The CDISC Standard for Exchange of Nonclinical Data (SEND) data standard has created new opportunities for collaborative development of open-source software solutions to facilitate cross-study analyses of toxicology study data. A public–private partnership between BioCelerate and the FDA/Center for Drug Evaluation and Research (CDER) was established in part to develop and publicize novel methods to facilitate cross-study analysis of SEND datasets. As part of this work in collaboration with the Pharmaceutical Users Software Exchange (PHUSE), an R package sendigR has been developed to enable users to construct a relational database from a collection of SEND datasets and then query that database to perform cross-study analyses. The sendigR package also includes an integrated Python package, xptcleaner, which can be used to harmonize the terminology used in SEND datasets by mapping to CDISC controlled terminologies. The sendigR R package is freely available on the comprehensive R Archive Network (CRAN) and at https://github.com/phuse-org/sendigR. An R Shiny web application was included in the R package to enable toxicologists with no coding experience to perform historical control analyses. Experienced R programmers will be able to integrate the package functions into their own custom scripts/packages and potentially contribute improvements to the functionality of sendigR.sendigR reference manual: https://phuse-org.github.io/sendigR/.sendigR R Shiny demo app: https://phuse-org.shinyapps.io/sendigR/.

The Adverse Event Reporting System (AERS) is a computerized information database designed to support the FDA's post-marketing safety surveillance program for all approved drug and therapeutic biologic products. The FDA uses AERS to monitor for new adverse events and medication errors that might occur with these marketed products. Reporting of adverse events from the point of care is voluntary in the United States. FDA receives some adverse event and medication error reports directly from health care professionals (such as physicians, pharmacists, nurses and others) and consumers (such as patients, family members, lawyers and others). Healthcare professionals and consumers may also report these events to the products' manufacturers. If a manufacturer receives an adverse event report, it is required to send the report to FDA as specified by regulations. The files listed on this page contain raw data extracted from the AERS database for the indicated time ranges and are not cumulative. Users of these files need to be familiar with creation of relational databases using applications such as ORACLE, Microsoft Office Access, MySQL and IBM DB2 or the use of ASCII files with SAS analytic tools. A simple search of AERS data cannot be performed with these files by persons who are not familiar with creation of relational databases.

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Large scale analysis of in vivo toxicology studies has been hindered by the lack of a standardized digital format for data analysis. The SEND standard enables the analysis of data from multiple studies performed by different laboratories. The objective of this work is to develop methods to transform, sort, and analyze data to automate cross study analysis of toxicology studies. Cross study analysis can be applied to use cases such as understanding a single compound’s toxicity profile across all studies performed and/or evaluating on- versus off-target toxicity for multiple compounds intended for the same pharmacological target. This collaborative work between BioCelerate and FDA involved development of data harmonization/transformation strategies and analytic techniques to enable cross-study analysis of both numerical and categorical SEND data. Four de-identified SEND data sets from the BioCelerate Toxicology Data Sharing module of DataCelerate® were used for the analyses. Toxicity prof..., Deidentified SEND data was donated by companies participating in BioCelerate’s Toxicology Data Sharing Initiative (TDS module in DataCelerate®).The data included 1-Month Rat and 1-Month Dog SEND datasets for two different compounds intended for the same pharmacological target. To facilitate cross-study analysis of toxicology studies, it is practical to categorize findings within organ systems to provide insights into target organ toxicity. In the proof-of-concept for this application, we focused on the target organs with compound-related effects, namely the kidney, liver, hematopoietic system, endocrine system, and reproductive tract (male). The body weights (BW), food and water consumption (FW), laboratory test results (LB), organ measurements (OM), and microscopic findings (MI) SEND domains were included in the analysis. Each parameter was then assigned to the relevant organ system(s) (Table 1) based on veterinary literature (Faqi 2017) (Stockham 2008), scientific literature on ..., , # Dataset for Cross Study Analyses of SEND Data: Toxicity Profile Classification

https://doi.org/10.5061/dryad.s1rn8pkgr

The data included 1-Month Rat and 1-Month Dog SEND datasets for two different compounds (Compound A and Compound B) intended for the same pharmacological target.Â

