CORA - a knowledge based system for the analysis of case control studies

Carrying out a statistical analysis the researcher is concerned with the problem of choosing an appropriate statistical technique from a large number of competing methods. Most common statistical software offer different methods for analysing the data without giving any support concerning the adequacy of a method for a particular data set. This paper outlines the main features of the computer system CORA which provides a statistical analysis of stratified contingency tables and additionally supports the researcher at the different steps of this analysis. Here, the support given by the system consists of two different aspects. On the one hand, the help system of CORA contains general information on the implemented statistical methods which can be obtained on request. On the other hand an advice tool recommends an adequate statistical method which depends on the actual empirical casecontrol data to be analysed. To build up the advice tool a set of rules being discovered by machine learning from simulation studies is integrated into the system CORA. The paper is written in English

Experimentelle Analyse zweier logik-basierter Lernverfahren

Ein entscheidendes Problem des logik-basierten Lernens liegt in der Grösse des Hypothesenraumes. Möglichkeiten der Einschränkung sind das heuristische Durchsuchen eines vollständigen Hypothesenraums (z.B. FOIL) oder das vollständige Durchsuchen eines eingeschränkten Hypothesenraums (z.B. RDT). Während die theoretische Analyse die Lernbarkeit untersucht, wollen wir durch einen experimentellen Vergleich von RDT und FOIL feststellen, wie sich die unterschiedlichen Einschränkungen des Suchraums in der Praxis auswirken. Für unsere Experimente haben wir zum einen den KRK-Sachbereich und ausserdem einen neu modellierten Sachbereich, die Wohnortwahl für Studenten, verwendet. The paper is written in German

CORA -- A Knowledge-Based System for the Analysis of Case-Control Studies

Carrying out a statistical analysis of empirical data the researcher is typically concerned with the problem of choosing an appropriate statistical technique from a large number of competing methods. Most of the common statistical software only allows to analyse the data by applying certain methods that are implemented in this software without giving any support to the researcher with respect to the adequacy of a method for a particular data set. This paper outlines the main features of the computer system CORA which provides a statistical analysis of stratified contingency tables and additionally supports the researcher at the different steps of this analysis. The support given by the system consists of two different aspects. On the one hand the help system of CORA contains general information on the implemented statistical methods which can be obtained on request by the user. On the other hand an advice tool recommends an adequate statistical method. This advice depends on the actual..

The Use of Inductive Logic Programming for the Development of the Statistical Software Tool CORA

This paper presents the knowledge acquisition process for the system CORA, which provides a statistical analysis of stratified case--control data and additionally supports the researcher at the different steps of this analysis. In addition to the general information given by the help system, the advice tool recommends an adequate statistical method. This recommendation depends on the actual data to be analysed. The underlying rule base containing the recommendations was discovered by inductive logic programming (ILP) methods. 1 Introduction In epidemiology it is of interest to investigate possible associations between a potential risk factor and a certain disease. To answer such questions data on the disease and on the exposure are typically collected by conducting a case--control study. The collected data are then often analysed by stratified contingency tables where as quantifying statistical measure for the investigated association the so--called odds ratio / is estimated from the ..

Abstract 160: High target binding affinity with long lasting cellular target engagement and high dose intermittent schedule of PI3K inhibitor copanlisib contribute to the potent anti-tumor activity and good safety profile

Abstract Introduction: Several generations of PI3K inhibitors have been tested in clinic. However, thus far, clinical activity has been moderate. Different from other oral PI3K inhibitors dosed continuously, copanlisib (BAY 80-6946) is an intravenous PI3K inhibitor given intermittently to patients. Copanlisib dosed once weekly demonstrated clinical benefit with an improved safety profile, and therefore challenges the concept of default continuous dosing of PI3K inhibitors. However, it is still unclear if this concept can be generalized and whether ‘micropharmacokinetic parameters’ also contributed to the potent anti-tumor profile of copanlisib. Here, we report the characterization of binding kinetics for copanlisib, as well as the functional consequence in vivo. Methods: A set of PI3K inhibitors were characterized in 1) a kinetic probe competition assay (kPCA); 2) a cellular nanoBRET target engagement assay; 3) a cellular washout study with the assessment on pathway engagement; and 4) in vivo pharmacokinetics analysis. Results: Copanlisib showed nearly diffusion-controlled on- and relatively slow off-rates with kon = 3.45E+7 [M-1*s-1] and koff = 1.67E-3 [s-1] to PI3Kα. Consequently, it exhibited very high affinity to PI3Kα ( Ki ePCA = 9.31E-11[M] and KD kPCA = 4.77E-11 [M]). In a cellular nanoBRET target engagement assay, the apparent half-life (t1/2) of ca. 2 hours greatly surpassed the 6.9 min measured using kPCA. The high affinity to PI3Kα also translated into potent cellular pathway engagement demonstrated by inhibition of p-AKT and p-PRAS40 in the PIK3CAmut KPL4 cell line. In a cellular washout study, p-AKT and p-PRAS40 were assessed till 168 h after incubation with copanlisib for 1 h followed by a washout step. A dose- and time-dependent pathway engagement was observed even at 72 h post washout. This result indicated that in cells, copanlisib engages PI3Kα for an extremely long time, likely due to rebinding effects facilitated by the fast equilibration kinetics of the compound and its micropharmacokinetic properties. Interestingly, in vivo, BAY 80-6946 levels were approximately 100-fold higher in the tumor than in plasma at 48 hours and drug clearance from the tumor occurred more slowly than from plasma. This high and prolonged tumor exposure might be explained, at least in part, by the high expression of PI3Kα and long lasting target occupancy of copanlisib in tumors. Conclusion: Copanlisib demonstrated high affinity to PI3Kα with protracted target engagement at cellular and in vivo levels. This ‘micropharmacokinetic feature’ not only supports intermittent dosing but likely also explains the high exposure in tumors vs plasma, potent anti-tumor activity and good safety profiles. Citation Format: Amaury E. Fernández-Montalván, Victoria Georgi, James Vasta, Sarah Glaeske, Vera Puetter, Matthew B. Robers, Ursula Moenning, Andrea Sturz, Julien Lefranc, Karl Ziegelbauer, Michael Brands, Christian Stegmann, William J. Scott, Ningshu Liu. High target binding affinity with long lasting cellular target engagement and high dose intermittent schedule of PI3K inhibitor copanlisib contribute to the potent anti-tumor activity and good safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 160. doi:10.1158/1538-7445.AM2017-160</jats:p