Charles Crichton

Effects of control interventions on Clostridium difficile infection in England: an observational study

Summary Background The control of Clostridium difficile infections is an international clinical challenge. The incidence of C difficile in England declined by roughly 80% after 2006, following the implementation of national control policies; we tested two hypotheses to investigate their role in this decline. First, if C difficile infection declines in England were driven by reductions in use of particular antibiotics, then incidence of C difficile infections caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes. Second, if C difficile infection declines were driven by improvements in hospital infection control, then transmitted (secondary) cases should decline regardless of susceptibility. Methods Regional (Oxfordshire and Leeds, UK) and national data for the incidence of C difficile infections and antimicrobial prescribing data (1998–2014) were combined with whole genome sequences from 4045 national and international C difficile isolates. Genotype (multilocus sequence type) and fluoroquinolone susceptibility were determined from whole genome sequences. The incidence of C difficile infections caused by fluoroquinolone-resistant and fluoroquinolone-susceptible isolates was estimated with negative-binomial regression, overall and per genotype. Selection and transmission were investigated with phylogenetic analyses. Findings National fluoroquinolone and cephalosporin prescribing correlated highly with incidence of C difficile infections (cross-correlations >0·88), by contrast with total antibiotic prescribing (cross-correlations <0·59). Regionally, C difficile decline was driven by elimination of fluoroquinolone-resistant isolates (approximately 67% of Oxfordshire infections in September, 2006, falling to approximately 3% in February, 2013; annual incidence rate ratio 0·52, 95% CI 0·48–0·56 vs fluoroquinolone-susceptible isolates: 1·02, 0·97–1·08). C difficile infections caused by fluoroquinolone-resistant isolates declined in four distinct genotypes (p<0·01). The regions of phylogenies containing fluoroquinolone-resistant isolates were short-branched and geographically structured, consistent with selection and rapid transmission. The importance of fluoroquinolone restriction over infection control was shown by significant declines in inferred secondary (transmitted) cases caused by fluoroquinolone-resistant isolates with or without hospital contact (p<0·0001) versus no change in either group of cases caused by fluoroquinolone-susceptible isolates (p>0·2). Interpretation Restricting fluoroquinolone prescribing appears to explain the decline in incidence of C difficile infections, above other measures, in Oxfordshire and Leeds, England. Antimicrobial stewardship should be a central component of C difficile infection control programmes. Funding UK Clinical Research Collaboration (Medical Research Council, Wellcome Trust, National Institute for Health Research); NIHR Oxford Biomedical Research Centre; NIHR Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance (Oxford University in partnership with Public Health England [PHE]), and on Modelling Methodology (Imperial College, London in partnership with PHE); and the Health Innovation Challenge Fund.

Formality, Evolution, and Model-driven Software Engineering

This paper introduces an approach to software development in which a series of working implemen- tations are generated automatically from a series of formal specifications. The implementations are data stores, communicating through standard protocols. The specifications are precise object models, in which operations are described in terms of pre- and post-conditions. The approach is evolutionary, in the sense that the specification may evolve while the system is in use, in response to changes in requirements, and any changes to the specification are automatically reflected in the structure of the implementation, and in the representation of any data currently stored.

Metadata standards for semantic interoperability in electronic government

Effective data sharing, across government agencies and other organisations, relies upon agreed meanings and representations. A key, technological challenge in electronic governance is to ensure that the meaning of data items is accurately recorded, and accessible in an economical---effectively, automatic---fashion. In response, a variety of data and metadata standards have been put forward: from government departments, from industry groups, and from organisations such as the ISO and W3C. This paper shows how the leading standard for metadata registration---ISO 11179---can be deployed without the need for a single, monolithic conceptualisation of the domain, and hence without the need for universal agreement upon a particular model of electronic governance. The advantages of this approach are discussed with regard to the UK eGovernment Interoperability Framework (eGIF) and the UK Integrated Public Sector Vocabulary (IPSV).

