Analyzing adverse drug reaction using statistical and machine learning methods: A systematic review

Background: Adverse drug reactions (ADRs) are unintended negative drug-induced responses. Determining the association between drugs and ADRs is crucial, and several methods have been proposed to demonstrate this association. This systematic review aimed to examine the analytical tools by considering original articles that utilized statistical and machine learning methods for detecting ADRs. Methods: A systematic literature review was conducted based on articles published between 2015 and 2020. The keywords used were statistical, machine learning, and deep learning methods for detecting ADR signals. The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) guidelines. Results: We reviewed 72 articles, of which 51 and 21 addressed statistical and machine learning methods, respectively. Electronic medical record (EMR) data were exclusively analyzed using the regression method. For FDA Adverse Event Reporting System (FAERS) data, components of the disproportionality method were preferable. DrugBank was the most used database for machine learning. Other methods accounted for the highest and supervised methods accounted for the second highest. Conclusions: Using the 72 main articles, this review provides guidelines on which databases are frequently utilized and which analysis methods can be connected. For statistical analysis, >90% of the cases were analyzed by disproportionate or regression analysis with each spontaneous reporting system (SRS) data or electronic medical record (EMR) data; for machine learning research, however, there was a strong tendency to analyze various data combinations. Only half of the DrugBank database was occupied, and the k-nearest neighbor method accounted for the greatest proportion.ope

Strategies for Automating Pharmacovigilance Adverse Event Case Processing

Business leaders who fail to implement innovative technology solutions in their companies face economic distress in these organizations. Guided by the task technology fit model as the conceptual framework, the purpose of this qualitative single case study was to explore strategies used by pharmacovigilance (PV) systems leaders to implement innovative technology solutions. The participants were 4 PV systems managers working in a pharmaceutical company in the Boston area of Massachusetts, United States, who used successful strategies to implement innovative technology solutions to automate adverse events case processing. Data were collected using semistructured interviews and company documents. The collected data were analyzed using Yinâs 5-step data analysis, which included compiling, disassembling, reassembling, interpreting data, and concluding the findings. Three key themes emerged: automation solution selection and implementation strategies, business operation model changes, and communication and training strategies. The key recommendation is for PV leaders to implement automation solutions and redirect the savings from PV operations in terms of cost and workforce tasks toward investing in the actual PV tasks such as benefit-risk assessments of products. The implications for positive social change include the potential to identify strategies to improve patient outcomes and assist in making pharmaceutical medicines more efficacious and safer for human use in reducing unnecessary deaths

Information retrieval and text mining technologies for chemistry

Efficient access to chemical information contained in scientific literature, patents, technical reports, or the web is a pressing need shared by researchers and patent attorneys from different chemical disciplines. Retrieval of important chemical information in most cases starts with finding relevant documents for a particular chemical compound or family. Targeted retrieval of chemical documents is closely connected to the automatic recognition of chemical entities in the text, which commonly involves the extraction of the entire list of chemicals mentioned in a document, including any associated information. In this Review, we provide a comprehensive and in-depth description of fundamental concepts, technical implementations, and current technologies for meeting these information demands. A strong focus is placed on community challenges addressing systems performance, more particularly CHEMDNER and CHEMDNER patents tasks of BioCreative IV and V, respectively. Considering the growing interest in the construction of automatically annotated chemical knowledge bases that integrate chemical information and biological data, cheminformatics approaches for mapping the extracted chemical names into chemical structures and their subsequent annotation together with text mining applications for linking chemistry with biological information are also presented. Finally, future trends and current challenges are highlighted as a roadmap proposal for research in this emerging field.A.V. and M.K. acknowledge funding from the European Community’s Horizon 2020 Program (project reference: 654021 - OpenMinted). M.K. additionally acknowledges the Encomienda MINETAD-CNIO as part of the Plan for the Advancement of Language Technology. O.R. and J.O. thank the Foundation for Applied Medical Research (FIMA), University of Navarra (Pamplona, Spain). This work was partially funded by Consellería de Cultura, Educación e Ordenación Universitaria (Xunta de Galicia), and FEDER (European Union), and the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684). We thank Iñigo Garciá -Yoldi for useful feedback and discussions during the preparation of the manuscript.info:eu-repo/semantics/publishedVersio

