Exploring drug-target interaction networks of illicit drugs.

BACKGROUND: Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. RESULTS: In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. CONCLUSIONS: This study presents the first systematic review of the network characteristics of illicit drugs, their targets, and other drugs that share the targets of these illicit drugs. The results, though preliminary, provide some novel insights into the molecular mechanisms of drug addiction. The observation of illicit-related drugs, with partial verification from previous studies, demonstrated that the network-assisted approach is promising for the identification of drug repositioning.

Development and Validation of an Electronic Medical Record Algorithm to Identify Phenotypes of Rotator Cuff Tear.

BACKGROUND: A lack of studies with large sample sizes of patients with rotator cuff tears is a barrier to performing clinical and genomic research. OBJECTIVE: To develop and validate an electronic medical record (EMR)-based algorithm to identify individuals with and without rotator cuff tear. DESIGN: We used a deidentified version of the EMR of more than 2 million subjects. A screening algorithm was applied to classify subjects into likely rotator cuff tear and likely normal rotator cuff groups. From these subjects, 500 likely rotator cuff tear and 500 likely normal rotator cuff were randomly chosen for algorithm development. Chart review of all 1000 subjects confirmed the true phenotype of rotator cuff tear or normal rotator cuff based on magnetic resonance imaging and operative report. An algorithm was then developed based on logistic regression and validation of the algorithm was performed. RESULTS: The variables significantly predicting rotator cuff tear included the number of times a Current Procedural Terminology code related to rotator cuff procedures was used (odds ratio [OR] = 3.3; 95% confidence interval [CI]: 1.6-6.8 for ≥3 vs 0), the number of times a term related to rotator cuff lesions occurred in radiology reports (OR = 2.2; 95% CI: 1.2-4.1 for ≥1 vs 0), and the number of times a term related to rotator cuff lesions occurred in physician notes (OR = 4.5; 95% CI: 2.2-9.1 for 1 or 2 times vs 0). This phenotyping algorithm had a specificity of 0.89 (95% CI: 0.79-0.95) for rotator cuff tear, area under the curve (AUC) of 0.842, and diagnostic likelihood ratios (DLRs), DLR+ and DLR- of 5.94 (95% CI: 3.07-11.48) and 0.363 (95% CI: 0.291-0.453). CONCLUSION: Our informatics algorithm enables identification of cohorts of individuals with and without rotator cuff tear from an EMR-based data set with moderate accuracy.

Human monocyte transcriptional profiling identifies IL-18 receptor accessory protein and lactoferrin as novel immune targets in hypertension.

BACKGROUND AND PURPOSE: Monocytes play a critical role in hypertension. The purpose of our study was to use an unbiased approach to determine whether hypertensive individuals on conventional therapy exhibit an altered monocyte gene expression profile and to perform validation studies of selected genes to identify novel therapeutic targets for hypertension. EXPERIMENTAL APPROACH: Next generation RNA sequencing identified differentially expressed genes in a small discovery cohort of normotensive and hypertensive individuals. Several of these genes were further investigated for association with hypertension in multiple validation cohorts using qRT-PCR, regression analysis, phenome-wide association study and case-control analysis of a missense polymorphism. KEY RESULTS: We identified 60 genes that were significantly differentially expressed in hypertensive monocytes, many of which are related to IL-1ß. Uni- and multivariate regression analyses of the expression of these genes with mean arterial pressure (MAP) revealed four genes that significantly correlated with MAP in normotensive and/or hypertensive individuals. Of these, lactoferrin (LTF), peptidoglycan recognition protein 1 and IL-18 receptor accessory protein (IL18RAP) remained significantly elevated in peripheral monocytes of hypertensive individuals in a separate validation cohort. Interestingly, IL18RAP expression associated with MAP in a cohort of African Americans. Furthermore, homozygosity for a missense single nucleotide polymorphism in LTF that decreases antimicrobial function and increases protein levels (rs1126478) was over-represented in patients with hypertension relative to controls (odds ratio 1.16). CONCLUSIONS AND IMPLICATIONS: These data demonstrate that monocytes exhibit enhanced pro-inflammatory gene expression in hypertensive individuals and identify IL18RAP and LTF as potential novel mediators of human hypertension. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.

CUSTOM-SEQ: a prototype for oncology rapid learning in a comprehensive EHR environment.

BACKGROUND: As targeted cancer therapies and molecular profiling become widespread, the era of "precision oncology" is at hand. However, cancer genomes are complex, making mutation-specific outcomes difficult to track. We created a proof-of-principle, CUSTOM-SEQ: Continuously Updating System for Tracking Outcome by Mutation, to Support Evidence-based Querying, to automatically calculate and display mutation-specific survival statistics from electronic health record data. METHODS: Patients with cancer genotyping were included, and clinical data was extracted through a variety of algorithms. Results were refreshed regularly and injected into a standard reporting platform. Significant results were highlighted for visual cueing. A subset was additionally stratified by stage, smoking status, and treatment exposure. RESULTS: By August 2015, 4310 patients with a median follow-up of 17 months had sufficient data for survival calculation. As expected, epidermal growth factor receptor (EGFR) mutations in lung cancer were associated with superior overall survival, hazard ratio (HR) = 0.53 (P < .001), validating the approach. Guanine nucleotide binding protein (G protein), q polypeptide (GNAQ) mutations in melanoma were associated with inferior overall survival, a novel finding (HR = 3.42, P < .001). Smoking status was not prognostic for epidermal growth factor receptor-mutated lung cancer patients, who also lived significantly longer than their counterparts, even with advanced disease (HR = 0.54, P = .001). INTERPRETATION: CUSTOM-SEQ represents a novel rapid learning system for a precision oncology environment. Retrospective studies are often limited by study of specific time periods and can lead to incomplete conclusions. Because data is continuously updated in CUSTOM-SEQ, the evidence base is constantly growing. Future work will allow users to interactively explore populations by demographics and treatment exposure, in order to further investigate significant mutation-specific signals.

Reducing patient re-identification risk for laboratory results within research datasets.

OBJECTIVE: To try to lower patient re-identification risks for biomedical research databases containing laboratory test results while also minimizing changes in clinical data interpretation. MATERIALS AND METHODS: In our threat model, an attacker obtains 5-7 laboratory results from one patient and uses them as a search key to discover the corresponding record in a de-identified biomedical research database. To test our models, the existing Vanderbilt TIME database of 8.5 million Safe Harbor de-identified laboratory results from 61 280 patients was used. The uniqueness of unaltered laboratory results in the dataset was examined, and then two data perturbation models were applied-simple random offsets and an expert-derived clinical meaning-preserving model. A rank-based re-identification algorithm to mimic an attack was used. The re-identification risk and the retention of clinical meaning for each model's perturbed laboratory results were assessed. RESULTS: Differences in re-identification rates between the algorithms were small despite substantial divergence in altered clinical meaning. The expert algorithm maintained the clinical meaning of laboratory results better (affecting up to 4% of test results) than simple perturbation (affecting up to 26%). DISCUSSION AND CONCLUSION: With growing impetus for sharing clinical data for research, and in view of healthcare-related federal privacy regulation, methods to mitigate risks of re-identification are important. A practical, expert-derived perturbation algorithm that demonstrated potential utility was developed. Similar approaches might enable administrators to select data protection scheme parameters that meet their preferences in the trade-off between the protection of privacy and the retention of clinical meaning of shared data.