Proteomics biomarker discovery for individualized prevention of familial pancreatic cancer using statistical learning

BACKGROUND: The low five-year survival rate of pancreatic ductal adenocarcinoma (PDAC) and the low diagnostic rate of early-stage PDAC via imaging highlight the need to discover novel biomarkers and improve the current screening procedures for early diagnosis. Familial pancreatic cancer (FPC) describes the cases of PDAC that are present in two or more individuals within a circle of first-degree relatives. Using innovative high-throughput proteomics, we were able to quantify the protein profiles of individuals at risk from FPC families in different potential pre-cancer stages. However, the high-dimensional proteomics data structure challenges the use of traditional statistical analysis tools. Hence, we applied advanced statistical learning methods to enhance the analysis and improve the results’ interpretability. METHODS: We applied model-based gradient boosting and adaptive lasso to deal with the small, unbalanced study design via simultaneous variable selection and model fitting. In addition, we used stability selection to identify a stable subset of selected biomarkers and, as a result, obtain even more interpretable results. In each step, we compared the performance of the different analytical pipelines and validated our approaches via simulation scenarios. RESULTS: In the simulation study, model-based gradient boosting showed a more accurate prediction performance in the small, unbalanced, and high-dimensional datasets than adaptive lasso and could identify more relevant variables. Furthermore, using model-based gradient boosting, we discovered a subset of promising serum biomarkers that may potentially improve the current screening procedure of FPC. CONCLUSION: Advanced statistical learning methods helped us overcome the shortcomings of an unbalanced study design in a valuable clinical dataset. The discovered serum biomarkers provide us with a clear direction for further investigations and more precise clinical hypotheses regarding the development of FPC and optimal strategies for its early detection

Bottleneck effects in turbulence: Scaling phenomena in r- versus p-space

We (analytically) calculate the energy spectrum corresponding to various experimental and numerical turbulence data analyzed by Benzi et al.. We find two bottleneck phenomena: While the local scaling exponent $\zeta_r(r)$ of the structure function decreases monotonically, the local scaling exponent $\zeta_p(p)$ of the corresponding spectrum has a minimum of $\zeta_p(p_{min})\approx 0.45$ at $p_{min}\approx (10 \eta)^{-1}$ and a maximum of $\zeta_p(p_{max})\approx 0.77$ at $p_{max}\approx 8 L^{-1}$. A physical argument starting from the constant energy flux in p--space reveals the general mechanism underlying the energy pileups at both ends of the p--space scaling range. In the case studied here, they are induced by viscous dissipation and the reduced spectral strength on the scale of the system size, respectively.Comment: 9 pages, 3figures on reques

Collinear helium under periodic driving: stabilization of the asymmetric stretch orbit

The collinear eZe configuration of helium, with the electrons on opposite sides of the nucleus, is studied in the presence of an external electromagnetic (laser or microwave) field. We show that the classically unstable "asymmetric stretch" orbit, on which doubly excited intrashell states of helium with maximum interelectronic angle are anchored, can be stabilized by means of a resonant driving where the frequency of the electromagnetic field equals the frequency of Kepler-like oscillations along the orbit. A static magnetic field, oriented parallel to the oscillating electric field of the driving, can be used to enforce the stability of the configuration with respect to deviations from collinearity. Quantum Floquet calculations within a collinear model of the driven two-electron atom reveal the existence of nondispersive wave packets localized on the stabilized asymmetric stretch orbit, for double excitations corresponding to principal quantum numbers of the order of N > 10.Comment: 13 pages, 12 figure

Adiabatic Pair Creation

We give here the proof that pair creation in a time dependent potentials is possible. It happens with probability one if the potential changes adiabatically in time and becomes overcritical, that is when an eigenvalue enters the upper spectral continuum. The potential may be assumed to be zero at large negative and positive times. The rigorous treatment of this effect has been lacking since the pioneering work of Beck, Steinwedel and Suessmann in 1963 and Gershtein and Zeldovich in 1970.Comment: 53 pages, 1 figure. Editorial changes on page 22 f

Insights from regional and short-term biodiversity monitoring datasets are valuable: a reply to Daskalova et al. 2021

Reports of major losses in insect biodiversity have stimulated an increasing interest in temporal population changes. Existing datasets are often limited to a small number of study sites, few points in time, a narrow range of land-use intensities and only some taxonomic groups, or they lack standardised sampling. While new monitoring programs have been initiated, they still cover rather short time periods. Daskalova et al. 2021 (Insect Conservation and Diversity, 14, 1-18) argue that temporal trends of insect populations derived from short time series are biased towards extreme trends, while their own analysis of an assembly of shorter- and longer-term time series does not support an overall insect decline. With respect to the results of Seibold et al. 2019 (Nature, 574, 671–674) based on a 10-year multi-site time series, they claim that the analysis suffers from not accounting for temporal pseudoreplication. Here, we explain why the criticism of missing statistical rigour in the analysis of Seibold et al. (2019) is not warranted. Models that include ‘year’ as random effect, as suggested by Daskalova et al. (2021), fail to detect non-linear trends and assume that consecutive years are independent samples which is questionable for insect time-series data. We agree with Daskalova et al. (2021) that the assembly and analysis of larger datasets is urgently needed, but it will take time until such datasets are available. Thus, short-term datasets are highly valuable, should be extended and analysed continually to provide a more detailed understanding of insect population changes under the influence of global change, and to trigger immediate conservation actions

