Genetic analyses of inflammatory polyneuropathy and chronic inflammatory demyelinating polyradiculoneuropathy identified candidate genes.

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 UK biobank (UKBB) 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, 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 analysis should be conducted to further confirm these associations.

Drug-food Interactions in the Era of Molecular Big Data, Machine Intelligence, and Personalized Health.

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.

Breakthroughs and Applications of Organ-on-a-Chip Technology.

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.

StarGazer: A Hybrid Intelligence Platform for Drug Target Prioritization and Digital Drug Repositioning Using Streamlit.

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.

OSPred Tool: A Digital Health Aid for Rapid Predictive Analysis of Correlations Between Early End Points and Overall Survival in Non-Small-Cell Lung Cancer Clinical Trials.

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.

Predictive Modelling of Susceptibility to Substance Abuse, Mortality and Drug-Drug Interactions in Opioid Patients.

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.

SAEgnal: A Predictive Assessment Framework for Optimizing Safety Profiles in Immuno-Oncology Combination Trials.

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.

Correlation Between Early Endpoints and Overall Survival in Non-Small-Cell Lung Cancer: A Trial-Level Meta-Analysis.

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.

The role of machine learning in clinical research: transforming the future of evidence generation.

BACKGROUND: Interest in the application of machine learning (ML) to the design, conduct, and analysis of clinical trials has grown, but the evidence base for such applications has not been surveyed. This manuscript reviews the proceedings of a multi-stakeholder conference to discuss the current and future state of ML for clinical research. Key areas of clinical trial methodology in which ML holds particular promise and priority areas for further investigation are presented alongside a narrative review of evidence supporting the use of ML across the clinical trial spectrum. RESULTS: Conference attendees included stakeholders, such as biomedical and ML researchers, representatives from the US Food and Drug Administration (FDA), artificial intelligence technology and data analytics companies, non-profit organizations, patient advocacy groups, and pharmaceutical companies. ML contributions to clinical research were highlighted in the pre-trial phase, cohort selection and participant management, and data collection and analysis. A particular focus was paid to the operational and philosophical barriers to ML in clinical research. Peer-reviewed evidence was noted to be lacking in several areas. CONCLUSIONS: ML holds great promise for improving the efficiency and quality of clinical research, but substantial barriers remain, the surmounting of which will require addressing significant gaps in evidence.

High Precision Mammography Lesion Identification From Imprecise Medical Annotations.

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%.

Proposed Requirements for Cardiovascular Imaging-Related Machine Learning Evaluation (PRIME): A Checklist: Reviewed by the American College of Cardiology Healthcare Innovation Council.

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.

MicroRNA-195 controls MICU1 expression and tumor growth in ovarian cancer.

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.

KRCC1: A potential therapeutic target in ovarian cancer.

Using a systems biology approach to prioritize potential points of intervention in ovarian cancer, we identified the lysine rich coiled-coil 1 (KRCC1), as a potential target. High-grade serous ovarian cancer patient tumors and cells express significantly higher levels of KRCC1 which correlates with poor overall survival and chemoresistance. We demonstrate that KRCC1 is predominantly present in the chromatin-bound nuclear fraction, interacts with HDAC1, HDAC2, and with the serine-threonine phosphatase PP1CC. Silencing KRCC1 inhibits cellular plasticity, invasive properties, and potentiates apoptosis resulting in reduced tumor growth. These phenotypes are associated with increased acetylation of histones and with increased phosphorylation of H2AX and CHK1, suggesting the modulation of transcription and DNA damage that may be mediated by the action of HDAC and PP1CC, respectively. Hence, we address an urgent need to develop new targets in cancer.

Sepsis in the era of data-driven medicine: personalizing risks, diagnoses, treatments and prognoses.

Sepsis is a series of clinical syndromes caused by the immunological response to infection. The clinical evidence for sepsis could typically attribute to bacterial infection or bacterial endotoxins, but infections due to viruses, fungi or parasites could also lead to sepsis. Regardless of the etiology, rapid clinical deterioration, prolonged stay in intensive care units and high risk for mortality correlate with the incidence of sepsis. Despite its prevalence and morbidity, improvement in sepsis outcomes has remained limited. In this comprehensive review, we summarize the current landscape of risk estimation, diagnosis, treatment and prognosis strategies in the setting of sepsis and discuss future challenges. We argue that the advent of modern technologies such as in-depth molecular profiling, biomedical big data and machine intelligence methods will augment the treatment and prevention of sepsis. The volume, variety, veracity and velocity of heterogeneous data generated as part of healthcare delivery and recent advances in biotechnology-driven therapeutics and companion diagnostics may provide a new wave of approaches to identify the most at-risk sepsis patients and reduce the symptom burden in patients within shorter turnaround times. Developing novel therapies by leveraging modern drug discovery strategies including computational drug repositioning, cell and gene-therapy, clustered regularly interspaced short palindromic repeats -based genetic editing systems, immunotherapy, microbiome restoration, nanomaterial-based therapy and phage therapy may help to develop treatments to target sepsis. We also provide empirical evidence for potential new sepsis targets including FER and STARD3NL. Implementing data-driven methods that use real-time collection and analysis of clinical variables to trace, track and treat sepsis-related adverse outcomes will be key. Understanding the root and route of sepsis and its comorbid conditions that complicate treatment outcomes and lead to organ dysfunction may help to facilitate identification of most at-risk patients and prevent further deterioration. To conclude, leveraging the advances in precision medicine, biomedical data science and translational bioinformatics approaches may help to develop better strategies to diagnose and treat sepsis in the next decade.

Correction to: Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits.

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Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits.

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.

Genome-wide analysis indicates association between heterozygote advantage and healthy aging in humans.

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.

A transcriptomic model to predict increase in fibrous cap thickness in response to high-dose statin treatment: Validation by serial intracoronary OCT imaging.

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.

CANDI: an R package and Shiny app for annotating radiographs and evaluating computer-aided diagnosis.

MOTIVATION: Radiologists have used algorithms for Computer-Aided Diagnosis (CAD) for decades. These algorithms use machine learning with engineered features, and there have been mixed findings on whether they improve radiologists' interpretations. Deep learning offers superior performance but requires more training data and has not been evaluated in joint algorithm-radiologist decision systems. RESULTS: We developed the Computer-Aided Note and Diagnosis Interface (CANDI) for collaboratively annotating radiographs and evaluating how algorithms alter human interpretation. The annotation app collects classification, segmentation, and image captioning training data, and the evaluation app randomizes the availability of CAD tools to facilitate clinical trials on radiologist enhancement. AVAILABILITY AND IMPLEMENTATION: Demonstrations and source code are hosted at (https://candi.nextgenhealthcare.org), and (https://github.com/mbadge/candi), respectively, under GPL-3 license. SUPPLEMENTARY INFORMATION: Supplementary material is available at Bioinformatics online.