A Silver Standard Corpus of Human Phenotype-Gene Relations

Human phenotype-gene relations are fundamental to fully understand the origin of some phenotypic abnormalities and their associated diseases. Biomedical literature is the most comprehensive source of these relations, however, we need Relation Extraction tools to automatically recognize them. Most of these tools require an annotated corpus and to the best of our knowledge, there is no corpus available annotated with human phenotype-gene relations. This paper presents the Phenotype-Gene Relations (PGR) corpus, a silver standard corpus of human phenotype and gene annotations and their relations. The corpus consists of 1712 abstracts, 5676 human phenotype annotations, 13835 gene annotations, and 4283 relations. We generated this corpus using Named-Entity Recognition tools, whose results were partially evaluated by eight curators, obtaining a precision of 87.01%. By using the corpus we were able to obtain promising results with two state-of-the-art deep learning tools, namely 78.05% of precision. The PGR corpus was made publicly available to the research community.Comment: NAACL 201

Large-scale automated protein function prediction

Includes bibliographical references.2016 Summer.Proteins are the workhorses of life, and identifying their functions is a very important biological problem. The function of a protein can be loosely defined as everything it performs or happens to it. The Gene Ontology (GO) is a structured vocabulary which captures protein function in a hierarchical manner and contains thousands of terms. Through various wet-lab experiments over the years scientists have been able to annotate a large number of proteins with GO categories which reflect their functionality. However, experimentally determining protein functions is a highly resource-intensive task, and a large fraction of proteins remain un-annotated. Recently a plethora automated methods have emerged and their reasonable success in computationally determining the functions of proteins using a variety of data sources – by sequence/structure similarity or using various biological network data, has led to establishing automated function prediction (AFP) as an important problem in bioinformatics. In a typical machine learning problem, cross-validation is the protocol of choice for evaluating the accuracy of a classifier. But, due to the process of accumulation of annotations over time, we identify the AFP as a combination of two sub-tasks: making predictions on annotated proteins and making predictions on previously unannotated proteins. In our first project, we analyze the performance of several protein function prediction methods in these two scenarios. Our results show that GOstruct, an AFP method that our lab has previously developed, and two other popular methods: binary SVMs and guilt by association, find it hard to achieve the same level of accuracy on these two tasks compared to the performance evaluated through cross-validation, and that predicting novel annotations for previously annotated proteins is a harder problem than predicting annotations for uncharacterized proteins. We develop GOstruct 2.0 by proposing improvements which allows the model to make use of information of a protein's current annotations to better handle the task of predicting novel annotations for previously annotated proteins. Experimental results on yeast and human data show that GOstruct 2.0 outperforms the original GOstruct, demonstrating the effectiveness of the proposed improvements. Although the biomedical literature is a very informative resource for identifying protein function, most AFP methods do not take advantage of the large amount of information contained in it. In our second project, we conduct the first ever comprehensive evaluation on the effectiveness of literature data for AFP. Specifically, we extract co-mentions of protein-GO term pairs and bag-of-words features from the literature and explore their effectiveness in predicting protein function. Our results show that literature features are very informative of protein function but with further room for improvement. In order to improve the quality of automatically extracted co-mentions, we formulate the classification of co-mentions as a supervised learning problem and propose a novel method based on graph kernels. Experimental results indicate the feasibility of using this co-mention classifier as a complementary method that aids the bio-curators who are responsible for maintaining databases such as Gene Ontology. This is the first study of the problem of protein-function relation extraction from biomedical text. The recently developed human phenotype ontology (HPO), which is very similar to GO, is a standardized vocabulary for describing the phenotype abnormalities associated with human diseases. At present, only a small fraction of human protein coding genes have HPO annotations. But, researchers believe that a large portion of currently unannotated genes are related to disease phenotypes. Therefore, it is important to predict gene-HPO term associations using accurate computational methods. In our third project, we introduce PHENOstruct, a computational method that directly predicts the set of HPO terms for a given gene. We compare PHENOstruct with several baseline methods and show that it outperforms them in every respect. Furthermore, we highlight a collection of informative data sources suitable for the problem of predicting gene-HPO associations, including large scale literature mining data

