Integrated bioinformatics analysis identified leucine rich repeat containing 15 and secreted phosphoprotein 1 as hub genes for calcific aortic valve disease and osteoarthritis.

Calcific aortic valve disease (CAVD) and osteoarthritis (OA) are common diseases in the ageing population and share similar pathogenesis, especially in inflammation. This study aims to discover potential diagnostic and therapeutic targets in patients with CAVD and OA. Three CAVD datasets and one OA dataset were obtained from the Gene Expression Omnibus database. We used bioinformatics methods to search for key genes and immune infiltration, and established a ceRNA network. Immunohistochemical staining was performed to verify the expression of candidate genes in human and mice aortic valve tissues. Two key genes obtained, leucine rich repeat containing 15 (LRRC15) and secreted phosphoprotein 1 (SPP1), were further screened using machine learning and verified in human and mice aortic valve tissues. Compared to normal tissues, the infiltration of immune cells in CAVD tissues was significantly higher, and the expressions of LRRC15 and SPP1 were positively correlated with immune cells infiltration. Moreover, the ceRNA network showed extensive regulatory interactions based on LRRC15 and SPP1. The authors' findings identified LRRC15 and SPP1 as hub genes in immunological mechanisms during CAVD and OA initiation and progression, as well as potential targets for drug development.

Methods of strategic road safety management: a systematic review.

A well-developed road network plays a crucial role in fostering social and economic progress within a region. However, road crashes resulting in massive injuries and deaths profoundly affect socioeconomic development. There is a need therefore to identify working approaches used in road safety strategic management which provide evidence and a foundation to achieve safer road transport. This may be achieved through a systematic literature review considering both state-of-the-art technologies and best practice. Such a review is presented in this paper. The review involved searching twenty-six bibliographic databases and twenty-four websites of road-related organizations. Following the EPPI-Reviewer methodology, the researchers identified 30 studies that demonstrated various methods employed in the strategy development process. The review highlighted the prevalence of information technology in crash data analysis, particularly concerning big data applications. Moreover, existing resource allocation methods primarily focus on local countermeasures prioritization and ranking based on benefit cost analysis. However, the review identified a gap in comprehensive crash database understanding, and only a few single-objective optimization methods have been developed for strategy development, while there is a need for data mining methods and multi-objective optimisation methods supported by expert knowledge.

Livestock and environmental characterization of Colombian municipalities: study of vesicular stomatitis.

Amid the surge in data volume generated across various fields of knowledge, there is an increasing necessity for advanced analytical methodologies to effectively process and utilize this information. Particularly in the field of animal health, this approach is pivotal for enhancing disease understanding, surveillance, and management. The main objective of the study was to conduct a comprehensive livestock and environmental characterization of Colombian municipalities and examine their relationship with the distribution of vesicular stomatitis (VS). Utilizing satellite imagery to delineate climatic and land use profiles, along with data from the Colombian Agricultural Institute (ICA) concerning animal populations and their movements, the research employed Principal Component Analysis (PCA) to explore the correlation between environmental and livestock-related variables. Additionally, municipalities were grouped through a Hierarchical Clustering process. The assessment of risk associated with VS was carried out using a Generalized Linear Model. This process resulted in the formation of four distinct clusters: three primarily characterized by climatic attributes and one predominantly defined by livestock characteristics. Cluster 1, identified as "Andino" due to its climatic and environmental features, exhibited the highest odds ratio for VS occurrence. The adopted methodology not only provides a deeper understanding of the local population and its context, but also offers valuable insights for enhancing disease surveillance and control programs.

SEB: a computational tool for symbolic derivation of the small-angle scattering from complex composite structures.

