PENALIZED LIKELIHOOD AND BAYESIAN METHODS FOR SPARSE CONTINGENCY TABLES: AN ANALYSIS OF ALTERNATIVE SPLICING IN FULL-LENGTH cDNA LIBRARIES

We develop methods to perform model selection and parameter estimation in loglinear models for the analysis of sparse contingency tables to study the interaction of two or more factors. Typically, datasets arising from so-called full-length cDNA libraries, in the context of alternatively spliced genes, lead to such sparse contingency tables. Maximum Likelihood estimation of log-linear model coefficients fails to work because of zero cell entries. Therefore new methods are required to estimate the coefficients and to perform model selection. Our suggestions include computationally efficient penalization (Lasso-type) approaches as well as Bayesian methods using MCMC. We compare these procedures in a simulation study and we apply the proposed methods to full-length cDNA libraries, yielding valuable insight into the biological process of alternative splicing

SEVERE OSTEOPOROSIS DUE TO SYSTEMIC MAST CELL DISEASE: SUCCESSFUL TREATMENT WITH INTERFERON ALPHA-2B

We describe a 33-yr-old man suffering from severe vertebral osteoporosis and urticaria pigmentosa due to systemic mast cell disease (SMCD). Because i.v. clodronate therapy could not prevent further vertebral fractures, an additional treatment with interferon alpha-2b was initiated. During 24 months of treatment, our patient had no further pain episodes, no new vertebral fractures were discovered, trabecular bone mineral density (BMD) increased significantly and urticarial symptoms improved. Nevertheless, the extent of skin lesions remained unchanged. On histological examination, a remarkable decrease of mast cells was observed in the bone marrow, but not in the skin. Five months after discontinuation of interferon alpha-2b, trabecular BMD decreased and urticarial symptoms deteriorated. These findings illustrate a beneficial effect of interferon alpha-2b on SMCD-induced osteoporosis as well as urticarial symptoms, and raise the question whether this treatment may have a diverse impact on mast cell populations in different tissue

Impact of climate change and development scenarios on flow patterns in the Okavango River

This paper lays the foundation for the use of scenario modelling as a tool for integrated water resource management in the Okavango River basin. The Pitman hydrological model is used to assess the impact of various development and climate change scenarios on downstream river flow. The simulated impact on modelled river discharge of increased water use for domestic use, livestock, and informal irrigation (proportional to expected population increase) is very limited. Implementation of all likely potential formal irrigation schemes mentioned in available reports is expected to decrease the annual flow by 2% and the minimum monthly flow by 5%. The maximum possible impact of irrigation on annual average flow is estimated as 8%, with a reduction of minimum monthly flow by 17%. Deforestation of all areas within a 1 km buffer around the rivers is estimated to increase the flow by 6%. However, construction of all potential hydropower reservoirs in the basin may change the monthly mean flow distribution dramatically, although under the assumed operational rules, the impact of the dams is only substantial during wet years. The simulated impacts of climate change are considerable larger that those of the development scenarios (with exception of the high development scenario of hydropower schemes) although the results are sensitive to the choice of GCM and the IPCC SRES greenhouse gas (GHG) emission scenarios. The annual mean water flow predictions for the period 2020-2050 averaged over scenarios from all the four GCMs used in this study are close to the present situation for both the A2 and B2 GHG scenarios. For the 2050-2080 and 2070-2099 periods the all-GCM mean shows a flow decrease of 20% (14%) and 26% (17%) respectively for the A2 (B2) GHG scenarios. However, the uncertainty in the magnitude of simulated future changes remains high. The simulated effect of climate change on minimum monthly flow is proportionally higher

"Kultur" als Form symbolischer Gewalt: Grenzziehungsprozesse im Kontext von Migration am Beispiel der Schweiz

Die Schweiz gilt international als Modell eines gelungenen Multikulturalismus, dann nämlich wenn es das Zusammenleben der vier Sprachgruppen (Romands, DeutschschweizerInnen, TessinerInnen, RäteromanInnen) betrifft. Ein sprachlicher wie auch religiöser Pluralismus ist und war stets ein Grundbaustein des Selbstverständnisses der „Willensnation“ Schweiz. Geht es aber um MigrantInnen präsentiert sich die Geschichte anders, denn in diesem Falle erscheinen religiöse und ethnisch-kulturelle Pluralität vorwiegend als problematisch. MigrantInnen gehören entsprechend den öffentlichen und politischen Diskursen nicht zum multikulturellen Staat, vielmehr sind Prozesse kollektiver Grenzziehungen und damit Schließungsmechanismen zu beobachten, in denen Ethnizität, Religion und Kultur zu den wichtigsten Differenzierungsmerkmale werden, wie Gemeinsamkeiten gegen innen (SchweizerInnen) und Barrieren gegen außen (Ausländer, Migranten, Muslims, etc.) hergestellt werden. Ich argumentiere in diesem Kapitel, dass sich dieser „Kulturdiskurs“ im letzten Jahrzehnt verstärkt hat und gleichzeitig semantischen Verschiebungen unterworfen war. Mittels der Grenzziehungsperspektive wird historisch nachvollzogen, wie Zuwanderung und Integration in politischen Debatten und Gesetz zunehmend kulturalisiert und ethnisiert wurden. Ein Fallbeispiel aus der Forschung dient mir anschließend der Veranschaulichung dieser theoretischen Perspektive und dieses „neuen“ Essentialismus

