The Human Brain Project: neuroinformatics tools for integrating, searching and modeling multidisciplinary neuroscience data.

What is neuroinformatics? What is the Human Brain Project? Why should you care? Supported by a consortium of US funding agencies, the Human Brain Project aims to bring to the analysis of brain function the same advantages of Internet-accessible databases and database tools that have been crucial to the development of molecular biology and the Human Genome Project. The much greater complexity of neural data, however, makes this a far more challenging task. As a pilot project in this new initiative, we review some of the progress that has been made and indicate some of the problems, challenges and opportunities that lie ahead.

The Common Data Elements for cancer research: remarks on functions and structure.

OBJECTIVES: The National Cancer Institute (NCI) has developed the Common Data Elements (CDE) to serve as a controlled vocabulary of data descriptors for cancer research, to facilitate data interchange and inter-operability between cancer research centers. We evaluated CDE's structure to see whether it could represent the elements necessary to support its intended purpose, and whether it could prevent errors and inconsistencies from being accidentally introduced. We also performed automated checks for certain types of content errors that provided a rough measure of curation quality. METHODS: Evaluation was performed on CDE content downloaded via the NCI's CDE Browser, and transformed into relational database form. Evaluation was performed under three categories: 1) compatibility with the ISO/IEC 11179 metadata model, on which CDE structure is based, 2) features necessary for controlled vocabulary support, and 3) support for a stated NCI goal, set up of data collection forms for cancer research. RESULTS: Various limitations were identified both with respect to content (inconsistency, insufficient definition of elements, redundancy) as well as structure--particularly the need for term and relationship support, as well as the need for metadata supporting the explicit representation of electronic forms that utilize sets of common data elements. CONCLUSIONS: While there are numerous positive aspects to the CDE effort, there is considerable opportunity for improvement. Our recommendations include review of existing content by diverse experts in the cancer community; integration with the NCI thesaurus to take advantage of the latter's links to nationally used controlled vocabularies, and various schema enhancements required for electronic form support.

Flow cytometric analysis of deoxyribonucleic acid in human granulosa cells as a function of chronological age and ovulation induction regimen.

We examined whether the proliferative index of granulosa cells as determined by flow cytometry varied with a women's age or ovulation induction regimen that included leuprolide acetate (LA). This prospective cohort study included three groups of patients undergoing assisted reproductive technologies. Group I consisted of 9 women age less than or equal to 30 yr, who received LA plus human menopausal gonadotropin (hMG). Group II included 9 women age more than or equal to 40 yr, who received LA plus hMG. Group III consisted of 6 women age less than or equal to 30 yr who received hMG alone. A total of 79 preovulatory follicles containing greater than 10(4) granulosa cells were obtained from these 24 women and examined by flow cytometry. Group I was compared to group II to match for ovulation induction regimen and to examine proliferative index as a function of age. Group I was compared to group III to match for age and to examine proliferative index as a function of ovulation induction regimen. Outcome measures included proliferative index of granulosa cells as a function of age, ovulation induction regimen, ampules of hMG, estradiol on day of hCG, and serum FSH. Group I demonstrated a greater proliferative index than group II: 23.4% +/- 1.4 vs. 18.4% +/- 0.96 (P less than 0.01). Group I had a greater proliferative index than group III: 23.4% +/- 1.4 vs. 11.9 +/- 0.61 (P less than 0.001). Although both age and the presence of LA appeared to affect the PI, multiple linear regression demonstrated that only the addition of LA and not age, per se, had an independent effect upon granulosa cells undergoing proliferation (P less than 0.0005). We conclude that LA followed by hMG leads to an increase in the percentage of granulosa cells undergoing proliferation when compared to ovulation induction regimens that include hMG alone. Chronological age does not appear to have a significant independent influence upon the proliferative index.

Data extraction and ad hoc query of an entity-attribute-value database.

