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Genomic clocks and evolutionary timescales.

For decades, molecular clocks have helped to illuminate the evolutionary timescale of life, but now genomic data pose a challenge for time estimation methods. It is unclear how to integrate data from many genes, each potentially evolving under a different model of substitution and at a different rate. Current methods can be grouped by the way the data are handled (genes considered separately or combined into a 'supergene') and the way gene-specific rate models are applied (global versus local clock). There are advantages and disadvantages to each of these approaches, and the optimal method has not yet emerged. Fortunately, time estimates inferred using many genes or proteins have greater precision and appear to be robust to different approaches.

Amino Acid Substitution↗

Reducing disparity in behavioral health services: a report from the American College of Mental Health Administration.

UNLABELLED: The 2003 AMCHA Summit was an initial step. It served to provide a broad outline of the socio-political context and key issues involved in reducing disparities, and it provided some momentum for change. However, much more work remains to be done. The summit clearly demonstrated that the reduction of disparities requires a multi-level approach and multi-disciplinary leaders. As a neutral convener, AMCHA is in a unique position to help advance the debate and lead the field. The membership includes researchers, administrators, clinicians, and policy makers from all levels of the behavioral health system. As noted, a change agenda needs to include efforts at national, state, and local levels involving consumers, providers, purchasers, oversight organizations, and researchers. ACMHA is committed to advancing the field and helping the national effort to reduce disparities. Examples of potential projects include the following: Training: Much has been done to develop effective cultural-competency training modules and to guide states in its implementation. No one should reinvent the wheel at this time. Funding should be targeted to provide incentives to states for dissemination of existing training curricula and the documentation of effectiveness to all providers and administrators. DATA: Nationally, the field will benefit from data standards for the collection of and reporting on system disparities. This will facilitate interstate comparisons and provide baseline data for change efforts. Conducting surveys of providers, health plans, and public behavioral health systems on the availability and current uses of data by race and ethnicity is one example of a useful first step in this process of setting data standards. RESEARCH: Further research on the nature and causes of disparity is needed. There should be systematic research on factors influencing access, treatment, and outcomes for people of different cultures. Initially, because of the difficulties in deciding on standardized outcome measures, the encounter and claims data will provide the most useful information for analysis. Later, as standardized outcome measures are more widely utilized and the data collected, it may be possible to look for racial and ethnic differences in outcomes. The research agenda needs to be developed with a focus on services and health systems research data. Demonstrations: Demonstration efforts are urgently needed, similar to Connecticut's initiative, that integrate data on disparities with provider reporting, performance contracting, and system-wide interventions. These best practices need to be shared with the field. Coordination: The Summit showed that many are eager to learn from others in this area. As we move from further research to demonstration initiatives, AMCHA can play a role in coordinating these projects, particularly at the state and perhaps local levels. State efforts can benefit from best-practice presentations from other states and by an improved understanding of the nature and scope of the change required at a programmatic and local level. Local efforts need to clearly incorporate the views and perspectives of members of the community and consumers. The 2003 ACMHA Summit provided a foundation and a framework for work to proceed at all levels of the behavioral health delivery system. To accomplish meaningful change, we challenge SAMHSA, and the other federal agencies to provide the leadership to (1) develop common and core-performance measures focused on the reduction of disparities, (2) coordinate the research agenda, and (3) facilitate the use of new information technologies to collect and review these data. This is completely consistent with the vision of federal "leadership by example" that has been outlined by the Institute of Medicine (2003b) for the implementation of the "Crossing the Quality Chasm" report. We need to facilitate the efforts of the states and the federal government to identify and reduce disparities and provide a forum for states to share the results of their efforts, to benchmark their performance, and seek technical assistance. Over the next several years, we also expect that states will expand their efforts to implement evidence-based practices. However, we urge these states to implement existing evidence-based practices cautiously, especially with culturally diverse populations, due to the limited representation of ethnically diverse subjects in the research evidence on current practices. We strongly recommend collecting data on practice-based evidence-where effective interventions are routinely identified from existing practice and shared with the field, particularly those practices that seem effective with minority populations.

California↗

ToxoDB: accessing the Toxoplasma gondii genome.

