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Background: Genetic diversity is known to confer survival advantage in many species across the tree of life. Here, we hypothesize that such pattern applies to humans as well and could be a result of higher fitness in individuals with higher genomic heterozygosity. Results: We use healthy aging as a proxy for better health and fitness, and observe greater heterozygosity in healthy-aged individuals. Specifically, we find that only common genetic variants show significantly higher excess of heterozygosity in the healthy-aged cohort. Lack of difference in heterozygosity for low-frequency variants or disease-associated variants excludes the possibility of compensation for deleterious recessive alleles as a mechanism. In addition, coding SNPs with the highest excess of heterozygosity in the healthy-aged cohort are enriched in genes involved in extracellular matrix and glycoproteins, a group of genes known to be under long-term balancing selection. We also find that individual heterozygosity rate is a significant predictor of electronic health record (EHR)-based estimates of 10-year survival probability in men but not in women, accounting for several factors including age and ethnicity. Conclusions: Our results demonstrate that the genomic heterozygosity is associated with human healthspan, and that the relationship between higher heterozygosity and healthy aging could be explained by heterozygote advantage. Further characterization of this relationship will have important implications in aging-associated disease risk prediction. [ABSTRACT FROM AUTHOR]

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Background: Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. Results: We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. Conclusion: In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation. [ABSTRACT FROM AUTHOR]

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, immune-mediated disorder in which an aberrant immune response causes demyelination and axonal damage of the peripheral nerves. Genetic contribution to CIDP is unclear and no genome-wide association study (GWAS) has been reported so far. In this study, we aimed to identify CIDP-related risk loci, genes, and pathways. We first focused on CIDP, and 516 CIDP cases and 403,545 controls were included in the GWAS analysis. We also investigated genetic risk for inflammatory polyneuropathy (IP), in which we performed a GWAS study using FinnGen data and combined the results with GWAS from the UK Biobank using a fixed-effect meta-analysis. A total of 1,261 IP cases and 823,730 controls were included in the analysis. Stratified analyses by gender were performed. Mendelian randomization (MR), colocalization, and transcriptome-wide association study (TWAS) analyses were performed to identify associated genes. Gene-set analyses were conducted to identify associated pathways. We identified one genome-wide significant locus at 20q13.33 for CIDP risk among women, the top variant located at the intron region of gene CDH4. Sex-combined MR, colocalization, and TWAS analyses identified three candidate pathogenic genes for CIDP and five genes for IP. MAGMA gene-set analyses identified a total of 18 pathways related to IP or CIDP. Sex-stratified analyses identified three genes for IP among males and two genes for IP among females. Our study identified suggestive risk genes and pathways for CIDP and IP. Functional analyses should be conducted to further confirm these associations., Competing Interests: Declaration of interests All authors were employees of Sanofi US Services at the time of study and hold shares and/or stock options in the company., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The drug-food interaction brings forth changes in the clinical effects of drugs. While favourable interactions bring positive clinical outcomes, unfavourable interactions may lead to toxicity. This article reviews the impact of food intake on drug-food interactions, the clinical effects of drugs, and the effect of drug-food in correlation with diet and precision medicine. Emerging areas in drug-food interactions are the food-genome interface (nutrigenomics) and nutrigenetics. Understanding the molecular basis of food ingredients, including genomic sequencing and pharmacological implications of food molecules, helps to reduce the impact of drug-food interactions. Various strategies are being leveraged to alleviate drug-food interactions; measures including patient engagement, digital health, approaches involving machine intelligence, and big data are a few of them. Furthermore, delineating the molecular communications across dietmicrobiome- drug-food-drug interactions in a pharmacomicrobiome framework may also play a vital role in personalized nutrition. Determining nutrient-gene interactions aids in making nutrition deeply personalized and helps mitigate unwanted drug-food interactions, chronic diseases, and adverse events from their onset. Translational bioinformatics approaches could play an essential role in the next generation of drug-food interaction research. In this landscape review, we discuss important tools, databases, and approaches along with key challenges and opportunities in drug-food interaction and its immediate impact on precision medicine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Organ-on-a-chip (OOAC) is an emerging technology based on microfluid platforms and in vitro cell culture that has a promising future in the healthcare industry. The numerous advantages of OOAC over conventional systems make it highly popular. The chip is an innovative combination of novel technologies, including lab-on-a-chip, microfluidics, biomaterials, and tissue engineering. This paper begins by analyzing the need for the development of OOAC followed by a brief introduction to the technology. Later sections discuss and review the various types of OOACs and the fabrication materials used. The implementation of artificial intelligence in the system makes it more advanced, thereby helping to provide a more accurate diagnosis as well as convenient data management. We introduce selected OOAC projects, including applications to organ/disease modelling, pharmacology, personalized medicine, and dentistry. Finally, we point out certain challenges that need to be surmounted in order to further develop and upgrade the current systems.