Entity--attribute--value (EAV) tables form the major component of several mainstream electronic patient record systems (EPRSs). Such systems have been optimized for real-time retrieval of individual patient data. Data warehousing, on the other hand, involves cross-patient data retrieval based on values of patient attributes, with a focus on ad hoc query. Attribute-centric query is inherently more difficult when data are stored in EAV form than when they are stored conventionally. The authors illustrate their approach to the attribute-centric query problem with ACT/DB, a database for managing clinical trials data. This approach is based on metadata supporting a query front end that essentially hides the EAV/non-EAV nature of individual attributes from the user. The authors' work does not close the query problem, and they identify several complex subproblems that are still to be solved.

Use of general-purpose negation detection to augment concept indexing of medical documents: a quantitative study using the UMLS.

OBJECTIVES: To test the hypothesis that most instances of negated concepts in dictated medical documents can be detected by a strategy that relies on tools developed for the parsing of formal (computer) languages-specifically, a lexical scanner ("lexer") that uses regular expressions to generate a finite state machine, and a parser that relies on a restricted subset of context-free grammars, known as LALR(1) grammars. METHODS: A diverse training set of 40 medical documents from a variety of specialties was manually inspected and used to develop a program (Negfinder) that contained rules to recognize a large set of negated patterns occurring in the text. Negfinder's lexer and parser were developed using tools normally used to generate programming language compilers. The input to Negfinder consisted of medical narrative that was preprocessed to recognize UMLS concepts: the text of a recognized concept had been replaced with a coded representation that included its UMLS concept ID. The program generated an index with one entry per instance of a concept in the document, where the presence or absence of negation of that concept was recorded. This information was used to mark up the text of each document by color-coding it to make it easier to inspect. The parser was then evaluated in two ways: 1) a test set of 60 documents (30 discharge summaries, 30 surgical notes) marked-up by Negfinder was inspected visually to quantify false-positive and false-negative results; and 2) a different test set of 10 documents was independently examined for negatives by a human observer and by Negfinder, and the results were compared. RESULTS: In the first evaluation using marked-up documents, 8,358 instances of UMLS concepts were detected in the 60 documents, of which 544 were negations detected by the program and verified by human observation (true-positive results, or TPs). Thirteen instances were wrongly flagged as negated (false-positive results, or FPs), and the program missed 27 instances of negation (false-negative results, or FNs), yielding a sensitivity of 95.3 percent and a specificity of 97.7 percent. In the second evaluation using independent negation detection, 1,869 concepts were detected in 10 documents, with 135 TPs, 12 FPs, and 6 FNs, yielding a sensitivity of 95.7 percent and a specificity of 91.8 percent. One of the words "no," "denies/denied," "not," or "without" was present in 92.5 percent of all negations. CONCLUSIONS: Negation of most concepts in medical narrative can be reliably detected by a simple strategy. The reliability of detection depends on several factors, the most important being the accuracy of concept matching.

WebEAV: automatic metadata-driven generation of web interfaces to entity-attribute-value databases.

The task of creating and maintaining a front end to a large institutional entity-attribute-value (EAV) database can be cumbersome when using traditional client-server technology. Switching to Web technology as a delivery vehicle solves some of these problems but introduces others. In particular, Web development environments tend to be primitive, and many features that client-server developers take for granted are missing. WebEAV is a generic framework for Web development that is intended to streamline the process of Web application development for databases having a significant EAV component. It also addresses some challenging user interface issues that arise when any complex system is created. The authors describe the architecture of WebEAV and provide an overview of its features with suitable examples.

ModelDB: an environment for running and storing computational models and their results applied to neuroscience.

Research groups within the Human Brain Project are developing technologies to help organize and make accessible the vast quantities of information being accumulated in the neurosciences. The goal of this work is to provide systems that enable this complex information from many diverse sources to be synthesized into a coherent theory of nervous system function. Our initial approach to this problem has been to create several small databases. While addressing the issues of each individual database, we are also considering how each might be incorporated into an integrated cluster of databases. In this paper, we describe a pilot project in which we construct a database of computational models of neuronal function. This database allows models to be created and run and their results reviewed through a World Wide Web interface. Because models encapsulate knowledge in a formal manner about how neuronal systems function, we also discuss how this database forms a natural center for our initial attempts at creating a cluster of related databases. General issues of database development in the context of the Web are also discussed.