ToxoDB (http://ToxoDB.org) provides a genome resource for the protozoan parasite Toxoplasma gondii. Several sequencing projects devoted to T. gondii have been completed or are in progress: an EST project (http://genome.wustl.edu/est/index.php?toxoplasma=1), a BAC clone end-sequencing project (http://www.sanger.ac.uk/Projects/T_gondii/) and an 8X random shotgun genomic sequencing project (http://www.tigr.org/tdb/e2k1/tga1/). ToxoDB was designed to provide a central point of access for all available T. gondii data, and a variety of data mining tools useful for the analysis of unfinished, un-annotated draft sequence during the early phases of the genome project. In later stages, as more and different types of data become available (microarray, proteomic, SNP, QTL, etc.) the database will provide an integrated data analysis platform facilitating user-defined queries across the different data types.

Animals↗

Psychobiological models of hippocampal function in learning and memory.

We review current computational models of hippocampal function in learning and memory, concentrating on those that make strongest contact with psychological issues and behavioral data. Some models build upon Marr's early theories for modeling hippocampal field CA3's putative role in the fast, temporary storage of episodic memories. Other models focus on hippocampal involvement in incrementally learned associations, such as classical conditioning. More recent efforts have attempted to bring functional interpretations of the hippocampal region in closer contact with underlying anatomy and physiology. In reviewing these psychobiological models, three major themes emerge. First, computational models provide the conceptual glue to bind together data from multiple levels of analysis. Second, models serve as important tools to integrate data from both animal and human studies. Third, previous psychological models that capture important behavioral principles of memory provide an important top-down constraint for developing computational models of the neural bases of these behaviors.

Animals↗

Barriers integrating dedicated software for quality management in pain centres.

OBJECTIVES: Explore the feasibility of integrating a dedicated pain centre information system as part of a quality management network with a number of different Hospital Information Systems. MATERIAL & METHODS: A systematic approach integrating and implementing the system in 15 selected hospital organisations (a nationwide 15% non-random sample). RESULTS: Hospitals have widely varying policies on integration and implementation of additional clinically required 3rd party software. Financial and organisational constraints are considerable. Partial data integration could be realised in one third of the hospital organisations within the project timeframe. Linking with various types of Hospital Information Systems from the same or different vendors caused no technical difficulties. The total effort required, however, varies considerably; different versions of a HIS of the same vendor require substantial additional effort. IT departments hardly use standard rules to accept this type of systems, causing substantial increases in completion time for installation. CONCLUSIONS: Although it is feasible to integrate a local departmental system as required (download of general patient, provider and referrer data basically, and also upload of certain data) the workload of scaling to the national level is considered far beyond what is reasonable for a national quality management network for pain. Alternatives for recording and capturing data (which comply with the requirements of the national system) are currently being explored.

Diffusion of Innovation↗

Interactive multi-window integration of two-parameter flow cytometric data fields.

Integration is necessary to determine the particle content of regions of interest of flow cytometric two-parameter fields. The improved program of the Cytomic 12 analyzer (1) offers: window trace integration for relatively simple window structures. The field of interest is surrounded by an integration trace (window). Eight independent windows can be stored and successively evaluated. It also offers painted field integration for complicated window structures. The pointer or a small window is interactively moved over the structures to be integrated like the brush of a painter. The "painted field" defines the window to be integrated. Window sets and painted fields can be stored on a floppy disk. Painted fields can be added and may also serve as look up tables for sorting.

Cell Count↗

Biokinetic and toxicodynamic modelling and its role in toxicological research and risk assessment.

Toxicological risk assessment for chemicals is still mainly based on highly standardised protocols for animal experimentation and exposure assessment. However, developments in our knowledge of general physiology, in chemicobiological interactions and in (computer-supported) modelling, have resulted in a tremendous change in our understanding of the molecular mechanisms underlying the toxicity of chemicals. This permits the development of biologically based models, in which the biokinetics as well as the toxicodynamics of compounds can be described. In this paper, the possibilities are discussed of developing systems in which the systemic (acute and chronic) toxicities of chemicals can be quantified without the heavy reliance on animal experiments. By integrating data derived from different sources, predictions of toxicity can be made. Key elements in this integrated approach are the evaluation of chemical functionalities representing structural alerts for toxic actions, the construction of biokinetic models on the basis of non-animal data (for example, tissue-blood partition coefficients, in vitro biotransformation parameters), tests or batteries of tests for determining basal cytotoxicity, and more-specific tests for evaluating tissue or organ toxicity. It is concluded that this approach is a useful tool for various steps in toxicological hazard and risk assessment, especially for those forms of toxicity for which validated in vitro and other non-animal tests have already been developed.

