Is the Application of SNOMED CT Concept Model sufficiently Quality Assured?

The terminological content of SNOMED CT, the world's largest clinical terminology is linked to description logics expressions, which give support to consider SNOMED CT a formal ontology. The Terminology Quality Assurance (TQA) of such a terminology resource is hampered by errors in modeling, which act as a barrier for the successful use of electronic health records to ensure semantic interoperability. One application case is the new version of ICD, now in its pre-final form, the content of which is based on a subset of SNOMED CT. The ongoing alignment exercise has highlighted significant modeling issues in more than one third of cases that contrasted SNOMED CT concept model instances with the intuitive meaning given by their Fully Specified Names or synonyms lexically mapped to ICD-11 class names. We recommend prioritizing SNOMED CT TQA on the subset of the core SNOMED CT content to constitute the always true common ontology between SNOMED CT and ICD-11.

Security and confidentiality approach for the Clinical E-Science Framework (CLEF).

OBJECTIVES: CLEF is an MRC sponsored project in the E-Science programme that aims to establish methodologies and a technical infrastructure for the next generation of integrated clinical and bioscience research. METHODS: The heart of the CLEF approach to this challenge is to design and develop a pseudonymised repository of histories of cancer patients that can be accessed by researchers. Robust mechanisms and policies have been developed to ensure that patient privacy and confidentiality are preserved while delivering a repository of such medically rich information for the purposes of scientific research. RESULTS: This paper summarises the overall approach adopted by CLEF to meet data protection requirements, including the data flows, pseudonymisation measures and additional monitoring policies that are currently being developed. CONCLUSION: Once evaluated, it is hoped that the CLEF approach can serve as a model for other distributed electronic health record repositories to be accessed for research.

Attitudes and access to electronic exchange of information on occupational disease.

BACKGROUND: THOR is a network of work-related disease surveillance schemes dependent on volunteer case reporting by medical specialists. Data collection and dissemination has hitherto been paper-based. AIMS: To elicit the opinion of existing reporters in THOR on electronic exchange of information and to assess the practical capabilities of the same reporters to participate in electronic communication. METHODS: A mail-based questionnaire of randomly selected THOR reporters using closed format questions. RESULTS: The response rate to the questionnaire was 66% (253/383). Almost half (47%) of the responders wanted dissemination of information solely in an electronic form, 35% favoured paper-based reports, while 16% wanted both paper and electronic reports. Two-thirds (66%) would make use of electronic archives of reports and 59% would use this facility to resolve questions by accessing accumulated data. The majority (82%) read e-mail more than once a week and 34% browsed the web as frequently. However, 5% did not have e-mail and 6% never browsed the web. Most responders judged their internet connectivity to be rapid (68%) and convenient (83%), and 91% could receive e-mail attachments. CONCLUSIONS: Most responders have the skills and infrastructure required to engage in electronic information exchange, and are favourably disposed to electronic means of communication. However it is also relevant to note that one-third of responders have a preference for the existing paper-based system.

Defaults, context, and knowledge: alternatives for OWL-indexed knowledge bases.

The new Web Ontology Language (OWL) and its Description Logic compatible sublanguage (OWL-DL) explicitly exclude defaults and exceptions, as do all logic based formalisms for ontologies. However, many biomedical applications appear to require default reasoning, at least if they are to be engineered in a maintainable way. Default reasoning has always been one of the great strengths of Frame systems such as Protégé. Resolving this conflict requires analysis of the different uses for defaults and exceptions. In some cases, alternatives can be provided within the OWL framework; in others, it appears that hybrid reasoning about a knowledge base of contingent facts built around the core ontology is necessary. Trade-offs include both human factors and the scaling of computational performance. The analysis presented here is based on the OpenGALEN experience with large scale ontologies using a formalism, GRAIL, which explicitly incorporates constructs for hybrid reasoning, numerous experiments with OWL, and initial work on combining OWL and Protégé.

OpenGALEN: open source medical terminology and tools.

The GALEN programme of research into medical terminology began in 1991. In 1999 OpenGALEN was formed to provide an open source route both for disseminating the results of that programme and as a framework for its future development. Currently available open source resources include a sophisticated ontology development environment and a large open source description logic-based ontology for the medical domain.

