Examination of the current top candidate genes for AD in a genome-wide association study.

With the advent of technologies that allow simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) across the genome, the genetic contributions to complex diseases can be explored at an unprecedented detail. This study is among the first to apply the genome-wide association study (GWAS) approach to Alzheimer disease (AD). We present our GWAS results from the German population for genes included in the 'Top Results' list on the AlzGene database website. In addition to the apolipoprotein E locus, we identified nominally significant association signals in six of the ten genes investigated, albeit predominantly for SNPs other than those already published as being disease associated. Further, all of the four AD genes previously identified through GWAS also showed nominally significant association signals in our data. The results of our comparative study reinforce the necessity for replication and validation, not only of GWAS but also of candidate gene case-control studies, in different populations. Furthermore, cross-platform comparison of genotyping results can also identify new association signals. Finally, our data confirm that GWAS, regardless of the platform, are valuable for the identification of genetic variants associated with AD.

Informatics and medicine--from molecules to populations.

OBJECTIVES: To clarify challenges and research topics for informatics in health and to describe new approaches for interdisciplinary collaboration and education. METHODS: Research challenges and possible solutions were elaborated by scientists of two universities using an interdisciplinary approach, in a series of meetings over several months. RESULTS AND CONCLUSION: In order to translate scientific results from bench to bedside and further into an evidence-based and efficient health system, intensive collaboration is needed between experts from medicine, biology, informatics, engineering, public health, as well as social and economic sciences. Research challenges can be attributed to four areas: bioinformatics and systems biology, biomedical engineering and informatics, health informatics and individual healthcare, and public health informatics. In order to bridge existing gaps between different disciplines and cultures, we suggest focusing on interdisciplinary education, taking an integrative approach and starting interdisciplinary practice at early stages of education.

Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity.

Interactions between the microbiota and distal gut are important for the maintenance of a healthy intestinal barrier; dysbiosis of intestinal microbial communities has emerged as a likely contributor to diseases that arise at the level of the mucosa. Intraepithelial lymphocytes (IELs) are positioned within the epithelial barrier, and in the small intestine they function to maintain epithelial homeostasis. We hypothesized that colon IELs promote epithelial barrier function through the expression of cytokines in response to interactions with commensal bacteria. Profiling of bacterial 16S ribosomal RNA revealed that candidate bacteria in the order Bacteroidales are sufficient to promote IEL presence in the colon that in turn produce interleukin-6 (IL-6) in a MyD88 (myeloid differentiation primary response 88)-dependent manner. IEL-derived IL-6 is functionally important in the maintenance of the epithelial barrier as IL-6-/- mice were noted to have increased paracellular permeability, decreased claudin-1 expression, and a thinner mucus gel layer, all of which were reversed by transfer of IL-6+/+ IELs, leading to protection of mice in response to Citrobacter rodentium infection. Therefore, we conclude that microbiota provide a homeostatic role for epithelial barrier function through regulation of IEL-derived IL-6.

Expanding the scope of health information systems - from hospitals to regional networks, to national infrastructures, and beyond.

OBJECTIVES: To identify current developments, obstacles, and opportunities for health information systems. METHODS: International reports were discussed during an IMIA HIS Working Conference with a focus on architectural design, project goals and drivers, obstacles, and opportunities. RESULTS: Technology and standards are available to build regional and national health IT networks, and successful implementations are currently being realized. There is, however, little consensus and communication concerning goals, benefits and risks of large-scale health IT initiatives. Complexity tends to be under-estimated, and the public needs to be more involved in the decision-making process. CONCLUSION: On all levels and across borders, a climate of exchange of ideas, experiences - both successes and failures-, policies, standards, systems, and information should be created.

Improving pathway compliance and clinician performance by using information technology.

To deliver patient-specific advice at the time and place of a consultation is an important contribution to improving clinician performance. Using computer-based decision support on the basis of clinical pathways is a promising strategy to achieve this goal. Thereby integration of IT applications into the clinical workflow is a core precondition for success. User acceptance and usability play a critical role: additional effort has to be balanced with enough benefit for the users and interaction design and evaluation should be handled as an intertwined, continuous process. Experiences from routine use of an online surgical pathway at Marburg University Medical Center show that it is possible to successfully address this issue by seamlessly integrating patient-specific pathway recommendations with documentation tasks which have to be done anyway, by substantially reusing entered data to accelerate routine tasks (e.g. by automatically generating orders and reports), and by continuously and systematically monitoring pathway conformance and documentation quality.

Demand-driven evolution of IT systems in healthcare--a case study for improving interdisciplinary processes.