Animal Use Alternatives↗

An integrative network approach for longitudinal stratification in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms resulting from the loss of dopamine-producing neurons in the brain. Currently, there is no cure for the disease which is in part due to the heterogeneity in patient symptoms, trajectories and manifestations. There is a known genetic component of PD and genomic datasets have helped to uncover some aspects of the disease. Understanding the longitudinal variability of PD is essential as it has been theorised that there are different triggers and underlying disease mechanisms at different points during disease progression. In this paper, we perform longitudinal and cross-sectional experiments to identify which data modalities or combinations of modalities are informative at different time points. We use clinical, genomic, and proteomic data from the Parkinson's Progression Markers Initiative. We validate the importance of flexible data integration by highlighting the varying combinations of data modalities for optimal stratification at different disease stages in idiopathic PD. We show there is a shared signal in the DNAm signatures of participants with a mutation in a causal gene of PD and participants with idiopathic PD. We also show that integration of SNPs and DNAm data modalities has potential for use as an early diagnostic tool for individuals with a genetic cause of PD.

Parkinson Disease↗

MeMo: a hybrid SQL/XML approach to metabolomic data management for functional genomics.

BACKGROUND: The genome sequencing projects have shown our limited knowledge regarding gene function, e.g. S. cerevisiae has 5-6,000 genes of which nearly 1,000 have an uncertain function. Their gross influence on the behaviour of the cell can be observed using large-scale metabolomic studies. The metabolomic data produced need to be structured and annotated in a machine-usable form to facilitate the exploration of the hidden links between the genes and their functions. DESCRIPTION: MeMo is a formal model for representing metabolomic data and the associated metadata. Two predominant platforms (SQL and XML) are used to encode the model. MeMo has been implemented as a relational database using a hybrid approach combining the advantages of the two technologies. It represents a practical solution for handling the sheer volume and complexity of the metabolomic data effectively and efficiently. The MeMo model and the associated software are available at http://dbkgroup.org/memo/. CONCLUSION: The maturity of relational database technology is used to support efficient data processing. The scalability and self-descriptiveness of XML are used to simplify the relational schema and facilitate the extensibility of the model necessitated by the creation of new experimental techniques. Special consideration is given to data integration issues as part of the systems biology agenda. MeMo has been physically integrated and cross-linked to related metabolomic and genomic databases. Semantic integration with other relevant databases has been supported through ontological annotation. Compatibility with other data formats is supported by automatic conversion.

Computer Simulation↗

Cognitive computer-based video analysis: its application in assessing the usability of medical systems.

This paper describes a methodology, based on cognitive research, for assessing the usability of medical computing systems. The issue of developing appropriate evaluation tools, both for use in the design process and for analysis of end products, is beginning to be recognized as being of great importance. In this paper, the use of video recording for collecting empirical data on system usability is detailed. The techniques described allow for the collection of an integrated data set consisting of the transcripts of physicians as they "think aloud" in interacting with a medical system, along with video records of user-computer interaction. The use of coding methodologies and a computer-based annotation system for the analysis of video data are described. Our preliminary experience indicates that this methodology offers a powerful way for assessing physicians' informational needs. Implications for the development and evaluation of medical information systems are discussed.

Computer Systems↗

Analytical reproducibility in (1)H NMR-based metabonomic urinalysis.

Metabonomic analysis of biofluids and tissues utilizing high-resolution NMR spectroscopy and chemometric techniques has proven valuable in characterizing the biochemical response to toxicity for many xenobiotics. To assess the analytical reproducibility of metabonomic protocols, sample preparation and NMR data acquisition were performed at two sites (one using a 500 MHz and the other using a 600 MHz system) using two identical (split) sets of urine samples from an 8-day acute study of hydrazine toxicity in the rat. Despite the difference in spectrometer operating frequency, both datasets were extremely similar when analyzed using principal components analysis (PCA) and gave near-identical descriptions of the metabolic responses to hydrazine treatment. The main consistent difference between the datasets was related to the efficiency of water resonance suppression in the spectra. In a 4-PC model of both datasets combined, describing all systematic dose- and time-related variation (88% of the total variation), differences between the two datasets accounted for only 3% of the total modeled variance compared to ca. 15% for normal physiological (pre-dose) variation. Furthermore, <3% of spectra displayed distinct inter-site differences, and these were clearly identified as outliers in their respective dose-group PCA models. No samples produced clear outliers in both datasets, suggesting that the outliers observed did not reflect an unusual sample composition, but rather sporadic differences in sample preparation leading to, for example, very dilute samples. Estimations of the relative concentrations of citrate, hippurate, and taurine were in >95% correlation (r(2)) between sites, with an analytical error comparable to normal physiological variation in concentration (4-8%). The excellent analytical reproducibility and robustness of metabonomic techniques demonstrated here are highly competitive compared to the best proteomic analyses and are in significant contrast to genomic microarray platforms, both of which are complementary techniques for predictive and mechanistic toxicology. These results have implications for the quantitative interpretation of metabonomic data, and the establishment of quality control criteria for both regulatory agencies and for integrating data obtained at different sites.