Description of the data and file structure

The files contain data from toxicology studies performed in rats and dogs to support clinical development for two different drugs intended for the same pharmacological target. The studies were donated by the pharmaceutical companies involved in development of the compounds. All proprietary and identifying information has been removed and deidentified. Â

The toxicology data is organized based on the CDISC - Standard for Exchange of Nonclinical Data (SEND) data standard (https://www.cdisc.org/standards/foundational/send/sendig-v3-1) and stored in .json a...,

BackgroundNiclosamide, an FDA-approved anti-helminthic drug, has activity in preclinical models of castration-resistant prostate cancer (CRPC). Potential mechanisms of action include degrading constitutively active androgen receptor splice variants (AR-Vs) or inhibiting other drug-resistance pathways (e.g., Wnt-signaling). Published pharmacokinetics data suggests that niclosamide has poor oral bioavailability, potentially limiting its use as a cancer drug. Therefore, we launched a Phase I study testing oral niclosamide in combination with enzalutamide, for longer and at higher doses than those used to treat helminthic infections.MethodsWe conducted a Phase I dose-escalation study testing oral niclosamide plus standard-dose enzalutamide in men with metastatic CRPC previously treated with abiraterone. Niclosamide was given three-times-daily (TID) at the following dose-levels: 500, 1000 or 1500mg. The primary objective was to assess safety. Secondary objectives, included measuring AR-V expression from circulating tumor cells (CTCs) using the AdnaTest assay, evaluating PSA changes and determining niclosamide’s pharmacokinetic profile.Results20 patients screened and 5 enrolled after passing all screening procedures. 13(65%) patients had detectable CTCs, but only one was AR-V+. There were no dose-limiting toxicities (DLTs) in 3 patients on the 500mg TID cohort; however, both (N = 2) subjects on the 1000mg TID cohort experienced DLTs (prolonged grade 3 nausea, vomiting, diarrhea; and colitis). The maximum plasma concentration ranged from 35.7–82 ng/mL and was not consistently above the minimum effective concentration in preclinical studies. There were no PSA declines in any enrolled subject. Because plasma concentrations at the maximum tolerated dose (500mg TID) were not consistently above the expected therapeutic threshold, the Data Safety Monitoring Board closed the study for futility.ConclusionsOral niclosamide could not be escalated above 500mg TID, and plasma concentrations were not consistently above the threshold shown to inhibit growth in CRPC models. Oral niclosamide is not a viable compound for repurposing as a CRPC treatment.Clinical trial registryClinicaltrials.gov: NCT02532114

The dataset contains data collected from patients suffering from cancer-related pain. The features extracted from clinical data (including typical cancer phenomena such as breakthrough pain) and the biosignal acquisitions contributed to the definition of a multidimensional dataset. This unique database can be useful for the characterization of the patient’s pain experience from a qualitative and quantitative perspective. We implemented measurable biosignals-related indicators of the individual’s pain response and of the overall Autonomic Nervous System (ANS) functioning. The most peculiar features extracted from EDA and ECG signals can be adopted to investigate the status and complex functioning of the ANS through the study of sympatho-vagal activations. Specifically, while EDA is mainly related sympathetic activation, the Heart Rate Variability (HRV), which can be derived from ECG recordings, is strictly related to the interplay between sympathetic and parasympathetic functioning.

As far as the EDA signal, two types of analyzes have been performed: (i) the Trough-To-Peak analysis (TTP), or min-max analysis, aimed at measuring the difference between the Skin Conductance (SC) at the peak of a response and its previous minimum within pre-established time-windows; (ii) the Continuous Decomposition Analysis (CDA), aimed at performing a decomposition of SC data into continuous signals of tonic (basic level of conductance) and phasic (short-duration changes in the SC) activity. Before applying the TPP analysis or the CDA, the signal was filtered by means of a fifth-order Butterworth low-pass filter with a cutoff frequency of 1 Hz and downsampled up to 10 Hz to reducing the computational burden of the analysis. The application of TPP and CDA allowed the detection and measurement of SC Responses (SCR) and the following parameters have been calculated for both TPP and CDA methodologies:

• Total number of detected SCRs.
• Maximum value of SCRs [measured in μS].
• Minimum value of SCRs [measured in μS].
• Arithmetic mean of the SCRs [measured in μS].
• Maximum interval between SCRs [measured in ms].
• Minimum interval between SCRs [measured in ms].
• Arithmetic mean of the intervals between SCRs [measured in ms].

