CleanEx: a database of heterogeneous gene expression data based on a consistent gene nomenclature.

The main goal of CleanEx is to provide access to public gene expression data via unique gene names. A second objective is to represent heterogeneous expression data produced by different technologies in a way that facilitates joint analysis and cross-data set comparisons. A consistent and up-to-date gene nomenclature is achieved by associating each single experiment with a permanent target identifier consisting of a physical description of the targeted RNA population or the hybridization reagent used. These targets are then mapped at regular intervals to the growing and evolving catalogues of human genes and genes from model organisms. The completely automatic mapping procedure relies partly on external genome information resources such as UniGene and RefSeq. The central part of CleanEx is a weekly built gene index containing cross-references to all public expression data already incorporated into the system. In addition, the expression target database of CleanEx provides gene mapping and quality control information for various types of experimental resource, such as cDNA clones or Affymetrix probe sets. The web-based query interfaces offer access to individual entries via text string searches or quantitative expression criteria. CleanEx is accessible at: http://www.cleanex.isb-sib.ch/.

Second neoplasms after invasive and borderline ovarian cancer.

Excess risk of subsequent cancers has been documented in women diagnosed with ovarian cancer. We updated to 2006 data on second cancers in women diagnosed with invasive and borderline ovarian cancer in the Swiss canton of Vaud. Between 1974 and 2006, 304 borderline and 1530 invasive first ovarian tumours were abstracted from the Vaud Cancer Registry database and followed up till the end of 2006. Calculation of expected numbers of tumours in the cohorts was based on site-specific, age-specific and calendar-year-specific incidence rates. We computed the standardized incidence ratios (SIRs) of second cancers, and the corresponding 95% confidence intervals (CI). There was no change in the incidence of malignant cancers, but that of borderline tumours increased over more recent years. Overall, 110 second neoplasms were observed versus 49.7 expected after invasive ovarian cancer (SIR 2.21; 95% CI: 1.82-2.67). Significant excess risks were observed for cancers of the breast, corpus uteri and leukaemias. When synchronous cancers were excluded, the overall SIR for all sites declined to 1.05. Thirty-one second neoplasms were observed after borderline tumours compared with 21.1 expected (SIR=1.47; 95% CI: 1.00-2.09). SIRs were above unity for ovary, colorectum and uterus. After exclusion of synchronous neoplasms, SIR for all neoplasms declined to 1.09, and remained significant only for second ovarian cancers (SIR=4.93). The present record linkage cohort study shows an excess risk for selected synchronous neoplasms in women diagnosed with both borderline and invasive ovarian cancer, likely because of shared genetic and perhaps environmental factors.

A database to aid the identification of chemicals potentially posing a health risk through percutaneous exposure

In the context of recent attempts to redefine the 'skin notation' concept, a position paper summarizing an international workshop on the topic stated that the skin notation should be a hazard indicator related to the degree of toxicity and the potential for transdermal exposure of a chemical. Within the framework of developing a web-based tool integrating this concept, we constructed a database of 7101 agents for which a percutaneous permeation constant can be estimated (using molecular weight and octanol-water partition constant), and for which at least one of the following toxicity indices could be retrieved: Inhalation occupational exposure limit (n=644), Oral lethal dose 50 (LD50, n=6708), cutaneous LD50 (n=1801), Oral no observed adverse effect level (NOAEL, n=1600), and cutaneous NOAEL (n=187). Data sources included the Registry of toxic effects of chemical substances (RTECS, MDL information systems, Inc.), PHYSPROP (Syracuse Research Corp.) and safety cards from the International Programme on Chemical Safety (IPCS). A hazard index, which corresponds to the product of exposure duration and skin surface exposed that would yield an internal dose equal to a toxic reference dose was calculated. This presentation provides a descriptive summary of the database, correlations between toxicity indices, and an example of how the web tool will help industrial hygienist decide on the possibility of a dermal risk using the hazard index.