Analysis of small-angle scattering (SAS) data requires intensive modeling to infer and characterize the structures present in a sample. This iterative improvement of models is a time-consuming process. Presented here is Scattering Equation Builder (SEB), a C++ library that derives exact analytic expressions for the form factors of complex composite structures. The user writes a small program that specifies how the sub-units should be linked to form a composite structure and calls SEB to obtain an expression for the form factor. SEB supports e.g. Gaussian polymer chains and loops, thin rods and circles, solid spheres, spherical shells and cylinders, and many different options for how these can be linked together. The formalism behind SEB is presented and simple case studies are given, such as block copolymers with different types of linkage, as well as more complex examples, such as a random walk model of 100 linked sub-units, dendrimers, polymers and rods attached to the surfaces of geometric objects, and finally the scattering from a linear chain of five stars, where each star is built up of four diblock copolymers. These examples illustrate how SEB can be used to develop complex models and hence reduce the cost of analyzing SAS data.

The Pixel Anomaly Detection Tool: a user-friendly GUI for classifying detector frames using machine-learning approaches.

Data collection at X-ray free electron lasers has particular experimental challenges, such as continuous sample delivery or the use of novel ultrafast high-dynamic-range gain-switching X-ray detectors. This can result in a multitude of data artefacts, which can be detrimental to accurately determining structure-factor amplitudes for serial crystallography or single-particle imaging experiments. Here, a new data-classification tool is reported that offers a variety of machine-learning algorithms to sort data trained either on manual data sorting by the user or by profile fitting the intensity distribution on the detector based on the experiment. This is integrated into an easy-to-use graphical user interface, specifically designed to support the detectors, file formats and software available at most X-ray free electron laser facilities. The highly modular design makes the tool easily expandable to comply with other X-ray sources and detectors, and the supervised learning approach enables even the novice user to sort data containing unwanted artefacts or perform routine data-analysis tasks such as hit finding during an experiment, without needing to write code.

Data cleaning for clinician researchers: Application and explanation of a data-quality framework.

BACKGROUND: Data cleaning is the series of procedures performed before a formal statistical analysis, with the aim of reducing the number of error values in a dataset and improving the overall quality of subsequent analyses. Several study-reporting guidelines recommend the inclusion of data-cleaning procedures; however, little practical guidance exists for how to conduct these procedures. OBJECTIVES: This paper aimed to provide practical guidance for how to perform and report rigorous data-cleaning procedures. METHODS: A previously proposed data-quality framework was identified and used to facilitate the description and explanation of data-cleaning procedures. The broader data-cleaning process was broken down into discrete tasks to create a data-cleaning checklist. Examples of the how the various tasks had been undertaken for a previous study using data from the Australia and New Zealand Intensive Care Society Adult Patient Database were also provided. RESULTS: Data-cleaning tasks were described and grouped according to four data-quality domains described in the framework: data integrity, consistency, completeness, and accuracy. Tasks described include creation of a data dictionary, checking consistency of values across multiple variables, quantifying and managing missing data, and the identification and management of outlier values. The data-cleaning task checklist provides a practical summary of the various aspects of the data-cleaning process and will assist clinician researchers in performing this process in the future. CONCLUSIONS: Data cleaning is an integral part of any statistical analysis and helps ensure that study results are valid and reproducible. Use of the data-cleaning task checklist will facilitate the conduct of rigorous data-cleaning processes, with the aim of improving the quality of future research.

Data Collection and Sharing for Pathogen Surveillance: Making Sense of a Fragmented Global System.

RAND Europe was commissioned by the Novo Nordisk Foundation to conduct a study on pathogen surveillance and current initiatives. The study aims to provide an overview of the pathogen surveillance space internationally and the stakeholders involved, as well as to understand the strengths and weaknesses of different initiatives, the challenges of pathogen surveillance and how they have been addressed, and how data has been used to inform public health decision making. To do this, a scoping review of pathogen surveillance initiatives was conducted, and ten case studies were developed and selected for further review following a workshop attended by the Novo Nordisk Foundation and RAND Europe study team. Interviews were conducted with individuals involved in pathogen surveillance initiatives to gather additional information to develop case studies, and expert interviews addressed gaps in the pathogen surveillance space and models that would be helpful in filling these gaps.