Animals↗

The HUPO PSI's molecular interaction format--a community standard for the representation of protein interaction data.

A major goal of proteomics is the complete description of the protein interaction network underlying cell physiology. A large number of small scale and, more recently, large-scale experiments have contributed to expanding our understanding of the nature of the interaction network. However, the necessary data integration across experiments is currently hampered by the fragmentation of publicly available protein interaction data, which exists in different formats in databases, on authors' websites or sometimes only in print publications. Here, we propose a community standard data model for the representation and exchange of protein interaction data. This data model has been jointly developed by members of the Proteomics Standards Initiative (PSI), a work group of the Human Proteome Organization (HUPO), and is supported by major protein interaction data providers, in particular the Biomolecular Interaction Network Database (BIND), Cellzome (Heidelberg, Germany), the Database of Interacting Proteins (DIP), Dana Farber Cancer Institute (Boston, MA, USA), the Human Protein Reference Database (HPRD), Hybrigenics (Paris, France), the European Bioinformatics Institute's (EMBL-EBI, Hinxton, UK) IntAct, the Molecular Interactions (MINT, Rome, Italy) database, the Protein-Protein Interaction Database (PPID, Edinburgh, UK) and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING, EMBL, Heidelberg, Germany).

Database Management Systems↗

Management of Information in Radiation Oncology: An Integrated System for Scheduling, Treatment, Billing, and Verification.

An effective information system is an essential prerequisite to delivering quality patient care at competitive costs. From scheduling and billing to complex treatment machine control and verification, the quality of the information system strongly affects the efficiency and accuracy with which patient care is delivered. The standard paper-based information system used in many clinics suffers form inefficiencies and incompleteness in scheduling and billing, no centralized database and the inability to generate routine reports and communicate with other information systems. Many of these problems are resolved by the introduction of an electronic information system. The implementation, gains, and limitations of two electronic information systems are discussed. While limitations such as the lack of complete seamless integration of all information still exist, major improvements have been made in efficiency, accuracy, data integrity, and reporting and billing completeness.

Journal Article↗

Pattern motion integration in infants.

To investigate the development of motion integration in infants, we used an eye movement technique to measure subjects' ability to track leftward versus rightward pattern motion in a stimulus consisting of a field of spatially segregated moving gratings. Each grating moved in one of two oblique directions, with the two directions interleaved across the display. When spatially integrated, pattern motion for these paired component motions was either rightward or leftward. To control for the possibility that horizontal eye movements elicited by this stimulus were due to the horizontal motion vector present in each obliquely moving grating, we also measured responses to a field where every grating moved in the same oblique direction. The difference in performance between the integration stimulus and this control stimulus was taken as a measure of integration. Data from 2-, 3-, 4-, and 5-month-old infants revealed significant motion integration, suggesting that higher order motion areas, such as the middle temporal area (MT) may develop at a relatively early age. In addition, the integration effect decreased consistently and significantly with age (p <.005), suggesting a reduction in the spatial extent of motion integration over the course of development.

Adult↗

Issues in identification and linkage of patient records across an integrated delivery system.

Historically, the health information systems community has viewed linking personal records as a mundane task. The oversimplified view that routine database manipulation can accurately identify multiple records for a single individual is erroneous, an assumption based on a misperception of the quality of the underlying data. Such data have been adversely affected by the evolution of individual facility patient indexes from multiple systems and the results of backload procedures, and the lack of focus on the need for data integrity by users of the automated systems. Much of the random, invalid data we identify on a daily basis is directly associated with the need for system users to place data in the patient record while they face the situation of having no obvious data field in which to place them. Combined with an underlying lack of standards for the collection of personal identification information, this results in pure chaos when reviewing an MPI file containing a million records at the start of a linkage evaluation project. We have documented the considerable effort that must therefore be made in standardizing the MPI files using stringent analytical procedures and applying common edit routines before commencing record linkage. This preprocessing effort must then be supplemented with sophisticated matching procedures that can handle the dual challenge of minimizing false negatives (the failure to identify true linkages) and false positives (the incorrect linking of records that do not represent the same person). The identification of pairs of linked records does not, however, complete an EPI loading. Because it is fairly common for a multiple facility linkage evaluation to identify more than two medical record numbers for the same patient, and the primary goal of an EPI is to assign a unique identifier for the patient which will link that patient's multiple files, it becomes necessary to develop a means of readily associating three or more records for the same patient. One approach we have used with great success is to assign a common, sequential identification number to all linked medical record numbers for the same patient regardless of facility. The assignment of linkage identification numbers is computer-intensive and is generally accomplished with a highly iterative process. Both system memory and hard disk resources are fully tested as the number of good linkages in an overlap evaluation reaches the half-million mark or greater. Because the primary linkage analysis goal is to develop linkages on pairs of records, with confidence levels based on the comparison of information for those two records, thresholds must be set to decide which linkages should be accepted as true without any human evaluation. If the threshold is set too low, the defined linkage groups may incorrectly join the medical record numbers for different persons. But if the threshold is set too high, there will be undesired duplication of persons in the enterprise system. As in the identification of the underlying linkage pairs, the development of a confidence measure greatly facilitates the assignment of the unique identification numbers needed in the EPI implementation.

