Tal Lorberbaum

Systems Pharmacology Augments Drug Safety Surveillance

Small molecule drugs are the foundation of modern medical practice, yet their use is limited by the onset of unexpected and severe adverse events (AEs). Regulatory agencies rely on postmarketing surveillance to monitor safety once drugs are approved for clinical use. Despite advances in pharmacovigilance methods that address issues of confounding bias, clinical data of AEs are inherently noisy. Systems pharmacology—the integration of systems biology and chemical genomics—can illuminate drug mechanisms of action. We hypothesize that these data can improve drug safety surveillance by highlighting drugs with a mechanistic connection to the target phenotype (enriching true positives) and filtering those that do not (depleting false positives). We present an algorithm, the modular assembly of drug safety subnetworks (MADSS), to combine systems pharmacology and pharmacovigilance data and significantly improve drug safety monitoring for four clinically relevant adverse drug reactions.

Systems biology approaches for identifying adverse drug reactions and elucidating their underlying biological mechanisms

Small molecules are indispensable to modern medical therapy. However, their use may lead to unintended, negative medical outcomes commonly referred to as adverse drug reactions (ADRs). These effects vary widely in mechanism, severity, and populations affected, making ADR prediction and identification important public health concerns. Current methods rely on clinical trials and postmarket surveillance programs to find novel ADRs; however, clinical trials are limited by small sample size, whereas postmarket surveillance methods may be biased and inherently leave patients at risk until sufficient clinical evidence has been gathered. Systems pharmacology, an emerging interdisciplinary field combining network and chemical biology, provides important tools to uncover and understand ADRs and may mitigate the drawbacks of traditional methods. In particular, network analysis allows researchers to integrate heterogeneous data sources and quantify the interactions between biological and chemical entities. Recent work in this area has combined chemical, biological, and large‐scale observational health data to predict ADRs in both individual patients and global populations. In this review, we explore the rapid expansion of systems pharmacology in the study of ADRs. We enumerate the existing methods and strategies and illustrate progress in the field with a model framework that incorporates crucial data elements, such as diet and comorbidities, known to modulate ADR risk. Using this framework, we highlight avenues of research that may currently be underexplored, representing opportunities for future work. WIREs Syst Biol Med 2016, 8:104–122. doi: 10.1002/wsbm.1323

A Computational Drug Repositioning Approach for Targeting Oncogenic Transcription Factors

Mutations in transcription factor (TF) genes are frequently observed in tumors, often leading to aberrant transcriptional activity. Unfortunately, TFs are often considered undruggable due to the absence of targetable enzymatic activity. To address this problem, we developed CRAFTT, a computational drug-repositioning approach for targeting TF activity. CRAFTT combines ChIP-seq with drug-induced expression profiling to identify small molecules that can specifically perturb TF activity. Application to ENCODE ChIP-seq datasets revealed known drug-TF interactions, and a global drug-protein network analysis supported these predictions. Application of CRAFTT to ERG, a pro-invasive, frequently overexpressed oncogenic TF, predicted that dexamethasone would inhibit ERG activity. Dexamethasone significantly decreased cell invasion and migration in an ERG-dependent manner. Furthermore, analysis of electronic medical record data indicates a protective role for dexamethasone against prostate cancer. Altogether, our method provides a broadly applicable strategy for identifying drugs that specifically modulate TF activity.

Improving Detection of Arrhythmia Drug- Drug Interactions in Pharmacovigilance Data through the Implementation of Similarity- Based Modeling

Identification of Drug-Drug Interactions (DDIs) is a significant challenge during drug development and clinical practice. DDIs are responsible for many adverse drug effects (ADEs), decreasing patient quality of life and causing higher care expenses. DDIs are not systematically evaluated in pre-clinical or clinical trials and so the FDA U. S. Food and Drug Administration relies on post-marketing surveillance to monitor patient safety. However, existing pharmacovigilance algorithms show poor performance for detecting DDIs exhibiting prohibitively high false positive rates. Alternatively, methods based on chemical structure and pharmacological similarity have shown promise in adverse drug event detection. We hypothesize that the use of chemical biology data in a post hoc analysis of pharmacovigilance results will significantly improve the detection of dangerous interactions. Our model integrates a reference standard of DDIs known to cause arrhythmias with drug similarity data. To compare similarity between drugs we used chemical structure (both 2D and 3D molecular structure), adverse drug side effects, chemogenomic targets, drug indication classes, and known drug-drug interactions. We evaluated the method on external reference standards. Our results showed an enhancement of sensitivity, specificity and precision in different top positions with the use of similarity measures to rank the candidates extracted from pharmacovigilance data. For the top 100 DDI candidates, similarity-based modeling yielded close to twofold precision enhancement compared to the proportional reporting ratio (PRR). Moreover, the method helps in the DDI decision making through the identification of the DDI in the reference standard that generated the candidate.

Disease Heritability Inferred from Familial Relationships Reported in Medical Records

Heritability is essential for understanding the biological causes of disease but requires laborious patient recruitment and phenotype ascertainment. Electronic health records (EHRs) passively capture a wide range of clinically relevant data and provide a resource for studying the heritability of traits that are not typically accessible. EHRs contain next-of-kin information collected via patient emergency contact forms, but until now, these data have gone unused in research. We mined emergency contact data at three academic medical centers and identified 7.4 million familial relationships while maintaining patient privacy. Identified relationships were consistent with genetically derived relatedness. We used EHR data to compute heritability estimates for 500 disease phenotypes. Overall, estimates were consistent with the literature and between sites. Inconsistencies were indicative of limitations and opportunities unique to EHR research. These analyses provide a validation of the use of EHRs for genetics and disease research.

