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ObjectiveThe trade-off between the speed and simplicity of dictionary-based term recognition and the richer linguistic information provided by more advanced natural language processing (NLP) is an area of active discussion in clinical informatics. In this paper, we quantify this trade-off among text processing systems that make different trade-offs between speed and linguistic understanding. We tested both types of systems in three clinical research tasks: phase IV safety profiling of a drug, learning adverse drug-drug interactions, and learning used-to-treat relationships between drugs and indications.MaterialsWe first benchmarked the accuracy of the NCBO Annotator and REVEAL in a manually annotated, publically available dataset from the 2008 i2b2 Obesity Challenge. We then applied the NCBO Annotator and REVEAL to 9 million clinical notes from the Stanford Translational Research Integrated Database Environment (STRIDE) and used the resulting data for three research tasks.ResultsThere is no significant difference between using the NCBO Annotator and REVEAL in the results of the three research tasks when using large datasets. In one subtask, REVEAL achieved higher sensitivity with smaller datasets.ConclusionsFor a variety of tasks, employing simple term recognition methods instead of advanced NLP methods results in little or no impact on accuracy when using large datasets. Simpler dictionary-based methods have the advantage of scaling well to very large datasets. Promoting the use of simple, dictionary-based methods for population level analyses can advance adoption of NLP in practice.

Background and aimsProton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches.MethodsUsing a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population.ResultsIn multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09-1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07-3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.ConclusionsConsistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.

Background and objectiveElectronic health records (EHRs) are increasingly being used to complement the FDA Adverse Event Reporting System (FAERS) and to enable active pharmacovigilance. Over 30% of all adverse drug reactions are caused by drug-drug interactions (DDIs) and result in significant morbidity every year, making their early identification vital. We present an approach for identifying DDI signals directly from the textual portion of EHRs.MethodsWe recognize mentions of drug and event concepts from over 50 million clinical notes from two sites to create a timeline of concept mentions for each patient. We then use adjusted disproportionality ratios to identify significant drug-drug-event associations among 1165 drugs and 14 adverse events. To validate our results, we evaluate our performance on a gold standard of 1698 DDIs curated from existing knowledge bases, as well as with signaling DDI associations directly from FAERS using established methods.ResultsOur method achieves good performance, as measured by our gold standard (area under the receiver operator characteristic (ROC) curve >80%), on two independent EHR datasets and the performance is comparable to that of signaling DDIs from FAERS. We demonstrate the utility of our method for early detection of DDIs and for identifying alternatives for risky drug combinations. Finally, we publish a first of its kind database of population event rates among patients on drug combinations based on an EHR corpus.ConclusionsIt is feasible to identify DDI signals and estimate the rate of adverse events among patients on drug combinations, directly from clinical text; this could have utility in prioritizing drug interaction surveillance as well as in clinical decision support.

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.

The current state of the art in post-marketing drug surveillance utilizes voluntarily submitted reports of suspected adverse drug reactions. We present data mining methods that transform unstructured patient notes taken by doctors, nurses and other clinicians into a de-identified, temporally ordered, patient-feature matrix using standardized medical terminologies. We demonstrate how to use the resulting high-throughput data to monitor for adverse drug events based on the clinical notes in the EHR.

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.

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.

BackgroundPeripheral arterial disease (PAD) is a growing problem with few available therapies. Cilostazol is the only FDA-approved medication with a class I indication for intermittent claudication, but carries a black box warning due to concerns for increased cardiovascular mortality. To assess the validity of this black box warning, we employed a novel text-analytics pipeline to quantify the adverse events associated with Cilostazol use in a clinical setting, including patients with congestive heart failure (CHF).Methods and resultsWe analyzed the electronic medical records of 1.8 million subjects from the Stanford clinical data warehouse spanning 18 years using a novel text-mining/statistical analytics pipeline. We identified 232 PAD patients taking Cilostazol and created a control group of 1,160 PAD patients not taking this drug using 1:5 propensity-score matching. Over a mean follow up of 4.2 years, we observed no association between Cilostazol use and any major adverse cardiovascular event including stroke (OR = 1.13, CI [0.82, 1.55]), myocardial infarction (OR = 1.00, CI [0.71, 1.39]), or death (OR = 0.86, CI [0.63, 1.18]). Cilostazol was not associated with an increase in any arrhythmic complication. We also identified a subset of CHF patients who were prescribed Cilostazol despite its black box warning, and found that it did not increase mortality in this high-risk group of patients.ConclusionsThis proof of principle study shows the potential of text-analytics to mine clinical data warehouses to uncover 'natural experiments' such as the use of Cilostazol in CHF patients. We envision this method will have broad applications for examining difficult to test clinical hypotheses and to aid in post-marketing drug safety surveillance. Moreover, our observations argue for a prospective study to examine the validity of a drug safety warning that may be unnecessarily limiting the use of an efficacious therapy.