Target prioritization is essential for drug discovery and repositioning. Applying computational methods to analyze and process multi-omics data to find new drug targets is a practical approach for achieving this. Despite an increasing number of methods for generating datasets such as genomics, phenomics, and proteomics, attempts to integrate and mine such datasets remain limited in scope. Developing hybrid intelligence solutions that combine human intelligence in the scientific domain and disease biology with the ability to mine multiple databases simultaneously may help augment drug target discovery and identify novel drug-indication associations. We believe that integrating different data sources using a singular numerical scoring system in a hybrid intelligent framework could help to bridge these different omics layers and facilitate rapid drug target prioritization for studies in drug discovery, development or repositioning. Herein, we describe our prototype of the StarGazer pipeline which combines multi-source, multi-omics data with a novel target prioritization scoring system in an interactive Python-based Streamlit dashboard. StarGazer displays target prioritization scores for genes associated with 1844 phenotypic traits, and is available via https://github.com/AstraZeneca/StarGazer., Competing Interests: Authors CL, AP, VG, RNH, EP, AF, SP, WY, MH, A-SS, KT, BS, TC, JM, FMK, and KS are or were employed by AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Lin, Prokop, Gopalakrishnan, Hanna, Papa, Freeman, Patel, Yu, Huhn, Sheikh, Tan, Sellman, Cohen, Mangion, Khan, Gusev and Shameer.)

Purpose: Overall survival (OS) is the gold standard end point for establishing clinical benefits in phase III oncology trials. However, these trials are associated with low success rates, largely driven by failure to meet the primary end point. Surrogate end points such as progression-free survival (PFS) are increasingly being used as indicators of biologic drug activity and to inform early go/no-go decisions in oncology drug development. We developed OSPred, a digital health aid that combines actual clinical data and machine intelligence approaches to visualize correlation trends between early (PFS-based) and late (OS) end points and provide support for shared decision making in the drug development pipeline., Methods: OSPred is based on a trial-level data set of 81 reports (35 anticancer drugs with various mechanisms of action; 156 observations) in non-small-cell lung cancer (NSCLC). OSPred was developed using R Shiny, with packages ggplot2, metafor, boot, dplyr, and mvtnorm, to analyze and visualize correlation results and predict OS hazard ratio (HR OS) on the basis of user-inputted PFS-based data, namely, HR PFS, or the odds ratio of PFS at 4 (OR PFS4) or 6 (OR PFS6) months., Results: The three main features of the tool are as follows: prediction of HR OS on the basis of user-inputted early end point values; visualization of comparisons of the user's investigational drug with other drugs in the NSCLC setting, including by specific MoA; and creation of a probability density chart, providing point prediction and CIs for HR OS. A working version of the tool for download is linked., Conclusion: The OSPred tool offers interactive visualization of clinical trial end point correlations with reference to a large pool of historical NSCLC studies. Its focused capability has the potential to digitally transform and accelerate data-driven decision making as part of the drug development process., Competing Interests: Shameer KhaderEmployment: AstraZenecaPatents, Royalties, Other Intellectual Property: Coauthor of an AI patent for Automation for Clinical Event Adjudication Andrzej ProkopEmployment: AstraZeneca Pharma PolandHonoraria: AstraZeneca Sreenath NampallyEmployment: AstraZeneca/MedImmune, BayerStock and Other Ownership Interests: AstraZeneca Jim WeatherallEmployment: AstraZenecaStock and Other Ownership Interests: AstraZeneca Renee Bailey IaconaEmployment: AstraZenecaStock and Other Ownership Interests: AstraZeneca Faisal M. KhanEmployment: AstraZeneca, Novo NordiskStock and Other Ownership Interests: AstraZeneca, Novo NordiskPatents, Royalties, Other Intellectual Property: Patent applied through AstraZenecaTravel, Accommodations, Expenses: AstraZeneca, Novo NordiskNo other potential conflicts of interest were reported.

Objective: Opioids are a class of drugs that are known for their use as pain relievers. They bind to opioid receptors on nerve cells in the brain and the nervous system to mitigate pain. Addiction is one of the chronic and primary adverse events of prolonged usage of opioids. They may also cause psychological disorders, muscle pain, depression, anxiety attacks etc. In this study, we present a collection of predictive models to identify patients at risk of opioid abuse and mortality by using their prescription histories. Also, we discover particularly threatening drug-drug interactions in the context of opioid usage. Methods and Materials: Using a publicly available dataset from MIMIC-III, two models were trained, Logistic Regression with L2 regularization (baseline) and Extreme Gradient Boosting (enhanced model), to classify the patients of interest into two categories based on their susceptibility to opioid abuse. We've also used K-Means clustering, an unsupervised algorithm, to explore drug-drug interactions that might be of concern. Results: The baseline model for classifying patients susceptible to opioid abuse has an F1 score of 76.64% (accuracy 77.16%) while the enhanced model has an F1 score of 94.45% (accuracy 94.35%). These models can be used as a preliminary step towards inferring the causal effect of opioid usage and can help monitor the prescription practices to minimize the opioid abuse. Discussion and Conclusion: Results suggest that the enhanced model provides a promising approach in preemptive identification of patients at risk for opioid abuse. By discovering and correlating the patterns contributing to opioid overdose or abuse among a variety of patients, machine learning models can be used as an efficient tool to help uncover the existing gaps and/or fraudulent practices in prescription writing. To quote an example of one such incidental finding, our study discovered that insulin might possibly be interacting with opioids in an unfavourable way leading to complications in diabetic patients. This indicates that diabetic patients under long term opioid usage might need to take increased amounts of insulin to make it more effective. This observation backs up prior research studies done on a similar aspect. To increase the translational value of our work, the predictive models and the associated software code are made available under the MIT License., Competing Interests: LS reports being a co-founder of Entrupy Inc, Velai Inc and Gaius Networks Inc and has consulted with the World Bank and the Governance Lab. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vunikili, Glicksberg, Johnson, Dudley, Subramanian and Shameer.)