Extracting Negative Biomedical Relations from Literature

Tese de mestrado, Bioinformática e Biologia Computacional, Universidade de Lisboa, Faculdade de Ciências, 2021The prevalent source for obtaining scientific knowledge remains the scientific literature. Considering that the focus of biomedical research has shifted from individual entities to whole biological systems, understanding the relations between those entities has become paramount for generating knowledge. Relations between entities can either be positive, if there is evidence of an association, or negative, if there is no evidence of an association. To this date, most relation extraction systems focus on extracting positive relations, therefore few knowledge bases contain negative relations. Disregarding negative relations leads to the loss of valuable information that could be used to advance biomedical research. This work presents the Negative Phenotype¬Disease Relations (NPDR) dataset, which describes a subset of negative disease¬phenotype relations from a gold¬standard knowledge base made available by the Human Phenotype Ontology (HPO), and an automatic extraction system developed to automatically annotate the entities and extract the relations from the NPDR dataset. The NPDR dataset was constructed by analysing 177 medical documents and consists of 347 manually annotated at the document¬level relations, from which 222 were inferred from the HPO gold¬standard knowledge base, and 125 were new annotated relations. The main categories of the dataset are the characterization of the entities that participate in the negative relation; the characterization of the sentence that implies the negative relation; and the characterization of the location of the entities and sentences in the article. The automatic extraction system was created to evaluate the impact of the NPDR dataset on the Named-Entity Recognition (NER), Named¬Entity Linking (NEL) and Relation Extraction (RE) text mining tasks. The NER task showed an average of 20.77% more entities annotated when using disease and phenotype synonyms lexica generated from the NPDR dataset, when comparing the number of annotations produced by the OMIM and HPO lexica. The increase in annotated entities also resulted in 15.11% more relations extracted. The RE task performed poorly, with the highest accuracy being 8.84%.Texto livre continua a ser, aos dias de hoje, o principal meio de produção e partilha de conhecimento. Mais concretamente, a literatura biomédica é a principal fonte de conhecimento clínico e biológico para investigadores e clínicos. Porém, à medida que a informação contida em texto livre, correspondente ao número de publicações de artigos científicos aumenta a um ritmo exponencial, torna¬se difícil para os investigadores manterem¬se a par dos desenvolvimentos dos variados domínios científicos. Para além disso, extrair informação textual relevante é uma tarefa laboriosa e morosa para seres humanos, uma vez que a maioria da informação se encontra retida em texto livre não estruturado. Embora esta tarefa possa resultar em erros quando realizada por computadores, só poderá ser alcançada por meio de processos automáticos. Nesse sentido, métodos de prospeção de texto são uma alternativa interessante para reduzir o tempo despendido por especialistas na obtenção de informação relevante, para além de também cobrirem um largo volume de dados provenientes da literatura biomédica. Métodos de prospeção de texto incluem várias tarefas, tais como Named¬Entity Recognition (NER), Named¬Entity Linking (NEL) e Extração de Relações (ER). O NER identifica as entidades mencionadas no texto, o NEL mapeia as entidades reconhecidas a entradas numa base de dados, e o ER identifica relações entre as entidades reconhecidas. Visto que o foco da investigação biomédica mudou de entidades individuais, tais como genes, proteínas ou fármacos, para sistemas biológicos num todo, métodos de ER automáticos tornaram¬se fundamentais para entender relações entre entidades, tais como interações proteína¬proteína, interações fármaco¬fármaco, ou relações gene¬doença. Estas relações podem ser classificadas como negativas, caso haja evidência de não associação entre as entidades, ou positivas, caso haja evidência de associação entre as entidades. ER pode ser efetuada através de múltiplas abordagens que diferem nos métodos que empregam. Essas abordagens podem ser divididas nos seguintes grupos: coocorrência, que é a abordagem mais simples, uma vez que apenas visa a identificação das entidades na mesma frase; baseada em regras, que são definidas manualmente ou automaticamente; e aprendizagem automática, que utiliza corpora biomédica anotada para aplicar supervisão distante. Métodos de supervisão distante podem ainda ser categorizados em feature¬based e kernel¬based. Aos dias de hoje, a maioria dos sistemas de ER não diferenciam entre relações positivas, negativas ou falsas, porém podem¬se salientar algumas excepções, tais como os sistemas Excerbt e BeFree. O primeiro combina análises sintáticas e semânticas com abordagens de regras e