The conduct of clinical and translational research regularly involves the use of a variety of heterogeneous and large-scale data resources. Scalable methods for the integrative analysis of such resources, particularly when attempting to leverage computable domain knowledge in order to generate actionable hypotheses in a high-throughput manner, remain an open area of research. In this report, we describe both a generalizable design pattern for such integrative knowledge-anchored hypothesis discovery operations and our experience in applying that design pattern in the experimental context of a set of driving research questions related to the publicly available Osteoarthritis Initiative data repository. We believe that this 'test bed' project and the lessons learned during its execution are both generalizable and representative of common clinical and translational research paradigms.

Tobacco use is increasingly prevalent among vulnerable populations, such as people living in rural Appalachian communities. Owing to limited access to a reliable internet service in such settings, there is no widespread adoption of electronic data capture tools for conducting community-based research. By integrating the REDCap data collection application with a custom synchronization tool, the authors have enabled a workflow in which field research staff located throughout the Ohio Appalachian region can electronically collect and share research data. In addition to allowing the study data to be exchanged in near-real-time among the geographically distributed study staff and centralized study coordinator, the system architecture also ensures that the data are stored securely on encrypted laptops in the field and centrally behind the Ohio State University Medical Center enterprise firewall. The authors believe that this approach can be easily applied to other analogous study designs and settings.

OBJECTIVE: The conduct of investigational studies that involve large-scale data sets presents significant challenges related to the discovery and testing of novel hypotheses capable of supporting in silico discovery science. The use of what are known as Conceptual Knowledge Discovery in Databases (CKDD) methods provides a potential means of scaling hypothesis discovery and testing approaches for large data sets. Such methods enable the high-throughput generation and evaluation of knowledge-anchored relationships between complexes of variables found in targeted data sets. METHODS: The authors have conducted a multipart model formulation and validation process, focusing on the development of a methodological and technical approach to using CKDD to support hypothesis discovery for in silico science. The model the authors have developed is known as the Translational Ontology-anchored Knowledge Discovery Engine (TOKEn). This model utilizes a specific CKDD approach known as Constructive Induction to identify and prioritize potential hypotheses related to the meaningful semantic relationships between variables found in large-scale and heterogeneous biomedical data sets. RESULTS: The authors have verified and validated TOKEn in the context of a translational research data repository maintained by the NCI-funded Chronic Lymphocytic Leukemia Research Consortium. Such studies have shown that TOKEn is: (1) computationally tractable; and (2) able to generate valid and potentially useful hypotheses concerning relationships between phenotypic and biomolecular variables in that data collection. CONCLUSIONS: The TOKEn model represents a potentially useful and systematic approach to knowledge synthesis for in silico discovery science in the context of large-scale and multidimensional research data sets.

Investigators in the translational research and systems medicine domains require highly usable, efficient and integrative tools and methods that allow for the navigation of and reasoning over emerging large-scale data sets. Such resources must cover a spectrum of granularity from bio-molecules to population phenotypes. Given such information needs, we report upon the initial design and evaluation of an ontology-anchored integrative query tool, Research-IQ, which employs a combination of conceptual knowledge engineering and information retrieval techniques to enable the intuitive and rapid construction of queries, in terms of semi-structured textual propositions, that can subsequently be applied to integrative data sets. Our initial results, based upon both quantitative and qualitative evaluations of the efficacy and usability of Research-IQ, demonstrate its potential to increase clinical and translational research throughput.

BACKGROUND: Given the rapid growth of translational research and personalized healthcare paradigms, the ability to relate and reason upon networks of bio-molecular and phenotypic variables at various levels of granularity in order to diagnose, stage and plan treatments for disease states is highly desirable. Numerous techniques exist that can be used to develop networks of co-expressed or otherwise related genes and clinical features. Such techniques can also be used to create formalized knowledge collections based upon the information incumbent to ontologies and domain literature. However, reports of integrative approaches that bridge such networks to create systems-level models of disease or wellness are notably lacking in the contemporary literature. RESULTS: In response to the preceding gap in knowledge and practice, we report upon a prototypical series of experiments that utilize multi-modal approaches to network induction. These experiments are intended to elicit meaningful and significant biomarker-phenotype complexes spanning multiple levels of granularity. This work has been performed in the experimental context of a large-scale clinical and basic science data repository maintained by the National Cancer Institute (NCI) funded Chronic Lymphocytic Leukemia Research Consortium. CONCLUSIONS: Our results indicate that it is computationally tractable to link orthogonal networks of genes, clinical features, and conceptual knowledge to create multi-dimensional models of interrelated biomarkers and phenotypes. Further, our results indicate that such systems-level models contain interrelated bio-molecular and clinical markers capable of supporting hypothesis discovery and testing. Based on such findings, we propose a conceptual model intended to inform the cross-linkage of the results of such methods. This model has as its aim the identification of novel and knowledge-anchored biomarker-phenotype complexes.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. It is a highly heterogeneous disease, and can be divided roughly into indolent and progressive stages based on classic clinical markers. Immunoglobin heavy chain variable region (IgVH) mutational status was found to be associated with patient survival outcome, and biomarkers linked to the IgVH status has been a focus in the CLL prognosis research field. However, biomarkers highly correlated with IgVH mutational status which can accurately predict the survival outcome are yet to be discovered. RESULTS: In this paper, we investigate the use of gene co-expression network analysis to identify potential biomarkers for CLL. Specifically we focused on the co-expression network involving ZAP70, a well characterized biomarker for CLL. We selected 23 microarray datasets corresponding to multiple types of cancer from the Gene Expression Omnibus (GEO) and used the frequent network mining algorithm CODENSE to identify highly connected gene co-expression networks spanning the entire genome, then evaluated the genes in the co-expression network in which ZAP70 is involved. We then applied a set of feature selection methods to further select genes which are capable of predicting IgVH mutation status from the ZAP70 co-expression network. CONCLUSIONS: We have identified a set of genes that are potential CLL prognostic biomarkers IL2RB, CD8A, CD247, LAG3 and KLRK1, which can predict CLL patient IgVH mutational status with high accuracies. Their prognostic capabilities were cross-validated by applying these biomarker candidates to classify patients into different outcome groups using a CLL microarray datasets with clinical information.