Employing machine learning to enhance fracture recovery insights through gait analysis.

This study aimed to explore the potential of gait analysis coupled with supervised machine learning models as a predictive tool for assessing post-injury complications such as infection, malunion, or hardware irritation among individuals with lower extremity fractures. We prospectively identified participants with lower extremity fractures at a tertiary academic center. These participants underwent gait analysis with a chest-mounted inertial measurement unit device. Using customized software, the raw gait data were preprocessed, emphasizing 12 essential gait variables. The data were standardized, and several machine learning models, including XGBoost, logistic regression, support vector machine, LightGBM, and Random Forest, were trained, tested, and evaluated. Special attention was given to class imbalance, addressed using the synthetic minority oversampling technique (SMOTE). Additionally, we introduced a novel methodology to compute the post-injury recovery rate for gait variables, which operates independently of the time difference between the gait analyses of different participants. XGBoost was identified as the optimal model both before and after the application of SMOTE. Before using SMOTE, the model achieved an average test area under the ROC curve (AUC) of 0.90, with a 95% confidence interval (CI) of [0.79, 1.00], and an average test accuracy of 86%, with a 95% CI of [75%, 97%]. Through feature importance analysis, a pivotal role was attributed to the duration between the occurrence of the injury and the initial gait analysis. Data patterns over time revealed early aggressive physiological compensations, followed by stabilization phases, underscoring the importance of prompt gait analysis. χ2 analysis indicated a statistically significant higher readmission rate among participants with underlying medical conditions (p = 0.04). Although the complication rate was also higher in this group, the association did not reach statistical significance (p = 0.06), suggesting a more pronounced impact of medical conditions on readmission rates rather than on complications. This study highlights the transformative potential of integrating advanced machine learning techniques like XGBoost with gait analysis for orthopedic care. The findings underscore a shift toward a data-informed, proactive approach in orthopedics, enhancing patient outcomes through early detection and intervention. The χ2 analysis added crucial insights into the broader clinical implications, advocating for a comprehensive treatment strategy that accounts for the patient's overall health profile. The research paves the way for personalized, predictive medical care in orthopedics, emphasizing the importance of timely and tailored patient assessments.

The role of correspondence analysis in medical research.

Correspondence analysis (CA) is a multivariate statistical and visualization technique. CA is extremely useful in analyzing either two- or multi-way contingency tables, representing some degree of correspondence between columns and rows. The CA results are visualized in easy-to-interpret "bi-plots," where the proximity of items (values of categorical variables) represents the degree of association between presented items. In other words, items positioned near each other are more associated than those located farther away. Each bi-plot has two dimensions, named during the analysis. The naming of dimensions adds a qualitative aspect to the analysis. Correspondence analysis may support medical professionals in finding answers to many important questions related to health, wellbeing, quality of life, and similar topics in a simpler but more informal way than by using more complex statistical or machine learning approaches. In that way, it can be used for dimension reduction and data simplification, clustering, classification, feature selection, knowledge extraction, visualization of adverse effects, or pattern detection.

Spatial analysis toolkits for RNA in situ sequencing.

Spatial transcriptomics (ST) is featured by high-throughput gene expression profiling within their native cell and tissue context, offering a means to investigate gene regulatory networks in tissue microenvironment. In situ sequencing (ISS) is an imaging-based ST technology that simultaneously detects hundreds to thousands of genes at subcellular resolution. As a highly reproducible and robust technique, ISS has been widely adapted and undergone a series of technical iterations. As the interest in ISS-based spatial transcriptomic analysis grows, scalable and integrated data analysis workflows are needed to facilitate the applications of ISS in different research fields. This review presents the state-of-the-art bioinformatic toolkits for ISS data analysis, which covers the upstream and downstream analysis workflows, including image analysis, cell segmentation, clustering, functional enrichment, detection of spatially variable genes and cell clusters, spatial cell-cell interactions, and trajectory inference. To assist the community in choosing the right tools for their research, the application of each tool and its compatibility with ISS data are reviewed in detailed. Finally, future perspectives and challenges concerning how to integrate heterogeneous tools into a user-friendly analysis pipeline are discussed. This article is categorized under: RNA Methods > RNA Analyses In Vitro and In Silico.