Breast cancer screening using Mammography serves as the earliest defense against breast cancer, revealing anomalous tissue years before it can be detected through physical screening. Despite the use of high resolution radiography, the presence of densely overlapping patterns challenges the consistency of human-driven diagnosis and drives interest in leveraging state-of-art localization ability of deep convolutional neural networks (DCNN). The growing availability of digitized clinical archives enables the training of deep segmentation models, but training using the most widely available form of coarse hand-drawn annotations works against learning the precise boundary of cancerous tissue in evaluation, while producing results that are more aligned with the annotations rather than the underlying lesions. The expense of collecting high quality pixel-level data in the field of medical science makes this even more difficult. To surmount this fundamental challenge, we propose LatentCADx, a deep learning segmentation model capable of precisely annotating cancer lesions underlying hand-drawn annotations, which we procedurally obtain using joint classification training and a strict segmentation penalty. We demonstrate the capability of LatentCADx on a publicly available dataset of 2,620 Mammogram case files, where LatentCADx obtains classification ROC of 0.97, AP of 0.87, and segmentation AP of 0.75 (IOU = 0.5), giving comparable or better performance than other models. Qualitative and precision evaluation of LatentCADx annotations on validation samples reveals that LatentCADx increases the specificity of segmentations beyond that of existing models trained on hand-drawn annotations, with pixel level specificity reaching a staggering value of 0.90. It also obtains sharp boundary around lesions unlike other methods, reducing the confused pixels in the output by more than 60 % ., Competing Interests: KS was employed by Northwell Health and KS was employed by AstraZeneca. LS reports being a co-founder of Entrupy Inc, Velai Inc and Gaius Networks Inc and has consulted with the World Bank and the Governance Lab. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 An, Bhardwaj, Shameer and Subramanian.)

Early endpoints, such as progression-free survival (PFS), are increasingly used as surrogates for overall survival (OS) to accelerate approval of novel oncology agents. Compiling trial-level data from randomized controlled trials (RCTs) could help to develop a predictive framework to ascertain correlation trends between treatment effects for early and late endpoints. Through trial-level correlation and random-effects meta-regression analysis, we assessed the relationship between hazard ratio (HR) OS and (1) HR PFS and (2) odds ratio (OR) PFS at 4 and 6 months, stratified according to the mechanism of action of the investigational product. Using multiple source databases, we compiled a data set including 81 phase II-IV RCTs (35 drugs and 156 observations) of patients with non-small-cell lung cancer. Low-to-moderate correlations were generally observed between treatment effects for early endpoints (based on PFS) and HR OS across trials of agents with different mechanisms of action. Moderate correlations were seen between treatment effects for HR PFS and HR OS across all trials, and in the programmed cell death-1/programmed cell death ligand-1 and epidermal growth factor receptor trial subsets. Although these results constitute an important step, caution is advised, as there are some limitations to our evaluation, and an additional patient-level analysis would be needed to establish true surrogacy., Competing Interests: KR, EH, FL, AS, JW, RI, and FK are full-time employees of AstraZeneca and own AstraZeneca stock. SK, YZ, DJ, SN, AP, JY, and CD are full-time employees of AstraZeneca. PM was a full-time employee of AstraZeneca at the time that the study was conducted and owns AstraZeneca stock. IK and VM were full-time employees of AstraZeneca at the time that the study was conducted. The authors declare that this study received funding from AstraZeneca. The funder had the following involvement with the study: Study design and concept, collection, analysis and interpretation of the data, review and approval of the final draft and approval to submit for publication., (Copyright © 2021 Shameer, Zhang, Jackson, Rhodes, Neelufer, Nampally, Prokop, Hutchison, Ye, Malkov, Liu, Sabin, Weatherall, Duran, Iacona, Khan and Mukhopadhyay.)

Combination therapies are an emerging drug development strategy in cancer, particularly in the immunooncology (IO) space. Many combination studies do not meet their safety objectives due to serious adverse events (SAEs). Prediction of SAEs based on evidence from single and combination studies would be highly beneficial. To address the emerging challenge of optimizing the safety and efficacy of combination studies, we have assembled a novel oncology clinical trial data set with 329 trials, 685 arms (279 unique treatment arms), including 200 combinations, 79 mono arms, and 59 curated adverse event categories in the setting of non-small cell lung cancer (NSCLC). We integrated the database with an analytical framework: SAEgnal. Using SAEgnal, we have investigated the difference in the risk of 39 adverse event types between combination and monotherapy arms across a subset of 34 combination trials. We observed different risk profiles between combination and monotherapies; interestingly, while the risk of elevated AST/ALT is lower in combination arms (in 1/8 trials, p-value < 0.05), it is higher for bleeding (7/8 trials, p-value < 0.05). We envisage that the SAEgnal framework would enable rapid predictive analytics of SAEs in oncology and accelerate drug development in oncology., (©2021 AMIA - All rights reserved.)

