Answering clinical questions with knowledge-based and statistical techniques

The combination of recent developments in question-answering research and the availability of unparalleled resources developed specifically for automatic semantic processing of text in the medical domain provides a unique opportunity to explore complex question answering in the domain of clinical medicine. This article presents a system designed to satisfy the information needs of physicians practicing evidence-based medicine. We have developed a series of knowledge extractors, which employ a combination of knowledge-based and statistical techniques, for automatically identifying clinically relevant aspects of MEDLINE abstracts. These extracted elements serve as the input to an algorithm that scores the relevance of citations with respect to structured representations of information needs, in accordance with the principles of evidencebased medicine. Starting with an initial list of citations retrieved by PubMed, our system can bring relevant abstracts into higher ranking positions, and from these abstracts generate responses that directly answer physicians ’ questions. We describe three separate evaluations: one focused on the accuracy of the knowledge extractors, one conceptualized as a document reranking task, and finally, an evaluation of answers by two physicians. Experiments on a collection of real-world clinical questions show that our approach significantly outperforms the already competitive PubMed baseline. 1

Hot-spot analysis for drug discovery targeting protein-protein interactions

Introduction: Protein-protein interactions are important for biological processes and pathological situations, and are attractive targets for drug discovery. However, rational drug design targeting protein-protein interactions is still highly challenging. Hot-spot residues are seen as the best option to target such interactions, but their identification requires detailed structural and energetic characterization, which is only available for a tiny fraction of protein interactions. Areas covered: In this review, the authors cover a variety of computational methods that have been reported for the energetic analysis of protein-protein interfaces in search of hot-spots, and the structural modeling of protein-protein complexes by docking. This can help to rationalize the discovery of small-molecule inhibitors of protein-protein interfaces of therapeutic interest. Computational analysis and docking can help to locate the interface, molecular dynamics can be used to find suitable cavities, and hot-spot predictions can focus the search for inhibitors of protein-protein interactions. Expert opinion: A major difficulty for applying rational drug design methods to protein-protein interactions is that in the majority of cases the complex structure is not available. Fortunately, computational docking can complement experimental data. An interesting aspect to explore in the future is the integration of these strategies for targeting PPIs with large-scale mutational analysis.This work has been funded by grants BIO2016-79930-R and SEV-2015-0493 from the Spanish Ministry of Economy, Industry and Competitiveness, and grant EFA086/15 from EU Interreg V POCTEFA. M Rosell is supported by an FPI fellowship from the Severo Ochoa program. The authors are grateful for the support of the the Joint BSC-CRG-IRB Programme in Computational Biology.Peer ReviewedPostprint (author's final draft

Pretrained Transformers for Text Ranking: BERT and Beyond

The goal of text ranking is to generate an ordered list of texts retrieved from a corpus in response to a query. Although the most common formulation of text ranking is search, instances of the task can also be found in many natural language processing applications. This survey provides an overview of text ranking with neural network architectures known as transformers, of which BERT is the best-known example. The combination of transformers and self-supervised pretraining has been responsible for a paradigm shift in natural language processing (NLP), information retrieval (IR), and beyond. In this survey, we provide a synthesis of existing work as a single point of entry for practitioners who wish to gain a better understanding of how to apply transformers to text ranking problems and researchers who wish to pursue work in this area. We cover a wide range of modern techniques, grouped into two high-level categories: transformer models that perform reranking in multi-stage architectures and dense retrieval techniques that perform ranking directly. There are two themes that pervade our survey: techniques for handling long documents, beyond typical sentence-by-sentence processing in NLP, and techniques for addressing the tradeoff between effectiveness (i.e., result quality) and efficiency (e.g., query latency, model and index size). Although transformer architectures and pretraining techniques are recent innovations, many aspects of how they are applied to text ranking are relatively well understood and represent mature techniques. However, there remain many open research questions, and thus in addition to laying out the foundations of pretrained transformers for text ranking, this survey also attempts to prognosticate where the field is heading

Neural Representations of Concepts and Texts for Biomedical Information Retrieval

Information retrieval (IR) methods are an indispensable tool in the current landscape of exponentially increasing textual data, especially on the Web. A typical IR task involves fetching and ranking a set of documents (from a large corpus) in terms of relevance to a user\u27s query, which is often expressed as a short phrase. IR methods are the backbone of modern search engines where additional system-level aspects including fault tolerance, scale, user interfaces, and session maintenance are also addressed. In addition to fetching documents, modern search systems may also identify snippets within the documents that are potentially most relevant to the input query. Furthermore, current systems may also maintain preprocessed structured knowledge derived from textual data as so called knowledge graphs, so certain types of queries that are posed as questions can be parsed as such; a response can be an output of one or more named entities instead of a ranked list of documents (e.g., what diseases are associated with EGFR mutations? ). This refined setup is often termed as question answering (QA) in the IR and natural language processing (NLP) communities. In biomedicine and healthcare, specialized corpora are often at play including research articles by scientists, clinical notes generated by healthcare professionals, consumer forums for specific conditions (e.g., cancer survivors network), and clinical trial protocols (e.g., www.clinicaltrials.gov). Biomedical IR is specialized given the types of queries and the variations in the texts are different from that of general Web documents. For example, scientific articles are more formal with longer sentences but clinical notes tend to have less grammatical conformity and are rife with abbreviations. There is also a mismatch between the vocabulary of consumers and the lingo of domain experts and professionals. Queries are also different and can range from simple phrases (e.g., COVID-19 symptoms ) to more complex implicitly fielded queries (e.g., chemotherapy regimens for stage IV lung cancer patients with ALK mutations ). Hence, developing methods for different configurations (corpus, query type, user type) needs more deliberate attention in biomedical IR. Representations of documents and queries are at the core of IR methods and retrieval methodology involves coming up with these representations and matching queries with documents based on them. Traditional IR systems follow the approach of keyword based indexing of documents (the so called inverted index) and matching query phrases against the document index. It is not difficult to see that this keyword based matching ignores the semantics of texts (synonymy at the lexeme level and entailment at phrase/clause/sentence levels) and this has lead to dimensionality reduction methods such as latent semantic indexing that generally have scale-related concerns; such methods also do not address similarity at the sentence level. Since the resurgence of neural network methods in NLP, the IR field has also moved to incorporate advances in neural networks into current IR methods. This dissertation presents four specific methodological efforts toward improving biomedical IR. Neural methods always begin with dense embeddings for words and concepts to overcome the limitations of one-hot encoding in traditional NLP/IR. In the first effort, we present a new neural pre-training approach to jointly learn word and concept embeddings for downstream use in applications. In the second study, we present a joint neural model for two essential subtasks of information extraction (IE): named entity recognition (NER) and entity normalization (EN). Our method detects biomedical concept phrases in texts and links them to the corresponding semantic types and entity codes. These first two studies provide essential tools to model textual representations as compositions of both surface forms (lexical units) and high level concepts with potential downstream use in QA. In the third effort, we present a document reranking model that can help surface documents that are likely to contain answers (e.g, factoids, lists) to a question in a QA task. The model is essentially a sentence matching neural network that learns the relevance of a candidate answer sentence to the given question parametrized with a bilinear map. In the fourth effort, we present another document reranking approach that is tailored for precision medicine use-cases. It combines neural query-document matching and faceted text summarization. The main distinction of this effort from previous efforts is to pivot from a query manipulation setup to transforming candidate documents into pseudo-queries via neural text summarization. Overall, our contributions constitute nontrivial advances in biomedical IR using neural representations of concepts and texts

Using Learning to Rank Approach to Promoting Diversity for Biomedical Information Retrieval with Wikipedia

In most of the traditional information retrieval (IR) models, the independent relevance assumption is taken, which assumes the relevance of a document is independent of other documents. However, the pitfall of this is the high redundancy and low diversity of retrieval result. This has been seen in many scenarios, especially in biomedical IR, where the information need of one query may refer to different aspects. Promoting diversity in IR takes the relationship between documents into account. Unlike previous studies, we tackle this problem in the learning to rank perspective. The main challenges are how to find salient features for biomedical data and how to integrate dynamic features into the ranking model. To address these challenges, Wikipedia is used to detect topics of documents for generating diversity biased features. A combined model is proposed and studied to learn a diversified ranking result. Experiment results show the proposed method outperforms baseline models