Interleukin-1 receptor antagonist VNTR-polymorphism in inflammatory bowel disease.

Both genetic and environmental factors have been implicated in the etiology of inflammatory bowel diseases (IBD) i.e., Crohn's disease (CD) and ulcerative colitis (UC). Polymorphisms in cytokine genes are likely to influence an individual's predisposition to IBD. In intron 2 of the interleukin-1 receptor antagonist (IL-1ra) gene, a variable number of an 86-bp tandem repeat (VNTR) polymorphism leads to the existence of five different alleles. In order to analyze the association between certain IL-1ra VNTR-alleles and IBD, we investigated the IL-1ra genotype and allele frequencies in 342 unrelated IBD patients and in 401 healthy control individuals. CD patients were also genotyped for the three main associated variants in the NOD2/CARD15 gene. In the IBD group, a significant decrease in the frequency of IL-1ra allele 1 (P=0.048) compared to controls was observed. The frequency of IL-1ra genotype 1/1 was significantly lower in the IBD population vs the control group (P=0.018). Analysis of the CD population without NOD2 homozygotes and compound heterozygotes revealed a more significant decrease in IL-1ra genotype 1/1 compared to controls (P=0.038). These results support the hypothesis that the IL-1ra VNTR-polymorphism could be among the genetic factors that are of importance in IBD susceptibility.

The interface between information, terminology, and inference models.

The interface between information, terminology, and inference (problem solving) models is now a central issue for the development of standards and of principled information systems. There is potential overlap amongst the models, and principled means are required to choose how to allocate information items amongst them. Any given set of choices implies mutual constraints and obligations amongst the models which together form a well defined interface allowing work on each to proceed independently of the other. This paper outlines the criteria for these choices and a possible notation for recording these choices and their consequences.

GALEN ten years on: tasks and supporting tools.

The GALEN technology has matured over more than a decade of use. We describe a set of software tools and associated methodologies that together are supporting ontological engineering in a production, rather than a research setting.

Mannan-binding lectin (MBL) gene polymorphisms in ulcerative colitis and Crohn's disease.

The inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC), are complex multifactorial traits involving both environmental and genetic factors. Mannan-binding lectin (MBL) plays an important role in non-specific immunity and complement activation. Point mutations in codons 52, 54 and 57 of exon 1 of the MBL gene are associated with decreased MBL plasma concentrations and increased susceptibility to various infectious diseases. If these MBL mutations could lead to susceptibility to putative IBD-etiological microbial agents, or could temper the complement-mediated mucosal damage in IBD, MBL could function as the link between certain microbial, immunological and genetic factors in IBD. In this study, we investigated the presence of the codon 52, 54 and 57 mutations of the MBL gene in 431 unrelated IBD patients, 112 affected and 141 unaffected first-degree relatives, and 308 healthy control individuals. In the group of sporadic IBD patients (n = 340), the frequency of the investigated MBL variants was significantly lower in UC patients when compared with CD patients (P = 0.01) and with controls (P = 0.02). These results suggest that MBL mutations which decrease the formation of functional MBL could protect against the clinical development of sporadic UC, but not of CD. This could be explained by the differential T-helper response in both diseases.

AIM: a personal view of where I have been and where we might be going.

My own career in medical informatics and AI in medicine has oscillated between concerns with medical records and concerns with knowledge representation with decision support as a pivotal integrating issue. It has focused on using AI to organise information and reduce 'muddle' and improve the user interfaces to produce 'useful and usable systems' to help doctors with a 'humanly impossible task'. Increasingly knowledge representation and ontologies have become the fulcrum for orchestrating re-use of information and integration of systems. Encouragingly, the dilemma between computational tractability and expressiveness is lessening, and ontologies and description logics are joining the mainstream both in AI in Medicine and in Intelligent Information Management generally. It has been shown possible to scale up ontologies to meet medical needs, and increasingly ontologies are playing a key role in meeting the requirements to scale up the complexity of clinical systems to meet the ever increasing demands brought about by new emphasis on reduction of errors, clinical accountability, and the explosion of knowledge on the Web.

Analysis of the CC chemokine receptor 5 (CCR5) delta-32 polymorphism in inflammatory bowel disease.

The inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) are complex multifactorial traits involving both environmental and genetic factors. Recent studies have shown the important role of pro-inflammatory cytokines and chemokines, including RANTES, in IBD. RANTES is the natural ligand for the CC-chemokine receptor 5 (CCR5). The chromosomal location of the CCR5 gene on 3p21 coincides with an IBD-susceptibility locus identified by genome-wide scanning. A 32-bp deletion (A32) in the CCR5 gene results in a nonfunctional receptor and is found with high frequency in Caucasians. In this study, we investigated the presence of the CCR5delta32 allele in a large cohort of IBD patients and in a healthy control population. Blood samples were obtained from 538 unselected IBD cases (433 unrelated IBD patients: 289 CD, 142 UC, 2 indeterminate colitis; 105 affected first-degree relatives) and 135 unaffected first-degree family members. Of the IBD patients, 36% had familial IBD with at least two members being affected. There were no significant differences in the CCR5delta32 mutation frequency between IBD patients and healthy controls, nor between CD and UC patients. There was no correlation between the CCR5delta32 genotype and the age at IBD-diagnosis, the frequency of surgical intervention, or disease localization. Only the association between CCR5delta32 homozygosity and the presence of anal lesions in CD patients was statistically significant (P=0.007). Analysis by the transmission/disequilibrium test showed no significant transmission distortion to the probands or their clinically silent siblings. Based on these results, it is unlikely that the CCR5delta32 allele is an important marker for predisposition to IBD.

Structural validation of nursing terminologies.

OBJECTIVE: The purpose of the study is twofold: 1) to explore the applicability of combinatorial terminologies as the basis for building enumerated classifications, and 2) to investigate the usefulness of formal terminological systems for performing such classification and for assisting in the refinement of both combinatorial terminologies and enumerated classifications. DESIGN: A formal model of the beta version of the International Classification for Nursing Practice (ICNP) was constructed in the compositional terminological language GRAIL (GALEN Representation and Integration Language). Terms drawn from the North American Nursing Diagnosis Association Taxonomy I (NANDA taxonomy) were mapped into the model and classified automatically using GALEN technology. MEASUREMENTS: The resulting generated hierarchy was compared with the NANDA taxonomy to assess coverage and accuracy of classification. RESULTS: In terms of coverage, in this study ICNP was able to capture 77 percent of NANDA terms using concepts drawn from five of its eight axes. Three axes-Body Site, Topology, and Frequency-were not needed. In terms of accuracy, where hierarchic relationships existed in the generated hierarchy or the NANDA taxonomy, or both, 6 were identical, 19 existed in the generated hierarchy alone (2 of these were considered suitable for incorporation into the NANDA taxonomy and 17 were considered inaccurate), and 23 appeared in the NANDA taxonomy alone (8 of these were considered suitable for incorporation into ICNP, 9 were considered inaccurate, and 6 reflected different, equally valid perspectives). Sixty terms appeared at the top level, with no indenting, in both the generated hierarchy and the NANDA taxonomy. CONCLUSIONS: With appropriate refinement, combinatorial terminologies such as ICNP have the potential to provide a useful foundation for representing enumerated classifications such as NANDA. Technologies such as GALEN make possible the process of building automatically enumerated classifications while providing a useful means of validating and refining both combinatorial terminologies and enumerated classifications.

Integrating existing drug formulation terminologies into an HL7 standard classification using OpenGALEN.

Many terminologies exist for the form of drugs--i.e. tablets, capsules, sprays, suppositories, etc. However, they have surprisingly different content. To communicate medication messages effectively, a mechanism is needed to translate between these existing terminologies. An ontological approach, based on techniques developed by OpenGALEN, has been used to build a drug form terminology for HL7 version 3. It integrates existing terminologies from commercial drug information vendors and regulatory authorities, and provides a framework for translating between them. To date, term sets have been included from First DataBank, the FDA, Multum and Micromedex, to produce a terminology of 820 concepts. The approach is made practical by distributing the knowledge engineering effort to volunteers with experience of the domain, and then integrating the knowledge into a logically consistent classification.

NLP techniques associated with the OpenGALEN ontology for semi-automatic textual extraction of medical knowledge: abstracting and mapping equivalent linguistic and logical constructs.

