dataesr/scientific-paragraphs-categorization huggingface dataset:
Introduction In 2010, the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were published  [1]  to address the growing concerns with poor experimental design and lack of transparent reporting of in vivo experiments in the published literature  [2] [3] [4]. The guidelines consist of a checklist of 20 items, which are considered key to describing a study comprehensively and transparently (Fig  1 ). Transparent reporting is a fundamental component required to ensure reproducibility of animal research and allow later inclusion in meta-analytic studies  [5]. To our knowledge, no specific guidelines exist for an in vivo database, and there has been no report of the use of the ARRIVE guidelines to inform the collection, analysis, and presentation of data in a pre-publication database.
Yet the transparency needed is equally essential in this situation. The International Mouse Phenotyping Consortium (IMPC)  [6]  aims to phenotype knockouts for all protein coding genes in the mouse genome and hence provide an invaluable resource to the community, given that the mouse is the premier model organism for understanding gene function in development and disease. The IMPC community has defined a core set of procedures to assess multiple biological systems and has developed a central resource (www. mousephenotype. org) to disseminate the data. The database contains continuous, categorical, count, and image data for over 734,284 experiments on 46,972 mice as of January 2015. Here, we describe how the IMPC applied the ARRIVE guidelines to a large data resource and highlight the challenges and how we addressed them.
The Aims and Challenges of Setting Up a Large-Scale Database A large-scale database aims to consolidate information into one site for maximum exposure and to add functionality to mine and explore data. The scale of the project, with many types of variables and data from many sources, brings many challenges in capturing the data (defining what to capture and methods of capture), data organisation, and data presentation. A significant challenge for a database portal is how to organise the information in a logical way that leads to readable pages that do not overwhelm a user upon first inspection. The ARRIVE guidelines were developed specifically for peer-reviewed scientific publications of in vivo data, but the goals of transparency are equally applicable to databases and critical to allow reproducible research.
ARRIVE Guidelines-Methods-Experimental Procedures (Item 7) and Experimental Outcomes (Item 12) The experimental procedures in IMPC are defined by standardised data format in the International Mouse Phenotyping Resource of Standardised Screens (IMPReSS) database (https:// www. mousephenotype. org/impress/). IMPReSS is based on a pipeline concept, which is a series of experimental procedures performed in a specified order. Each procedure defines the purpose, experimental design, the protocol, the measured variables, potential QC failure criteria, methodology, variables measured, and the metadata to be captured. The information is organised such that each data point can be associated with the relevant procedural and mouse information. To provide traceability, IMPReSS also stores a record of change histories.
IMPReSS thus provides the framework not only for transparency in the procedure and what data are required to be captured but also stores information to facilitate subsequent analysis, hence making it the backbone of the database and web portal. The development of this resource has required extensive collaboration with the institutes, area experts, and database engineers. The scale of the project necessitated the development of an International MicroInjection Tracking System (iMITS), which is the repository of the genotypes and coordinates production and phenotyping. The scale has also required an automated method of data capture from phenotyping centres. It is supported by a strict data standard that defines, in addition to the variables defined in the procedures at IMPReSS, data about each animal (Local ID, date of birth, strain, sex, and centre).
g. , an alternate anesthetic is used or selected tests are omitted). The Alternate Mouse Pipeline is a bespoke phenotyping pipeline in which the age and procedures are adapted to manage the welfare of the line. Currently the community is in the process of defining the Alternate Mouse Pipeline within IMPReSS that will, in the future, allow this data to be captured and disseminated. These two complementary approaches allow us to maximise the value of information extracted from the lines while minimising welfare issues. If mice or cryopreserved sperm are requested, any welfare concerns are provided in a GA passport  [8].