External controls (eControls) leverage historical data to create non‐randomized control arms. The lack of randomization can result in confounding between the experimental and eControl cohorts. To balance potentially confounding variables between the cohorts, one of the proposed methods is to match on prognostic scores. Still, the performance of prognostic scores to construct eControls in oncology has not been analyzed yet. Using an electronic health record‐derived de‐identified database, we constructed eControls using one of three methods: ROPRO, a state‐of‐the‐art prognostic score, or either a propensity score composed of five (5Vars) or 27 covariates (ROPROvars). We compared the performance of these methods in estimating the overall survival (OS) hazard ratio (HR) of 11 recent advanced non‐small cell lung cancer. The ROPRO eControls had a lower OS HR error (median absolute deviation (MAD), 0.072, confidence interval (CI): 0.036–0.185), than the 5Vars (MAD 0.081, CI: 0.025–0.283) and ROPROvars eControls (MAD 0.087, CI: 0.054–0.383). Notably, the OS HR errors for all methods were even lower in the phase III studies. Moreover, the ROPRO eControl cohorts included, on average, more patients than the 5Vars (6.54%) and ROPROvars cohorts (11.7%). The eControls matched with the prognostic score reproduced the controls more reliably than propensity scores composed of the underlying variables. Additionally, prognostic scores could allow eControls to be built on many prognostic variables without a significant increase in the variability of the propensity score, which would decrease the number of matched patients. [ABSTRACT FROM AUTHOR]

DisGeNET is a comprehensive discovery platform designed to address a variety of questions concerning the genetic underpinning of human diseases. DisGeNET contains over 380 000 associations between >16 000 genes and 13 000 diseases, which makes it one of the largest repositories currently available of its kind. DisGeNET integrates expert-curated databases with text-mined data, covers information on Mendelian and complex diseases, and includes data from animal disease models. It features a score based on the supporting evidence to prioritize gene-disease associations. It is an open access resource available through a web interface, a Cytoscape plugin and as a Semantic Web resource. The web interface supports user-friendly data exploration and navigation. DisGeNET data can also be analysed via the DisGeNET Cytoscape plugin, and enriched with the annotations of other plugins of this popular network analysis software suite. Finally, the information contained in DisGeNET can be expanded and complemented using Semantic Web technologies and linked to a variety of resources already present in the Linked Data cloud. Hence, DisGeNET offers one of the most comprehensive collections of human gene-disease associations and a valuable set of tools for investigating the molecular mechanisms underlying diseases of genetic origin, designed to fulfill the needs of different user profiles, including bioinformaticians, biologists and health-care practitioners. Database URL: http://www.disgenet.org/ [ABSTRACT FROM AUTHOR]

Background: Drug-related adverse events remain an important cause of morbidity and mortality and impose huge burden on healthcare costs. Routinely collected electronic healthcare data give a good snapshot of how drugs are being used in ‘real-world’ settings. Objective: To describe a strategy that identifies potentially drug-induced acute myocardial infarction (AMI) from a large international healthcare data network. Methods: Post-marketing safety surveillance was conducted in seven population-based healthcare databases in three countries (Denmark, Italy, and the Netherlands) using anonymised demographic, clinical, and prescription/dispensing data representing 21,171,291 individuals with 154,474,063 person-years of follow-up in the period 1996–2010. Primary care physicians’ medical records and administrative claims containing reimbursements for filled prescriptions, laboratory tests, and hospitalisations were evaluated using a three-tier triage system of detection, filtering, and substantiation that generated a list of drugs potentially associated with AMI. Outcome of interest was statistically significant increased risk of AMI during drug exposure that has not been previously described in current literature and is biologically plausible. Results: Overall, 163 drugs were identified to be associated with increased risk of AMI during preliminary screening. Of these, 124 drugs were eliminated after adjustment for possible bias and confounding. With subsequent application of criteria for novelty and biological plausibility, association with AMI remained for nine drugs (‘prime suspects’): azithromycin; erythromycin; roxithromycin; metoclopramide; cisapride; domperidone; betamethasone; fluconazole; and megestrol acetate. Limitations: Although global health status, co-morbidities, and time-invariant factors were adjusted for, residual confounding cannot be ruled out. Conclusion: A strategy to identify potentially drug-induced AMI from electronic healthcare data has been proposed that takes into account not only statistical association, but also public health relevance, novelty, and biological plausibility. Although this strategy needs to be further evaluated using other healthcare data sources, the list of ‘prime suspects’ makes a good starting point for further clinical, laboratory, and epidemiologic investigation. [ABSTRACT FROM AUTHOR]

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.

The current state of the art in post-marketing drug surveillance utilizes voluntarily submitted reports of suspected adverse drug reactions. We present data mining methods that transform unstructured patient notes taken by doctors, nurses and other clinicians into a de-identified, temporally ordered, patient-feature matrix using standardized medical terminologies. We demonstrate how to use the resulting high-throughput data to monitor for adverse drug events based on the clinical notes in the EHR.

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.

Cytoscape is an open-source software for visualizing, analyzing, and modeling biological networks. This chapter explains how to use Cytoscape to analyze the functional effect of sequence variations in the context of biological networks such as protein-protein interaction networks and signaling pathways. The chapter is divided into five parts: (1) obtaining information about the functional effect of sequence variation in a Cytoscape readable format, (2) loading and displaying different types of biological networks in Cytoscape, (3) integrating the genomic information (SNPs and mutations) with the biological networks, and (4) analyzing the effect of the genomic perturbation onto the network structure using Cytoscape built-in functions. Finally, we briefly outline how the integrated data can help in building mathematical network models for analyzing the effect of the sequence variation onto the dynamics of the biological system. Each part is illustrated by step-by-step instructions on an example use case and visualized by many screenshots and figures.