Automatic inference of causal reasoning chains from student essays

While there has been an increasing focus on higher-level thinking skills arising from the Common Core Standards, many high-school and middle-school students struggle to combine and integrate information from multiple sources when writing essays. Writing is an important learning skill, and there is increasing evidence that writing about a topic develops a deeper understanding in the student. However, grading essays is time consuming for teachers, resulting in an increasing focus on shallower forms of assessment that are easier to automate, such as multiple-choice tests. Existing essay grading software has attempted to ease this burden but relies on shallow lexico-syntactic features and is unable to understand the structure or validity of a student’s arguments or explanations. Without the ability to understand a student’s reasoning processes, it is impossible to write automated formative assessment systems to assist students with improving their thinking skills through essay writing. In order to understand the arguments put forth in an explanatory essay in the science domain, we need a method of representing the causal structure of a piece of explanatory text. Psychologists use a representation called a causal model to represent a student\u27s understanding of an explanatory text. This consists of a number of core concepts, and a set of causal relations linking them into one or more causal chains, forming a causal model. In this thesis I present a novel system for automatically constructing causal models from student scientific essays using Natural Language Processing (NLP) techniques. The problem was decomposed into 4 sub-problems - assigning essay concepts to words, detecting causal-relations between these concepts, resolving coreferences within each essay, and using the structure of the whole essay to reconstruct a causal model. Solutions to each of these sub-problems build upon the predictions from the solutions to earlier problems, forming a sequential pipeline of models. Designing a system in this way allows later models to correct for false positive predictions from downstream models. However, this also has the disadvantage that errors made in earlier models can propagate through the system, negatively impacting the upstream models, and limiting their accuracy. Producing robust solutions for the initial 2 sub problems, detecting concepts, and parsing causal relations between them, was critical in building a robust system. A number of sequence labeling models were trained to classify the concepts associated with each word, with the most effective approach being a bidirectional recurrent neural network (RNN), a deep learning model commonly applied to word labeling problems. This is because the RNN used pre-trained word embeddings to better generalize to rarer words, and was able to use information from both ends of each sentence to infer a word\u27s concept. The concepts predicted by this model were then used to develop causal relation parsing models for detecting causal connections between these concepts. A shift-reduce dependency parsing model was trained using the SEARN algorithm and out-performed a number of other approaches by better utilizing the structure of the problem and directly optimizing the error metric used. Two pre-trained coreference resolution systems were used to resolve coreferences within the essays. However a word tagging model trained to predict anaphors combined with a heuristic for determining the antecedent out-performed these two systems. Finally, a model was developed for parsing a causal model from an entire essay, utilizing the solutions to the three previous problems. A beam search algorithm was used to produce multiple parses for each sentence, which in turn were combined to generate multiple candidate causal models for each student essay. A reranking algorithm was then used to select the optimal causal model from all of the generated candidates. An important contribution of this work is that it represents a system for parsing a complete causal model of a scientific essay from a student\u27s written answer. Existing systems have been developed to parse individual causal relations, but no existing system attempts to parse a sequence of linked causal relations forming a causal model from an explanatory scientific essay. It is hoped that this work can lead to the development of more robust essay grading software and formative assessment tools, and can be extended to build solutions for extracting causality from text in other domains. In addition, I also present 2 novel approaches for optimizing the micro-F1 score within the design of two of the algorithms studied: the dependency parser and the reranking algorithm. The dependency parser uses a custom cost function to estimate the impact of parsing mistakes on the overall micro-F1 score, while the reranking algorithm allows the micro-F1 score to be optimized by tuning the beam search parameter to balance recall and precision

Transcription factor binding specificity and occupancy : elucidation, modelling and evaluation

The major contributions of this thesis are addressing the need for an objective quality evaluation of a transcription factor binding model, demonstrating the value of the tools developed to this end and elucidating how in vitro and in vivo information can be utilized to improve TF binding specificity models. Accurate elucidation of TF binding specificity remains an ongoing challenge in gene regulatory research. Several in vitro and in vivo experimental techniques have been developed followed by a proliferation of algorithms, and ultimately, the binding models. This increase led to a choice problem for the end users: which tools to use, and which is the most accurate model for a given TF? Therefore, the first section of this thesis investigates the motif assessment problem: how scoring functions, choice and processing of benchmark data, and statistics used in evaluation affect motif ranking. This analysis revealed that TF motif quality assessment requires a systematic comparative analysis, and that scoring functions used have a TF-specific effect on motif ranking. These results advised the design of a Motif Assessment and Ranking Suite MARS, supported by PBM and ChIP-seq benchmark data and an extensive collection of PWM motifs. MARS implements consistency, enrichment, and scoring and classification-based motif evaluation algorithms. Transcription factor binding is also influenced and determined by contextual factors: chromatin accessibility, competition or cooperation with other TFs, cell line or condition specificity, binding locality (e.g. proximity to transcription start sites) and the shape of the binding site (DNA-shape). In vitro techniques do not capture such context; therefore, this thesis also combines PBM and DNase-seq data using a comparative k-mer enrichment approach that compares open chromatin with genome-wide prevalence, achieving a modest performance improvement when benchmarked on ChIP-seq data. Finally, since statistical and probabilistic methods cannot capture all the information that determine binding, a machine learning approach (XGBooost) was implemented to investigate how the features contribute to TF specificity and occupancy. This combinatorial approach improves the predictive ability of TF specificity models with the most predictive feature being chromatin accessibility, while the DNA-shape and conservation information all significantly improve on the baseline model of k-mer and DNase data. The results and the tools introduced in this thesis are useful for systematic comparative analysis (via MARS) and a combinatorial approach to modelling TF binding specificity, including appropriate feature engineering practices for machine learning modelling