Ulrich Sax

Mutated KRAS results in overexpression of DUSP4, a MAP‐kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas

Mutations of the KRAS oncogene are predictive for resistance to treatment with antibodies against the epithelial growth factor receptor in patients with colorectal cancer. Overcoming this therapeutic dilemma could potentially be achieved by the introduction of drugs that inhibit signaling pathways that are activated by KRAS mutations. To identify comprehensively such signaling pathways, we profiled pretreatment biopsies and normal mucosa from 65 patients with locally advanced rectal cancer—30 of which carried mutated KRAS—using global gene expression microarrays. By comparing all tumor tissues exclusively to matched normal mucosa, we could improve assay sensitivity, and identified a total of 22,297 features that were differentially expressed (adjusted P‐value <0.05) between normal mucosa and cancer, including several novel potential rectal cancer genes. We then used this comprehensive description of the rectal cancer transcriptome as the baseline for identifying KRAS‐dependent alterations. The presence of activating KRAS mutations is significantly correlated to an upregulation of 13 genes (adjusted P‐value <0.05), among them DUSP4, a MAP‐kinase phosphatase, and SMYD3, a histone methyltransferase. Inhibition of the expression of both genes has previously been shown using the MEK1‐inhibitor PD98059 and the antibacterial compound Novobiocin, respectively. These findings suggest a potential approach to overcome resistance to treatment with antibodies against the epithelial growth factor receptor in patients with KRAS‐mutant rectal carcinomas.

Unlocking Data for Clinical Research - The German i2b2 Experience

OBJECTIVE Data from clinical care is increasingly being used for research purposes. The i2b2 platform has been introduced in some US research communities as a tool for data integration and querying by clinical users. The purpose of this project was to assess the applicability of i2b2 in Germany regarding use cases, functionality and integration with privacy enhancing tools. METHODS A set of four research usage scenarios was chosen, including the transformation and import of ontology and fact data from existing clinical data collections into i2b2 v1.4 instances. Query performance was measured in comparison to native SQL queries. A setup and administration tool for i2b2 was developed. An extraction tool for CDISC ODM data was programmed. Interfaces for the TMF privacy enhancing tools (PID Generator, Pseudonymization Service) were implemented. RESULTS Data could be imported in all tested scenarios from various source systems, including the generation of i2b2 ontology definitions. The integration of TMF privacy enhancing tools was possible without modification of the platform. Limitations were found regarding query performance in comparison to native SQL and certain temporal queries. CONCLUSIONS i2b2 is a viable platform for data query tasks in use cases typical for networked medical research in Germany. The integration of privacy enhancing tools facilitates the use of i2b2 within established data protection concepts. Entry barriers should be lowered by providing tools for simplified setup and import of medical standard formats like CDISC ODM.

IT Infrastructure Components for Biobanking

OBJECTIVE Within translational research projects in the recent years large biobanks have been established, mostly supported by homegrown, proprietary software solutions. No general requirements for biobanking IT infrastructures have been published yet. This paper presents an exemplary biobanking IT architecture, a requirements specification for a biorepository management tool and exemplary illustrations of three major types of requirements. METHODS We have pursued a comprehensive literature review for biobanking IT solutions and established an interdisciplinary expert panel for creating the requirements specification. The exemplary illustrations were derived from a requirements analysis within two university hospitals. RESULTS The requirements specification comprises a catalog with more than 130 detailed requirements grouped into 3 major categories and 20 subcategories. Special attention is given to multitenancy capabilities in order to support the project-specific definition of varying research and bio-banking contexts, the definition of workflows to track sample processing, sample transportation and sample storage and the automated integration of preanalytic handling and storage robots. CONCLUSION IT support for biobanking projects can be based on a federated architectural framework comprising primary data sources for clinical annotations, a pseudonymization service, a clinical data warehouse with a flexible and user-friendly query interface and a biorepository management system. Flexibility and scalability of all such components are vital since large medical facilities such as university hospitals will have to support biobanking for varying monocentric and multicentric research scenarios and multiple medical clients.

Visualization in Health Grid Environments: A Novel Service and Business Approach

Advanced visualization technologies are gaining major importance to allow presentation and manipulation of high dimensional data. Since new health technologies are constantly increasing in complexity, adequate information processing is required for diagnostics and treatment. Therefore, the German D-Grid initiative started to build visualization centers in 2008, which have recently been embedded into the existing compute and storage infrastructure. This paper describes an analysis of this infrastructure and the interplay with life science applications for 3D and 4D visualization and manipulation. Furthermore, the performance and business aspects regarding accounting, pricing and billing are investigated. The results show the viability and the opportunities for further optimization of this novel service approach and the possibilities for a sustainable business scenario.

Solutions for biomedical grid computing—Case studies from the D-Grid project Services@MediGRID

The project Services@MediGRID consortium established a tool set of grid-based biomedical services since 2008. The services are related to genetic analysis, genome data visualization, and pharmacokinetic modeling. Furthermore, business concepts for these services have been examined which are supported by an accounting and billing service. While the tools cover a whole service chain for biomedicine, the business concepts are rather heterogeneous. However, the overall addressed target market areas show promising potential. In addition, a structured coaching process reduces friction in the technology transfer from grid computing to biomedicine. This should be considered for similar future endeavors.