Governance im Politikfeld Wirtschaftspolitik

This paper gives an overview of the topic "economic governance". This term is used in economics and neighboring social sciences as a generic term under which usually all activities are subsumed that are conducted by economic policymakers to 'steer' or 'control' the economic system, individual markets therein or certain economic actors (e.g., businesses, consumers). In addition to a more detailed clarification of the concept of "economic governance" and the presentation of actors and instruments of economic governance, the paper discusses why and in what situations economic governance is necessary. The latter issue is the subject of a continuing debate in politics, the public and the social sciences

Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy

Background Nephronophthisis associated ciliopathies (NPHP-AC) comprise a group of autosomal recessive cystic kidney diseases that includes nephronophthisis (NPHP), Senior-Loken syndrome (SLS), Joubert syndrome (JBTS), and Meckel-Gruber syndrome (MKS). To date, causative mutations in NPHP-AC have been described for 18 different genes, rendering mutation analysis tedious and expensive. To overcome the broad genetic locus heterogeneity, a strategy of DNA pooling with consecutive massively parallel resequencing (MPR) was devised.Methods In 120 patients with severe NPHP-AC phenotypes, five pools of genomic DNA with 24 patients each were prepared which were used as templates in order to PCR amplify all 376 exons of 18 NPHP-AC genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L, NEK8, TMEM67, INPP5E, TMEM216, AHI1, ARL13B, CC2D2A, TTC21B, MKS1, and XPNPEP3). PCR products were then subjected to MPR on an Illumina Genome-Analyser and mutations were subsequently assigned to their respective mutation carrier via CEL I endonuclease based heteroduplex screening and confirmed by Sanger sequencing.Results For proof of principle, DNA from patients with known mutations was used and detection of 22 out of 24 different alleles (92% sensitivity) was demonstrated. MPR led to the molecular diagnosis in 30/120 patients (25%) and 54 pathogenic mutations (27 novel) were identified in seven different NPHP-AC genes. Additionally, in 24 patients only single heterozygous variants of unknown significance were found.Conclusions The combined approach of DNA pooling followed by MPR strongly facilitates mutation analysis in broadly heterogeneous single gene disorders. The lack of mutations in 75% of patients in this cohort indicates further extensive heterogeneity in NPHP-AC

Soziale Reproduktionsstrategien und Mechanismen sozialen Aufstiegs - Thema verfehlt! Kommentar zu den Beiträgen von Carola Groppe und Gerhard Kluchert

Der Autor äußert sich kritisch zu den Vortrags- und Diskussionsthemen des DGfE-Kongresses 2006 und vertritt die Auffassung, dass das Anliegen des Kongresses nicht die Bestätigung von Vor- und Fehlurteilen bundesdeutscher Erziehungswissenschaftler hätte sein sollen, "sondern das Hinterfragen der donimierenden Diskurse und Lehrangebote." Bezugnehmend auf die Beiträge von Groppe und Kluchert kritisiert er, dass der Untertitel des Symposions [(Re)Produktion von sozialer Ungleichheit] nicht ausreichend Berücksichtigung fand. (DIPF/Mar.

The process of school system building in Prussia during the second half of the nineteenth century

Die Reform der Bildungsanstalten in Preußen am Beginn des 19. Jahrhunderts leitete eine Entwicklung ein, in deren Verlauf aus einem Konglomerat unterschiedlichster Schulformen und Fachanstalten ein Bildungssystem entstand, das zum idealtypischen Modell des Bildungswesens moderner Industriegesellschaften geworden ist. Nicht - wie in England oder Frankreich - der Besuch exklusiver Privatschulen eröffnete in Preußen den Zugang zu den Universitäten und höheren Beamtenstellen, sondern ein breites, über den ganzen Staat verteiltes Angebot von Gymnasien verlieh den Zugang zu den, wiederum regional verteilten, Universitäten und zu den höheren und mittleren Beamtenpositionen. Die sozial offene multifunktionale Struktur des preußischen Gymnasiums ("Gesamtschule") führte zu Krisenphasen ("akademisches Proletariat", "Überfüllung"), die gegen Ende des 19. Jahrhunderts einen Strukturwandel des Gymnasiums zu einer Eliteanstalt innerhalb eines differenzierten Gesamtsystems erzwangen. In diesem Aufsatz werden die unterschiedlichen Bedingungen und Zusammenhange der Entwicklung des Schulwesens zu einem Schulsystem und die damit verbundenen sozialen Selektionsprozesse analysiert. (DIPF/Orig.