Climatic and anthropogenic influence on the stable isotope record from bulk carbonates and ostracodes in Lake Neuchatel, Switzerland, during the last two millennia

Lake Neuchatel is a medium sized, hard-water lake, lacking varved sediments, situated in the western Swiss Lowlands at the foot of the Jura Mountains. Stable isotope data (delta(18)O and delta(13)C) from both bulk carbonate and ostracode calcite in an 81 cm long, radiocarbon-dated sediment core represent the last 1500 years of Lake Neuchatel's environmental history. Comparison between this isotopic and other palaeolimnologic data (mineralogical, geochemical, palynological, etc.) helps to differentiate between anthropogenic and natural factors most recently affecting the lake. An increase in lacustrine productivity (450-650AD ca), inferred from the positive trend in delta(13)C values of bulk carbonate, is related to medieval forest clearances and the associated nutrient budget changes. A negative trend in both the bulk carbonate and ostracode calcite delta(18)O values between approximately 1300 and 1500AD, is tentatively interpreted as due to a cooling in mean air temperature at the transition from the Medieval Warm Period to the Little Ice Age. Negative trends in bulk carbonate delta(18)O and delta(13)C values through the uppermost sediments, which have no equivalent in ostracode calcite isotopic values, are concomitant with the recent onset of eutrophication in the lake. Isotopic disequilibrium during calcite precipitation, probably due to kinetic factors in periods of high productivity is postulated as the mechanism to explain the associated negative isotopic trends, although the effect of a shift of the calcite precipitation towards the warmer months cannot be excluded.

Schizophrenia: glutathione deficit as a new vulnerability factor for disconnectivity syndrome

(from the journal abstract) Schizophrenia, a major psychiatric disease, affects individuals in the centre of their personality. Its aetiology is not clearly established. In this review, we will present evidence that patients suffering of schizophrenia present a brain deficit in glutathione, a major endogenous redox regulator and antioxidant. We will also show that, in experimental models, a decrease in glutathione, particularly during development, induces morphological, electrophysiological and behavioural anomalies consistent with those observed in the disease. In the cerebrospinal fluid of drug-naive schizophrenics, glutathione level was decreased by 27% and its direct metabolite of glutathione by 16%. Glutathione level in prefrontal cortex of patients, measured by magnetic resonance spectroscopy, was 52% lower than in controls. Patients' fibroblasts reveal a decrease in mRNA levels of the two glutathione synthesising enzymes, glutamatecysteine ligase modulatory subunit (GCLM) and glutathione synthetase. GCLM expression level in fibroblasts correlates negatively with symptoms severity. Glutathione is an important endogenous redox regulator and neuroactive substance. It is protecting cells from damage by reactive oxygen species generated, among others, by dopamine metabolism. A glutathione deficit-induced oxidative stress would lead to lipid peroxidation and micro-lesions at the level of dendritic spines, a synaptic damage responsible for abnormal nervous connections or structural disconnectivity. On the other hand, a glutathione deficit could also lead to a functional disconnectivity by depressing NMDA neurotransmission, in analogy to phencyclidine effects. Present experimental data are consistent with the proposed hypothesis: decreasing pharmacologically glutathione level in experimental models, with or without blocking dopamine (DA) uptake (GBR12909), induces morphological, electrophysiological and behavioural changes similar to those observed in patients. In summary, a deficit of glutathione and/or glutathione-related enzymes during early development would lead to both a functional and a structural disconnectivity, which could be at the basis of some perceptive, cognitive and behavioural troubles of the disease. It could constitute a major vulnerability factor for schizophrenia. Attempts to restore physiological glutathione functions could open new therapeutic avenues. This translational research, made possible by a close interaction between clinicians and neuroscientists, should also pave the way to the identification of biological markers for schizophrenia. In turn, they should allow early diagnostic and hopefully preventive intervention to this devastating disease. (PsycINFO Database Record (c) 2005 APA, all rights reserved)

Development of a cross-European virtual sample repository and HIV resistance database