Large-scale adverse effects related to treatment evidence standardization (LAERTES): an open scalable system for linking pharmacovigilance evidence sources with clinical data.

BackgroundIntegrating multiple sources of pharmacovigilance evidence has the potential to advance the science of safety signal detection and evaluation. In this regard, there is a need for more research on how to integrate multiple disparate evidence sources while making the evidence computable from a knowledge representation perspective (i.e., semantic enrichment). Existing frameworks suggest well-promising outcomes for such integration but employ a rather limited number of sources. In particular, none have been specifically designed to support both regulatory and clinical use cases, nor have any been designed to add new resources and use cases through an open architecture. This paper discusses the architecture and functionality of a system called Large-scale Adverse Effects Related to Treatment Evidence Standardization (LAERTES) that aims to address these shortcomings.ResultsLAERTES provides a standardized, open, and scalable architecture for linking evidence sources relevant to the association of drugs with health outcomes of interest (HOIs). Standard terminologies are used to represent different entities. For example, drugs and HOIs are represented in RxNorm and Systematized Nomenclature of Medicine -- Clinical Terms respectively. At the time of this writing, six evidence sources have been loaded into the LAERTES evidence base and are accessible through prototype evidence exploration user interface and a set of Web application programming interface services. This system operates within a larger software stack provided by the Observational Health Data Sciences and Informatics clinical research framework, including the relational Common Data Model for observational patient data created by the Observational Medical Outcomes Partnership. Elements of the Linked Data paradigm facilitate the systematic and scalable integration of relevant evidence sources.ConclusionsThe prototype LAERTES system provides useful functionality while creating opportunities for further research. Future work will involve improving the method for normalizing drug and HOI concepts across the integrated sources, aggregated evidence at different levels of a hierarchy of HOI concepts, and developing more advanced user interface for drug-HOI investigations.Background Integrating multiple sources of pharmacovigilance evidence has the potential to advance the science of safety signal detection and evaluation. In this regard, there is a need for more research on how to integrate multiple disparate evidence sources while making the evidence computable from a knowledge representation perspective (i.e., semantic enrichment). Existing frameworks suggest well-promising outcomes for such integration but employ a rather limited number of sources. In particular, none have been specifically designed to support both regulatory and clinical use cases, nor have any been designed to add new resources and use cases through an open architecture. This paper discusses the architecture and functionality of a system called Large-scale Adverse Effects Related to Treatment Evidence Standardization (LAERTES) that aims to address these shortcomings. Results LAERTES provides a standardized, open, and scalable architecture for linking evidence sources relevant to the association of drugs with health outcomes of interest (HOIs). Standard terminologies are used to represent different entities. For example, drugs and HOIs are represented in RxNorm and Systematized Nomenclature of Medicine -- Clinical Terms respectively. At the time of this writing, six evidence sources have been loaded into the LAERTES evidence base and are accessible through prototype evidence exploration user interface and a set of Web application programming interface services. This system operates within a larger software stack provided by the Observational Health Data Sciences and Informatics clinical research framework, including the relational Common Data Model for observational patient data created by the Observational Medical Outcomes Partnership. Elements of the Linked Data paradigm facilitate the systematic and scalable integration of relevant evidence sources. Conclusions The prototype LAERTES system provides useful functionality while creating opportunities for further research. Future work will involve improving the method for normalizing drug and HOI concepts across the integrated sources, aggregated evidence at different levels of a hierarchy of HOI concepts, and developing more advanced user interface for drug-HOI investigations.

Reply: Combination Therapy With Ceftriaxone and Lansoprazole, Acquired Long QT Syndrome and Torsades de Pointes Risk

We thank Dr. Lazzerini and colleagues for sharing their clinical observations supporting the drug−drug interaction (DDI) findings in our recent paper [(1)][1]. In isolation, their observations could be dismissed as idiosyncratic by skeptics, but data science—the application of rigorous

Data science identifies novel drug interactions that prolong the QT interval

Drug-induced prolongation of the QT interval on the electrocardiogram (long QT syndrome, LQTS) can lead to a potentially fatal ventricular arrhythmia called torsades de pointes (TdP). 180 drugs with both cardiac and non-cardiac indications have been found to increase risk for TdP, but drug-drug interactions contributing to LQTS (QT-DDIs) remain poorly characterized. Traditional methods for mining observational healthcare data are poorly equipped to detect QT- DDI signals due to low reporting numbers and a lack of direct evidence for LQTS. In this study we present an integrative data science pipeline that addresses these limitations by identifying latent signals for QT-DDIs in the FDA’s Adverse Event Reporting System and retrospectively validating these predictions using electrocardiogram data in electronic health records. We present 26 novel QT-DDIs flagged using this method that warrant further investigation. Key Points - Drug-induced long QT syndrome (LQTS) can lead to potentially fatal arrhythmias (torsades de pointes, TdP). Drug-drug interactions that prolong the QT interval (QT- DDIs) can be clinically significant but remain poorly characterized. - Observational health data (such as adverse event spontaneous reporting systems and electronic health records) offer an opportunity to mine for new QT-DDIs, but when used individually these datasets have a number of limitations that prevent identification of true signals. - We present an integrative data science approach that combines mining for latent QT- DDI signals in the FDA Adverse Event Reporting System and retrospective analysis of electrocardiogram lab results in electronic health records at Columbia University Medical Center to identify 26 novel QT-DDIs.