" The workflow data are recorded annually via a survey using the MEDO ontology. The practical reality of experimental design is that there is no perfect solution; therefore, transparency is needed to capture how experiments were implemented to allow users to independently assess the potential strengths and weaknesses in the design. This level of transparency also encourages good practice within the consortium. For example, the Japan Mouse Clinic switched from an "alternate mouse" method to a "cage active randomisation method" to minimise potential order effects when assaying mice. The standardised language developed is specific to the variation in implementation that could occur within our community, but also to variation sources that were felt to have the potential to have a biological impact on the experimental outcome that were not controlled by standardisation within our studies.
bioconductor. org/packages/release/bioc/html/PhenStat. html), and the application is version-controlled, as there is still active research ongoing in this area of data analysis. We also provide an explanation of the analysis, which can be accessed from the IMPC ARRIVE landing page. On the web portal, each graphical representation includes a statistical summary with p-values and effect sizes, with the ability for users to obtain more information about the statistical method implemented (S1 Fig). As data can be analysed in many ways, and each way has strengths and weaknesses, we have developed tools and procedures to enable users to obtain raw data for independent analysis, either via spreadsheet downloads, file transfer protocol (ftp) access, or automatic programmatic interfaces.
Firstly, data points may fail quality control (QC) during data collection. An explanation is provided using a standardised set of options as agreed by area experts. An example is the explanation "Procedure Failed-Insufficient Sample-Blood sample. " Secondly, data are QC'd after upload from the institute to the database, where data of concern are investigated using Phenodcc, a set of tools that visualise the data and track concerns. This approach is essential when dealing which large volumes of data. Data are only QC-failed if clear technical reasons can be found for a measurement being an outlier. Reasons for QC failure are provided and tracked within the database.
There has been growing concern over the sex imbalance in biomedical research  [12] [13] [14]  and this had led to the United States National Institutes of Health now requiring all grant applicants to consider both sexes in preclinical studies  [15]. Fortunately, IMPC decided at the start of the project that phenotype data should be collected from both sexes, and this design supports the generalizability of any findings. In addition, our continuous analysis pipeline is designed to detect sexual dimorphism and we associated a tag to the MP terms to classify the effect observed (S2 Fig). Mouse knockout (or null) mutations lead to the absence of the gene product and are recognized as a standard approach in all model organisms for assessing gene function. However, not all aspects of gene function will be revealed by the generation of a knockout mutation.
Conclusions Applying the ARRIVE guidelines for a phenotype resource generated by an international community introduced many challenges, some specific to a data resource and others that are more general. The first set of challenges arose in applying guidelines intended for a scientific publication to a data resource. The detail needed to meet the guidelines required significant organisation and informatics infrastructure to enable the capture, QC, analysis, and storage of the raw and derived information. To do this, the IMPC developed several resources: the IMPReSS database, which standardizes procedures and captures information needed to reproduce experiments; the PhenStat analysis package, which defines the statistical procedures to enable others to replicate analysis; iMITS, which tracks mouse production and phenotyping milestones; and finally, Phenodcc, which supports QC of the data.
This necessitated the development of a standardised language with defined terms and definitions, coupled with the use of surveys to clarify each centres' implementation strategy. Our experiences are likely to reflect a general issue in the biological community and could help explain the lack of progress in applying the ARRIVE guidelines  [9]. As a first step, we needed to give priority to detailed explanation of experimental implementation. The development of a standardised language has allowed us to capture and provide transparency in the experimental design, which also encourages best practice. The ARRIVE guidelines have provided a framework to consider our ethical responsibilities in assessing what is necessary to communicate to the consumers of our data. Meeting the guidelines involved the development of multiple databases, bespoke software packages, and an ontology.
Materials and Methods For the example presented in S1 Fig, looking at the impact of the Nptn gene knockout on the lean mass phenotype, mice carrying the Nptn tm1b(EUCOMM)Hmgu targeted allele were created by blastocyst injection of targeted ES cells, and bred on the C57BL/6NTac genetic background (accession number: MGI:5548382). Phenotyping data was collected on nine female and eight male homozygous mice and 1,079 female and 1,107 male baseline control mice collected during the project.