Computational Methods for the Analysis of Genomic Data and Biological Processes

In recent decades, new technologies have made remarkable progress in helping to understand biological systems. Rapid advances in genomic profiling techniques such as microarrays or high-performance sequencing have brought new opportunities and challenges in the fields of computational biology and bioinformatics. Such genetic sequencing techniques allow large amounts of data to be produced, whose analysis and cross-integration could provide a complete view of organisms. As a result, it is necessary to develop new techniques and algorithms that carry out an analysis of these data with reliability and efficiency. This Special Issue collected the latest advances in the field of computational methods for the analysis of gene expression data, and, in particular, the modeling of biological processes. Here we present eleven works selected to be published in this Special Issue due to their interest, quality, and originality

Pharmacovigilance Decision Support : The value of Disproportionality Analysis Signal Detection Methods, the development and testing of Covariability Techniques, and the importance of Ontology

The cost of adverse drug reactions to society in the form of deaths, chronic illness, foetal malformation, and many other effects is quite significant. For example, in the United States of America, adverse reactions to prescribed drugs is around the fourth leading cause of death. The reporting of adverse drug reactions is spontaneous and voluntary in Australia. Many methods that have been used for the analysis of adverse drug reaction data, mostly using a statistical approach as a basis for clinical analysis in drug safety surveillance decision support. This thesis examines new approaches that may be used in the analysis of drug safety data. These methods differ significantly from the statistical methods in that they utilize co variability methods of association to define drug-reaction relationships. Co variability algorithms were developed in collaboration with Musa Mammadov to discover drugs associated with adverse reactions and possible drug-drug interactions. This method uses the system organ class (SOC) classification in the Australian Adverse Drug Reaction Advisory Committee (ADRAC) data to stratify reactions. The text categorization algorithm BoosTexter was found to work with the same drug safety data and its performance and modus operandi was compared to our algorithms. These alternative methods were compared to a standard disproportionality analysis methods for signal detection in drug safety data including the Bayesean mulit-item gamma Poisson shrinker (MGPS), which was found to have a problem with similar reaction terms in a report and innocent by-stander drugs. A classification of drug terms was made using the anatomical-therapeutic-chemical classification (ATC) codes. This reduced the number of drug variables from 5081 drug terms to 14 main drug classes. The ATC classification is structured into a hierarchy of five levels. Exploitation of the ATC hierarchy allows the drug safety data to be stratified in such a way as to make them accessible to powerful existing tools. A data mining method that uses association rules, which groups them on the basis of content, was used as a basis for applying the ATC and SOC ontologies to ADRAC data. This allows different views of these associations (even very rare ones). A signal detection method was developed using these association rules, which also incorporates critical reaction terms.Doctor of Philosoph

Integrative bioinformatics and graph-based methods for predicting adverse effects of developmental drugs

Adverse drug effects are complex phenomena that involve the interplay between drug molecules and their protein targets at various levels of biological organisation, from molecular to organismal. Many factors are known to contribute toward the safety profile of a drug, including the chemical properties of the drug molecule itself, the biological properties of drug targets and other proteins that are involved in pharmacodynamics and pharmacokinetics aspects of drug action, and the characteristics of the intended patient population. A multitude of scattered publicly available resources exist that cover these important aspects of drug activity. These include manually curated biological databases, high-throughput experimental results from gene expression and human genetics resources as well as drug labels and registered clinical trial records. This thesis proposes an integrated analysis of these disparate sources of information to help bridge the gap between the molecular and the clinical aspects of drug action. For example, to address the commonly held assumption that narrowly expressed proteins make safer drug targets, an integrative data-driven analysis was conducted to systematically investigate the relationship between the tissue expression profile of drug targets and the organs affected by clinically observed adverse drug reactions. Similarly, human genetics data were used extensively throughout the thesis to compare adverse symptoms induced by drug molecules with the phenotypes associated with the genes encoding their target proteins. One of the main outcomes of this thesis was the generation of a large knowledge graph, which incorporates diverse molecular and phenotypic data in a structured network format. To leverage the integrated information, two graph-based machine learning methods were developed to predict a wide range of adverse drug effects caused by approved and developmental therapies

Front-Line Physicians' Satisfaction with Information Systems in Hospitals

Day-to-day operations management in hospital units is difficult due to continuously varying situations, several actors involved and a vast number of information systems in use. The aim of this study was to describe front-line physicians' satisfaction with existing information systems needed to support the day-to-day operations management in hospitals. A cross-sectional survey was used and data chosen with stratified random sampling were collected in nine hospitals. Data were analyzed with descriptive and inferential statistical methods. The response rate was 65 % (n = 111). The physicians reported that information systems support their decision making to some extent, but they do not improve access to information nor are they tailored for physicians. The respondents also reported that they need to use several information systems to support decision making and that they would prefer one information system to access important information. Improved information access would better support physicians' decision making and has the potential to improve the quality of decisions and speed up the decision making process.Peer reviewe

To what extent do cell-penetrating peptides selectively cross the blood-brain barrier?

