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The comprehensive IT-Infrastructure for epidemiological Research in LIFE
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Introduction LIFE is a large epidemiological study aiming at causes of common civilization diseases including adiposity, dementia, and depression. Participants of the study are probands and patients. … Probands are randomly selected and invited from the set of Leipzig (Germany) inhabitants while patients with known diseases are recruited from several local hospitals. The management of these participants, their invitation and contact after successful attendance as well as the support of nearly all ambulance processes requires a complex ambulance management. Each participant is examined by a set of investigation instruments including interviews, questionnaires, device-specific investigations, specimen extrac- tions and analyses. This necessitates a complex management of the participantspecific examination program but also specific input forms and systems allowing to capture administrative (measurement and process environment or specific set-ups) and scientific data. Additionally, the taken and prepared specimens need to be labeled and registered from which participant they stem and in which fridge or bio-tank they are stored. At the end, all captured data from ambu- lance management, investigation instruments and laboratory analyses need to be integrated before they can be analyzed. These complex processes and requirements necessitate a comprehensive IT-infrastructure. Methods Our IT-infrastructure modularly consists of several software applications. A main application is responsible for the complex participant and ambulance man- agement. The participant management cope with selected participant data and contact information. To protect participant’s privacy, a participant identifier (PID) is created for each participant that is associated to all data which is managed and captured in the following. In ambulance management, each participant is associated with a predefined investigation program. This investigation program is represented in our systems by a tracking card that is available as print-out and electronically. The electronic version of tracking cards is utilized by two software applications, the Assessment Battery and the CryoLab. The former system coordinates the input of scientific data into online input forms. The input forms are designed in the open source system LimeSurvey. Moreover, the Assessment Battery is used to monitor the input process, i.e., it shows which investigations are already completed and which of them are still to do. The Cryolab system registers and tracks all taken specimens and is used to annotate extraction and specific preparation processes, e.g., for DNA isolation. Moreover, it tracks specimen storage in fridges and bio-tanks. A central component is the metadata repository collecting metadata from ambulance management and data input systems. It is the base for the integra- tion of relevant scientific data into a central research database. The integration follows a mapping-based approach. The research database makes raw data and special pre-computations called derivatives available for later data analysis. Results & Discussion We designed and implemented a complex and comprehensive IT-infrastructure for the epidemiological research in LIFE. This infrastructure consists of several software applications which are loosely coupled over specified interfaces. Most of the software applications are new implementations; only for capturing scientific data external software application are applied.

Authors: Toralf Kirsten, A. Kiel, M. Kleinert, R. Speer, M. Rühle, Hans Binder, Markus Löffler

Date Published: 30th Sep 2013

Publication Type: Not specified

Curation-DB: Curating Scientific Data in LIFE
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Introduction LIFE is a epidemiological study aiming at discovering causes of common disorders as well as therapy and diagnostic possibilities. It applies a huge set (currently more then 400) of complex … instruments including different kinds of interviews, questionnaires, and technically founded investigations on thousands of Leipzig inhabitants. Correlations in data, e.g., between diseases on the one hand and a combination of life conditions on the other requires high quality data. Data errors affect this data quality. However, avoiding every error is nearly impossible. Therefore, the captured data routinely needs to be validated and revised (curated) in case of error. Methods From the data-perspective, we differentiate between two main types of data errors, syntax or format errors and semantic errors. Syntax errors mostly occur when the data needs to be converted to change its data type, e.g., from text to number or from text to date/time fields. This is often the case when data is captured as text by the data input system but should be centrally managed and analyzed in a different format. Hence, the data conversion is only successful when the input data contains the data in the right format. Data conversion is applied when the data is transfered from data input systems to the central research database collecting all captured data in an integrated and harmonized form. Corrupted data that cannot be converted to the target data type is replaced by a missing value (also called null value, nil etc.). The definition of a default value is not sufficient since the default usually depends on the corresponding question or measurement input field and can strain analysis results when they are not concerned. Moreover, the definition process for every question/input field would be to time-consuming. Semantic errors are much harder to detect than syntax errors. Typically, they are semantically implausible outliers or are part of other artefacts, e.g.,when data of two input fields is mixed up. Currently, we let the detection of semantic errors to a epidemiological quality analysis that is performed by several statisticians. Conversely, syntax errors can be easily technically detected; they are logged when they occur in the process of transferring data from data input systems to the central research database. With respect to both types of errors, syntax and semantic errors, we designed and implemented a software application called Curation-DB allowing to curate (adapt and change) data. In particular, the system lists the logged syntax errors occurring during the data conversion step daily at night. A user can adapt the current input value by specifying a new (target) value for a listed syntax problem. With this specification, the corresponding input value is replaced by the specified value before the next conversion step is started. This specification process can be iteratively applied for a corresponding input value when the syntax problem is not solved by the current specification. The semantic errors need to be first detected separately. Then, a user can specify value changes replacing an existing value with the new specified one. Results & Discussion The Curation-DB application is already in use. Currently, selected quality managers routinely check the listed syntax errors. There are currently more than 2000 of such errors curated. In near future, we will extend this software to manage rules validating research data semantically to automatically detect obvious semantic errors.