Dual-Energy X-ray Absorptiometry (DEXA) At 14 weeks of age, the DEXA procedure was followed as detailed in the standardised protocol specified at https://www. mousephenotype. org/impress/protocol/90/7 using a Lunar Piximus II Bone Densitometer (GE Medical Systems, UK) after the animals were anaesthetized with isoflurane (2% Abbott Animal Health, US). The details of blinding and randomisation methods implemented are described at http://www. mousephenotype. org/about-impc/arrive-guidelines. As the majority of the phenotyping data are collected on both sexes, this has enabled the regression methods to include an assessment of sexual dimorphism. The output of the model fitting can then be used to classify the genotype effect observed in relationship to the sex of the animals. For example, whether the genotype effect was observed in both sexes equally will lead to the tag "both sexes equally" or specifically to one sex (e.
TS and YH were supported by the  French  state aid managed by the  National Agency for Research  under the program of future investments ( PHENOMIN ,  ANR-10-INSB-07 ), the  CNRS , The  INSERM  and the  University of Strasbourg. HM and SW were supported by the  Management Expenses Grant  for  RIKEN BioResource Center, MEXT , http://www. mext. go. jp/ and the Database Integration Coordination Program of  National Bioscience Database Center, Japan Science and Technology Agency. The  National Institute of Health (NIH)  funding arises from a cooperative agreement, an assistance mechanism (rather than an acquisition mechanism) in which substantial  NIH  scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activities. For example, they have influenced the design of the phenotyping pipeline and reviewed the web-portal.
S1 Fig. Organising the information for rapid user access. Organising the information in a web user interface is challenging. Shown are screen shots from a genotype-phenotype page to highlight how the information is organised and presented. A: An example visualisation of phenotyping data. B: An example presentation of associated statistical output. The example shown is the lean mass output from the Dual Energy X-ray Absorptiometry screen for the Nptn tm1b(EUCOMM)Hmgu knockout line (accession number: MGI:5548382). (TIFF) S2 Fig. Classification of the observed genotype effect.
Comparing naked eye and autofluorescence detection of colonies For each M. marinum and M. ulcerans strain, 100 μL of a 10 5 mycobacteria/mL bacterial suspension were seeded on a plate containing Middlebrook 7H11 medium, incubated at 32°C. Negative control plates were inoculated with sterile PBS. Two days, four days, eight days and sixteen days after inoculation, colonies were observed both by the naked-eye and using a MZ-FLIII fluorescence microscope (Leica, Nanterre, France) equipped with a GFP filter and an ICA digital camera (Leica) to detect mycobacterial autofluorescence. Counting of fluorescent colonies was performed using the Leica Application Suite software (Leica). Experiments were performed in three replicates.
Negative control plates inoculated with sterile PBS were incubated in parallel in the ratio of one negative control plate for six inoculated plates. Cultures were observed by autofluorescence and naked-eye every day for seven days for M. marinum and every two days for 16 days for M. ulcerans in order to numerate the colonies. The counting of fluorescent colonies was performed using Leica Application Suite software (Leica). Colonies were identified using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF-MS)  [18]. All experiments were performed in six replicates. Delay of detection of the first colony and the number of colonies at day seven (M. marinum) or day 16 post-inoculation (M. ulcerans) were used as two endpoints to compare the growth of mycobacteria on Middlebrook 7H11 medium with and without tropical aquatic plant extracts.
Use of in vitro tests peaked at >190 000 tests per annum in 2012; >99% of this usage was in the three main areas reported of ADME, safety pharmacology and genotoxicity. Trends and step changes in uptake were most notable in the three main areas of ADME, safety pharmacology and genotoxicity and may be explained by the timing of adoption of the relevant International Committee on Harmonisation (ICH) guidelines. Trends in uptake may also be explained by perceptions of utility where scores varied from poor (Eye Irritation -flourescein leakage) to excellent (Genotoxicity -Ames and Skin irritation -EpiSkin/Epiderm). In summary, the data show a large increase and a continuing upwards trend in development and adoption of in vitro alternatives to animal testing in pharmaceutical drug development providing new opportunities to improve success rates coupled with a strong commitment to the 3Rs.
