occurrences of all entities present in the query. Then, we perform searches in the textual collection in order to find documents satisfying the query of each matrix cell (Figure 2 (b) ).

The VSM assigns weight values for each query entity based on the TFIDF strategy (Equation 1). We use these weights to measure the importance of the entity for a query of the matrix and also for a document of the textual collection.

(1)

In the TFIDF weight strategy w_x,i is the weight of entity e _x in a document d _i in the textual collection, tf_x,i is the normalized frequency of entity e _x in document d _i , idf _x is the inverse document frequency of entity e _x , f_x,i is the frequency of entity e _x in document d _i , max_j,i is the number of times the most frequent entity e _j occurs in document d _i , N is the number of documents in the textual collection, and n _x is the number of documents in the textual collection in which entity e _x occurs.

Each query of the matrix receives a similarity value for each document in the textual collection based on the VSM (Equation 2). For the VSM similarity, q _j is a query j of the matrix representing a conjunction of entities, t is the number of biological entities of the network, w_x,i is the weight of entity e _x in document d _i , w_x,j is the weight of entity e _x in query q _j . In our model, the entity weights in a query are always 1 (w_x,j = 1). The similarity value stated in the VSM indicates the relevance of a document for a query.

(2)

We use the similarities returned by equation 2 to determine the interaction level of the query entities. The cell linking the query entities receives this interaction level which represents a known interaction in the subnetwork (Figure 2 (b)). In our current experiments we determine the interaction level of a known interaction in 3 different ways: (i) the arithmetic average of the similarities, (ii) the maximum similarity found, and (iii) the sum of all the similarities.

After all searches in the textual collection are concluded, we have established all known interactions of the network. However, some cells remain equal to 0 indicating that some entity interactions are not explicitly mentioned in the collection (Figure 2 (c)). These cells with value 0 represent the potential new interactions between the biological entities they relate.

The model infers a new interaction in the matrix whenever it finds three interactions satisfying the transitive closure (Figures 2 (d) and 2 (e)). In our current experiments the interaction level of a new interaction is the arithmetic average of the interaction level of the three interactions satisfying the transitive closure. If many interactions satisfy the transitive closure, the model chooses the one with highest arithmetic average (Figure 2 (f)).

We have applied several iterations of our model on the matrix of a subnetwork in order to infer new interactions from interactions previously inferred. In iteration 0 the model discovers all known interactions reported in the textual collection. In iteration 1 the model discovers new interactions based on the known interactions. In iteration 2 the model discovers new interactions based on interactions discovered in iterations 0 and 1. The model stops iterating when all cells of the matrix receives a value different from 0 or when it is no more possible to find interactions satisfying the transitive closure. Starting from iteration 1, our model divides the interaction level of new interactions by the number of iterations performed. This penalty ensures that interactions found in earlier iterations have higher interaction levels.

In our experiments, we have considered a sample of patent claims crawled from the USPTO Web site constituting a textual collection with 17,830 documents. All these patents were issued between 01/01/1976 and 12/31/2005. Besides, in the claim section of all these patents we are able to find at least one entity of the four biological categories considered in our crawling process, namely diseases, drugs, genes, and targets. In the USPTO Web site the query we have used to retrieve these patents is represented as aclm/”entity” and isd/1/1/1976 → 31/12/2005 where aclm specifies the patent claim section, entity is the biological entity name, and the isd specifies the patent issue date, respectively. The entity names are quoted in order to specify the phrase search mode.

In order to detect the entity occurrences throughout the collection, we have used exact string matching over the entity names and we have also considered entity related names such as synonyms. For instance, we have considered diabetes mellitus type 2 and type 2 diabetes as the same biological entity of category disease. We have formed clusters of related names for each entity (Appendix B [additional file]). A representative single name in each cluster is used to represent the whole cluster during the network construction. Some syntactic variation in entity names are also considered in each cluster (e. g. Alzheimer’s disease and Alzheimer disease).

In the current implementation of our model we neither use natural language processing (NLP) [5, 15] nor heuristics to capture the context in which the entity names are applied in the documents. Notwithstanding, the entity names we have selected were satisfactory for our purpose of validating the model, as we shall see.

We have been able to achieve significant results in a strategy that combines the VSM with an inference process in order to predict new biological entity activities. We have used this strategy to model biological systems and to construct a network of biological entity interactions. Modeling biological systems is a complex task for many reasons. For example, we must consider a large number of biological parameters, we must identify entity concentrations and roles in different reactions, and we must bear in mind that biological systems are not linear systems and perturbations commonly give rise to unexpected results. Thus, we have abstracted details and studied biological systems in a higher level in order to decrease their complexities and conduct our analysis [39]. Our abstraction of biological systems is constructed from textual collections that represent a particular view of the technological advances in life sciences reported in patent claims.

In our model, we have focused on retrieving biological entity information from a textual collection consisting of patent claims using the VSM and expressing this information in a transitive closure. This approach has allowed several analysis with important findings. The approach has indicated the VSM as a useful tool to retrieve relevant information in an inference process and how the biological knowledge is interconnected in patent claims.

Texts in patents have a particular writing style characterized by a rich technical terminology and an intentional vagueness in order to promote wide protection to inventions [8, 33, 34, 36, 38]. This intentional vagueness may bring a potential benefit to our inference strategy of new interactions. The vagueness in patent texts can indicate some known interactions not easily observed in other literatures characterized by a more strict writing style, as scientific papers. From these known interactions we can infer new ones that are even more innovative than those predicted from texts with strict writing style.