A metadata approach for clinical data management in translational genomics studies in breast cancer

BackgroundIn molecular profiling studies of cancer patients, experimental and clinical data are combined in order to understand the clinical heterogeneity of the disease: clinical information for each subject needs to be linked to tumour samples, macromolecules extracted, and experimental results. This may involve the integration of clinical data sets from several different sources: these data sets may employ different data definitions and some may be incomplete.MethodsIn this work we employ semantic web techniques developed within the CancerGrid project, in particular the use of metadata elements and logic-based inference to annotate heterogeneous clinical information, integrate and query it.ResultsWe show how this integration can be achieved automatically, following the declaration of appropriate metadata elements for each clinical data set; we demonstrate the practicality of this approach through application to experimental results and clinical data from five hospitals in the UK and Canada, undertaken as part of the METABRIC project (Molecular Taxonomy of Breast Cancer International Consortium).ConclusionWe describe a metadata approach for managing similarities and differences in clinical datasets in a standardized way that uses Common Data Elements (CDEs). We apply and evaluate the approach by integrating the five different clinical datasets of METABRIC.

Semantic frameworks for e-government

This paper explains how semantic frameworks can be used to support successful e-Government initiatives by connecting system design to a shared understanding of interactions and processes. It shows how metadata standards and repositories can be used to establish and maintain such an understanding, and how they can be used in the automatic generation and instantiation of components and services. It includes an account of a successful implementation at an international level, and a brief review of related approaches.

When to trust mobile objects: access control in the Jini/sup TM/ Software System

Future developments in computing, and in consumer electronics, will involve a considerable degree of convergence: applications will work together to locate and provide services. If this convergence is to be implemented successfully, then a shared model for reliable service provision is required. The recently released Jini/sup TM/ Software System (1.0) is an attempt to meet this requirement through object orientation. Based entirely upon existing Java/sup TM/ 2 technology, Jini is a set of protocols and programming models for peer-to-peer service provision using downloaded code and remote method invocation. The paper examines the way in which the Jini Software System will be used. It shows that the existing mechanisms for access control and secure operation provided by Java may prove inadequate in a Jini environment: a Jini enabled device will be vulnerable to attack from its peers. Similar problems may be encountered in other related technologies, such as Enterprise Java Beans. An account of the Jini technology is followed by an exploration of the inadequacies and vulnerabilities; concrete examples are provided to illustrate the possible attacks. The paper ends by showing how the existing specification may be enhanced to produce a secure system without significantly reducing either functionality or flexibility.

The CancerGrid experience

The CancerGrid approach to software support for clinical trials is based on two principles: careful curation of semantic metadata about clinical observations, to enable subsequent data integration, and model-driven generation of trial-specific software artefacts from a trial protocol, to streamline the software development process. This paper explains the approach, presents four varied case studies, and discusses the lessons learned. Summary, philosophy, and lessons of the CancerGrid project and follow-ons.Software support for cancer clinical trials, and similar data collection exercises.Metadata support, to enable subsequent meta-analysis.Model-driven generation of software artefacts to run trial.Four case studies.

Concurrency and Refinement in the Unified Modeling Language

This paper defines a formal semantics for a subset of the Unified Modeling Language (UML). It shows how suitable combinations of class, object, state, and sequence diagrams can be associated with patterns of interaction, expressed in the event notation of Communicating Sequential Processes (CSP). The diagram semantics is then extended to give a meaning to complete models – suitable combinations of diagrams – and thus a concurrency semantics for object models written in UML. This model semantics is in turn used to define a theory of refinement, based upon existing notions of data and process refinement.

Models for forms

To make reliable, safe, and effective use of data outside the context of its collection, we require an adequate understanding of its meaning. In data-intensive science, as in many other applications of computing, this necessitates the association of each item of data with complex, detailed metadata. The most important, most useful piece of metadata is often a description of the form used in data acquisition. This paper discusses, with examples, the requirements for standard metamodels or languages for forms, sufficient for the automatic association of form data with a computable description of its semantics, and also for the automatic generation of form structures and completion workflows. It explains how form models in specific domains can be used to facilitate data sharing, and to improve data quality, and semantic interoperability.

Semantic technologies in electronic government

Joined-up government depends fundamentally on semantics --- on the computable representation of meaning, so that data is associated with appropriate metadata from the start, and this association is maintained as the data is manipulated. This paper summaries a tutorial and workshop on semantic technologies for supporting electronic government.