Organization of heterogeneous scientific data using the EAV/CR representation.

Entity-attribute-value (EAV) representation is a means of organizing highly heterogeneous data using a relatively simple physical database schema. EAV representation is widely used in the medical domain, most notably in the storage of data related to clinical patient records. Its potential strengths suggest its use in other biomedical areas, in particular research databases whose schemas are complex as well as constantly changing to reflect evolving knowledge in rapidly advancing scientific domains. When deployed for such purposes, the basic EAV representation needs to be augmented significantly to handle the modeling of complex objects (classes) as well as to manage interobject relationships. The authors refer to their modification of the basic EAV paradigm as EAV/CR (EAV with classes and relationships). They describe EAV/CR representation with examples from two biomedical databases that use it.

Managing attribute--value clinical trials data using the ACT/DB client-server database system.

ACT/DB is a client-server database application for storing clinical trials and outcomes data, which is currently undergoing initial pilot use. It stores most of its data in entity-attribute-value form. Such data are segregated according to data type to allow indexing by value when possible, and binary large object data are managed in the same way as other data. ACT/DB lets an investigator design a study rapidly by defining the parameters (or attributes) that are to be gathered, as well as their logical grouping for purposes of display and data entry. ACT/DB generates customizable data entry. The data can be viewed through several standard reports as well as exported as text to external analysis programs. ACT/DB is designed to encourage reuse of parameters across multiple studies and has facilities for dictionary search and maintenance. It uses a Microsoft Access client running on Windows 95 machines, which communicates with an Oracle server running on a UNIX platform. ACT/DB is being used to manage the data for seven studies in its initial deployment.

Internet-based support for bioscience research: a collaborative genome center for human chromosome 12.

This paper describes an approach that provides Internet-based support for a genome center to map human chromosome 12, as a collaboration between laboratories at the Albert Einstein College of Medicine in Bronx, New York, and the Yale University School of Medicine in New Haven, Connecticut. Informatics is well established as an important enabling technology within the genome mapping community. The goal of this paper is to use the chromosome 12 project as a case study to introduce a medical informatics audience to certain issues involved in genome informatics and in the Internet-based support of collaborative bioscience research. Central to the approach described is a shared database (DB/12) with Macintosh clients in the participating laboratories running the 4th Dimension database program as a user-friendly front end, and a Sun SPARCstation-2 server running Sybase. The central component of the database stores information about yeast artificial chromosomes (YACs), each containing a segment of human DNA from chromosome 12 to which genome markers have been mapped, such that an overlapping set of YACs (called a "contig") can be identified, along with an ordering of the markers. The approach also includes 1) a map assembly tool developed to help biologists interpret their data, proposing a ranked set of candidate maps, 2) the integration of DB/12 with external databases and tools, and 3) the dissemination of the results. This paper discusses several of the lessons learned that apply to many other areas of bioscience, and the potential role for the field of medical informatics in helping to provide such support.

Database tools for integrating and searching membrane property data correlated with neuronal morphology.