Enricherator: A Bayesian Method for Inferring Regularized Genome-wide Enrichments from Sequencing Count Data.

A pervasive question in biological research studying gene regulation, chromatin structure, or genomics is where, and to what extent, does a signal of interest arise genome-wide? This question is addressed using a variety of methods relying on high-throughput sequencing data as their final output, including ChIP-seq for protein-DNA interactions,1 GapR-seq for measuring supercoiling,2 and HBD-seq or DRIP-seq for R-loop positioning.3,4 Current computational methods to calculate genome-wide enrichment of the signal of interest usually do not properly handle the count-based nature of sequencing data, they often do not make use of the local correlation structure of sequencing data, and they do not apply any regularization of enrichment estimates. This can result in unrealistic estimates of the true underlying biological enrichment of interest, unrealistically low estimates of confidence in point estimates of enrichment (or no estimates of confidence at all), unrealistic gyrations in enrichment estimates at very close (<10 bp) genomic loci due to noise inherent in sequencing data, and in a multiple-hypothesis testing problem during interpretation of genome-wide enrichment estimates. We developed a tool called Enricherator to infer genome-wide enrichments from sequencing count data. Enricherator uses the variational Bayes algorithm to fit a generalized linear model to sequencing count data and to sample from the approximate posterior distribution of enrichment estimates (https://github.com/jwschroeder3/enricherator). Enrichments inferred by Enricherator more precisely identify known binding sites in cases where low coverage between binding sites leads to false-positive peak calls in these noisy regions of the genome; these benefits extend to published datasets.

The relationship between joint kinematic patterns during single-leg drop landing and perceived instability in individuals with chronic ankle instability.

BACKGROUND: Perceived instability is a primary symptom among individuals with chronic ankle instability. However, the relationship between joint kinematics during landing remains unclear. Therefore, we investigated the relationships between landing kinematics and perceived instability in individuals with chronic ankle instability. METHODS: In 32 individuals with chronic ankle instability, we recorded ankle, knee, and hip joint angles during a single-leg drop landing. Joint angle waveforms during 200 ms before and after initial contact were summarized into single values using two methods: peak joint angles and principal component scores via principal component analysis. Using Spearman's rank correlation coefficient (ρ), we examined the relationships of peak joint angles and principal component scores with the Cumberland Ankle Instability Tool score, with a lower score indicating a greater perceived instability (α = 0.05). FINDINGS: The second principal component scores of ankle angle in the horizontal and sagittal planes significantly correlated with the Cumberland Ankle Instability Tool score (Horizontal: ρ = 0.507, P = 0.003; Sagittal: ρ = -0.359, P = 0.044). These scores indicated the differences in the magnitude of angles before and after landing. Significant correlations indicated a greater perceived instability correlated with smaller internal rotation and plantarflexion before landing and smaller external rotation and dorsiflexion after landing. In contrast, no peak joint angles correlated with the Cumberland Ankle Instability Tool score (P > 0.05). INTERPRETATION: In individuals with chronic ankle instability, ankle movements during landing associated with perceived instability may be a protective strategy before landing and potentially cause ankle instability after landing.

Exploring gene regulation and biological processes in insects: Insights from omics data using gene regulatory network models.

Gene regulatory network (GRN) comprises complicated yet intertwined gene-regulator relationships. Understanding the GRN dynamics will unravel the complexity behind the observed gene expressions. Insect gene regulation is often complicated due to their complex life cycles and diverse ecological adaptations. The main interest of this review is to have an update on the current mathematical modelling methods of GRNs to explain insect science. Several popular GRN architecture models are discussed, together with examples of applications in insect science. In the last part of this review, each model is compared from different aspects, including network scalability, computation complexity, robustness to noise and biological relevancy.