Authors: J. Wagner, A. Kiel, Toralf Kirsten

Date Published: 30th Sep 2013

Publication Type: Not specified

Long-term survival in primary glioblastoma with versus without isocitrate dehydrogenase mutations.
GGN - German Glioma Network

Abstract (Expand)

PURPOSE: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II … and III gliomas, but rare in primary glioblastomas, and associated with longer survival. EXPERIMENTAL DESIGN: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival >36 months (LTS-36), including 33 patients surviving >60 months (LTS-60), with 257 patients surviving <36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques. RESULTS: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment. CONCLUSIONS: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

Authors: C. Hartmann, B. Hentschel, M. Simon, M. Westphal, G. Schackert, J. C. Tonn, M. Loeffler, G. Reifenberger, T. Pietsch, A. von Deimling, M. Weller

Date Published: 15th Sep 2013

Publication Type: Not specified

Human Diseases: glioblastoma multiforme

The role of rs2237781 within GRM8 in eating behavior
Genetical Statistics and Systems Biology

Abstract (Expand)

Introduction:The glutamate receptor, metabotropic 8 gene (GRM8) encodes a G-protein-coupled glutamate receptor and has been associated with smoking behavior and liability to alcoholism implying a role … in addiction vulnerability. Data from animal studies suggest that GRM8 may be involved in the regulation of the neuropeptide Y and melanocortin pathways and might influence food intake and metabolism. This study aimed to investigate the effects of the genetic variant rs2237781 within GRM8 on human eating behavior. Methods:The initial analysis included 548 Sorbs from Germany who have been extensively phenotyped for metabolic traits and who completed the German version of the three-factor eating questionnaire. In addition, we analyzed two independent sample sets comprising 293 subjects from another German cohort and 430 Old Order Amish individuals. Genetic associations with restraint, disinhibition, and hunger were assessed in an additive linear regression model. Results:Among the Sorbs the major G allele of rs2237781 was significantly associated with increased restraint scores in eating behavior (P = 1.9 \times 10(-4); \textgreekb = +1.936). The German cohort and the Old Order Amish population revealed a trend in the same direction for restraint (P = 0.242; \textgreekb = +0.874; P = 0.908; \textgreekb = +0.096; respectively). A meta-analysis resulted in a combined P = 3.1 \times 10(-3) (Z-score 2.948). Conclusion:Our data suggest that rs2237781 within GRM8 may influence human eating behavior factors probably via pathways involved in addictive behavior.

Authors: Marie-Therese Gast, Anke Tönjes, Maria Keller, Annette Horstmann, Nanette Steinle, Markus Scholz, Ines Müller, Arno Villringer, Michael Stumvoll, Peter Kovacs, Yvonne Böttcher

Date Published: 1st Sep 2013

Publication Type: Journal article

Comprehensive high-resolution genomic profiling and cytogenetics of two pediatric and one adult medulloblastoma
Genetical Statistics and Systems Biology

Abstract (Expand)

Medulloblastoma (WHO grade IV) is a rare, malignant, invasive, embryonal tumor which mainly occurs in children and represents less than 1% of all adult brain tumors. Systematic comprehensive genetic … analyses on medulloblastomas are rare but necessary to provide more detailed information. Therefore, we performed comprehensive cytogenetic analyses (blood and tissue) of two pediatric and one adult medulloblastoma, using trypsin-Giemsa staining, spectral karyotyping (tissues only), SNP-arrays, and gene expression analyses. We confirmed frequently detected chromosomal aberrations in medulloblastoma, such as +7q, -8p/q, -9q, -11q, -12q, and +17q and identified novel genetic events. Applying SNP-array, we identified constitutional de novo losses 5q21.1, 15q11.2, 17q21.31, 19p12 (pediatric medulloblastoma), 9p21.1, 19p12, 19q13.3, 21q11.2 (adult medulloblastoma) and gains 16p11.1-16p11.2, 18p11.32, Yq11.223-Yq11.23 (pediatric medulloblastoma), Xp22.31 (adult medulloblastoma) possibly representing inherited causal events for medulloblastoma formation. We show evidence for somatic segmental uniparental disomy in regions 1p36, 6q16.3, 6q24.1, 14q21.2, 17p13.3, and 17q22 not previously described for primary medulloblastoma. Gene expression analysis supported classification of the adult medulloblastoma to the WNT-subgroup and classification of pediatric medulloblastomas to group 3 tumors. Analyses of tumors and matched normal tissues (blood) with a combination of complementary techniques will help to further elucidate potentially causal genetic events for medulloblastomas.