MICU1 is a mitochondrial inner membrane protein that inhibits mitochondrial calcium entry; elevated MICU1 expression is characteristic of many cancers, including ovarian cancer. MICU1 induces both glycolysis and chemoresistance and is associated with poor clinical outcomes. However, there are currently no available interventions to normalize aberrant MICU1 expression. Here, we demonstrate that microRNA-195-5p (miR-195) directly targets the 3' UTR of the MICU1 mRNA and represses MICU1 expression. Additionally, miR-195 is under-expressed in ovarian cancer cell lines, and restoring miR-195 expression reestablishes native MICU1 levels and the associated phenotypes. Stable expression of miR-195 in a human xenograft model of ovarian cancer significantly reduces tumor growth, increases tumor doubling times, and enhances overall survival. In conclusion, miR-195 controls MICU1 levels in ovarian cancer and could be exploited to normalize aberrant MICU1 expression, thus reversing both glycolysis and chemoresistance and consequently improving patient outcomes., (© 2020 The Authors.)

Machine learning (ML) has been increasingly used within cardiology, particularly in the domain of cardiovascular imaging. Due to the inherent complexity and flexibility of ML algorithms, inconsistencies in the model performance and interpretation may occur. Several review articles have been recently published that introduce the fundamental principles and clinical application of ML for cardiologists. This paper builds on these introductory principles and outlines a more comprehensive list of crucial responsibilities that need to be completed when developing ML models. This paper aims to serve as a scientific foundation to aid investigators, data scientists, authors, editors, and reviewers involved in machine learning research with the intent of uniform reporting of ML investigations. An independent multidisciplinary panel of ML experts, clinicians, and statisticians worked together to review the theoretical rationale underlying 7 sets of requirements that may reduce algorithmic errors and biases. Finally, the paper summarizes a list of reporting items as an itemized checklist that highlights steps for ensuring correct application of ML models and the consistent reporting of model specifications and results. It is expected that the rapid pace of research and development and the increased availability of real-world evidence may require periodic updates to the checklist., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Plants are essential facilitators of human life on planet earth. Plants play a critical functional role in mediating the quality of air, availability of food and the sustainability of agricultural resources. However, plants are in constant interaction with its environment and often hampered by various types of stresses like biotic and abiotic ones. Biotic stress is a significant reason for crop-loss and causes yield loss in the range of 31-42%, post-harvest loss due to biotic stress is in the range of 6-20%, and abiotic stress causes 6-20% of the crop damage. Recognizing the molecular factors driving plant stress-related events, and developing molecular strategies to aid plants to tolerate, resist or adapt to biotic and abiotic stress are critical for sustainable agriculture practice. In this review, we discuss how recent advances in bioinformatics, plant genomics, and data science could help to improve our understanding of plant stress biology and improve the scale of global food production. We present various areas of scientific and technological advances, such as increased availability of genomics data through whole genome sequencing that require attention. We also discuss emerging techniques including CRISPR-Cas9 based genome engineering systems to develop plant varieties that can handle combinatorial stress signals. Growing trend of converging multiple omics technologies and availability of accurate, multi-scale models of plant stress through the study of orthologs and synteny studies, would improve our knowledge of how plants perceive, respond, and manage stress to thrive as resilient crop species and thus help to reduce global food crisis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Fibrous cap thickness (FCT), best measured by intravascular optical coherence tomography (OCT), is the most important determinant of plaque rupture in the coronary arteries. Statin treatment increases FCT and thus reduces the likelihood of acute coronary events. However, substantial statin-related FCT increase occurs in only a subset of patients. Currently, there are no methods to predict which patients will benefit. We use transcriptomic data from a clinical trial of rosuvastatin to predict if a patient's FCT will increase in response to statin therapy., Methods: FCT was measured using OCT in 69 patients at (1) baseline and (2) after 8-10 weeks of 40  mg rosuvastatin. Peripheral blood mononuclear cells were assayed via microarray. We constructed machine learning models with baseline gene expression data to predict change in FCT. Finally, we ascertained the biological functions of the most predictive transcriptomic markers., Findings: Machine learning models were able to predict FCT responders using baseline gene expression with high fidelity (Classification AUC = 0.969 and 0.972). The first model (elastic net) using 73 genes had an accuracy of 92.8%, sensitivity of 94.1%, and specificity of 91.4%. The second model (KTSP) using 18 genes has an accuracy of 95.7%, sensitivity of 94.3%, and specificity of 97.1%. We found 58 enriched gene ontology terms, including many involved with immune cell function and cholesterol biometabolism., Interpretation: In this pilot study, transcriptomic models could predict if FCT increased following 8-10 weeks of rosuvastatin. These findings may have significance for therapy selection and could supplement invasive imaging modalities., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Worldwide, over 14% of individuals hospitalized for psychiatric reasons have readmissions to hospitals within 30 days after discharge. Predicting patients at risk and leveraging accelerated interventions can reduce the rates of early readmission, a negative clinical outcome (i.e., a treatment failure) that affects the quality of life of patient. To implement individualized interventions, it is necessary to predict those individuals at highest risk for 30-day readmission. In this study, our aim was to conduct a data-driven investigation to find the pharmacological factors influencing 30-day all-cause, intra- and interdepartmental readmissions after an index psychiatric admission, using the compendium of prescription data (prescriptome) from electronic medical records (EMR)., Methods: The data scientists in the project received a deidentified database from the Mount Sinai Data Warehouse, which was used to perform all analyses. Data was stored in a secured MySQL database, normalized and indexed using a unique hexadecimal identifier associated with the data for psychiatric illness visits. We used Bayesian logistic regression models to evaluate the association of prescription data with 30-day readmission risk. We constructed individual models and compiled results after adjusting for covariates, including drug exposure, age, and gender. We also performed digital comorbidity survey using EMR data combined with the estimation of shared genetic architecture using genomic annotations to disease phenotypes., Results: Using an automated, data-driven approach, we identified prescription medications, side effects (primary side effects), and drug-drug interaction-induced side effects (secondary side effects) associated with readmission risk in a cohort of 1275 patients using prescriptome analytics. In our study, we identified 28 drugs associated with risk for readmission among psychiatric patients. Based on prescription data, Pravastatin had the highest risk of readmission (OR = 13.10; 95% CI (2.82, 60.8)). We also identified enrichment of primary side effects (n = 4006) and secondary side effects (n = 36) induced by prescription drugs in the subset of readmitted patients (n = 89) compared to the non-readmitted subgroup (n = 1186). Digital comorbidity analyses and shared genetic analyses further reveals that cardiovascular disease and psychiatric conditions are comorbid and share functional gene modules (cardiomyopathy and anxiety disorder: shared genes (n = 37; P = 1.06815E-06))., Conclusions: Large scale prescriptome data is now available from EMRs and accessible for analytics that could improve healthcare outcomes. Such analyses could also drive hypothesis and data-driven research. In this study, we explored the utility of prescriptome data to identify factors driving readmission in a psychiatric cohort. Converging digital health data from EMRs and systems biology investigations reveal a subset of patient populations that have significant comorbidities with cardiovascular diseases are more likely to be readmitted. Further, the genetic architecture of psychiatric illness also suggests overlap with cardiovascular diseases. In summary, assessment of medications, side effects, and drug-drug interactions in a clinical setting as well as genomic information using a data mining approach could help to find factors that could help to lower readmission rates in patients with mental illness.