BACKGROUND: Several European HIV observational data bases have, over the last decade, accumulated a substantial number of resistance test results and developed large sample repositories, There is a need to link these efforts together, We here describe the development of such a novel tool that allows to bind these data bases together in a distributed fashion for which the control and data remains with the cohorts rather than classic data mergers.METHODS: As proof-of-concept we entered two basic queries into the tool: available resistance tests and available samples. We asked for patients still alive after 1998-01-01, and between 180 and 195 cm of height, and how many samples or resistance tests there would be available for these patients, The queries were uploaded with the tool to a central web server from which each participating cohort downloaded the queries with the tool and ran them against their database, The numbers gathered were then submitted back to the server and we could accumulate the number of available samples and resistance tests.RESULTS: We obtained the following results from the cohorts on available samples/resistance test: EuResist: not availableI11,194; EuroSIDA: 20,71611,992; ICONA: 3,751/500; Rega: 302/302; SHCS: 53,78311,485, In total, 78,552 samples and 15,473 resistance tests were available amongst these five cohorts. Once these data items have been identified, it is trivial to generate lists of relevant samples that would be usefuI for ultra deep sequencing in addition to the already available resistance tests, Saon the tool will include small analysis packages that allow each cohort to pull a report on their cohort profile and also survey emerging resistance trends in their own cohort,CONCLUSIONS: We plan on providing this tool to all cohorts within the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN) and will provide the tool free of charge to others for any non-commercial use, The potential of this tool is to ease collaborations, that is, in projects requiring data to speed up identification of novel resistance mutations by increasing the number of observations across multiple cohorts instead of awaiting single cohorts or studies to reach the critical number needed to address such issues.

Population specific and up to date cardiovascular risk charts can be efficiently obtained with record linkage of routine and observational data.

BACKGROUND: Only few countries have cohorts enabling specific and up-to-date cardiovascular disease (CVD) risk estimation. Individual risk assessment based on study samples that differ too much from the target population could jeopardize the benefit of risk charts in general practice. Our aim was to provide up-to-date and valid CVD risk estimation for a Swiss population using a novel record linkage approach. METHODS: Anonymous record linkage was used to follow-up (for mortality, until 2008) 9,853 men and women aged 25-74 years who participated in the Swiss MONICA (MONItoring of trends and determinants in CVD) study of 1983-92. The linkage success was 97.8%, loss to follow-up 1990-2000 was 4.7%. Based on the ESC SCORE methodology (Weibull regression), we used age, sex, blood pressure, smoking, and cholesterol to generate three models. We compared the 1) original SCORE model with a 2) recalibrated and a 3) new model using the Brier score (BS) and cross-validation. RESULTS: Based on the cross-validated BS, the new model (BS = 14107×10(-6)) was somewhat more appropriate for risk estimation than the original (BS = 14190×10(-6)) and the recalibrated (BS = 14172×10(-6)) model. Particularly at younger age, derived absolute risks were consistently lower than those from the original and the recalibrated model which was mainly due to a smaller impact of total cholesterol. CONCLUSION: Using record linkage of observational and routine data is an efficient procedure to obtain valid and up-to-date CVD risk estimates for a specific population.

Community replacement of neritic carbonate organisms during the late Valanginian platform demise: A new record from the Provence Platform

The Valanginian is marked by a major platform demise inducing a hiatus in the northern Tethyan neritic carbonate record from the top of the lower Valanginian to the lower Hauterivian. New biostratigraphic and chemostratigraphic data from the Ollioules section (Provence Platform, southern France) are presented here, demonstrating that a large part of the upper Valanginian is preserved in an inner platform environment. The thick, upper Valanginian, aggrading carbonate succession is observed in an aborted rift domain, implying relatively low subsidence. In this context, a relatively long-term sea-level rise was required to sustain a keep-up style of carbonate production. Like the Apulian Platform, the remarkable preservation of the Provence Platform may have been favored by its remoteness from terrigenous source areas, as suggested by the low clastic inputs and low P-accumulation rates. Two main biotic community replacements are observed in Ollioules. The first saw the development of abundant microbialites and algae at the onset of the late Valanginian. A Tubiphytes concentration occurred during the coolest climatic conditions and the transition towards arid conditions, whereas the subsequent Lithocodium-Bacinella and orbitolinids assemblages developed under low nutrient conditions during a warmer interval. Both assemblages may have been triggered by increased alkalinity. The second community replacement saw the installation of coral- and rudist-dominated communities during the latest Valanginian to early Hauterivian. They indicate a change to oligotrophic, open marine conditions. Six medium-scale sequences have been defined in Ollioules, indicating short-term transgressive-regressive trends superimposed on a long-term transgression. Low nutrient inputs and relatively low subsidence in an aggradational context may explain the survival of the isolated Provence Carbonate Platform during a time of widespread drowning episodes and platform demise in the northern Tethyan domain. (c) 2012 Elsevier B.V. All rights reserved.