Analysis of post-market adverse events of istradefylline: a real-world study base on FAERS database.

Analyze the adverse event (AE) signals of istradefylline based on the FAERS database. By extracting large-scale data from the FAERS database, this study used various signal quantification techniques such as ROR, PRR, BCPNN, and MGPS to calculate and evaluate the ratio and association between istradefylline and specific AEs. In the FAERS database, this study extracted data from the third quarter of 2019 to the first quarter of 2023, totaling 6,749,750 AE reports. After data cleansing and drug screening, a total of 3633 AE reports related to istradefylline were included for analysis. Based on four calculation methods, this study unearthed 25 System Organ Class (SOC) AE signals and 82 potential preferred terms (PTs) related to istradefylline. The analysis revealed new AEs during istradefylline treatment, including reports of Parkinsonism hyperpyrexia syndrome (n = 3, ROR 178.70, PRR 178.63, IC 1.97, EBGM 165.63), Compulsions (n = 5, ROR 130.12, PRR 130.04, IC 2.53, EBGM 123.02), Deep brain stimulation (n = 10, ROR 114.42, PRR 114.27, IC 3.33, EBGM 108.83), and Freezing phenomenon (n = 60, ROR 97.52, PRR 96.76, IC 5.21, EBGM 92.83). This study provides new risk signals and important insights into the use of istradefylline, but further research and validation are needed, especially for those AE that may occur in actual usage scenarios but are not yet explicitly described in the instructions.

A survey into the current fitness testing practices of elite male soccer practitioners: from assessment to communicating results.

This study provides insight into the current fitness testing practices in elite male soccer. One hundred and two practitioners from professional soccer leagues across 24 countries completed an online survey comprising 29 questions, with five sections: a) background information, b) testing selection, c) testing implementation, d) data analysis, and e) data reporting. Frequency analysis was used to evaluate the responses to fixed response questions and thematic analysis was used for open-ended questions to generate clear and distinct themes. Strength (85%) and aerobic capacity (82%) represent the most frequently assessed physical qualities. Scientific literature (80%) is the most influential factor in testing selection and practitioners conduct fitness testing less frequently than their perceived ideal frequency per season (3.6 ± 2 vs. 4.5 ± 2). Time and competitive schedule were the greatest barriers to fitness testing administration. Practitioners mostly used a 'hybrid' approach (45%) to fitness testing, blending 'traditional' (i.e., a day dedicated to testing) and 'integrated' (i.e., testing within regular training sessions) methods. Microsoft Excel is the most used software for data analysis (95%) and visualization (79%). An equal use of the combination of best and mean scores of multiple trials (44%) and the best score (42%) was reported. Comparing a player's test performance with previous scores (89%) was the most common method for interpreting test results. However, only 38% considered measurement error. Digital displays and verbal feedback are the most common data reporting methods, with different data reporting processes for coaches and players. Practitioners can use data and findings from this study to inform their current testing practices and researchers to further identify areas for investigation, with the overarching aim of developing the field of fitness testing in elite male soccer.

Analyzing omics data based on sample network.

Identifying valuable features from complex omics data is of great significance for disease diagnosis study. This paper proposes a new feature selection algorithm based on sample network (FS-SN) to mine important information from omics data. The sample network is constructed according to the sample neighbor relationship at the molecular (feature) expression level, and the distinguishing ability of the feature is evaluated based on the topology of the sample network. The sample network established on a feature with a strong discriminating ability tends to have many edges between the same group samples and few edges between the different group samples. At the same time, FS-SN removes redundant features according to the gravitational interaction between features. To show the validation of FS-SN, it was compared on ten public datasets with ERGS, mRMR, ReliefF, ATSD-DN, and INDEED which are efficient in omics data analysis. Experimental results show that FS-SN performed better than the compared methods in accuracy, sensitivity and specificity in most cases. Hence, FS-SN making use of the topology of the sample network is effective for analyzing omics data, it can identify key features that reflect the occurrence and development of diseases, and reveal the underlying biological mechanism.

