Artificial intelligence in digital pathology: a roadmap to routine use in clinical practice

The use of artificial intelligence will likely transform clinical practice over the next decade and the early impact of this will likely be the integration of image analysis and machine learning into routine histopathology. In the UK and around the world, a digital revolution is transforming the reporting practice of diagnostic histopathology and this has sparked a proliferation of image analysis software tools. While this is an exciting development that could discover novel predictive clinical information and potentially address international pathology work-force shortages, there is a clear need for a robust and evidence-based framework in which to develop these new tools in a collaborative manner that meets regulatory approval. With these issues in mind, the NCRI Cellular Molecular Pathology (CM-Path) initiative and the British In Vitro Diagnostics Association (BIVDA) has set out a roadmap to help academia, industry and clinicians develop new software tools to the point of approved clinical use. This article is protected by copyright. All rights reserved. [Abstract copyright: This article is protected by copyright. All rights reserved.

Uncertainty in geomorphological responses to climate change

Acknowledgements We acknowledge the careful comments from two anonymous reviewers. Funding information This work was partly supported by a Middlesex University PhD Studentship to EA and a Coventry University PhD Studentship to PA. NERC for radiocarbon dating provided funding support.Peer reviewedPublisher PD

Multiscale modelling of vascular tumour growth in 3D: the roles of domain size & boundary condition

We investigate a three-dimensional multiscale model of vascular tumour growth, which couples blood flow, angiogenesis, vascular remodelling, nutrient/growth factor transport, movement of, and interactions between, normal and tumour cells, and nutrient-dependent cell cycle dynamics within each cell. In particular, we determine how the domain size, aspect ratio and initial vascular network influence the tumour's growth dynamics and its long-time composition. We establish whether it is possible to extrapolate simulation results obtained for small domains to larger ones, by constructing a large simulation domain from a number of identical subdomains, each subsystem initially comprising two parallel parent vessels, with associated cells and diffusible substances. We find that the subsystem is not representative of the full domain and conclude that, for this initial vessel geometry, interactions between adjacent subsystems contribute to the overall growth dynamics. We then show that extrapolation of results from a small subdomain to a larger domain can only be made if the subdomain is sufficiently large and is initialised with a sufficiently complex vascular network. Motivated by these results, we perform simulations to investigate the tumour's response to therapy and show that the probability of tumour elimination in a larger domain can be extrapolated from simulation results on a smaller domain. Finally, we demonstrate how our model may be combined with experimental data, to predict the spatio-temporal evolution of a vascular tumour

Interaction of ENSO-driven Flood Variability and Anthropogenic Changes in Driving Channel Evolution: Corryong/ Nariel Creek, Australia

This is an Accepted Manuscript of an article published by Taylor & Francis in Australian Geographer on 03/09/2015, available online: 10.1080/00049182.2015.1048595Understanding the relative contributions of climatic and anthropogenic drivers of channel change are important to inform river management, especially in the context of environmental change. This global debate is especially pertinent in Australia as catchments have been severely altered since recent European settlement, and there is also strong evidence of cyclical climate variability controlling environmental systems. Corryong/Nariel Creek is an ideal setting to further study the interaction between climate and anthropogenic changes on channel evolution as it has experienced both significant periods of flood and drought, controlled by the El Niño Southern Oscillation (ENSO), and extensive anthropogenic changes. Since European settlement the floodplain has been completely cleared, the riparian zone almost entirely invaded by willows, and every reach of the channel has experienced some form of direct channel modification. Through the combined analysis of channel evolution, climate changes and anthropogenic history of the river it was found that both the ENSO-driven climate and anthropogenic drivers are significant, although at different scales of channel change. Significant straightening in response to land clearing in the early twentieth century occurred before any records of direct channel modifications. Following this, most river management works were in response to instabilities created in the clearing period, or to instabilities created by flooding triggering a new phase of instability in reaches which had already undergone stabilisation works. Overall, human activities triggered channel instability via land clearing, and management works since then generally exacerbated erosion during high flows that are driven by climate fluctuations. This research raises the interesting question of whether rivers in Australia have become more responsive to the ENSO cycle since the clearing of catchment and riparian vegetation, or whether the past response to climate variability was different