Medical record search engines, using pseudonymised patient identity: an alternative to centralised medical records

Purpose The purpose of our multidisciplinary study was to define a pragmatic and secure alternative to the creation of a national centralised medical record which could gather together the different parts of the medical record of a patient scattered in the different hospitals where he was hospitalised without any risk of breaching confidentiality. Methods We first analyse the reasons for the failure and the dangers of centralisation (i.e. difficulty to define a European patients' identifier, to reach a common standard for the contents of the medical record, for data protection) and then propose an alternative that uses the existing available data on the basis that setting up a safe though imperfect system could be better than continuing a quest for a mythical perfect information system that we have still not found after a search that has lasted two decades. Results We describe the functioning of Medical Record Search Engines (MRSEs), using pseudonymisation of patients' identity. The MRSE will be able to retrieve and to provide upon an MD's request all the available information concerning a patient who has been hospitalised in different hospitals without ever having access to the patient's identity. The drawback of this system is that the medical practitioner then has to read all of the information and to create his own synthesis and eventually to reject extra data. Conclusions Faced with the difficulties and the risks of setting up a centralised medical record system, a system that gathers all of the available information concerning a patient could be of great interest. This low-cost pragmatic alternative which could be developed quickly should be taken into consideration by health authorities.

CleanEx: a database of heterogeneous gene expression data based on a consistent gene nomenclature and linked to an improved annotation system

Résumé: L'automatisation du séquençage et de l'annotation des génomes, ainsi que l'application à large échelle de méthodes de mesure de l'expression génique, génèrent une quantité phénoménale de données pour des organismes modèles tels que l'homme ou la souris. Dans ce déluge de données, il devient très difficile d'obtenir des informations spécifiques à un organisme ou à un gène, et une telle recherche aboutit fréquemment à des réponses fragmentées, voir incomplètes. La création d'une base de données capable de gérer et d'intégrer aussi bien les données génomiques que les données transcriptomiques peut grandement améliorer la vitesse de recherche ainsi que la qualité des résultats obtenus, en permettant une comparaison directe de mesures d'expression des gènes provenant d'expériences réalisées grâce à des techniques différentes. L'objectif principal de ce projet, appelé CleanEx, est de fournir un accès direct aux données d'expression publiques par le biais de noms de gènes officiels, et de représenter des données d'expression produites selon des protocoles différents de manière à faciliter une analyse générale et une comparaison entre plusieurs jeux de données. Une mise à jour cohérente et régulière de la nomenclature des gènes est assurée en associant chaque expérience d'expression de gène à un identificateur permanent de la séquence-cible, donnant une description physique de la population d'ARN visée par l'expérience. Ces identificateurs sont ensuite associés à intervalles réguliers aux catalogues, en constante évolution, des gènes d'organismes modèles. Cette procédure automatique de traçage se fonde en partie sur des ressources externes d'information génomique, telles que UniGene et RefSeq. La partie centrale de CleanEx consiste en un index de gènes établi de manière hebdomadaire et qui contient les liens à toutes les données publiques d'expression déjà incorporées au système. En outre, la base de données des séquences-cible fournit un lien sur le gène correspondant ainsi qu'un contrôle de qualité de ce lien pour différents types de ressources expérimentales, telles que des clones ou des sondes Affymetrix. Le système de recherche en ligne de CleanEx offre un accès aux entrées individuelles ainsi qu'à des outils d'analyse croisée de jeux de donnnées. Ces outils se sont avérés très efficaces dans le cadre de la comparaison de l'expression de gènes, ainsi que, dans une certaine mesure, dans la détection d'une variation de cette expression liée au phénomène d'épissage alternatif. Les fichiers et les outils de CleanEx sont accessibles en ligne (http://www.cleanex.isb-sib.ch/). Abstract: The automatic genome sequencing and annotation, as well as the large-scale gene expression measurements methods, generate a massive amount of data for model organisms. Searching for genespecific or organism-specific information througout all the different databases has become a very difficult task, and often results in fragmented and unrelated answers. The generation of a database which will federate and integrate genomic and transcriptomic data together will greatly improve the search speed as well as the quality of the results by allowing a direct comparison of expression results obtained by different techniques. The main goal of this project, called the CleanEx database, is thus to provide access to public gene expression data via unique gene names and to represent heterogeneous expression data produced by different technologies in a way that facilitates joint analysis and crossdataset comparisons. A consistent and uptodate gene nomenclature is achieved by associating each single gene expression experiment with a permanent target identifier consisting of a physical description of the targeted RNA population or the hybridization reagent used. These targets are then mapped at regular intervals to the growing and evolving catalogues of genes from model organisms, such as human and mouse. The completely automatic mapping procedure relies partly on external genome information resources such as UniGene and RefSeq. The central part of CleanEx is a weekly built gene index containing crossreferences to all public expression data already incorporated into the system. In addition, the expression target database of CleanEx provides gene mapping and quality control information for various types of experimental resources, such as cDNA clones or Affymetrix probe sets. The Affymetrix mapping files are accessible as text files, for further use in external applications, and as individual entries, via the webbased interfaces . The CleanEx webbased query interfaces offer access to individual entries via text string searches or quantitative expression criteria, as well as crossdataset analysis tools, and crosschip gene comparison. These tools have proven to be very efficient in expression data comparison and even, to a certain extent, in detection of differentially expressed splice variants. The CleanEx flat files and tools are available online at: http://www.cleanex.isbsib. ch/.