Currently, drug discovery approaches focus on the design of therapies that alleviate an index symptom by reengineering the underlying biological mechanism in agonistic or antagonistic fashion. For example, medicines are routinely developed to target an essential gene that drives the disease mechanism. Therapeutic overloading where patients get multiple medications to reduce the primary and secondary side effect burden is standard practice. This single-symptom based approach may not be scalable, as we understand that diseases are more connected than random and molecular interactions drive disease comorbidities. In this work, we present a proof-of-concept drug discovery strategy by combining network biology, disease comorbidity estimates, and computational drug repositioning, by targeting the risk factors and comorbidities of peripheral artery disease, a vascular disease associated with high morbidity and mortality. Individualized risk estimation and recommending disease sequelae based therapies may help to lower the mortality and morbidity of peripheral artery disease.

Hypertension is a major risk factor for ischemic cardiovascular disease and cerebrovascular disease, which are respectively the primary and secondary most common causes of morbidity and mortality across the globe. To alleviate the risks of hypertension, there are a number of effective antihypertensive drugs available. However, the optimal treatment blood pressure goal for antihypertensive therapy remains an area of controversy. The results of the recent Systolic Blood Pressure Intervention Trial (SPRINT) trial, which found benefits for intensive lowering of systolic blood pressure, have been debated for several reasons. We aimed to assess the benefits of treating to four different blood pressure targets and to compare our results to those of SPRINT using a method for causal inference called the parametric g formula. We applied this method to blood pressure measurements obtained from the electronic health records of approximately 200,000 patients who visited the Mount Sinai Hospital in New York, NY. We simulated the effect of four clinically relevant dynamic treatment regimes, assessing the effectiveness of treating to four different blood pressure targets: 150 mmHg, 140 mmHg, 130 mmHg, and 120 mmHg. In contrast to current American Heart Association guidelines and in concordance with SPRINT, we find that targeting 120 mmHg systolic blood pressure is significantly associated with decreased incidence of major adverse cardiovascular events. Causal inference methods applied to electronic methods are a powerful and flexible technique and medicine may benefit from their increased usage.

Accurate and robust cohort definition is critical to biomedical discovery using Electronic Health Records (EHR). Similar to prospective study designs, high quality EHR-based research requires rigorous selection criteria to designate case/control status particular to each disease. Electronic phenotyping algorithms, which are manually built and validated per disease, have been successful in filling this need. However, these approaches are time-consuming, leading to only a relatively small amount of algorithms for diseases developed. Methodologies that automatically learn features from EHRs have been used for cohort selection as well. To date, however, there has been no systematic analysis of how these methods perform against current gold standards. Accordingly, this paper compares the performance of a state-of-the-art automated feature learning method to extracting research-grade cohorts for five diseases against their established electronic phenotyping algorithms. In particular, we use word2vec to create unsupervised embeddings of the phenotype space within an EHR system. Using medical concepts as a query, we then rank patients by their proximity in the embedding space and automatically extract putative disease cohorts via a distance threshold. Experimental evaluation shows promising results with average F-score of 0.57 and AUC-ROC of 0.98. However, we noticed that results varied considerably between diseases, thus necessitating further investigation and/or phenotype-specific refinement of the approach before being readily deployed across all diseases.