Concerning the ECG, the RR series of interbeat intervals (i.e., the time between successive R waves of the QRS complex on the ECG waveform) has been computed to extract time-domain parameters of the HRV. The R peak detection was carried out by adopting the Pan–Tompkins algorithm for QRS detection and R peak identification. The corresponding RR series of interbeat intervals were derived as the difference between successive R peaks.

The ECG-derived RR time series was then filtered by means of a recursive procedure to remove the intervals differing most from the mean of the surrounding RR intervals. Then, both the Time-Domain Analysis (TDA) and Frequency-Domain Analysis (FDA) of the HRV have been carried out to extract the main features characterizing the variability of the heart rhythm. Time-domain parameters are obtained from statistical analysis of the intervals between heart beats and are used to describe how much variability in the heartbeats is present at various time scales.

The parameters computed through the TDA include the following:

• Arithmetic mean of the RR time series [measured in ms].
• The standard deviation of the RR time series [measured in ms].
• Mean value of heart rate [measured in bpm].
• Standard deviation of the heart rate [measured in bpm].
• Root Mean Square of Successive Differences of RR intervals [measured in ms], which is sensitive to high-frequency heart period fluctuations in the respiratory frequency range and has been used as an index of vagal cardiac control.
• Number of successive RR intervals whose difference is higher than 50 ms.
• Percentage of successive RR intervals higher than 50 ms.
• Number of successive RR intervals whose difference is higher than 50 ms.

Frequency-domain parameters reflect the distribution of spectral power across different frequencies bands and are used to assess specific components of HRV (e.g., thermoregulation control loop, baroreflex control loop, and respiration control loop, which are regulated by both sympathetic and vagal nerves of the ANS).
The parameters computed through the FDA have been computed by adopting the Welch's Fourier periodogram method based on the Discrete Fourier Transform (DFT), which allows the expression of the RR series in the discrete frequency domain. However, due to the non-stationarity of the RR series, Welch Fourier periodogram method is used for dealing with non-stationarity. Specifically, Welch's periodogram divides the signal into specific periods of constant length appliying the Fast Fourier Transform (FFT) trasforming individually these parts of the signal. The periodogram is basically a way of estimating power spectral density of a time series.

The FDA parameters include the following:

• Peak value in the Very Low Frequency Band of the HRV power density spectrum [measured in Hz].
• Peak value in the Low Frequency Band of the HRV power density spectrum [measured in Hz].
• Peak value in the High Frequency Band of the HRV power density spectrum [measured in Hz].
• Power in the Very Low Frequency Band of the HRV power density spectrum [measured in ms^2].
• Power in the Low Frequency Band of the HRV power density spectrum [measured in ms^2].
• Power in the High Frequency Band of the HRTotal Power of the HRV power density spectrum [measured in ms^2].
• Total Power of the HRV power density spectrum [measured in ms^2].
• Percentage power in the Very Low Frequency Band of the HRV power density spectrum with respect to the total power.
• Percentage power in the Low Frequency Band of the HRV power density spectrum with respect to the total power.
• Percentage power in the High Frequency Band of the HRV power density spectrum with respect to the total power.
• Normalized power in the Low Frequency Band of the HRV power density spectrum with respect to the sum of LF and HF power.
• Normalized power in the High Frequency Band of the HRV power density spectrum with respect to the sum of LF and HF power.
• Sympathovagal balance measured as the ration between power in LF and power in the LF band.

Prediction of antimicrobial potential using a dataset of 29537 compounds screened against the antibiotic resistant pathogen Burkholderia cenocepacia. The model uses the Chemprop Direct Message Passing Neural Network (D-MPNN) and has an AUC score of 0.823 for the test set. It has been used to virtually screen the FDA approved drugs as well as a collection of natural product list (>200k compounds) with hit rates of 26% and 12% respectively.

Model Type: Predictive machine learning model. Model Relevance: Probability that a compound inhibits bacterial pathogens with a focus on ESKAPE. Model Encoded by: Sarima Chiorlu (Ersilia) Metadata Submitted in BioModels by: Zainab Ashimiyu-Abdusalam

Implementation of this model code by Ersilia is available here: https://github.com/ersilia-os/eos5xng