A critical problem in neuroscience is the lack of database tools for integrating neuronal property data. We report here the development of a combined object oriented-relational database (NeuronDB, http://senselab.med.yale.edu/neurondb) that meets these needs by providing tools for integrating data within neurons and comparing data across neurons. It focuses on three types of neuronal properties voltage-gated channels, neurotransmitter receptors, and neurotransmitters. The data are organized in relation to different regions of neurons as represented in canonical forms; using simple canonical models of complex cells as a vehicle for indexing information permits the database to be searchable across different neurons. Using these multidimensional search tools, users can locate specific properties in specific regions of a neuron; obtain integrated summaries of all properties within a region; and carry out searches to compare properties across equivalent compartments in different neurons. These tools thus permit searches of the multidimensional neuron property space equivalent to homology searches of sequence databases. NeuronDB is accessible over the Internet; it provides immediate links to citation indexes and abstracts supporting the deposited data, and annotations that indicate the state of acceptance of the data. Users are encouraged to contribute data. The ability to input the data from NeuronDB directly to NEURON and GENESIS is being developed. As a shared Web resource, NeuronDB should enhance the efforts of neuroscientists and neuronal modellers to analyze and compare the functional operations of different types of neurons.

Using a computer database to monitor compliance with pharmacotherapeutic guidelines for schizophrenia.

OBJECTIVE: The study examined whether prescription data from a computerized database could be used to measure conformance with treatment recommendations of the Schizophrenia Patient Outcomes Research Team (PORT). METHODS: Records of an academically affiliated Veterans Affairs medical center were reviewed to identify patients who were hospitalized for schizophrenia and later seen for at least two outpatient visits in the six months after discharge (N=353). RESULTS: Conformance with only three of the 18 PORT pharmacotherapeutic recommendations could be measured with the available data. In regard to the recommendation to use antipsychotics other than clozapine as first-line treatments in acute episodes, 77 percent of the sample filled a prescription for an antipsychotic during the acute episode. Of these, only 6 percent received an antipsychotic regimen that included clozapine. In regard to the PORT recommendation on dosage during acute symptom episodes, 42 percent of the patients on conventional antipsychotics received dosages below the recommended range, 5 percent were above the range, and 53 percent were within it. In contrast, of the 53 patients who received clozapine or risperidone, 87 percent received prescriptions within the recommended dosage range. As for the recommendation to offer a trial of clozapine to patients who do not respond to adequate trials of two different classes of conventional drugs, 10 percent of patients who were switched from conventional regimens to clozapine were receiving dosages of conventional medications below the recommended range. CONCLUSIONS: Patient prescription data can provide preliminary measures to cost-effectively assess conformance with treatment. However, the approach has several limitations, and complementary analyses would enhance its usefulness.

Integration of Web-based and PC-based clinical research databases.

UNLABELLED: We have created a Web-based repository or data library of information about measurement instruments used in studies of multi-factorial geriatric health conditions (the Geriatrics Research Instrument Library - GRIL) based upon existing features of two separate clinical study data management systems. GRIL allows browsing, searching, and selecting measurement instruments based upon criteria such as keywords and areas of applicability. Measurement instruments selected can be printed and/or included in an automatically generated standalone microcomputer database application, which can be downloaded by investigators for use in data collection and data management. METHODS: Integration of database applications requires the creation of a common semantic model, and mapping from each system to this model. Various database schema conflicts at the table and attribute level must be identified and resolved prior to integration. Using a conflict taxonomy and a mapping schema facilitates this process. RESULTS: Critical conflicts at the table level that required resolution included name and relationship differences. CONCLUSIONS: A major benefit of integration efforts is the sharing of features and cross-fertilization of applications created for similar purposes in different operating environments. Integration of applications mandates some degree of metadata model unification.

Approaches and informatics tools to assist in the integration of similar clinical research questionnaires.

OBJECTIVE: The integration of similar clinical research questionnaires is a complex process that can benefit from informatics approaches and tools that provide a systematic structure for performing mapping and integration. This systematic approach is necessary to address complex issues in integration such as data heterogeneity, differing levels of granularity of questions and responses, and other issues involving semantic differences. Informatics tools and approaches have been successfully applied to various standard clinical vocabulary integration processes but not for questionnaire integration or mapping. METHODS: A systematic approach to questionnaire integration was developed in the context of a collaboration of researchers using Trial/DB, a database designed to support clinical research. This approach was applied to the integration of questionnaires involving breast cancer risk factors from each of three research sites. RESULTS: From 375 questions on the three original questionnaires, we identified 65 concepts that were measured by two or three of the sites. An algorithm was developed and used to formalize the process of mapping questions and answers across the questionnaires. The approach was applied to previously collected data and prospective data in disparate data-base systems to import and merge the data from these three sites into Trial/DB. CONCLUSION: Informatics tools that support a systematic approach to mapping questionnaires can be used throughout the research process from questionnaire integration and creation, legacy data integration to data library maintenance and curation.