The traditional paradigm of cardiovascular disease research derives insight from large-scale, broadly inclusive clinical studies of well-characterized pathologies. These insights are then put into practice according to standardized clinical guidelines. However, stagnation in the development of new cardiovascular therapies and variability in therapeutic response implies that this paradigm is insufficient for reducing the cardiovascular disease burden. In this state-of-the-art review, we examine 3 interconnected ideas we put forth as key concepts for enabling a transition to precision cardiology: 1) precision characterization of cardiovascular disease with machine learning methods; 2) the application of network models of disease to embrace disease complexity; and 3) using insights from the previous 2 ideas to enable pharmacology and polypharmacology systems for more precise drug-to-patient matching and patient-disease stratification. We conclude by exploring the challenges of applying a precision approach to cardiology, which arise from a deficit of the required resources and infrastructure, and emerging evidence for the clinical effectiveness of this nascent approach.

Whether disclosure of genetic risk for coronary heart disease (CHD) influences shared decision-making (SDM) regarding use of statins to reduce CHD risk is unknown. We randomized 207 patients, age 45-65 years, at intermediate CHD risk, and not on statins, to receive the 10-year risk of CHD based on conventional risk factors alone (n=103) or in combination with a genetic risk score (n=104). A genetic counselor disclosed this information followed by a physician visit for SDM regarding statin therapy. A novel decision aid was used in both encounters to disclose the CHD risk estimates and facilitate SDM regarding statin use. Patients reported their decision quality and physician visit satisfaction using validated surveys. There were no statistically significant differences between the two groups in the SDM score, satisfaction with the clinical encounter, perception of the quality of the discussion or of participation in decision-making and physician visit satisfaction scores. Quantitative analyses of a random subset of 80 video-recorded encounters using the OPTION5 scale also showed no significant difference in SDM between the two groups. Disclosure of CHD genetic risk using an electronic health record-linked decision aid did not adversely affect SDM or patients' satisfaction with the clinical encounter., Trial Registration Number: NCT01936675; Results., (Copyright © 2017 American Federation for Medical Research.)

Reduction of preventable hospital readmissions that result from chronic or acute conditions like stroke, heart failure, myocardial infarction and pneumonia remains a significant challenge for improving the outcomes and decreasing the cost of healthcare delivery in the United States. Patient readmission rates are relatively high for conditions like heart failure (HF) despite the implementation of high-quality healthcare delivery operation guidelines created by regulatory authorities. Multiple predictive models are currently available to evaluate potential 30-day readmission rates of patients. Most of these models are hypothesis driven and repetitively assess the predictive abilities of the same set of biomarkers as predictive features. In this manuscript, we discuss our attempt to develop a data-driven, electronic-medical record-wide (EMR-wide) feature selection approach and subsequent machine learning to predict readmission probabilities. We have assessed a large repertoire of variables from electronic medical records of heart failure patients in a single center. The cohort included 1,068 patients with 178 patients were readmitted within a 30-day interval (16.66% readmission rate). A total of 4,205 variables were extracted from EMR including diagnosis codes (n=1,763), medications (n=1,028), laboratory measurements (n=846), surgical procedures (n=564) and vital signs (n=4). We designed a multistep modeling strategy using the Naïve Bayes algorithm. In the first step, we created individual models to classify the cases (readmitted) and controls (non-readmitted). In the second step, features contributing to predictive risk from independent models were combined into a composite model using a correlation-based feature selection (CFS) method. All models were trained and tested using a 5-fold cross-validation method, with 70% of the cohort used for training and the remaining 30% for testing. Compared to existing predictive models for HF readmission rates (AUCs in the range of 0.6-0.7), results from our EMR-wide predictive model (AUC=0.78; Accuracy=83.19%) and phenome-wide feature selection strategies are encouraging and reveal the utility of such datadriven machine learning. Fine tuning of the model, replication using multi-center cohorts and prospective clinical trial to evaluate the clinical utility would help the adoption of the model as a clinical decision system for evaluating readmission status.

Monitoring and modeling biomedical, health care and wellness data from individuals and converging data on a population scale have tremendous potential to improve understanding of the transition to the healthy state of human physiology to disease setting. Wellness monitoring devices and companion software applications capable of generating alerts and sharing data with health care providers or social networks are now available. The accessibility and clinical utility of such data for disease or wellness research are currently limited. Designing methods for streaming data capture, real-time data aggregation, machine learning, predictive analytics and visualization solutions to integrate wellness or health monitoring data elements with the electronic medical records (EMRs) maintained by health care providers permits better utilization. Integration of population-scale biomedical, health care and wellness data would help to stratify patients for active health management and to understand clinically asymptomatic patients and underlying illness trajectories. In this article, we discuss various health-monitoring devices, their ability to capture the unique state of health represented in a patient and their application in individualized diagnostics, prognosis, clinical or wellness intervention. We also discuss examples of translational bioinformatics approaches to integrating patient-generated data with existing EMRs, personal health records, patient portals and clinical data repositories. Briefly, translational bioinformatics methods, tools and resources are at the center of these advances in implementing real-time biomedical and health care analytics in the clinical setting. Furthermore, these advances are poised to play a significant role in clinical decision-making and implementation of data-driven medicine and wellness care., (© The Author 2016. Published by Oxford University Press.)