OBJECTIVE: To formulate a model for translating manual infection control surveillance methods to automated, algorithmic approaches. DESIGN: We propose a model for creating electronic surveillance algorithms by translating existing manual surveillance practices into automated electronic methods. Our model suggests that three dimensions of expert knowledge be consulted: clinical, surveillance, and informatics. Once collected, knowledge should be applied through a process of conceptualization, synthesis, programming, and testing. RESULTS: We applied our framework to central vascular catheter associated bloodstream infection surveillance, a major healthcare performance outcome measure. We found that despite major barriers such as differences in availability of structured data, in types of databases used and in semantic representation of clinical terms, bloodstream infection detection algorithms could be deployed at four very diverse medical centers. CONCLUSIONS: We present a framework that translates existing practice-manual infection detection-to an automated process for surveillance. Our experience details barriers and solutions discovered during development of electronic surveillance for central vascular catheter associated bloodstream infections at four hospitals in a variety of data environments. Moving electronic surveillance to the next level-availability at a majority of acute care hospitals nationwide-would be hastened by the incorporation of necessary data elements, vocabularies and standards into commercially available electronic health records.

In this paper, we present a study on the relationships between Chronic Lymphocytic Leukemia (CLL) related clinical attributes using network visualization and analysis techniques. This work is the first step of our long-term project to identify novel biomarkers for CLL, working in coordination with the NCI-funded CLL Research Consortium (cll.ucsd.edu). By computing Spearman correlation coefficients for 125 clinical attributes, we established an attribute network for CLL. Using network visualization techniques we identified a core network with peripheral nodes around it. An important observation is that many cytogenetic attributes are in the core network, indicating the connection between karyotypes (e.g., abnormality in Chromosome 17) and other clinical attributes. Since these karyotypes are linked to CLL etiology in many ways, the corresponding clinical attributes may be further selected and tested as markers for disease screening. The correlation analysis results are also consistent with previous studies using a knowledge engineering based approach for establishing relationships between such attributes.

MOTIVATION: Natural language processing (NLP) techniques are increasingly being used in biology to automate the capture of new biological discoveries in text, which are being reported at a rapid rate. Yet, information represented in NLP data structures is classically very different from information organized with ontologies as found in model organisms or genetic databases. To facilitate the computational reuse and integration of information buried in unstructured text with that of genetic databases, we propose and evaluate a translational schema that represents a comprehensive set of phenotypic and genetic entities, as well as their closely related biomedical entities and relations as expressed in natural language. In addition, the schema connects different scales of biological information, and provides mappings from the textual information to existing ontologies, which are essential in biology for integration, organization, dissemination and knowledge management of heterogeneous phenotypic information. A common comprehensive representation for otherwise heterogeneous phenotypic and genetic datasets, such as the one proposed, is critical for advancing systems biology because it enables acquisition and reuse of unprecedented volumes of diverse types of knowledge and information from text. RESULTS: A novel representational schema, PGschema, was developed that enables translation of phenotypic, genetic and their closely related information found in textual narratives to a well-defined data structure comprising phenotypic and genetic concepts from established ontologies along with modifiers and relationships. Evaluation for coverage of a selected set of entities showed that 90% of the information could be represented (95% confidence interval: 86-93%; n = 268). Moreover, PGschema can be expressed automatically in an XML format using natural language techniques to process the text. To our knowledge, we are providing the first evaluation of a translational schema for NLP that contains declarative knowledge about genes and their associated biomedical data (e.g. phenotypes). AVAILABILITY: http://zellig.cpmc.columbia.edu/PGschema