Understanding the ethical and legal considerations of Digital Pathology

Digital Pathology (DP) is a platform which has the potential to develop a truly integrated and global pathology community. The generation of DP data at scale creates novel challenges for the histopathology community in managing, processing, and governing the use of these data. The current understanding of, and confidence in, the legal and ethical aspects of DP by pathologists is unknown. We developed an electronic survey (e‐survey) comprising of 22 questions, which was developed with input from the Royal College of Pathologists (RCPath) Digital Pathology Working Group. The e‐survey was circulated via e‐mail and social media (Twitter) through the RCPath Digital Pathology Working Group network, RCPath Trainee Committee network, the Pathology image data Lake for Analytics, Knowledge and Education (PathLAKE) digital pathology consortium, National Pathology Imaging Co‐operative (NPIC), local contacts, and to the membership of both The Pathological Society of Great Britain and Ireland and the British Division of the International Academy of Pathology (BDIAP). Between 14 July 2020 and 6 September 2020, we collected 198 responses representing a cross section of histopathologists, including individuals with experience of DP research. We ascertained that in the UK, DP is being used for diagnosis, research, and teaching, and that the platform is enabling data sharing. Our survey demonstrated that there is often a lack of confidence and understanding of the key issues of consent, legislation, and ethical guidelines. Of 198 respondents, 82 (41%) did not know when the use of digital scanned slide images would fall under the relevant legislation and 93 (47%) were ‘Not confident at all’ in their interpretation of consent for scanned slide images in research. With increasing uptake of DP, a working knowledge of these areas is essential but histopathologists often express a lack of confidence in these topics. The need for specific training in these areas is highlighted by the findings of this study

Modeling Evolutionary Dynamics of Epigenetic Mutations in Hierarchically Organized Tumors

The cancer stem cell (CSC) concept is a highly debated topic in cancer research. While experimental evidence in favor of the cancer stem cell theory is apparently abundant, the results are often criticized as being difficult to interpret. An important reason for this is that most experimental data that support this model rely on transplantation studies. In this study we use a novel cellular Potts model to elucidate the dynamics of established malignancies that are driven by a small subset of CSCs. Our results demonstrate that epigenetic mutations that occur during mitosis display highly altered dynamics in CSC-driven malignancies compared to a classical, non-hierarchical model of growth. In particular, the heterogeneity observed in CSC-driven tumors is considerably higher. We speculate that this feature could be used in combination with epigenetic (methylation) sequencing studies of human malignancies to prove or refute the CSC hypothesis in established tumors without the need for transplantation. Moreover our tumor growth simulations indicate that CSC-driven tumors display evolutionary features that can be considered beneficial during tumor progression. Besides an increased heterogeneity they also exhibit properties that allow the escape of clones from local fitness peaks. This leads to more aggressive phenotypes in the long run and makes the neoplasm more adaptable to stringent selective forces such as cancer treatment. Indeed when therapy is applied the clone landscape of the regrown tumor is more aggressive with respect to the primary tumor, whereas the classical model demonstrated similar patterns before and after therapy. Understanding these often counter-intuitive fundamental properties of (non-)hierarchically organized malignancies is a crucial step in validating the CSC concept as well as providing insight into the therapeutical consequences of this model

The human body at cellular resolution: the NIH Human Biomolecular Atlas Program

Abstract: Transformative technologies are enabling the construction of three-dimensional maps of tissues with unprecedented spatial and molecular resolution. Over the next seven years, the NIH Common Fund Human Biomolecular Atlas Program (HuBMAP) intends to develop a widely accessible framework for comprehensively mapping the human body at single-cell resolution by supporting technology development, data acquisition, and detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies, programs, consortia, and the biomedical research community at large towards the shared vision of a comprehensive, accessible three-dimensional molecular and cellular atlas of the human body, in health and under various disease conditions

CM-Path Molecular Diagnostics Forum-consensus statement on the development and implementation of molecular diagnostic tests in the United Kingdom.

BACKGROUND: Pathology has evolved from a purely morphological description of cellular alterations in disease to our current ability to interrogate tissues with multiple 'omics' technologies. By utilising these techniques and others, 'molecular diagnostics' acts as the cornerstone of precision/personalised medicine by attempting to match the underlying disease mechanisms to the most appropriate targeted therapy. METHODS: Despite the promises of molecular diagnostics, significant barriers have impeded its widespread clinical adoption. Thus, the National Cancer Research Institute (NCRI) Cellular Molecular Pathology (CM-Path) initiative convened a national Molecular Diagnostics Forum to facilitate closer collaboration between clinicians, academia, industry, regulators and other key stakeholders in an attempt to overcome these. RESULTS: We agreed on a consensus 'roadmap' that should be followed during development and implementation of new molecular diagnostic tests. We identified key barriers to efficient implementation and propose possible solutions to these. In addition, we discussed the recent reconfiguration of molecular diagnostic services in NHS England and its likely impacts. CONCLUSIONS: We anticipate that this consensus statement will provide practical advice to those involved in the development of novel molecular diagnostic tests. Although primarily focusing on test adoption within the United Kingdom, we also refer to international guidelines to maximise the applicability of our recommendations