Learning signals of adverse drug-drug interactions from the unstructured text of electronic health records.

Drug-drug interactions (DDI) account for 30% of all adverse drug reactions, which are the fourth leading cause of death in the US. Current methods for post marketing surveillance primarily use spontaneous reporting systems for learning DDI signals and validate their signals using the structured portions of Electronic Health Records (EHRs). We demonstrate a fast, annotation-based approach, which uses standard odds ratios for identifying signals of DDIs from the textual portion of EHRs directly and which, to our knowledge, is the first effort of its kind. We developed a gold standard of 1,120 DDIs spanning 14 adverse events and 1,164 drugs. Our evaluations on this gold standard using millions of clinical notes from the Stanford Hospital confirm that identifying DDI signals from clinical text is feasible (AUROC=81.5%). We conclude that the text in EHRs contain valuable information for learning DDI signals and has enormous utility in drug surveillance and clinical decision support

Profiling risk factors for chronic uveitis in juvenile idiopathic arthritis: a new model for EHR-based research.

BackgroundJuvenile idiopathic arthritis is the most common rheumatic disease in children. Chronic uveitis is a common and serious comorbid condition of juvenile idiopathic arthritis, with insidious presentation and potential to cause blindness. Knowledge of clinical associations will improve risk stratification. Based on clinical observation, we hypothesized that allergic conditions are associated with chronic uveitis in juvenile idiopathic arthritis patients.MethodsThis study is a retrospective cohort study using Stanford's clinical data warehouse containing data from Lucile Packard Children's Hospital from 2000-2011 to analyze patient characteristics associated with chronic uveitis in a large juvenile idiopathic arthritis cohort. Clinical notes in patients under 16 years of age were processed via a validated text analytics pipeline. Bivariate-associated variables were used in a multivariate logistic regression adjusted for age, gender, and race. Previously reported associations were evaluated to validate our methods. The main outcome measure was presence of terms indicating allergy or allergy medications use overrepresented in juvenile idiopathic arthritis patients with chronic uveitis. Residual text features were then used in unsupervised hierarchical clustering to compare clinical text similarity between patients with and without uveitis.ResultsPreviously reported associations with uveitis in juvenile idiopathic arthritis patients (earlier age at arthritis diagnosis, oligoarticular-onset disease, antinuclear antibody status, history of psoriasis) were reproduced in our study. Use of allergy medications and terms describing allergic conditions were independently associated with chronic uveitis. The association with allergy drugs when adjusted for known associations remained significant (OR 2.54, 95% CI 1.22-5.4).ConclusionsThis study shows the potential of using a validated text analytics pipeline on clinical data warehouses to examine practice-based evidence for evaluating hypotheses formed during patient care. Our study reproduces four known associations with uveitis development in juvenile idiopathic arthritis patients, and reports a new association between allergic conditions and chronic uveitis in juvenile idiopathic arthritis patients

Network analysis of unstructured EHR data for clinical research.

In biomedical research, network analysis provides a conceptual framework for interpreting data from high-throughput experiments. For example, protein-protein interaction networks have been successfully used to identify candidate disease genes. Recently, advances in clinical text processing and the increasing availability of clinical data have enabled analogous analyses on data from electronic medical records. We constructed networks of diseases, drugs, medical devices and procedures using concepts recognized in clinical notes from the Stanford clinical data warehouse. We demonstrate the use of the resulting networks for clinical research informatics in two ways-cohort construction and outcomes analysis-by examining the safety of cilostazol in peripheral artery disease patients as a use case. We show that the network-based approaches can be used for constructing patient cohorts as well as for analyzing differences in outcomes by comparing with standard methods, and discuss the advantages offered by network-based approaches

Pathway databases and tools for their exploitation: benefits, current limitations and challenges

In past years, comprehensive representations of cell signalling pathways have been developed by manual curation from literature, which requires huge effort and would benefit from information stored in databases and from automatic retrieval and integration methods. Once a reconstruction of the network of interactions is achieved, analysis of its structural features and its dynamic behaviour can take place. Mathematical modelling techniques are used to simulate the complex behaviour of cell signalling networks, which ultimately sheds light on the mechanisms leading to complex diseases or helps in the identification of drug targets. A variety of databases containing information on cell signalling pathways have been developed in conjunction with methodologies to access and analyse the data. In principle, the scenario is prepared to make the most of this information for the analysis of the dynamics of signalling pathways. However, are the knowledge repositories of signalling pathways ready to realize the systems biology promise? In this article we aim to initiate this discussion and to provide some insights on this issue

From SNPs to pathways: integration of functional effect of sequence variations on models of cell signalling pathways

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Gene-Disease Network Analysis Reveals Functional Modules in Mendelian, Complex and Environmental Diseases

Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases. The gene-disease networks used in this study and part of the analysis are available at http://ibi.imim.es/DisGeNET/DisGeNETweb.html#Download

Automatic Filtering and Substantiation of Drug Safety Signals

Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions