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TEAM: a tool for the integration of expression, and linkage and association maps.

The identification of genes primarily responsible for complex genetic disorders is a daunting task. Despite the assignment of many susceptibility loci, there has only been limited success in identifying disease genes based solely on positional information from genome-wide screens. The incorporation of several complementary strategies in a single integrated approach should facilitate and further enhance the efficacy of this search for genes. To permit the integration of linkage, association and expression data, together with functional annotations, we have developed a Java-based software tool: TEAM (tool for the integration of expression, and linkage and association maps). TEAM includes a genome viewer, capable of overlaying karyobands, genes, markers, linkage graphs, association data, gene expression levels and functional annotations in one composite view. Data management, analysis and filtering functionality was implemented and extended with links to the Ensembl, Unigene and Gene Ontology databases to facilitate gene annotation. Filtering functionality can help prevent the exclusion of poorly annotated, but differentially expressed, genes that reside in candidate regions that show linkage or association. Here we demonstrate the program's functionality in our study on coeliac disease (OMIM 212750), a multifactorial gluten-sensitive enteropathy. We performed a combined data analysis of a genome-wide linkage screen in 82 Dutch families with affected siblings and the microarray expression profiles of 18,110 cDNAs in 22 intestinal biopsies.

Celiac Disease↗

Development and preliminary evaluation of the VPS ReplaySuite: a virtual double-headed microscope for pathology.

BACKGROUND: Advances in computing and telecommunications have resulted in the availability of a range of online tools for use in pathology training and quality assurance. The majority focus on either enabling pathologists to examine and diagnose cases, or providing image archives that serve as reference material. Limited emphasis has been placed on analysing the diagnostic process used by pathologists to reach a diagnosis and using this as a resource for improving diagnostic performance. METHODS: The ReplaySuite is an online pathology software tool that presents archived virtual slide examinations to pathologists in an accessible video-like format, similar to observing examinations with a double-headed microscope. Delivered through a customized web browser, it utilises PHP (Hypertext PreProcessor) to interact with a remote database and retrieve data describing virtual slide examinations, performed using the Virtual Pathology Slide (VPS). To demonstrate the technology and conduct a preliminary evaluation of pathologists opinions on its potential application in pathology training and quality assurance, 70 pathologists were invited to use the application to review their own and other pathologists examinations of 10 needle-core breast biopsies and complete an electronic survey. 9 pathologists participated, and all subsequently completed an exit survey. RESULTS: Of those who replayed an examination by another pathologist, 83.3% (5/6) agreed that replays provided an insight into the examining pathologists diagnosis and 33.3% (2/6) reconsidered their own diagnosis for at least one case. Of those who reconsidered their original diagnosis, all re-classified either concordant with group consensus or original glass slide diagnosis. 77.7% (7/9) of all participants, and all 3 participants who replayed more than 10 examinations stated the ReplaySuite to be of some or great benefit in pathology training and quality assurance. CONCLUSION: Participants conclude the ReplaySuite to be of some or of great potential benefit to pathology training and quality assurance and consider the ReplaySuite to be beneficial in evaluating the diagnostic trace of an examination. The ReplaySuite removes temporal and spatial issues that surround the use of double-headed microscopes by allowing examinations to be reviewed at different times and in different locations to the original examination. While the evaluation set was limited and potentially subject to bias, the response of participants was favourable. Further work is planned to determine whether use of the ReplaySuite can result in improved diagnostic ability.

Archives↗

Microcomputer software and interface for control of a microscope scanning stage.

Motorized scanning stages are valuable in microscopy systems that employ digital image analysis and for the development of semiautomatic computer-assisted microscope systems; the development of standard software "tools" to control such stages will facilitate their integration into a variety of computer-based systems. A set of Microsoft BASIC and Turbo PASCAL programs that interfaces a microprocessor-controlled stepper motor microscope stage (MDACE 1000) to an IBM PC or PC-AT or compatible microcomputer via a serial interface (RS-232) is described. These programs can be integrated into other software written in either BASIC or PASCAL, or used via a menu program that directs the routines to control scanning patterns and to locate the microscope stage to a selected area of the slide. Coordinates of significant events on a slide can be stored on a disk file to allow future examination. The software and interface also provide control of a filter wheel in the microscope for use in multicolor fluorescence assays.

Computers↗

Interactive DICOM image transmission and telediagnosis over the European ATM network.

The European High-Performance Information Infrastructure in Medicine, n(o)B3014 (HIM3) project of the Trans-European Network--Integrated Broadband Communications (TEN-IBC) program, started on March 1996 and finished on February 1997, aimed to test the medical usability of the European asynchronous transfer mode (ATM) network in medical image transmission. The Department of Radiology, University of Pisa, Pisa, Italy, and St-Luc University Hospital, Brussels, Belgium, involved in the project as healthcare partners in the radiological domain, established several connection sessions finalized to test the usability of Digital Imaging and Communication (DICOM) image transmission and interactive telediagnosis tools in the daily radiological practice. The Pisa site was connected to the Italian ATM pilot (Sirius Network) through the Tuscany metropolitan area network (MAN), while St-Luc University Hospital was connected to Belgium ATM network through the Brussels MAN. By means of international connections provided by the European JAMES project, a link between the two sites was established, connecting both national ATM networks. Due to the large variety of hardware present in the medical centers, multiplatform software tools were used and tested: central test node (CTN) release 2.8 [3], VAT [6], NV-3.3 [7], and IDI (UCL homemade multiplatform teleradiology tool for interactive visualization and processing of DICOM images). During the telediagnosis session, lead by radiologists in both hospitals, each site submitted neuroradiological clinical cases to the other for remote consultation. The connection, available for a period of two weeks, at 2-Mbit/s bandwidth, allowed the transmission of MR images (256 x 256 x 12 bit) and simultaneous multimedia interactive discussion of the cases. Both off-line transmission and review of the images, using the CTN DICOM transfer routines, and on-line interactive image discussion, using the IDI telediagnosis software, were tested successfully from the technical and medical point of view.

Computer Communication Networks↗

Disseminating medical knowledge: the PROforma approach.

Medical knowledge is traditionally disseminated via the publication of documents and through participation in clinical practice. Information technology offers to extend both modes of dissemination, via electronic publishing and virtual reality training, for example. AI promises even more radical changes through the possibility of publishing clinical expertise in the form of expert systems, which assist patient care through active decision support and workflow management. PROforma is a knowledge representation language that is designed to support this new mode of dissemination. It is based on an intuitive model of the processes of care and well-understood logical semantics. This paper provides a description of the language and associated software tools, and discusses its potential roles in, and implications for, medical knowledge publishing.

Artificial Intelligence↗

Advances in high content screening for drug discovery.

Cell-based target validation, secondary screening, lead optimization, and structure-activity relationships have been recast with the advent of HCS. Prior to HCS, a computational approach to the characterization of the functions of specific target proteins and other cellular constituents, along with whole-cell functions employing fluorescence cell-based assays and microscopy, required extensive interaction among the researcher, instrumentation, and software tools. Early HCS platforms were instrument-centric and addressed the need to interface fully automated fluorescence microscopy, plate-handling automation, and seamless image analysis. HCS has since evolved into an integrated solution for accelerated drug discovery by encompassing the workflow components of assay and reagent design, robust instrumentation for automated fixed-end-point and live cell kinetic analysis, generalized and specific BioApplication software (Cellomics, Pittsburgh, PA) modules that produce information on drug responses from cell image data, and informatics/bioinformatics solutions that build knowledge from this information while providing a means to globalize HCS throughout an entire organization. This review communicates how these recent advances are incorporated into the drug discovery workflow by presenting a real-world use case.

Drug Design↗

STAR/mmCIF: an ontology for macromolecular structure.

MOTIVATION: Crystallographers were motivated 10 years ago to develop a simple and consistent data representation for the exchange and archiving of data associated with the crystallographic experiment and the final structure. As this process evolved (and the data grew at near exponential rates) came the recognition that this representation should also facilitate the automated management of the data and, with the aid of additional software for verification and validation, provide improved consistency and accuracy and hence improved scientific inquiry. This realization led to a new Dictionary Definition Language (DDL) and an extensive dictionary based on this DDL for describing macromolecular structure. In broad terms this could be considered an ontology. An important feature in the development of the ontology was the endorsement and ongoing maintenance and support of the International Union of Crystallography (IUCr). While the description of macromolecular structure and the x-ray crystallographic experiment used to derive it represent explicit data, the ontology is extensible and applicable to other less well-characterized data domains. RESULTS: Details of the DDL, the dictionaries that have been developed, and software for reading and using this ontology are presented. AVAILABILITY: Extensive documentation, software tools and the DDL and dictionaries are available from http://ndbserver.rutgers.edu/mmcif and associated mirror sites. CONTACT: Bourne: bourne@sdsc.edu and Westbrook:jwest@rcsp.rutgers.edu

Crystallography, X-Ray↗

'PePApipe': A complete bioinformatics analysis pipeline for African Swine Fever Virus genome.

African Swine Fever Virus (ASFV) is of high concern in porcine livestock across the world due to both the high mortality rates and the trade restrictions imposed on affected regions. The viral genome is large and complex, and genomic analysis is essential for tracing its origin and evolution. Although several bioinformatics tools exist for genome assembly and analysis, no single platform integrates all necessary steps in an accessible and systematic way. In this study the authors developed 'PePApipe', a custom-built, user-friendly pipeline that enables rapid, complete, and efficient ASFV genome analysis. It is specifically designed for laboratory professionals with limited bioinformatics experience, requiring only basic command-line knowledge. Starting from raw sequencing data, PePApipe integrates thirteen software tools into one automated workflow, covering quality control and pre-processing of raw reads, de novo genome assembly and variant calling. Programmed in Python, it can be executed locally through bash scripts, or using a Slurm protocol for batch processing of multiple samples. The main outputs are the ASFV consensus genome sequence and a file listing its putative variants compared to the selected reference genome. PePApipe classifies generated files into structured folders and produces intermediate files that can be used as inputs for further or parallel analyses; users can also enable or disable specific steps in each particular case. This pipeline is adaptable and complementary to downstream steps such as viral genome annotation or genome visualization. By consolidating all stages of viral genome analysis into a single automated workflow, PePApipe reduces the likelihood of user error, and enhances reproducibility and efficiency. This user-friendly pipeline facilitates the transition from sequencing to assembly and downstream analysis of viral genomes, ensuring a fast and reliable response to molecular analysis demands. Finally, the pipeline can be easily adapted to the study of other viral species, expanding its application in infectious diseases surveillance.

African Swine Fever Virus↗

DIALIGN: multiple DNA and protein sequence alignment at BiBiServ.

DIALIGN is a widely used software tool for multiple DNA and protein sequence alignment. The program combines local and global alignment features and can therefore be applied to sequence data that cannot be correctly aligned by more traditional approaches. DIALIGN is available online through Bielefeld Bioinformatics Server (BiBiServ). The downloadable version of the program offers several new program features. To compare the output of different alignment programs, we developed the program AltAVisT. Our software is available at http://bibiserv.TechFak.Uni-Bielefeld.DE/dialign/.

Algorithms↗

[Dosimetric verification of IMRT treatment plans at the German Cancer Research Center (DKFZ)].

The present paper describes a method for the individual dosimetric verification of IMRT treatment plans. The German Cancer Research Center (Deutsches Krebsforschungszentrum; DKFZ) has implemented the intensity modulated radiotherapy (IMRT) since 1997. So far, 246 patients with head and neck cancer, cancer of the prostate, breast, and vertebral column, as well as mesothelioma of the pleura have been treated. Every IMRT plan is transferred into a special IMRT verification phantom, recalculated, and dosimetrically verified. Absolute dose distributions are measured with Kodak EDR films and compared with the results of the dose calculation. After correction of the optical density in relationship to the dose, EDR films are able to measure the absolute dose with an accuracy of +/- 2% compared to an ionization chamber. A visual C++ software tool has been developed to correlate and evaluate the film dose distributions with the corresponding slices of the 3D dose cube. Beside the overlay of absolute or relative isodoses and dose profiles, the median dose within correlated regions of interest (ROIs) is also included in the quantitative dose evaluation. The deviation between EDR film dosimetry and dose calculation is delta D = -0.3% +/- 2.3%. After introduction of the verification software, the total verification time (including handling, correlation, evaluation, and documentation of the data), could be reduced to less than 2 hours.

Germany↗

[Automatic classification of liver segments according to Couinaud: development of a new algorithm and evaluation spiral CT data].

PURPOSE: To develop a software tool that analyzes the anatomy of the portal vein branches and assigns segmental and subsegmental branches according to Couinaud's classification system and to evaluate its accuracy. MATERIALS AND METHODS: The algorithm was developed in C++ on a PC. The algorithm recognizes the three major branching patterns of the portal vein. Segmental and subsegmental branches are assigned to 8 segments following Couinaud and encoded by 8 colors. The software was evaluated using CT data sets of 39 patients. After the individual segmental anatomy of each patient was determined by an experienced radiologist, automatic classification was performed and the results were compared on a branch by branch basis. RESULTS: The numbering was accurate according to Couinaud's system in 358 of 409 segmental and subsegmental branches (88 %). The assignment failed in 51 of 409 branches due to unexpected anatomy or software problems. CONCLUSION: Automatic classification of portal vein branches and their appendant parenchyma is possible. The automatic designation of liver segments enables the three-dimensional visualization of the segmental anatomy. In the future, automatic analysis might facilitate the reporting and communication of CT findings.

Algorithms↗

Merkel complexes of human digital skin: three-dimensional imaging with confocal laser microscopy and double immunofluorescence.

Three-dimensional (3-D) reconstruction of images provided by confocal scanning laser microscopy (CSLM) is a powerful tool in a morpho-functional approach to cutaneous innervation studies. To investigate mechanoreceptors in the hand, a study of Merkel complexes was performed in human finger. A double fluorescent-conjugated immunolabeling with antibodies against neurofilament (NF 200) and cytokeratin (CK 20) on floating, thick cutaneous samples (80 to 100 microm), was used. After acquisition of serial optical planes by CSLM, reconstruction was performed with 3-D reconstruction software tools. Merkel cells were clearly labeled with CK 20, whereas nerve components were only NF 200 reactive. The cells, localized on the basal lamina of the epidermis, were usually arranged in clusters of five to eight cells. Each cell was connected to a nerve process ramification originating from a unique fiber. Quantitative data, compiled from a sample of 25 Merkel complexes, gave a mean cell diameter of 13 +/- 1 microm and a mean nerve fiber size of 3 +/- 1 microm. Surface measurements were done on a single reconstructed cluster with a mean and standard error which only refers to the optical 3-D resolution. It gives a surface of 12 +/- 1 microm2 for the contact zone between cell and nerve fiber and a cluster area of about 500 microm2. The great precision of reconstructed images provides a detailed analysis of spatial relationships between abutting nerve fibers and Merkel cells. Data interpretation is improved with complementary ultrastructural and physiological studies results, and this allows an accurate investigation of cutaneous sensory endings.

Antibodies↗

Comparison of dose distributions in IMRT planning using the gamma function.

Intensity-modulated radiotherapy (IMRT) (1) is an advanced form of 3-D conformal radiotherapy. It uses non uniform spatial modifications in the intensity of the beams across the irradiated field. Consequently, it is necessary to develop sophisticated tools to compare measured and calculated dose distributions in order to verify the accuracy of the results of the planned dose distribution. Different methods have been developed to evaluate the accordance between measured and calculated doses, such as the point-to-point dose difference or the evaluation of the distance between two closed points having the same dose value (2-4). The verification method proposed by Low (5-7) seems to be more complete since it takes into account both the dose difference (DD) and the distance to agreement (DTA), allowing to define a "score", the gamma value, at each point of interest. A software tool (DDE: Dose Distribution Evaluator), based on Low's method, to evaluate the agreement between dose distribution matrices has been implemented. In particular, the proposed gamma curve, as a function of the isodose levels, gives real-time information useful for decision making about the treatment plan. The paper describes the software, and reports the obtained results in a simple geometry and in several clinical cases (head-neck and prostate). Comparison between measured data (film and MapCheck) and calculated data (CadPlan) using DDE has shown very good agreements. Thanks to its higher resolution, film dosimetry showed better accuracy than the MapCheck technique. Similar results can be obtained also with the MapCheck technique when proper measurement methods are used.

Dose-Response Relationship, Radiation↗

Curriculum for building medical resources on the Internet--experience in Taiwan.

This paper describes our experience with a one-semester course on how to build a medically-related homepage on the Internet, designed for fourth-year medical students. Based on the assumption of limited technical knowledge of the Internet, this class taught students Internet-exploring skills, multimedia authoring and HTML (Hypertext Markup Language) in the first eight-week period. Students were then divided into four-person teams and asked to select a topic for a homepage. These teams were then asked to collect the necessary resources for the development of the homepage both through individual work and, consultation with an advisor. Each group project for building medically-related homepage was accomplished and presented in the remaining four-week period. The resultant projects of these fourth-year medical students were of surprisingly good content and high quality. Medical students rapidly learned to use the software tools, and through proper instruction and provision of equipment, they were able to build significant medical resources on the Internet that can potentially be useful in education, clinical applications and research.