Penalized likelihood for sparse contingency tables with an application to full-length cDNA libraries

<p>Abstract</p> <p>Background</p> <p>The joint analysis of several categorical variables is a common task in many areas of biology, and is becoming central to systems biology investigations whose goal is to identify potentially complex interaction among variables belonging to a network. Interactions of arbitrary complexity are traditionally modeled in statistics by log-linear models. It is challenging to extend these to the high dimensional and potentially sparse data arising in computational biology. An important example, which provides the motivation for this article, is the analysis of so-called full-length cDNA libraries of alternatively spliced genes, where we investigate relationships among the presence of various exons in transcript species.</p> <p>Results</p> <p>We develop methods to perform model selection and parameter estimation in log-linear models for the analysis of sparse contingency tables, to study the interaction of two or more factors. Maximum Likelihood estimation of log-linear model coefficients might not be appropriate because of the presence of zeros in the table's cells, and new methods are required. We propose a computationally efficient ℓ₁-penalization approach extending the Lasso algorithm to this context, and compare it to other procedures in a simulation study. We then illustrate these algorithms on contingency tables arising from full-length cDNA libraries.</p> <p>Conclusion</p> <p>We propose regularization methods that can be used successfully to detect complex interaction patterns among categorical variables in a broad range of biological problems involving categorical variables.</p

Evaluation of C-terminal Agrin Fragment as a marker of muscle wasting in patients after acute stroke during early rehabilitation.

BACKGROUND C-terminal Agrin Fragment (CAF) has been proposed as a novel biomarker for sarcopenia originating from the degeneration of the neuromuscular junctions. In patients with stroke muscle wasting is a common observation that predicts functional outcome. We aimed to evaluate agrin sub-fragment CAF22 as a marker of decreased muscle mass and physical performance in the early phase after acute stroke. METHODS Patients with acute ischaemic or haemorrhagic stroke (n = 123, mean age 70 ± 11 y, body mass index BMI 27.0 ± 4.9 kg/m(2)) admitted to inpatient rehabilitation were studied in comparison to 26 healthy controls of similar age and BMI. Functional assessments were performed at begin (23 ± 17 days post stroke) and at the end of the structured rehabilitation programme (49 ± 18 days post stroke) that included physical assessment, maximum hand grip strength, Rivermead motor assessment, and Barthel index. Body composition was assessed by bioelectrical impedance analysis (BIA). Serum levels of CAF22 were measured by ELISA. RESULTS CAF22 levels were elevated in stroke patients at admission (134.3 ± 52.3 pM) and showed incomplete recovery until discharge (118.2 ± 42.7 pM) compared to healthy controls (95.7 ± 31.8 pM, p < 0.001). Simple regression analyses revealed an association between CAF22 levels and parameters of physical performance, hand grip strength, and phase angle, a BIA derived measure of the muscle cellular integrity. Improvement of the handgrip strength of the paretic arm during rehabilitation was independently related to the recovery of CAF22 serum levels only in those patients who showed increased lean mass during the rehabilitation. CONCLUSIONS CAF22 serum profiles showed a dynamic elevation and recovery in the subacute phase after acute stroke. Further studies are needed to explore the potential of CAF22 as a serum marker to monitor the muscle status in patients after stroke

Thermal history of the central Gotthard and Aar massifs, European Alps: Evidence for steady state, long-term exhumation

International audienceQuantifying long-term exhumation rates is a prerequisite for understanding the geodynamic evolution of orogens and their exogenic and endogenic driving forces. Here we reconstruct the exhumation history of the central Aar and Gotthard external crystalline massifs in the European Alps using apatite and zircon fission track and apatite (U-Th)/He data. Age-elevation relationships and time-temperature paths derived from thermal history modeling are interpreted to reflect nearly constant exhumation of ∼0.5 km/Ma since ∼14 Ma. A slightly accelerated rate (∼0.7 km/Ma) occurred from 16 to 14 Ma and again from 10 to 7 Ma. Faster exhumation between 16 and 14 Ma is most likely linked to indentation of the Adriatic wedge and related thrusting along the Alpine sole thrust, which, in turn, caused uplift and exhumation in the external crystalline massifs. The data suggest nearly steady, moderate exhumation rates since ∼14 Ma, regardless of major exogenic and endogenic forces such as a change to wetter climate conditions around 5 Ma or orogen-perpendicular extension initiated in Pliocene times. Recent uplift and denudation rates, interpreted to be the result of climate fluctuations and associated increase in erosional efficiency, are nearly twice this ∼0.5 km/Ma paleoexhumation rate