Authors: Heidrun Holland, Li-Xin Xu, Peter Ahnert, Holger Kirsten, Ronald Koschny, Manfred Bauer, Ralf Schober, Jürgen Meixensberger, Wolfgang Krupp

Date Published: 1st Sep 2013

Publication Type: Journal article

Comparison and modelling of pegylated or unpegylated G-CSF schedules in CHOP-14 regimen of elderly patients with aggressive B-cell lymphoma.
GLA - German Lymphoma Alliance, Genetical Statistics and Systems Biology

Abstract (Expand)

Bi-weekly (R)-CHOP therapy is one of the standard treatmentS for elderly patients with aggressive B-cell lymphoma, but it is only feasible with supportive G-CSF treatment. In the trials of the DSHNHL, … either unpegylated G-CSF was given daily over 7 or 10 days or pegylated G-CSF was applied at day 4 of each cycle. These schedules were planned on the basis of simulations of a biomathematical pharmacokinetic/pharmacodynamic model. By analysing the observed data, we investigated whether our model predictions were correct and whether even better schedules can be proposed. We used data on 249 matched patients of two prospective trials, RICOVER-60 and PEGFILGRASTIM. The three G-CSF-schedules showed similar outcomes regarding leukocytopenia, infections and days in hospital, with pegylated G-CSF having slightly but not significantly better scores in all three endpoints. Regarding pegylated G-CSF, the best timing is predicted to be any day between days 4 and 7. With respect to unpegylated G-CSF, the starting day is less important, but it should be continued until the end of each cycle.The three G-CSF-schedules are interchangeable in (R)-CHOP-14 for elderly patients with aggressive B-cell lymphoma. Our model correctly predicts time courses of leukocytes. Further model predictions are presented, which can be tested in subsequent clinical trials.

Authors: S. Zeynalova, M. Ziepert, M. Scholz, S. Schirm, C. Zwick, M. Pfreundschuh, M. Loeffler

Date Published: 30th Jul 2013

Publication Type: Not specified

Human Diseases: B-cell lymphoma

Mice overexpressing CD97 in intestinal epithelial cells provide a unique model for mammalian postnatal intestinal cylindrical growth
Genetical Statistics and Systems Biology

Abstract (Expand)

Postnatal enlargement of the mammalian intestine comprises cylindrical and luminal growth, associated with crypt fission and crypt/villus hyperplasia, respectively, which subsequently predominate before … and after weaning. The bipartite adhesion G protein-coupled receptor CD97 shows an expression gradient along the crypt-villus axis in the normal human intestine. We here report that transgenic mice overexpressing CD97 in intestinal epithelial cells develop an upper megaintestine. Intestinal enlargement involves an increase in length and diameter but does not affect microscopic morphology, as typical for cylindrical growth. The megaintestine is acquired after birth and before weaning, independent of the genotype of the mother, excluding altered availability of milk constituents as driving factor. CD97 overexpression does not regulate intestinal growth factors, stem cell markers, and Wnt signaling, which contribute to epithelial differentiation and renewal, nor does it affect suckling-to-weaning transition. Consistent with augmented cylindrical growth, suckling but not adult transgenic mice show enlarged crypts and thus more crypt fissions caused by a transient increase of the crypt transit-amplifying zone. Intestinal enlargement by CD97 requires its seven-span transmembrane/cytoplasmic C-terminal fragment but not the N-terminal fragment binding partner CD55. In summary, ectopic expression of CD97 in intestinal epithelial cells provides a unique model for intestinal cylindrical growth occurring in breast-fed infants.

Authors: Gabriela Aust, Christiane Kerner, Susann Gonsior, Doreen Sittig, Hartmut Schneider, Peter Buske, Markus Scholz, Norman Dietrich, Sindy Oldenburg, Olga N. Karpus, Jörg Galle, Salah Amasheh, Jörg Hamann

Date Published: 15th Jul 2013

Publication Type: Journal article

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