As observed in some contemporary search engines, term co-occurrences is a good way to restrict the documents which can better satisfy an user information need. Thus, term co-occurrences is a good strategy to isolate good hits from a big mass of documents. In addition, previous work in the field of literature-based discovery have indicated many important findings relying on term co-occurrences [12, 13, 16]. Particularly, Jenssen et al. [10] have shown that co-occurrences reflect biologically meaningful relationships, thus providing an approach to extract and structure known biological knowledge. Accordingly, in our work we have relied on term co-occurrences in order to produce relevant results from a textual collection.

Our model has predicted 2,930 new interactions considering patent claims issued up to 2004. In 2005, we have 32 patent claims in which these new interactions are mentioned. These 32 patent claims issued in 2005 serve as confirmations for the new interactions predicted in 2004. We have also observed that using the VSM we have ranked up to 69% of these 32 new interactions among the 100 first new interactions of all subnetworks. In other words, 69% of the confirmed interactions would have been identified within the top 100 new indications of all subnetworks. These 32 confirmation patent claims also demonstrate that implicit interactions not easily observed in a textual collection must be recognized as important contributions in the field of literature-based discovery.

We consider the 32 new interactions with confirmations as a significant number mainly when considering the reduction in the number of biotechnological patents filed from 2001 to 2004 [40], and the fact that patents are not filed for the majority of scientific discoveries, being instead published as research papers [41–43]. In fact, we already expected a small number of confirmation patent claims for two main reasons. First due to the fact that these are patents filed in 2005, only one year after the new interactions were indicated by the collection issued up to 2004. A higher number of patents may have been filed in later years which would provide more indications. Second, filing a patent is the final step of a long sequence of activities related to scientific discovery, and most researchers stop in the scientific article publication phase. As such, a large number of confirmation patent claims should probably never been expected.

Our findings have encouraged us to further investigate biological parameters we have to use in order to improve our representation of biological systems and achieve better results in the inference process and ranking strategy. These parameters have another important function in preventing noise propagation. Interactions poorly established in the network propagate spurious interactions in the inference process. Thus, this study should help impose constraints to the identification of interactions during network construction. The definition of these parameters for several sources and their integration in our model is also an important concern.

In literature-based discovery, simple ranking strategies that promote new interactions based on the raw frequency of known interactions found in textual collections are often used. However, they show, in some situations, implicit interactions that have already been studied but were not documented because they are not feasible or are unwanted in practice. Our results demonstrate, on the other hand, that ranking strategies based on the VSM are good tools for the identification of significant implicit interactions occurring in texts, mainly those occurring in few documents of a textual collection. This is an important contribution because it is far more difficult to find relevant new interactions from knowledge not frequently co-occurring in a literature than that often observed. However, we must always keep in mind that relevance is a subjective concept. Therefore, biological entity interactions may be considered differently, i.e., with different importance, by different researchers. Then, we must consider strategies in literature-based discovery as complementary tools that help to identify the best new interactions based on the researcher’s interests. In this sense, we should even think of systems in which new ranking strategies may be integrated as add-ons.

We should also emphasize that our goal is not to ensure a complete coverage of the biological literature, creating an enormous network of known interactions. Instead, we focus in providing a proof of concept to show the VSM applicability to disclose and rank biological entity activities based on implicit connections found in biological literature. Accordingly, we have checked the existence of these implicit connections in patent claims using a small and restricted textual collection just for assessing the model. We are aware that many new interactions inferred by our model have already been reported in scientific papers. However, we have observed that these findings had not received patent protection at the USPTO until 2005 and we have used some of these scientific papers as validation of our results, mainly due to the inexistence of textual collections currently available for validating literature-based discovery systems [21, 22, 44]. For a production system we should index as much as possible of the current biological literature sources in order to filter prior art. Nevertheless, we have observed that our strategy provides a good tool for tracking scientific advances published in scientific papers but not yet protected under the intellectual property law.

In this work we have introduced a technique that employs the Vector Space Model (VSM) for the identification of biological entity activities based on a network of biological entity interactions extracted from textual collections. The algebraic framework of the VSM has demonstrated to be a helpful tool in the task of finding known biological entity activities. We have extended the VSM with a transitive closure approach in order to predict new potential biological entity activities. The transitive closure we have used explores the primary and secondary activities of entities in a biological system. In addition, we have imposed a constraint in this transitive closure in order to ensure that interactions established in the network connect entities of distinct categories. This constraint reduces the search space for new interactions, promoting more accurate results. Moreover, we have used the similarity values derived from the VSM to rank the new discovered entity activities.

Our experiments using a collection of USPTO patent claims demonstrate that the biotechnological patent literature has implicit connections that can be explored to provide further advances in life sciences. Iterating our model according to the years in which the patent claims were issued, new interactions found in a year were confirmed by patent claims not in the collection and issued in more recent years. The experiments also showed that many confirmation patent claims were found for interactions at the top of our ranks of results. For instance, considering the ranking strategy based on the sum of the similarities returned by the VSM we had 69% of the confirmation patents among the first 100 new interactions of all subnetworks. We have also found scientific papers that validate several of the suggested interactions.

For future work we intend to construct networks using other patent fields (e.g. title, abstract and description sections), the whole patent text, and other sources, such as paper abstracts, paper titles and drug labels. We will analyze the contribution of all these pieces of evidence in our inference process when they are considered separately and together. In addition, we intend to explore natural language processing techniques and ontologies in order to improve the identification of entity co-occurrences in the textual collection. Moreover, we also want to conduct our analyses by considering entities co-occurring in one sentence, in a window of sentences, and in a whole paragraph in order to evaluate a phrase-based VSM approach in the context of our model. Then, we will apply proximity criteria for these occurrences in order to ensure the semantic interaction between entities. Furthermore, we will evaluate a set of biological parameters extracted from the literature in order to help with the establishment of interactions in the networks. Finally, we intend to study other possible strategies to rank biological interactions and conduct a trend analysis on how the interaction value evolves when restricting the number of documents in the textual collection.