Data handling Completed surveys were anonimised and collated by the number of reported tests by year and utility scores values. Data returned on some tests were excluded from analysis, either because they are not in vitro tests or because data from both in vivo/in vitro tests were combined and could not be separated in a meaningful way. These are listed in Table  3. Where respondents provided data in absolute values, e. g. 7, 30, 699, 78 098 these were used in the analysis. Where respondents indicated a range (as given at the column head in the collection spreadsheet), midpoints of the ranges were used to provide a numerical figure for the analysis. For assays where more than 10 000 compounds were tested, a higher end value of a range could not be determined and thus, the lower end value of '10 000' was used (Table  4 ).
Analysis of data Raw data. Historical trends in the use of all in vitro tests reported were analysed by summing the total number of compounds tested in each year for all responding companies and presented graphically by year. Trends for the use of individual in vitro tests such as mouse lymphoma assay or the Ames test were analysed and presented in the same way. The relative use of in vitro assays in different fields was evaluated by comparing the total number of tests being carried out in each field with the overall total tests being carried out. In addition, comparisons were made between overall use and fields of use of in vitro tests in pharmaceutical companies and CROs from 1980 to 2013. Normalised data. As well as calculating raw data, additional information on overall historical trends in the use of in vitro tests across all companies was revealed by normalising data within each company.
Responses Responses from seven companies (four pharmaceutical companies and three contract research organisations (CROs)) were received in response to the ABPI survey. Some companies sub-mitted data for multiple sites, including global locations, whereas others submitted data from UK sites only. Four of the seven respondents provided data in absolute values wheares three of the companies supplied data in ranges. Five of the seven companies provided data across the full period of 1980 to 2013 although there were relatively low numbers of in vitro tests reported before 2005. One company provided data from 2005 onwards onlythese data were included in the historical trends analysis since missing data from before 2005 for this one company had a minimal effect on the analysis of historical trends against a background of low numbers of tests reported up to 2005 for the other five companies.
In contrast, one company provided data only from 2009 to 2013; responses from this company were not included in the analysis of historical use of in vitro tests since data from other companies showed that many of the tests were in use before 2009 and inclusion of the 2009-2013 data from this one company would result in a larger apparent increase from 2008 to 2009, thereby skewing the results. Although omitted from the historical trends analysis, data from this same company were used in analysis of breakdown of in vitro tests according to fields/disciplines where trends were not analysed historically. The scores and comments from this one company were also used in qualitative analysis of data and to support interpretation and discussion of the overall trends. Breakdown of in vitro tests used by the pharmaceutical industry by fields/disciplines Fig.
Affinity to humans by 3-week-old lambs: behavioral response Testing our hypothesis required the lambs to develop a strong level of affinity for their familiar caregiver. Boivin et al. [17]  and Coulon et al. [26]  showed a durable affiliative response of artificially lambs to humans when they had been stroked (at least up to 8 weeks of age). Accordingly, in the first step of this study and referring to their protocol, the level of lambs' affinity towards their familiar caregiver was checked at 3 weeks of age  [26]. All the tests were video-recorded (using a hard disk, handheld, JVC Everio GZ-MG255), and behavior was analyzed later on using The Observers 5. 0 software. The day before, the person wearing the lab coat carried each group of lambs from the home pen to the test pen (10 to 20 m away).