The blood-brain barrier protects the brain from toxic compounds. Its selective permeability is essential for the optimal function of the central nervous system. Some peptides can cross the blood-brain barrier. On the other hand, cell-penetrating peptides are able to overcome the cell membrane. During this research project, it was investigated whether these cell-penetrating peptides also can cross the blood-brain barrier. The chemical diversity of the already reported cell-penetrating peptides was investigated and a unified response for the extent of cellular uptake of peptides was introduced. Based on this study, a set of cell-penetrating peptides was rationally selected for further research. In order to more objectively compare the quantitative data on the blood-brain barrier influx of peptides, a classification system for blood-brain barrier influx was established. The purity of the selected synthetized cell-penetrating peptides was also investigated, which is essential for obtaining reliable research conclusions. Different chromatographic systems were compared for the analysis of the selected peptides. The investigated cell-penetrating peptides crossed the blood-brain barrier to a different extent. The influx varied from very low to very high and some peptides showed efflux out of the brain. There was no correlation observed between the blood-brain barrier transport kinetics and the extent of cellular uptake. During the aging process, the blood-brain barrier shows an increased permeability and, together with other age-related functional changes, should be taken into account during the development of medicines used by the elderly. Therefore, the current regulatory status of the development of geriatric medicines was investigated

Computational and human-based methods for knowledge discovery over knowledge graphs

The modern world has evolved, accompanied by the huge exploitation of data and information. Daily, increasing volumes of data from various sources and formats are stored, resulting in a challenging strategy to manage and integrate them to discover new knowledge. The appropriate use of data in various sectors of society, such as education, healthcare, e-commerce, and industry, provides advantages for decision support in these areas. However, knowledge discovery becomes challenging since data may come from heterogeneous sources with important information hidden. Thus, new approaches that adapt to the new challenges of knowledge discovery in such heterogeneous data environments are required. The semantic web and knowledge graphs (KGs) are becoming increasingly relevant on the road to knowledge discovery. This thesis tackles the problem of knowledge discovery over KGs built from heterogeneous data sources. We provide a neuro-symbolic artificial intelligence system that integrates symbolic and sub-symbolic frameworks to exploit the semantics encoded in a KG and its structure. The symbolic system relies on existing approaches of deductive databases to make explicit, implicit knowledge encoded in a KG. The proposed deductive database $DS$ can derive new statements to ego networks given an abstract target prediction. Thus, $DS$ minimizes data sparsity in KGs. In addition, a sub-symbolic system relies on knowledge graph embedding (KGE) models. KGE models are commonly applied in the KG completion task to represent entities in a KG in a low-dimensional vector space. However, KGE models are known to suffer from data sparsity, and a symbolic system assists in overcoming this fact. The proposed approach discovers knowledge given a target prediction in a KG and extracts unknown implicit information related to the target prediction. As a proof of concept, we have implemented the neuro-symbolic system on top of a KG for lung cancer to predict polypharmacy treatment effectiveness. The symbolic system implements a deductive system to deduce pharmacokinetic drug-drug interactions encoded in a set of rules through the Datalog program. Additionally, the sub-symbolic system predicts treatment effectiveness using a KGE model, which preserves the KG structure. An ablation study on the components of our approach is conducted, considering state-of-the-art KGE methods. The observed results provide evidence for the benefits of the neuro-symbolic integration of our approach, where the neuro-symbolic system for an abstract target prediction exhibits improved results. The enhancement of the results occurs because the symbolic system increases the prediction capacity of the sub-symbolic system. Moreover, the proposed neuro-symbolic artificial intelligence system in Industry 4.0 (I4.0) is evaluated, demonstrating its effectiveness in determining relatedness among standards and analyzing their properties to detect unknown relations in the I4.0KG. The results achieved allow us to conclude that the proposed neuro-symbolic approach for an abstract target prediction improves the prediction capability of KGE models by minimizing data sparsity in KGs

Novel therapeutics for complex diseases from genome-wide association data

The development of novel therapies is essential to lower the burden of complex diseases. The purpose of this study is to identify novel therapeutics for complex diseases using bioinformatic methods. Bioinformatic tools such as candidate gene prediction tools allow identification of disease genes by identifying the potential candidate genes linked to genetic markers of the disease. Candidate gene prediction tools can only identify candidates for further research, and do not identify disease genes directly. Integration of drug-target datasets with candidate gene data-sets can identify novel potential therapeutics suitable for repositioning in clinical trials. Drug repositioning can save valuable time and money spent in therapeutic development of complex diseases