Interdisciplinary approach towards a systems medicine toolbox using the example of inflammatory diseases

Abstract Electronic access to multiple data types, from generic information on biological systems at different functional and cellular levels to high-throughput molecular data from human patients, is a prerequisite of successful systems medicine research. However, scientists often encounter technical and conceptual difficulties that forestall the efficient and effective use of these resources. We summarize and discuss some of these obstacles, and suggest ways to avoid or evade them. The methodological gap between data capturing and data analysis is huge in human medical research. Primary data producers often do not fully apprehend the scientific value of their data, whereas data analysts maybe ignorant of the circumstances under which the data were collected. Therefore, the provision of easy-to-use data access tools not only helps to improve data quality on the part of the data producers but also is likely to foster an informed dialogue with the data analysts. We propose a means to integrate phenotypic data, questionnaire data and microbiome data with a user-friendly Systems Medicine toolbox embedded into i2b2/tranSMART. Our approach is exemplified by the integration of a basic outlier detection tool and a more advanced microbiome analysis (alpha diversity) script. Continuous discussion with clinicians, data managers, biostatisticians and systems medicine experts should serve to enrich even further the functionality of toolboxes like ours, being geared to be used by ‘informed non-experts’ but at the same time attuned to existing, more sophisticated analysis tools.

The Integrated Data Repository Toolkit (IDRT): accelerating translational research infrastructures

Description The Open Source software i2b2 [1] provides a translational research platform for storing biomedical data and querying these data with a user-friendly interface for researchers (Figure 1). Despite its powerful features, it is lacking user-friendly tools for installation and configuration, the import of source data and the creation of a comprehensive navigational structure (i2b2 ontology). To close these gaps, the Integrated Data Repository Toolkit (IDRT), consisting of three software tools, has been created. The i2b2 Wizard provides a shell GUI for the installation and configuration of i2b2 instances, projects and users. The i2b2 Import Tool offers a GUI for browsing i2b2 projects and importing data in various standard data formats into i2b2 (e.g., textual (CSV), relational (SQL) or structured data (CDISC ODM/XML)), as well as a dedicated extractor for biomaterial data. During import, i2b2 ontologies are automatically created from metadata included in the source data. The i2b2 Ontology Editor (IOE), being part of the i2b2 Import Tool, can be used for enhancing these i2b2 ontologies. Besides standard functions like rearranging, adding, deleting and renaming folders and items, the IOE is capable of augmenting i2b2 ontologies with more advanced i2b2 functions. By utilizing the two windows of the IOE (one showing the unaltered source i2b2 ontology and the other the manually created target i2b2 ontology), mappings can be achieved by simple drag-and-drop operations. For example, start and end dates can be added to items by dragging a date item onto a fact item. Medical terminologies can easily be imported with the IDRT (e. g. ICD-10, LOINC) and can also be mapped via the same drag-and-drop operations to data elements (expandable beyond the supplied terminologies via a regular expression editor in the IOE). The IDRT tools support the more advanced i2b2 functionalities for “fact nesting”, called “modifiers”. Since the i2b2 web browser query application (i2b2 Web Client) does not support simple access and visualization of modifiers, an IDRT plugin was created that is able to display, combine and export related facts. Additional documentation for enhanced i2b2 usage is provided on the IDRT website [2].

Whither systems medicine

New technologies to generate, store and retrieve medical and research data are inducing a rapid change in clinical and translational research and health care. Systems medicine is the interdisciplinary approach wherein physicians and clinical investigators team up with experts from biology, biostatistics, informatics, mathematics and computational modeling to develop methods to use new and stored data to the benefit of the patient. We here provide a critical assessment of the opportunities and challenges arising out of systems approaches in medicine and from this provide a definition of what systems medicine entails. Based on our analysis of current developments in medicine and healthcare and associated research needs, we emphasize the role of systems medicine as a multilevel and multidisciplinary methodological framework for informed data acquisition and interdisciplinary data analysis to extract previously inaccessible knowledge for the benefit of patients.

Neoadjuvant Therapy in Rectal Cancer - Biobanking of Preoperative Tumor Biopsies

Translational research relies on high-quality biospecimens. In patients with rectal cancer treated preoperatively with radiochemotherapy tissue based analyses are challenging. To assess quality challenges we analyzed tissue samples taken over the last years in a multicenter setting. We retrospectively evaluated overall 197 patients of the CAO/ARO/AIO-94- and 04-trial with locally advanced rectal cancer that were biopsied preoperatively at the University Medical Center Goettingen as well as in 10 cooperating hospitals in Germany. The cellular content of tumor, mucosa, stroma, necrosis and the amount of isolated DNA and RNA as well as the RNA integrity number (RIN) as quality parameters were evaluated. A high RNA yield (p = 2.75e–07) and the content of tumor (p = 0.004) is significantly associated to high RIN-values, whereas a high content of mucosa (p = 0.07) shows a trend and a high amount of necrosis (p = 0.01) is significantly associated with RNA of poor quality. Correlating biopsies from Goettingen and the cooperating centers showed comparable tumor content results. By taking small sized biopsies we could assess a clear correlation between a good RNA quality and a high amount of RNA and tumor cells. These results also indicate that specimens collected at different centers are of comparable quality.

An interdisciplinary practical course on the application of grid computing

This article gives an overview of the organization and realization of an interdisciplinary practical course on grid computing. Both the lecturers and the attendees came from diverse backgrounds and disciplines including computer science, physics, medicine, and the humanities. We describe the management of the course, the assignments, the infrastructure developed and experienced in this interdisciplinary practical course at the University of Göttingen. The challenges and issues, the benefits, the expectations and their fulfillment are discussed. The experiences of the course show that diverse disciplines can be brought together to convey the benefits of grid technology by experiencing varied grid applications in production-like grid environments.