This receiver was connected to a computer running a data processing system (Powerlab, ADInstruments, UK). After 15 min, the familiar caregiver entered the small pen, crouched down and remained immobile. This procedure was standardized and lasted for two minutes. In half of the cases, a lamb was stroked for 8 min by first putting it on her knees in the same manner as during the training sessions. The lamb was free to move away from the familiar caregiver. For the other half, a lamb was exposed to the familiar caregiver's immobile presence for the same duration, without being stroked. Heart rate was recorded during last 2 min of the first phase (lamb alone) for each subject, and during the 8 min of human presence. The following variables were analyzed by 2-min slots using Chart software (version 3.
Statistical analysis All data was analyzed using SAS software (version SAS 9. 1. , SAS Institute Inc, CA). For behavioral data collected on lambs at age three weeks, the effects of day of the test, phase and their interactions were tested using the MIXED procedure (generalization of the standard linear model with REML (restricted maximum likelihood) and ML (maximum likelihood) estimation methods implemented with a Newton-Raphson algorithm; SAS Institute Inc. , 1999) and with lamb as a random effect. The rearing pen and the position of the familiar caregiver in the test pen were initially included in the model but later removed due to the absence of any significant effect. We checked the condition of normality and homogeneity of the variance and the time spent near human was log transform. Post hoc comparisons after ANOVA were run using Tukey tests.
For HR parameters recorded on lambs at 8 weeks of age, we used the MIXED procedure for repeated data with an autoregressive (AR1) covariance structure of the R matrix to analyze the effect of the human presence or stroking: the effect of human (stroking vs. immobile), the effect of periods (4 periods of 2 min) and their interactions were tested on the cardiac activity of the lambs (HR, RMSSD and SDNN). The recording obtained on each variable (HR, RMSSD and SDNN) for each lamb when alone was used as co-variable in the model, and with lamb as a random effect. Post hoc comparisons after ANOVA were run using Least Square Differences (LSD). We checked the condition of normality and homogeneity of the variance. For behavioral data of the 8 week old lambs, a Principal Component Analysis (Proc princomp procedure in SAS software) was first performed to take into account possible strong relationship between the different variables recorded during the 8 min, help the interpretation, and minimize the number of statistical tests needed.
Animals and data collection Forty-four bitches from one breeding kennel were included in the study. Starting 2 weeks before parturition, each female was single housed and fed a dry balanced diet for growing dogs (Starter, Royal Canin, Aimargues, France) ad libitum. The bitches belonged to 13 different breeds: Bichon Frise (n = 4), Bichon Maltese (n = 4), Cocker Spaniel (n = 4), German Shepherd (n = 1), Golden Retriever (n = 8), Jack Russell Terrier (n = 1), Labrador Retriever (n = 4), Lhasa Apso (n = 6), Pomeranian (n = 1), Poodle (n = 4), Shih Tzu (n = 3), West Highland White Terrier (n = 3), Yorkshire Terrier (n = 1). The age of each bitch and the total number of puppies born (litter size) were recorded. Samples of blood and colostrum were collected once from each bitch after expulsion of the last puppy (between 8 and 24 h since the onset of parturition).
blast. ncbi. nlm. nih. gov/Blast. cgi)]. The results of the identification at species level according to the percentage similarity (the minimum percentage similarity requested was 99%) of our clinical isolates with the sequences of the type strains present in the GenBank database can be found in Table  1. Antimicrobial susceptibility testing was performed and the results analysed using the disc diffusion method on  cation-supplemented Mueller-Hinton medium according to the Clinical and Laboratory Standards Institute standard M24-A2 (CLSI, 2011) and SocieteFrancaise de Microbiologie guidelines  (CA-SFM, 2013; Rodriguez-Nava et al. , 2014). The drugs tested were amoxicillin/clavulanic acid (20/10 mg), ceftriaxone (30 mg), cefuroxime (30 mg), cefotaxime (30 mg), cefepime (30 mg), ciprofloxacin (5 mg), levofloxacin (5 mg), linezolid (30 mg), trimethoprim/sulfamethoxazole (1.