aprendizagem automática, e foi adaptado de forma a detetar representações léxicas negadas de itens léxicos (tais como verbos, nomes ou adjetivos) para a anotação do Negatome, uma base de dados de proteínas que não interagem entre si. O segundo sistema utiliza uma combinação de métodos kernelbased, nomeadamente o Shallow Linguistic Kernel e Dependency Kernel. Para a anotação do corpus GAD usando este sistema, também foi treinado um classificador para distinguir entre relações positivas, negativas e falsas entre genes e doenças. Estima¬se que 13.5% das frases de resumos da literatura biomédica possuem expressões negadas. Desconsiderar expressões que poderão, potencialmente, conter relações negativas pode levar à perda de informação valiosa. Porém, a maioria das bases de dados de extrações de relações biomédicas visam apenas recolher relações positivas entre entidades biomédicas. No entanto, exemplos negativos e positivos são igualmente importantes para treinar, afinar e avaliar sistemas de extração de relações. Contudo, uma vez que os exemplos negativos não se encontram tão documentados como os positivos, poucas bases de dados os contêm. Para além disso, a maioria das bases de dados de extração de relações biomédicas não diferencia entre relações falsas, em que duas relações não estão relacionadas, e negativas, em que existe afirmação de não associação entre duas entidades. Adicionalmente, alguns datasets de padrão prata (compostos por dados gerados de forma automática) também contêm relações negativas falsas que são desconhecidas ou não estão documentadas. Logo, a exploração dessas relações é um bom ponto de partida para expandir as bases de dados de relações biomédicas e populá¬las com exemplos negativos corretos. Este trabalho produziu um dataset de anotações de fenótipos e doenças humanas e as suas relações negativas, o datasetNegative Phenotype¬Disease Relations(NPDR), e um módulo de anotação automática de entidades e relações. Para a realização da primeira etapa da criação do dataset NPDR, foi necessário re alizar a recolha dos identificadores PubMed (PMIDs) associados à relações negativas descritas numa base de dados padrão¬ouro, disponibilizada pela Human Phenotype Ontology (HPO). A partir desses PMIDs foi possível extrair artigos completos que foram subsequentemente analisados manualmente. Essa análise consistiu na descrição das entidades que participam na relação negativa, que compreende a análise dos fenótipos, doenças e os seus genes associados; a descrição das frases que sugerem a relação a negativa, que engloba a caracterização do token de negação usado na frase e a coocorrência das entidades; e a descrição da localização das entidades e frases no artigo. O dataset NPDR contem um total de 347 relações anotadas ao nível do documento, das quais 222 foram obtidas a partir da base de dados padrão¬ouro da HPO, e 125 são novas relações. De forma a avaliar o impacto do dataset NPDR na anotação e extração automática de entidades e as suas relações, a partir dos artigos reunidos para o desenvolvimento da criação do dataset, um pipeline que realiza NER, ER e extrai frases de negação foi implementado. NER reconhece fenótipos humanos e doenças, e ER extrai e classifica a relação entre as entidades. De modo a obter os artigos num formato que fosse legível por máquina, dois métodos foram empregues. O primeiro método consistiu em reunir os PMIDs a partir do dataset NPDR, para os converter nos seus identificadores PubMed Central (PMCIDs) correspondentes, de forma a extrair os artigos completos usando a API do PubMed. O segundo método consistiu na conversão dos artigos reunidos para a construção do dataset NPDR em formato PDF para formato de texto, utilizando a ferramenta de extração de texto PDFMiner. A etapa NER foi realizada usando a ferramenta Minimal Name¬Entity Recognizer (MER) para extrair menções de fenótipos, doenças e genes a partir dos artigos. Por fim, utilizando uma abordagem de supervisão distante, a base de dados padrão¬ouro da HPO foi usada para obter as relações obtidas pela ocorrência de fenótipos nas frases que sugerem a relação negativa, e a ocorrência de doenças e genes relacionados presentes no ar tigo. As relações foram marcadas como Conhecida se a relação estivesse descrita na base de dados, ou Desconhecida caso contrário. Para a anotação de fenótipos dois léxicos foram utilizados, um de termos oficiais da HPO, e outro de sinónimos obtidos a partir do dataset NPDR. Para a anotação de doenças e genes, o léxico principal foi obtido a partir da base de dados da Online Mendelian Inheritance in Man (OMIM), e os restantes léxicos foram construídos a partir de sinónimos e abreviaturas de doenças presentes no dataset NPDR. A adição dos léxicos provenientes do dataset NPDR permitiram anotar, em média, mais 20.77% de entidades, comparativamente à anotação de entidades com os léxicos da HPO e OMIM. Este maior número de entidades também se refletiu num aumento de 15.11% de relações anotadas. A tarefa de ER teve um desempenho fraco, sendo que a precisão de relações negativas detetadas foi de 8.84%