OBJECTIVES: To analyze and to optimize interdisciplinary clinical processes, to introduce an IT-supported model for demand-driven system evolution in healthcare, and to demonstrate the feasibility of the approach for a clinical example and to present an evaluation. METHODS: System evolution and change management are viewed as two sides of the same coin, thus formal methods for process analysis and IT system evolution were embedded into a goal-oriented change management model. Based on a process model, a Failure Mode and Effects Analysis (FMEA) and a computer simulation were performed. A tool for rapid application development (RAD) was used to incrementally improve the healthcare information system according to newly arising needs. RESULTS: Each of the formal methods used contributed to the successful reorganization of the interdisciplinary clinical process. An evaluation demonstrated significant improvements. An integrated IT application was implemented to support the optimized process. CONCLUSIONS: Process improvement is feasible and effective when formal methods for process analysis and requirements specification are used in a reasonable and goal-oriented way. It might be necessary to trade off costs and benefits or simplify a given method in the context of a particular project. As the same information is utilized in different tools, it is supposed that the efforts for process analysis, documentation and implementation of adapted applications could be reduced if different tools were integrated and based on a single coherent reference model for description of clinical processes.

Discussion of "Combining Health Data Uses to Ignite Health System Learning".

This article is part of a For-Discussion-Section of Methods of Information in Medicine about the paper "Combining Health Data Uses to Ignite Health System Learning" written by John D. Ainsworth and Iain E. Buchan [1]. It is introduced by an editorial. This article contains the combined commentaries invited to independently comment on the paper of Ainsworth and Buchan. In subsequent issues the discussion can continue through letters to the editor. With these comments on the paper "Combining Health Data Uses to Ignite Health System Learning", written by John D. Ainsworth and Iain E. Buchan [1], the journal seeks to stimulate a broad discussion on new ways for combining data sources for the reuse of health data in order to identify new opportunities for health system learning. An international group of experts has been invited by the editor of Methods to comment on this paper. Each of the invited commentaries forms one section of this paper.

From hospital information systems to health information systems. Problems, challenges, perspectives.

OBJECTIVES: Hospital information systems are evolving towards health information systems. This article aims at identifying both proven benefits and critical issues, and at discussing problems and possible solutions. METHODS: Reports on HIS successes and failures were analyzed, and core challenges were identified. These challenges are discussed against state of the art solutions. RESULTS: In spite of demonstrated benefits, there are more severe problems than reports on successes suggest. Among today's core problems are integration, human-computer interaction, socio-technical issues, and support of processes. CONCLUSIONS: Significant efforts of all parties involved in the health care process are needed to improve, implement, and evaluate the concepts described.

Intranet meets hospital information systems: the solution to the integration problem?

Based on the results of an extensive market analysis and technology assessment, this paper summarizes the state of the art in web technology and compares it with the needs of integration in hospital information systems. Web technology and intranet have evolved to a core technology for distributed computing and distributed information systems. The advantage of platform independent distribution of information has led to euphoric visions of future integrated systems. However, true integration takes more than transparent access to heterogeneous information sources. To overcome the essential problems related to integration of autonomous systems it is important to find a common ontological basis for future component based systems.

Experiences with a generator tool for building clinical application modules.

OBJECTIVES: To elaborate main system characteristics and relevant deployment experiences for the health information system (HIS) Orbis/OpenMed, which is in widespread use in Germany, Austria, and Switzerland. METHODS: In a deployment phase of 3 years in a 1.200 bed university hospital, where the system underwent significant improvements, the system's functionality and its software design have been analyzed in detail. We focus on an integrated CASE tool for generating embedded clinical applications and for incremental system evolution. We present a participatory and iterative software engineering process developed for efficient utilization of such a tool. RESULTS: The system's functionality is comparable to other commercial products' functionality; its components are embedded in a vendor-specific application framework, and standard interfaces are being used for connecting subsystems. The integrated generator tool is a remarkable feature; it became a key factor of our project. Tool generated applications are workflow enabled and embedded into the overall data base schema. Rapid prototyping and iterative refinement are supported, so application modules can be adapted to the users' work practice. CONCLUSIONS: We consider tools supporting an iterative and participatory software engineering process highly relevant for health information system architects. The potential of a system to continuously evolve and to be effectively adapted to changing needs may be more important than sophisticated but hard-coded HIS functionality. More work will focus on HIS software design and on software engineering. Methods and tools are needed for quick and robust adaptation of systems to health care processes and changing requirements.

Towards a continuous evolution and adaptation of information systems in healthcare.

OBJECTIVES: To address the problem of alignment of health information systems to healthcare processes, which is a major challenge in healthcare organizations; to present a layered approach for system evolution and adaptation based on an application framework and rapid application development; to accomplish a demand-driven system evolution by embedding the software engineering process in business process optimization projects and by closely involving end users to improve their own work practices. METHODS: We have used a holistic health information system as a core application framework. System functionality is incrementally improved using an integrated "generator tool" for rapid application development. We have developed an iterative and participatory software engineering process, adapted to the conditions of the generator tool. The documentation techniques provided by the Unified Modeling Language (UML) were modified to achieve a straight forward documentation covering the whole development cycle from the business process model to generator-based computer applications. RESULTS AND CONCLUSION: The layered approach for system evolution did provide an environment in which a flexible and participatory software development process could be established. Today, generator-based applications are used in all clinical departments of our 1200-bed University Hospital. We expect that tools for rapid application development will be further improved and will play an increasingly important role to establish responsive IT-infrastructures where the application developer can concentrate on business process alignment instead of coding and debugging.