Utilizing the Glucose and Insulin Response Shape of an Oral Glucose Tolerance Test to Predict Dysglycemia in Children with Overweight and Obesity, Ages 8-18 Years.

Common dysglycemia measurements including fasting plasma glucose (FPG), oral glucose tolerance test (OGTT)-derived 2 h plasma glucose, and hemoglobin A1c (HbA1c) have limitations for children. Dynamic OGTT glucose and insulin responses may better reflect underlying physiology. This analysis assessed glucose and insulin curve shapes utilizing classifications-biphasic, monophasic, or monotonically increasing-and functional principal components (FPCs) to predict future dysglycemia. The prospective cohort included 671 participants with no previous diabetes diagnosis (BMI percentile ≥ 85th, 8-18 years old); 193 returned for follow-up (median 14.5 months). Blood was collected every 30 min during the 2 h OGTT. Functional data analysis was performed on curves summarizing glucose and insulin responses. FPCs described variation in curve height (FPC1), time of peak (FPC2), and oscillation (FPC3). At baseline, both glucose and insulin FPC1 were significantly correlated with BMI percentile (Spearman correlation r = 0.22 and 0.48), triglycerides (r = 0.30 and 0.39), and HbA1c (r = 0.25 and 0.17). In longitudinal logistic regression analyses, glucose and insulin FPCs predicted future dysglycemia (AUC = 0.80) better than shape classifications (AUC = 0.69), HbA1c (AUC = 0.72), or FPG (AUC = 0.50). Further research should evaluate the utility of FPCs to predict metabolic diseases.

Testing the Effectiveness of an Intervention to Improve Romanian Teachers' LGBT+-Related Attitudes, Cognitions, Behaviors, and Affect: Protocol for a Randomized Controlled Trial.

BACKGROUND: Repeated stigmatization due to group membership constitutes a recurrent stressor with negative impact on physical and mental health (minority stress model). Among European countries, Romania ranks low on LGBT+ (lesbian, gay, bisexual, and transgender people. The "+" represents individuals whose identities do not fit typical binary notions of male and female [nonbinary]) inclusion, with 45% of Romanian LGBT+ respondents reporting discrimination in at least 1 area of life in the year preceding the survey. Importantly, while all LGBT+ people might experience minority stress, younger sexual minority individuals are more prone to the detrimental impacts of stigma on their mental and physical health. As such, interventions are necessary to improve the inclusion climate within schools, where young people spend most of their time. Until now, most interventions addressing this topic have been conducted on undergraduate students in Western countries, with no studies conducted in countries that have widespread anti-LGBT+ attitudes. OBJECTIVE: This paper describes the research protocol for a randomized controlled trial investigating whether LGBT+ stigma and bias among Romanian school teachers can be reduced using an internet-based intervention focusing on education and contact as primary training elements. METHODS: A sample of 175 school teachers will be randomly assigned to either the control or experimental group. The experimental group participants will receive the intervention first and then complete the outcome measures, whereas the control group will complete the outcome measures first and then receive the intervention. The 1-hour multimedia intervention is developed for internet-based delivery under controlled conditions. It includes 2 interactive exercises, 2 recorded presentations, animations, and testimonies from LGBT+ individuals. Data for attitudinal, behavioral, cognitive, and affective measures will be collected during the same session (before or after the intervention, depending on the condition). We also plan to conduct a brief mixed methods follow-up study at 6 to 8 months post participation to investigate potential long-term effects of training. However, due to attrition and lack of experimental control (all participants will have completed the intervention, regardless of the condition), these data will be analyzed and reported separately using a mixed methods approach. RESULTS: This paper details the protocol for the teacher intervention study. Data collection began in December 2022 and was completed by February 2023. Data analysis will be performed upon protocol acceptance. Follow-up measures will be completed in 2024. Results are expected to be submitted for publication following analysis in the spring of 2024. CONCLUSIONS: The findings of this study will establish the effectiveness of an internet-based intervention intended to lessen anti-LGBT stigma and sentiment in a nation where these views have long been prevalent. If successful, the intervention could end up serving as a resource for Romanian teachers and guidance counselors in high schools. TRIAL REGISTRATION: ISRCTN 84290049; https://doi.org/10.1186/ISRCTN84290049. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54254.