Data in the biological, chemical, and clinical domains are accumulating at ever-increasing rates and have the potential to accelerate and inform drug development in new ways. Challenges and opportunities now lie in developing analytic tools to transform these often complex and heterogeneous data into testable hypotheses and actionable insights. This is the aim of computational pharmacology, which uses in silico techniques to better understand and predict how drugs affect biological systems, which can in turn improve clinical use, avoid unwanted side effects, and guide selection and development of better treatments. One exciting application of computational pharmacology is drug repurposing-finding new uses for existing drugs. Already yielding many promising candidates, this strategy has the potential to improve the efficiency of the drug development process and reach patient populations with previously unmet needs such as those with rare diseases. While current techniques in computational pharmacology and drug repurposing often focus on just a single data modality such as gene expression or drug-target interactions, we argue that methods such as matrix factorization that can integrate data within and across diverse data types have the potential to improve predictive performance and provide a fuller picture of a drug's pharmacological action. WIREs Syst Biol Med 2016, 8:186-210. doi: 10.1002/wsbm.1337 For further resources related to this article, please visit the WIREs website., (© 2016 Wiley Periodicals, Inc.)

Differentially evolved responses to various stress conditions in plants are controlled by complex regulatory circuits of transcriptional activators, and repressors, such as transcription factors (TFs). To understand the general and condition-specific activities of the TFs and their regulatory relationships with the target genes (TGs), we have used a homogeneous stress gene expression dataset generated on ten natural ecotypes of the model plant Arabidopsis thaliana, during five single and six combined stress conditions. Knowledge-based profiles of binding sites for 25 stress-responsive TF families (187 TFs) were generated and tested for their enrichment in the regulatory regions of the associated TGs. Condition-dependent regulatory sub-networks have shed light on the differential utilization of the underlying network topology, by stress-specific regulators and multifunctional regulators. The multifunctional regulators maintain the core stress response processes while the transient regulators confer the specificity to certain conditions. Clustering patterns of transcription factor binding sites (TFBS) have reflected the combinatorial nature of transcriptional regulation, and suggested the putative role of the homotypic clusters of TFBS towards maintaining transcriptional robustness against cis-regulatory mutations to facilitate the preservation of stress response processes. The Gene Ontology enrichment analysis of the TGs reflected sequential regulation of stress response mechanisms in plants., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

In the past decade there has been an explosion in genetic research that has resulted in the generation of enormous quantities of disease-related data. In the current study, we have compiled disease risk gene variant information and Electronic Medical Record (EMR) classification codes from various repositories for 305 diseases. Using such data, we developed a pipeline to test for clinical prevalence, gene-variant overlap, and literature presence for all 46,360 unique diseases pairs. To determine whether disease pairs were enriched we systematically employed both Fishers' Exact (medical and literature) and Term Frequency-Inverse Document Frequency (genetics) methodologies to test for enrichment, defining statistical significance at a Bonferonni adjusted threshold of (p < 1 × 10(-6)) and weighted q < 0.05 accordingly. We hypothesize that disease pairs that are statistically enriched in medical and genetic spheres, but not so in the literature have the potential to reveal non-obvious connections between clinically disparate phenotypes. Using this pipeline, we identified 2,316 disease pairs that were significantly enriched within an EMR and 213 enriched genetically. Of these, 65 disease pairs were statistically enriched in both, 19 of which are believed to be novel. These identified non-obvious relationships between disease pairs are suggestive of a shared underlying etiology with clinical presentation. Further investigation of uncovered disease-pair relationships has the potential to provide insights into the architecture of complex diseases, and update existing knowledge of risk factors.