The TREAT-NMD DMD Global Database: Analysis of More than 7,000 Duchenne Muscular Dystrophy Mutations.

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).

The REporting of Studies Conducted Using Observational Routinely-Collected Health Data (RECORD) Statement: Methods for Arriving at Consensus and Developing Reporting Guidelines.

OBJECTIVE: Routinely collected health data, collected for administrative and clinical purposes, without specific a priori research questions, are increasingly used for observational, comparative effectiveness, health services research, and clinical trials. The rapid evolution and availability of routinely collected data for research has brought to light specific issues not addressed by existing reporting guidelines. The aim of the present project was to determine the priorities of stakeholders in order to guide the development of the REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement. METHODS: Two modified electronic Delphi surveys were sent to stakeholders. The first determined themes deemed important to include in the RECORD statement, and was analyzed using qualitative methods. The second determined quantitative prioritization of the themes based on categorization of manuscript headings. The surveys were followed by a meeting of RECORD working committee, and re-engagement with stakeholders via an online commentary period. RESULTS: The qualitative survey (76 responses of 123 surveys sent) generated 10 overarching themes and 13 themes derived from existing STROBE categories. Highest-rated overall items for inclusion were: Disease/exposure identification algorithms; Characteristics of the population included in databases; and Characteristics of the data. In the quantitative survey (71 responses of 135 sent), the importance assigned to each of the compiled themes varied depending on the manuscript section to which they were assigned. Following the working committee meeting, online ranking by stakeholders provided feedback and resulted in revision of the final checklist. CONCLUSIONS: The RECORD statement incorporated the suggestions provided by a large, diverse group of stakeholders to create a reporting checklist specific to observational research using routinely collected health data. Our findings point to unique aspects of studies conducted with routinely collected health data and the perceived need for better reporting of methodological issues.

Protective behavioral strategies and future drinking behaviors: Effect of drinking intentions.

Alcohol use is common among United States and Swedish high school students and is related to negative consequences. Whereas drinking intentions are associated with future drinking behaviors, the use of protective behavioral strategies (PBS) is associated with decreased alcohol-related harm among young adults. The interactive effect of PBS and drinking intentions in predicting alcohol outcomes has not been examined. Further, because most PBS studies have been conducted among U.S. college students, PBS research among other populations is needed. The aims of this study were to evaluate longitudinally (a) the relationships between drinking intentions, PBS and alcohol outcomes, and (b) the moderating roles of drinking intentions and country in these relationships among United States and Swedish high school drinkers. Data were collected at baseline, 6- and 12-month follow-ups on 901 Swedish and 288 U.S. high school drinkers. Drinking intentions were associated with more alcohol use and consequences, and use of certain PBS was related to fewer alcohol-related consequences over time. Additionally, the negative prospective relationship between use of PBS and alcohol use, but not alcohol-related consequences, was moderated by intentions, such that the relationship was stronger among participants endorsing high drinking intentions. Country did not moderate these relationships. These results provide initial support for the generalizability of PBS college research to United States and Swedish high school students and suggest that interventions targeting the use of PBS may be most effective among high school drinkers endorsing high drinking intentions. (PsycINFO Database Record