Active surveillance pharmacovigilance for Clostridioides difficile infection and gastrointestinal bleeding: an analytic framework based on case-control studies.

BACKGROUND: Active surveillance pharmacovigilance is an emerging approach to identify medications with unanticipated effects. We previously developed a framework called pharmacopeia-wide association studies (PharmWAS) that limits false positive medication associations through high-dimensional confounding adjustment and set enrichment. We aimed to assess the transportability and generalizability of the PharmWAS framework by using medical claims data to reproduce known medication associations with Clostridioides difficile infection (CDI) or gastrointestinal bleeding (GIB). METHODS: We conducted case-control studies using Optum's de-identified Clinformatics Data Mart Database of individuals enrolled in large commercial and Medicare Advantage health plans in the United States. Individuals with CDI (from 2010 to 2015) or GIB (from 2010 to 2021) were matched to controls by age and sex. We identified all medications utilized prior to diagnosis and analysed the association of each with CDI or GIB using conditional logistic regression adjusted for risk factors for the outcome and a high-dimensional propensity score. FINDINGS: For the CDI study, we identified 55,137 cases, 220,543 controls, and 290 medications to analyse. Antibiotics with Gram-negative spectrum, including ciprofloxacin (aOR 2.83), ceftriaxone (aOR 2.65), and levofloxacin (aOR 1.60), were strongly associated. For the GIB study, we identified 450,315 cases, 1,801,260 controls, and 354 medications to analyse. Antiplatelets, anticoagulants, and non-steroidal anti-inflammatory drugs, including ticagrelor (aOR 2.81), naproxen (aOR 1.87), and rivaroxaban (aOR 1.31), were strongly associated. INTERPRETATION: These studies demonstrate the generalizability and transportability of the PharmWAS pharmacovigilance framework. With additional validation, PharmWAS could complement traditional passive surveillance systems to identify medications that unexpectedly provoke or prevent high-impact conditions. FUNDING: U.S. National Institute of Diabetes and Digestive and Kidney Diseases.

Data Processing Techniques Impact Quantification of Cortico-Cortical Evoked Potentials.

BACKGROUND: Cortico-cortical evoked potentials (CCEPs) are a common tool for probing effective connectivity in intracranial human electrophysiology. As with all human electrophysiology data, CCEP data are highly susceptible to noise. To address noise, filters and re-referencing are often applied to CCEP data, but different processing strategies are used from study to study. NEW METHOD: We systematically compare how common average re-referencing and filtering CCEP data impacts quantification. RESULTS: We show that common average re-referencing and filters, particularly filters that cut out more frequencies, can significantly impact the quantification of CCEP magnitude and morphology. We identify that high cutoff high pass filters (> 0.5Hz), low cutoff low pass filters (< 200Hz), and common average re-referencing impact quantification across subjects. However, we also demonstrate that the presence of noise may impact CCEP quantification, and preprocessing is necessary to mitigate this. We show that filtering is more effective than re-referencing or averaging across trials for reducing most common types of noise. COMPARISON WITH EXISTING METHODS: These results suggest that existing CCEP processing methods must be applied with care to maximize noise reduction and minimize changes to the data. We do not test every available processing strategy; rather we demonstrate that processing can influence the results of CCEP studies. We emphasize the importance of reporting all processing methods, particularly re-referencing methods. CONCLUSIONS: We propose a general framework for choosing an appropriate processing pipeline for CCEP data, taking into consideration the noise levels of a specific dataset. We suggest that minimal gentle filtering is preferable.