QAV: querying entity-attribute-value metadata in a biomedical database.

Entity-attribute-value (EAV) data organization is increasingly used for knowledge representation for complex heterogeneous biomedical databases. When delivered in relation form for production applications the simplicity of EAV storage is offset by difficulty of set-based data retrieval. We describe a client-server application, QAV, that is designed to perform set-based query on the Columbia MED dataset, a large medical metadata repository that has been the focus of much research. QAV interacts with the user through a graphical front end and generates a series of SQL statements that are sent to the server for the actual data retrieval.

Integration of a hematopoietic progenitor cell program using the ACT/DB database system.

Infusion of hematopoietic progenitor cells following high-dose chemotherapy is frequently used to treat patients with hematological malignancies and solid tumors. We have developed a comprehensive software system to monitor these patients once they are entered into an experimental protocol. The captured data encompasses all phases of progenitor cell therapy including progenitor cell mobilization and collection, stem cell processing, as well as cell infusion and engraftment kinetics. Particular attention was paid to the quality assurance and quality control functionality of the software during development of data entry forms and reports. The system was developed using the ACT/DB client-server database, which utilizes Microsoft Access as a front-end and accesses either an Oracle or SQL Server database. ACT/DB has been modified for deployment on the Internet in order to take advantage of Web-based technology. Information technology can help to integrate the diverse data requirements of complex therapeutic trials.

Sucralfate in the short-term treatment of duodenal ulcer. A double-blind comparison with cimetidine and placebo.

A phase III randomised, double-blind, placebo controlled study was conducted to compare the efficacy and adverse effects of sucralfate and cimetidine in the short-term management of active duodenal ulcer. Standard therapeutic doses were used. Antacids were permitted on an ad lib basis. Eighty patients with endoscopically proven DU were treated for 4 weeks with sucralfate (SUC) (n = 40), cimetidine (CIM) (n = 20) and placebo (PLA) (n = 20), of whom 60 patients--SUC (32), CIM (14) and PLA (14) completed the trial. Baseline clinical and endoscopic data were comparable amongst the 3 groups. The patients were reexamined clinically at 1, 2 and 4 weeks and endoscopically at 2 and 4 weeks. The data comprising pain and non-pain symptom scores, and ulcer size before and after the trial were analysed using the Mann-Whitney test. There were no significant differences in the rate of ulcer healing between SUC and CIM at 4 weeks. 71.8% of the SUC group had complete healing, as compared with 71.4% in the CIM group and 35% in the PLA group. Both SUC and CIM were superior to PLA. (p less than .05) Non-pain symptom scores at the end of 1 week were significantly lower with CIM (p less than 0.001), but levelled at 4 weeks when compared with SUC. Both SUC and CIM were superior to placebo (p less than .001). Day-time pain relief was significantly better with both SUC and CIM as compared to placebo (p less than 0.1). There was no significant difference in night-pain relief between the 3 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Automating identification of adverse events related to abnormal lab results using standard vocabularies.

Laboratory data need to be imported automatically into central Clinical Study Data Management Systems (CSDMSs), and abnormal laboratory data need to be linked to clinically related adverse events. This import of laboratory data can be automated through mapping to standard vocabularies with HL7/LOINC mapping to the metadata within a CSDMS. We have designed a system that uses the UMLS metathesaurus as a common source to map or link abnormal laboratory values to adverse event CTCAE coded terms and grades in the metadata of TrialDB, a generic CSDMS.