This research project presents methodological and theoretical issues related to the inter-relationship between linguistic and conceptual semantics, analysing the results obtained by the application of a NLP parser to a set of radiology reports. Our objective is to define a technique for associating linguistic methods with domain specific ontologies for semi-automatic extraction of intermediate representation (IR) information formats and medical ontological knowledge from clinical texts. We have applied the Edinburgh LTG natural language parser to 2810 clinical narratives describing radiology procedures. In a second step, we have used medical expertise and ontology formalism for identification of semantic structures and abstraction of IR schemas related to the processed texts. These IR schemas are an association of linguistic and conceptual knowledge, based on their semantic contents. This methodology aims to contribute to the elaboration of models relating linguistic and logical constructs based on empirical data analysis. Advance in this field might lead to the development of computational techniques for automatic enrichment of medical ontologies from real clinical environments, using descriptive knowledge implicit in large text corpora sources.

GALEN's model of parts and wholes: experience and comparisons.

Part-whole relations play a critical role in the OpenGALEN Common Reference Model. We describe how particular characteristics of the underlying formalism have influenced GALEN's view on partonomy, and in more detail discuss how specific modelling issues have driven development of an extended set of partitive semantic links.

Having our cake and eating it too: how the GALEN Intermediate Representation reconciles internal complexity with users' requirements for appropriateness and simplicity.

Clinical terminologies are complex objects, getting more complex as the requirements on them grow, and as more complex technologies are used in their construction. But to the clinical end-user, functionality and utility is important, not inherent complexity--the simpler a clinical terminology can be for the end-user, the better. To reconcile these contradictory requirements, the GALEN Programme has developed an Intermediate Representation that allows the OpenGALEN Clinical Terminology to retain a high degree of internal complexity, whilst allowing it to be efficiently maintained, and easily used. This paper describes the elements of the Intermediate Representation, how it works, and some experience of its use.

Mutants of the lactose carrier of Escherichia coli which show altered sugar recognition plus a severe defect in sugar accumulation.

Lactose and melibiose are actively accumulated by the wild-type Escherichia coli lactose carrier, which is an integral membrane protein energized by the proton motive force. Mutants of the E. coli lactose carrier were isolated by their ability to grow on minimal plates with succinate plus IPTG in the presence of the toxic lactose analog beta-thio-o-nitrophenylgalactoside (TONPG). TONPG-resistant mutants were streaked on melibiose MacConkey indicator plates, and red clones were picked. These melibiose positive mutants were then streaked on lactose MacConkey plates, and white clones were picked. Transport assays indicated that the mutants had altered sugar recognition and a defect in sugar accumulation. The mutants had a poor apparent K(m) for both lactose and melibiose in transport. One mutant had almost no ability to take up lactose, but melibiose downhill transport was 58% (V(max)) of normal. All of the mutants accumulated methyl-alpha-d-galactopyranoside (TMG) to only 8% or less of normal, and two failed to accumulate. Immunoblot analysis of the mutant lactose carrier proteins indicated that loss of sugar transport activity was not due to loss of expression in the membrane. Nucleotide sequencing of the lacY gene from the mutants revealed changes in the following amino acids of the lactose carrier: M23I, W151L, G257D, A295D and G377V. Two of the mutants (G257D and G377V) are novel in that they represent the first amino acids in periplasmic loops to be implicated with changes in sugar recognition. We conclude that the amino acids M23, W151, G257, A295 and G377 of the E. coli lactose carrier play either a direct or an indirect role in sugar recognition and accumulation.

A reference terminology for drugs.

GALEN technology for re-usable terminologies using formal classification is being applied to the creation and maintenance of a reference terminology for drugs. GALEN's techniques are being used to address specific deficiencies of existing drug classifications that make it difficult to create and maintain guidelines to support prescribing in the care of patients with chronic diseases. The reference terminology is in two parts; firstly, a re-usable and automatically-classified 'ontology' is built with GALEN technology; this describes generic drugs, their composition in terms of chemicals and chemical classes, their actions, indications and interactions. Secondly, a 'dictionary' of prescribable proprietary products is integrated with this ontology. The result is a drug resource designed to support both the traditional uses of a drug knowledge base (e.g. prescribing and messaging), and the specialized demands of guideline authoring and execution.