Global text mining and development of pharmacogenomic knowledge resource for precision medicine

Understanding patients' genomic variations and their effect in protecting or predisposing them to drug response phenotypes is important for providing personalized healthcare. Several studies have manually curated such genotype-phenotype relationships into organized databases from clinical trial data or published literature. However, there are no text mining tools available to extract high-accuracy information from such existing knowledge. In this work, we used a semiautomated text mining approach to retrieve a complete pharmacogenomic (PGx) resource integrating disease-drug-gene-polymorphism relationships to derive a global perspective for ease in therapeutic approaches. We used an R package, pubmed.mineR, to automatically retrieve PGx-related literature. We identified 1,753 disease types, and 666 drugs, associated with 4,132 genes and 33,942 polymorphisms collated from 180,088 publications. With further manual curation, we obtained a total of 2,304 PGx relationships. We evaluated our approach by performance (precision = 0.806) with benchmark datasets like Pharmacogenomic Knowledgebase (PharmGKB) (0.904), Online Mendelian Inheritance in Man (OMIM) (0.600), and The Comparative Toxicogenomics Database (CTD) (0.729). We validated our study by comparing our results with 362 commercially used the US- Food and drug administration (FDA)-approved drug labeling biomarkers. Of the 2,304 PGx relationships identified, 127 belonged to the FDA list of 362 approved pharmacogenomic markers, indicating that our semiautomated text mining approach may reveal significant PGx information with markers for drug response prediction. In addition, it is a scalable and state-of-art approach in curation for PGx clinical utility

Development of a text mining approach to disease network discovery

Scientific literature is one of the major sources of knowledge for systems biology, in the form of papers, patents and other types of written reports. Text mining methods aim at automatically extracting relevant information from the literature. The hypothesis of this thesis was that biological systems could be elucidated by the development of text mining solutions that can automatically extract relevant information from documents. The first objective consisted in developing software components to recognize biomedical entities in text, which is the first step to generate a network about a biological system. To this end, a machine learning solution was developed, which can be trained for specific biological entities using an annotated dataset, obtaining high-quality results. Additionally, a rule-based solution was developed, which can be easily adapted to various types of entities. The second objective consisted in developing an automatic approach to link the recognized entities to a reference knowledge base. A solution based on the PageRank algorithm was developed in order to match the entities to the concepts that most contribute to the overall coherence. The third objective consisted in automatically extracting relations between entities, to generate knowledge graphs about biological systems. Due to the lack of annotated datasets available for this task, distant supervision was employed to train a relation classifier on a corpus of documents and a knowledge base. The applicability of this approach was demonstrated in two case studies: microRNAgene relations for cystic fibrosis, obtaining a network of 27 relations using the abstracts of 51 recently published papers; and cell-cytokine relations for tolerogenic cell therapies, obtaining a network of 647 relations from 3264 abstracts. Through a manual evaluation, the information contained in these networks was determined to be relevant. Additionally, a solution combining deep learning techniques with ontology information was developed, to take advantage of the domain knowledge provided by ontologies. This thesis contributed with several solutions that demonstrate the usefulness of text mining methods to systems biology by extracting domain-specific information from the literature. These solutions make it easier to integrate various areas of research, leading to a better understanding of biological systems

Enhancing Phenotype Recognition in Clinical Notes Using Large Language Models: PhenoBCBERT and PhenoGPT

We hypothesize that large language models (LLMs) based on the transformer architecture can enable automated detection of clinical phenotype terms, including terms not documented in the HPO. In this study, we developed two types of models: PhenoBCBERT, a BERT-based model, utilizing Bio+Clinical BERT as its pre-trained model, and PhenoGPT, a GPT-based model that can be initialized from diverse GPT models, including open-source versions such as GPT-J, Falcon, and LLaMA, as well as closed-source versions such as GPT-3 and GPT-3.5. We compared our methods with PhenoTagger, a recently developed HPO recognition tool that combines rule-based and deep learning methods. We found that our methods can extract more phenotype concepts, including novel ones not characterized by HPO. We also performed case studies on biomedical literature to illustrate how new phenotype information can be recognized and extracted. We compared current BERT-based versus GPT-based models for phenotype tagging, in multiple aspects including model architecture, memory usage, speed, accuracy, and privacy protection. We also discussed the addition of a negation step and an HPO normalization layer to the transformer models for improved HPO term tagging. In conclusion, PhenoBCBERT and PhenoGPT enable the automated discovery of phenotype terms from clinical notes and biomedical literature, facilitating automated downstream tasks to derive new biological insights on human diseases