Curriculum↗

Computational expansion of genetic networks.

We present a new methodology for computational analysis of gene and protein networks. The aim is to generate new educated hypotheses on gene functions and on the logic of the biological network circuitry, based on gene expression profiles. The framework supports the incorporation of biologically motivated network constraints and rules to improve specificity. Since current data is insufficient for de-novo reconstruction, the method receives as input a known pathway core and suggests likely expansions to it. Network modeling is combinatorial, yet data can be probabilistic. At the heart of the approach are a fitness function which estimates the quality of suggested network expansions given the core and the data, and a specificity measure of the expansions. The approach has been implemented in an interactive software tool called GENESYS. We report encouraging results in preliminary analysis of yeast ergosterol pathway based on transcription profiles. In particular, the analysis suggests a novel ergosterol transcription factor.

Algorithms↗

Clinical assessment in dental education: a new method.

Among the many challenges that face modern dental schools is the development of appropriate assessment systems. The more litigious nature of modern education makes it important that the systems developed are transparent and can withstand the processes of legal challenge. Coupled with this demand for robust assessment is a growing demand from universities and health providers for dental schools to keep rigorous records of student clinical productivity. This brief review outlines a system developed at the School of Oral Health Sciences at the University of Western Australia. The system integrates both qualitative and quantitative assessment and uses criterion-based assessment as its foundation. Detailed analysis and real-time reporting mechanisms using a suite of personally written software tools is now possible. The system provides both students and staff with effective data to enhance the learning process.

Clinical Competence↗

[Topography-assisted correction of superficial irregularities of the cornea with the excimer laser].

BACKGROUND: A retinal image performance distorted by an asymmetric or irregular corneal surface cannot be compensated for with spherocylindric glasses completely. The best-corrected visual acuity is markedly decreased and contact lens fitting often impossible. The purpose of this study was to calculate the differential height between corneal topography raw data and any regular surface with mathematical methods in order to ablate the differential height with a computer-controlled laser beam, thereafter. METHODS: A Zernike decomposition of radial degree n = 16 was realized within a clinically relevant central corneal area of 8 mm in diameter based on corneal topography raw height data of a commercially available topographer (TMS-1, Tomey, Erlangen). Any target surface could be defined by varying weighting of the Zernike coefficients. The calculated differential height ablation between the raw data and the target surface given in a polar grid was transformed to a Cartesian grid to evaluate the sleeping time at each grid position considering the characteristic ablation curve for the intended ablation of the height difference. Subsequently, differential height ablation was simulated using an automated laser beam control for a modified excimer laser (MEL60, Aesculap-Meditec, Jena). We developed software tools for Zernike decomposition of corneal topography raw height data and time-regulated automatic laser beam control of the grid positions in the higher programming language C (Borland C++ 3.1, Borland Inc., München). RESULTS: Definition of a target surface can be realized alternatively by selecting a set of Zernike coefficients or defining a spherical or spherocylindrical surface by superposition of parabolic terms in a fixed proportion creating a best-fit target surface to the raw data. In originally "relatively flat" areas, the differential height profile indicates a "relatively deep" ablation resulting in relative steepening towards the periphery of the ablation zone. The resolution of the mechanical unit of the laser beam control consisting of two linear stepping motors is 9 microns in the focal plane with a reproducibility of 5 microns. The software unit is guiding the laser beam in a meandering fashion within the ablation area considering the calculated sleeping time for each grid position. Mean overlap of the 1 mm laser spots is 70%. The laser beam diameter of 1 mm effects a peripheral transition zone of 0.5 mm. CONCLUSIONS: Zernike decomposition of corneal topography height data is an efficient tool for localizing and quantifying superficial irregularities and for directly calculating an ablation profile from created differential height data. With an automatic laser beam control a well-defined laser ablation of superficial corneal irregularities is possible, subsequently.

Astigmatism↗

Low-cost data transfer from a questionnaire to standard software using a barcode pen.

Computer-aided transfer of questionnaire data simplifies the analysis of questionnaires. We present a solution based on an inexpensive barcode pen and its decoder, the software tool Barcode Wizard included in CorelDRAW, and a self-developed application written using Microsoft Visual Basic for Applications. The barcode may be provided on the questionnaire or on a transparency. Error correction is done by means of two different procedures. The present solution can be applied while looking over the completed questionnaire and thus allows time-saving, economic, and precise data transfer from the completed questionnaire directly into computer software.

Computer Peripherals↗