Rapid development of next generation sequencing technology has enabled the identification of genomic alterations from short sequencing reads. There are a number of software pipelines available for calling single nucleotide variants from genomic DNA but, no comprehensive pipelines to identify, annotate and prioritize expressed SNVs (eSNVs) from non-directional paired-end RNA-Seq data. We have developed the eSNV-Detect, a novel computational system, which utilizes data from multiple aligners to call, even at low read depths, and rank variants from RNA-Seq. Multi-platform comparisons with the eSNV-Detect variant candidates were performed. The method was first applied to RNA-Seq from a lymphoblastoid cell-line, achieving 99.7% precision and 91.0% sensitivity in the expressed SNPs for the matching HumanOmni2.5 BeadChip data. Comparison of RNA-Seq eSNV candidates from 25 ER+ breast tumors from The Cancer Genome Atlas (TCGA) project with whole exome coding data showed 90.6-96.8% precision and 91.6-95.7% sensitivity. Contrasting single-cell mRNA-Seq variants with matching traditional multicellular RNA-Seq data for the MD-MB231 breast cancer cell-line delineated variant heterogeneity among the single-cells. Further, Sanger sequencing validation was performed for an ER+ breast tumor with paired normal adjacent tissue validating 29 out of 31 candidate eSNVs. The source code and user manuals of the eSNV-Detect pipeline for Sun Grid Engine and virtual machine are available at http://bioinformaticstools.mayo.edu/research/esnv-detect/., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized genetic variants associated with MPV and PLT using functional, pathway and disease enrichment analyses; we assessed pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic network had data for PLT and 6,291 participants had data for MPV. We identified five chromosomal regions associated with PLT and eight associated with MPV at genome-wide significance (P < 5E-8). In addition, we replicated 20 SNPs [out of 56 SNPs (α: 0.05/56 = 9E-4)] influencing PLT and 22 SNPs [out of 29 SNPs (α: 0.05/29 = 2E-3)] influencing MPV in a published meta-analysis of GWAS of PLT and MPV. While our GWAS did not find any new associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development, and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1,368 diagnoses (0.05/1368 = 3.6E-5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune, and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis.

Predicting functions of proteins and alternatively spliced isoforms encoded in a genome is one of the important applications of bioinformatics in the post-genome era. Due to the practical limitation of experimental characterization of all proteins encoded in a genome using biochemical studies, bioinformatics methods provide powerful tools for function annotation and prediction. These methods also help minimize the growing sequence-to-function gap. Phylogenetic profiling is a bioinformatics approach to identify the influence of a trait across species and can be employed to infer the evolutionary history of proteins encoded in genomes. Here we propose an improved phylogenetic profile-based method which considers the co-evolution of the reference genome to derive the basic similarity measure, the background phylogeny of target genomes for profile generation and assigning weights to target genomes. The ordering of genomes and the runs of consecutive matches between the proteins were used to define phylogenetic relationships in the approach. We used Escherichia coli K12 genome as the reference genome and its 4195 proteins were used in the current analysis. We compared our approach with two existing methods and our initial results show that the predictions have outperformed two of the existing approaches. In addition, we have validated our method using a targeted protein-protein interaction network derived from protein-protein interaction database STRING. Our preliminary results indicates that improvement in function prediction can be attained by using coevolution-based similarity measures and the runs on to the same scale instead of computing them in different scales. Our method can be applied at the whole-genome level for annotating hypothetical proteins from prokaryotic genomes.

Objective: To identify common genetic variants influencing red blood cell (RBC) traits., Patients and Methods: We performed a genomewide association study from June 2008 through July 2011 of hemoglobin, hematocrit, RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration in 12,486 patients of European ancestry from the electronic MEdical Records and Genomics (eMERGE) network. We developed an electronic medical record-based algorithm that included individuals who had RBC measurements obtained for clinical care and excluded values measured in the setting of hematopoietic disorders, comorbid conditions, or medications known to affect RBC production or a recent history of blood loss., Results: We identified 4 new genetic loci and replicated 11 loci previously reported to be associated with one or more RBC traits in individuals of European ancestry. Notably, genes present in 3 of the 4 newly identified loci (THRB, PTPLAD1, CDT1) and in 6 of the 11 replicated loci (KLF1, ALDH8A1, CCND3, SPTA1, FBXO7, TFR2/EPO) are implicated in erythroid differentiation and regulation of cell cycle in hematopoietic stem cells., Conclusion: Genes in the erythroid differentiation and cell cycle regulation pathways influence interindividual variation in RBC indices. Our results provide insights into the molecular basis underlying variation in RBC traits., (Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Protein families could be related to each other at broad levels that group them as superfamilies. These relationships are harder to detect at the sequence level due to high evolutionary divergence. Sequence searches are strongly directed and influenced by the best representatives of families that are viewed as starting points. PSSMs are useful approximations and mathematical representations of protein alignments, with wide array of applications in bioinformatics approaches like remote homology detection, protein family analysis, detection of new members and evolutionary modelling. Computational intensive searches have been performed using the neural network based sensitive sequence search method called FASSM to identify the Best Representative PSSMs for families reported in Pfam database version 22., Results: We designed a novel data mining approach for the assessment of individual sequences from a protein family to identify a single Best Representative PSSM profile (BRP) per protein family. Using the approach, a database of protein family-specific best representative PSSM profiles called 3PFDB has been developed. PSSM profiles in 3PFDB are curated using performance of individual sequence as a reference in a rigorous scoring and coverage analysis approach using FASSM. We have assessed the suitability of 10, 85,588 sequences derived from seed or full alignments reported in Pfam database (Version 22). Coverage analysis using FASSM method is used as the filtering step to identify the best representative sequence, starting from full length or domain sequences to generate the final profile for a given family. 3PFDB is a collection of best representative PSSM profiles of 8,524 protein families from Pfam database., Conclusion: Availability of an approach to identify BRPs and a curated database of best representative PSI-BLAST derived PSSMs for 91.4% of current Pfam family will be a useful resource for the community to perform detailed and specific analysis using family-specific, best-representative PSSM profiles. 3PFDB can be accessed using the URL: http://caps.ncbs.res.in/3pfdb.