Hospital information systems: chances and obstacles on the way to integration.

Today, most large hospital information systems (HIS) comprise many heterogeneous application systems, loosely coupled via interfaces. Integration could offer many advantages, like the support of interdepartmental workflows or a consistent patient record. This cannot be achieved, however, by simply interfacing originally unrelated component systems. In this paper, we present relevant concepts of integration, the autonomy/consistency tradeoff, and technical alternatives in some detail. Based on our recent experiences in analyzing an existing HIS and selecting adequate vendors for the needs of our 1250-bed hospital, we then discuss strategies and tradeoffs on the way to a HIS that utilizes state-of-the-art technology to fill the users' needs.

Expanding the scope of health information systems. Challenges and developments.

OBJECTIVES: To identify current challenges and developments in health information systems. METHODS: Reports on HIS, eHealth and process support were analyzed, core problems and challenges were identified. RESULTS AND CONCLUSION: Health information systems are extending their scope towards regional networks and health IT infrastructures. Integration, interoperability and interaction design are still today's core problems. Additional problems arise through the integration of genetic information into the health care process. There are noticeable trends towards solutions for these problems.

Improving pathway compliance and clinician performance by using information technology.

To deliver patient-specific advice at the time and place of a consultation, to improve clinician performance and compliance by using computer-based decision support, and to integrate such IT solutions with the clinical workflow are important strategies for the implementation of clinical pathways. User acceptance plays a critical role: additional effort has to be balanced with enough benefit for the users. Experiences from routine use of an online surgical pathway at Marburg University Medical Center show that it is possible to successfully address this issue by seamlessly integrating patient-specific pat documentation tasks which have to be done anyway and by substantially reusing entered data to accelerate routine tasks (e.g. by automatically generating orders and reports).

Building a hospital information system: design considerations based on results from a Europe-wide vendor selection process.

A number of research and development projects in the U.S. and in Europe have shown that novel technologies can open significant perspectives for hospital information systems (HIS). The selection of software products for a HIS, however, is still nontrivial. Generalist vendors promise a broad scope of functionality and integration, while specialist vendors promise elaborated and highly adapted functionality. In 1997, the university hospital Marburg, a 1,250 bed teaching hospital, decided to introduce a new large-scale HIS. The objectives of the project included support of clinical workflows, cost effectiveness and a maximum standard of medical care. In 1997/98 a formal Europe-wide vendor contest was performed. 15 vendors, including several from the U.S., participated. Systems were checked against the hospital's objectives, functionality, and technological criteria. One of the results of both technology and market assessment was the identification of fundamental technological and design aspects strongly influencing functionality and flexibility.

The primary structure of hen ovotransferrin.

Peptide sequences obtained from hen ovotransferrin are compared with the complete amino acid sequence of the protein deduced from a cDNA sequence (Jeltsch and Chambon, preceding paper). Of the 705 positions of the whole protein 605 can be matched by the peptide sequences. Some possible discrepancies between the two methods are pointed out. The two halves of the chain show marked similarities in their sequences with 37% identical residues. The positions of the 15 disulphide bridges are shown; there are 6 homologous bridges in each half of the molecule and 3 extra bridges which occur only in the C-terminal half. The terminal residues of the half-molecule fragments obtained by limited proteolysis are identified. The two domains are joined by a 9-residue connecting peptide. Sequence variability has been found at 9 positions. The sequence of hen ovotransferrin is compared with the partial available for human transferrin. From this some tentative conclusions about the identities of the metal-binding residues and about the evolution of transferrin are reached.

NK cells secrete high levels of IFN-gamma in response to in vivo administration of IL-2.

Interleukin-2 is an immunotherapeutic agent for the treatment of metastatic tumors. Administration of recombinant human IL-2 (rhIL-2) in vivo activates lymphocytes and cell-mediated immune responses. In mice, we have recently observed a dramatic increase of serum IFN-gamma levels in response to in vivo administration of rhIL-2, which was necessary for the observed protective effects of IL-2 against the development of collagen-induced arthritis. To explore further the basis of this phenomenon, the kinetics and source of IFN-gamma in response to IL-2 was investigated. Highest serum levels of IFN-gamma were observed within 3 h of IL-2 administration, with levels decreasing over time. Anti-IL-2 receptor beta antibody blocked this IFN-gamma induction. Multiple doses of rhIL-2 resulted in corresponding increases in circulating IFN-gamma. IFN-gamma induction was dose-dependent between doses of 240 to 30,000 U of rhIL-2. Analysis of the cellular source of IFN-gamma secretion using NK- and T cell-deficient mice demonstrated that NK cells are the likely source of IFN-gamma. Furthermore, IFN-gamma secretion in response to IL-2 administration was not affected by the absence of IL-12, the pivotal cytokine for determination of Th1 responses. These results suggest that effects of IL-2 on immune responses in vivo may be mediated by IFN-gamma.