Algorithms↗

Implementation of a management information system for hospital use at the Policlinico Universitario A. Gemelli.

First, the experience with the implementation of HISs at the "Policlinico Gemelli", is reported. They were adopted since long for management support. In fact, they are playing an increasingly relevant role in health care facilities. Subsequently, operational applications are described with particular reference to the most recent ones, implemented within European projects with partial EEC financing. They are very useful to the medical and nursing personnel and for patient data management during treatment. Finally, the accounting system for cost centers, using, processing and integrating data of all used information systems, is described. It affords a low cost aggregation of all information about costs and services required for the management of four-hundred elementary operating units which constitute the structure. This system is representative of all managerial information of the "Policlinico" which is included in monthly reports, also described. They are sent to the Direction and managers of the organizational units. The system is a strategic tool of the utmost importance for rapid and effective management.

Hospital Information Systems↗

Preliminary experience in glioma surgery with intraoperative high-field MRI.

OBJECTIVE: To apply a new setup, combining the benefits of high-field magnetic resonance imaging (MRI) with microscope-based neuronavigation, providing anatomical and functional guidance, in glioma surgery. MATERIAL AND METHODS: MR imaging was performed using a 1.5 T scanner, located in a radiofrequency-shielded operating theatre. The patient is lying on a rotating operating table, which is locked at the 160 degree position for surgery at the 5 G zone and turned into the scanner for imaging. The microscope, placed in the 5 G zone, in combination with a ceiling mounted navigation system enables microscope-based neuronavigation; integrated data from magnetoencephalography and functional MRI provide functional guidance. RESULTS: 126 patients were investigated with intraoperative high-field MRI, among them were 37 patients with gliomas. In the biopsy/catheter group (n = 8) MRI reliably depicted the needle position or the location of catheter placement. In the group with glioma resection (n = 29) intraoperative MRI revealed that the surgical objective was not achieved in 28%, leading to further tumour removal. We did not observe complications attributable to intraoperative high-field MRI. Image quality was not diminished by the operating room equipment, so that there was nearly no noticeable difference between pre- and intraoperative image quality. Neuronavigational guidance was applied in 31 patients: the integrated use of functional data prevented an increased morbidity despite extended resections. CONCLUSION: Intraoperative high-field MRI allows a reliable delineation of the extent of resection in glioma surgery. If the surgical objective was not met, a modification of the surgical strategy during the same operation is possible, thus leading to more radical resections. Furthermore, high-field MRI offers increased image quality and a much broader spectrum of different imaging modalities, compared to previous intraoperative low-field systems.

Adolescent↗

IXDB, an X chromosome integrated database (update).

Chromosome specific databases are an important research tool as they integrate data from different directions, such as genetic and physical mapping data, expression data, sequences etc. They supplement the genome-wide repositories in molecular biology, such as GenBank, Swiss-Prot or OMIM, which usually concentrate on one type of information. The Integrated X Chromosome Database (IXDB, http://ixdb.mpimg-berlin-dahlem.mpg.de/) is a repository for physical mapping data of the human X chromosome and aims at providing a global view of genomic data at a chromosomal level. We present here an update of IXDB which includes schema extensions for storing submaps and sequence information, additional links to external databases, and the integration of an increasing number of physical and transcript mapping data. The gene data was completely updated according to the approved gene symbols of the HUGO Nomenclature Committee. IXDB receives over 1000 queries per month, an indication that its content is valuable to researchers seeking mapping data of the human X chromosome.

Chromosome Mapping↗