Sustaining large-scale infrastructure to promote pre-competitive biomedical research: lessons from mouse genomics.

Bio-repositories and databases for biomedical research enable the efficient community-wide sharing of reagents and data. These archives play an increasingly prominent role in the generation and dissemination of bioresources and data essential for fundamental and translational research. Evidence suggests, however, that current funding and governance models, generally short-term and nationally focused, do not adequately support the role of archives in long-term, transnational endeavours to make and share high-impact resources. Our qualitative case study of the International Knockout Mouse Consortium and the International Mouse Phenotyping Consortium examines new governance mechanisms for archive sustainability. Funders and archive managers highlight in interviews that archives need stable public funding and new revenue-generation models to be sustainable. Sustainability also requires archives, journal publishers, and funders to implement appropriate incentives, associated metrics, and enforcement mechanisms to ensure that researchers use archives to deposit reagents and data to make them publicly accessible for academia and industry alike.This work was supported by the NorCOMM2 Project funded by Genome Canada [AM and TB]; the Ontario Genome Institute [TB]; and the Canadian Stem Cell Network [TB]. The authors have no competing interests. The funders of the study exerted no influence on the design and conduct of the study or on the analysis and presentation of results. We thank Lesley Dacks, Lorna Skaley and Dr Ann Flenniken for research support and project coordination. We thank the participants who took time out of their busy schedules for interviews and to review our analyses. We thank Dr Farah Huzair for feedback and the IMPC leadership for permission to use a modified version (Figure 1) of the Consortium's map of its global membership (http://www.mousephenotype.org/about-impc/impc-members). We are grateful to Drs Andy Smith and John Hancock for advice on the ELIXIR funding and governance model.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.nbt.2015.10.00

Reuse of design pattern measurements for health data

Research using health data is challenged by its heterogeneous nature, description and storage. The COVID-19 outbreak made clear that rapid analysis of observations such as clinical measurements across a large number of healthcare providers can have enormous health benefits. This has brought into focus the need for a common model of quantitative health data that enables data exchange and federated computational analysis. The application of ontologies, Semantic Web technologies and the FAIR principles is an approach used by different life science research projects, such as the European Joint Programme on Rare Diseases, to make data and metadata machine readable and thereby reduce the barriers for data sharing and analytics and harness health data for discovery. Here, we show the reuse of a pattern for measurements to model diverse health data, to demonstrate and raise visibility of the usefulness of this pattern for biomedical research

All in the Name: A Review of Current Standards and the Evolution of Histopathological Nomenclature for Laboratory Animals

The need for international collaboration in rodent pathology has evolved since the 1970s, and was initially driven by the new field of toxicologic pathology. First initiated by the World Health Organization’s International Agency for Research on Cancer for rodents, it has evolved to include pathology of the major species (rats, mice, guinea pigs, nonhuman primates, pigs, dogs, fish, rabbits) used in medical research, safety assessment and mouse pathology. The collaborative effort today is driven by the needs of the regulatory agencies in multiple countries, and by needs of research involving genetically engineered animals, for “basic” research, and for more translational preclinical models of human disease. These efforts led to the establishment of an international rodent pathology nomenclature program. Since that time, multiple collaborations for standardization of laboratory animal pathology nomenclature and diagnostic criteria have been developed, and just a few are described herein. Recently, approaches to a nomenclature that is amenable to sophisticated computation have been made available and implemented for large-scale programs in functional genomics and ageing. Most terminologies continue to evolve as the science of human and veterinary pathology continues to develop, but standardization and successful implementation remain as critical for scientific communication, now as ever in the history of veterinary nosology.Government of Canada through Genome Canada and Ontario Genomics (OGI-051), Commission of the European Community QLRI-1999-CT-0320, the Ellison Medical Foundation, and the National Institutes of Health (CA34196, CA089713, and AG038070-05

A response to Rome: lessons from pre- and post-publication data-sharing in the C. elegans research community

<p>Abstract</p> <p>Background</p> <p>In recent years numerous studies have undertaken to measure the impact of patents, material transfer agreements, data-withholding and commercialization pressures on biomedical researchers. Of particular concern is the theory that such pressures may have negative effects on academic and other upstream researchers. In response to these concerns, commentators in some research communities have called for an increased level of access to, and sharing of, data and research materials. We have been studying how data and materials are shared in the community of researchers who use the nematode <it>Caenorhabditis elegans </it>(<it>C. elegans</it>) as a model organism for biological research. Specifically, we conducted a textual analysis of academic articles referencing <it>C. elegans</it>, reviewed <it>C. elegans </it>repository request lists, scanned patents that reference <it>C. elegans </it>and conducted a broad survey of <it>C. elegans </it>researchers. Of particular importance in our research was the role of the <it>C. elegans </it>Gene Knockout Consortium in the facilitation of sharing in this community.</p> <p>Results</p> <p>Our research suggests that a culture of sharing exists within the <it>C. elegans </it>research community. Furthermore, our research provides insight into how this sharing operates and the role of the culture that underpins it.</p> <p>Conclusions</p> <p>The greater scientific community is likely to benefit from understanding the factors that motivate <it>C. elegans </it>researchers to share. In this sense, our research is a 'response' to calls for a greater amount of sharing in other research communities, such as the mouse community, specifically, the call for increased investment and support of centralized resource sharing infrastructure, grant-based funding of data-sharing, clarity of third party recommendations regarding sharing, third party insistence of post-publication data sharing, a decrease in patenting and restrictive material transfer agreements, and increased attribution and reward.</p

Reproducibility of histopathological findings in experimental pathology of the mouse: a sorry tail

Reproducibility of $\textit{in vivo}$ research using the mouse as a model organism depends on many factors, including experimental design, strain or stock, experimental protocols, and methods of data evaluation. Gross and histopathology are often the endpoints of such research and there is increasing concern about the accuracy and reproducibility of diagnoses in the literature. To reproduce histopathological results, the pathology protocol, including necropsy methods and slide preparation, should be followed by interpretation of the slides by a pathologist familiar with reading mouse slides and familiar with the consensus medical nomenclature used in mouse pathology. Likewise, it is important that pathologists are consulted as reviewers of manuscripts where histopathology is a key part of the investigation. The absence of pathology expertise in planning, executing and reviewing $\textit{in vivo}$ research using mice leads to questionable pathology-based findings and conclusions from studies, even in high-impact journals. We discuss the various aspects of this problem, give some examples from the literature and suggest solutions.This work was supported in part by US National Institutes of Health grants R01 AR049288, CA089713 and R21 AR063781 (to J.P.S.) and by The Warden and Fellows of Robinson College, Cambridge (to P.N.S.)

When a duck is not a duck; a new interdisciplinary synthesis for environmental radiation protection

This consensus paper presents the results of a workshop held in Essen, Germany in September 2017, called to examine critically the current approach to radiological environmental protection. The meeting brought together participants from the field of low dose radiobiology and those working in radioecology. Both groups have a common aim of identifying radiation exposures and protecting populations and individuals from harmful effects of ionising radiation exposure, but rarely work closely together. A key question in radiobiology is to understand mechanisms triggered by low doses or dose rates, leading to adverse outcomes of individuals while in radioecology a key objective is to recognise when harm is occurring at the level of the ecosystem. The discussion provided a total of six strategic recommendations which would help to address these questions.Funding was provided for this workshop by the International Union for Radioecology and the University of Duisburg-Essen

Systematic screening for skin, hair, and nail abnormalities in a large-scale knockout mouse program

The International Knockout Mouse Consortium was formed in 2007 to inactivate (“knockout”) all protein-coding genes in the mouse genome in embryonic stem cells. Production and characterization of these mice, now underway, has generated and phenotyped 3,100 strains with knockout alleles. Skin and adnexa diseases are best defined at the gross clinical level and by histopathology. Representative retired breeders had skin collected from the back, abdomen, eyelids, muzzle, ears, tail, and lower limbs including the nails. To date, 169 novel mutant lines were reviewed and of these, only one was found to have a relatively minor sebaceous gland abnormality associated with follicular dystrophy. The B6N(Cg)-Far2tm2b(KOMP)Wtsi/2J strain, had lesions affecting sebaceous glands with what appeared to be a secondary follicular dystrophy. A second line, B6N(Cg)-Ppp1r9btm1.1(KOMP)Vlcg/J, had follicular dystrophy limited to many but not all mystacial vibrissae in heterozygous but not homozygous mutant mice, suggesting that this was a nonspecific background lesion. We discuss potential reasons for the low frequency of skin and adnexal phenotypes in mice from this project in comparison to those seen in human Mendelian diseases, and suggest alternative approaches to identification of human disease-relevant models.This work was supported by grants from the National Institutes of Health (R21-AR063781 and U42-OD011185). Shared services at The Jackson Laboratory are subsidized by a National Cancer Institute Core Grant (P30-CA034196). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Semantic prioritization of novel causative genomic variants

Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.NS was funded by Wellcome Trust (Grant 100585/Z/12/Z) and the National Institute for Health Research Cambridge Biomedical Research Centre. IB, RBMR, MK, YH, VBB, RH were funded by the King Abdullah University of Science and Technology. GVG acknowledges funding from the National Science Foundation (NSF grant number: IOS-1340112) and the European Commision H2020 (Grant Agreement No. 731075)