New pathway for qualification of novel methodologies in the European Medicines Agency

The European Medicines Agency (EMA) qualification process is a new, voluntary, scientific pathway leading to either a Committee for Medicinal Products for Human Use (CHMP) opinion or a Scientific Advice on innovative methods or drug development tools: (i) CHMP Qualification Opinion on the acceptability of a specific use of the proposed method, based on the assessment of submitted data and (ii) CHMP Qualification Advice on future protocols and methods for further method development towards qualification, based on the evaluation of the scientific rationale and on preliminary data submitted. The qualification procedure was established as a response to the drug development bottlenecks and inefficiencies, but also to the availability of new methodologies, not yet integrated in the drug development and clinical management paradigm. The qualification process addresses innovative methods developed by consortia, networks, public/private partnerships, learned societies or pharmaceutical industry. It is expected to facilitate communication between the scientific community and the regulators and to address challenges with the development and use of medicines. In this article, we will present an overview of the process and the up to now scientific advice working party (SAWP) experience.     

A Family of Directional Relation Models for Extended Objects

In this paper, we introduce a family of expressive models for qualitative spatial reasoning with directions. The proposed family is based on the cognitive plausible cone-based model. We formally define the directional relations that can be expressed in each model of the family. Then, we use our formal framework to study two interesting problems: computing the inverse of a directional relation and composing two directional relations. For the composition operator, in particular, we concentrate on two commonly used definitions, namely, consistency-based and existential composition. Our formal framework allows us to prove that our solutions are correct. The presented solutions are handled in a uniform manner and apply to all of the models of the family.     

Consumption of fruits and vegetables in relation to the risk of developing acute coronary syndromes; the CARDIO2000 case-control study

Background

The relation between diet and human health has long been investigated. The aim of this work is to evaluate the association between CHD risk and the consumption of fruit and vegetable, in a large sample of cardiac patients and controls.

Methods

Stratified sampling from all Greek regions, consisted of 848 (700 males, 58 ± 10 years old and 148 females, 65 ± 9 years old) randomly selected patients, admitted to the cardiology clinic for a first event of an acute coronary syndrome (ACS). In addition we selected 1078 frequency paired, by sex-age-region, controls in the same hospitals but without any clinical suspicion of CHD. Using validated food-frequency questionnaires we assessed total diet, including fruit and vegetable intake, on a weekly basis. Multiple logistic regression analysis estimated the relative risk of developing ACS by level of fruits and vegetables intake after taking into account the effect of several potential confounders.

Results

Data analysis revealed that the benefit of fruit or vegetable consumption increases proportionally by the number of servings consumed (P for trend < 0.001). After adjusting for the conventional cardiovascular risk factors, those in the upper quintile of fruit consumption (5 or more items/day) had 72% lower risk for CHD (odds ratio = 0.28, 95% CI 0.11 – 0.54, P < 0.001), compared with those in the lowest quintile of intake (<1 items/day). Similarly, consumption of vegetable more than 3 days / week was associated with 70% lower risk for CHD (odds ratio = 0.30, 95% CI 0.22 – 0.40, P < 0.001), compared with those that they did not consume vegetables. Of particular interest, a 10% reduction in coronary risk was observed for every one piece of fruit consumed per day (odds ratio = 0.90, 95% CI 0.85 – 0.97, P = 0.004).

Conclusions

Consumption of fruits and vegetables seems to offer significant protection against CHD.

     

Query containment under bag and bag-set semantics

Conjunctive queries (CQs) are at the core of query languages encountered in many logic-based research fields such as AI, or database systems. The majority of existing work assumes set semantics but often in real applications the manipulation of duplicate tuples is required. One of the major problems that arises as part of advanced features of query optimization, data integration, query reformulation and many other research topics is testing for containment of such queries. In this work, we investigate the complexity of query containment problem for CQs under bag semantics (i.e. duplicate tuples are allowed in both the database and the results of queries) and under bag-set semantics (i.e. duplicates are allowed in the result of the queries but not in the database). We derive complexity results for these problems for five major subclasses of CQs; and we also find necessary conditions for CQ query containment. The general case of these problems remains open.     

Temporal disjunctive logic programming

In this paper we introduce the logic programming languageDisjunctive Chronolog which combines the programming paradigms of temporal and disjunctive logic programming. Disjunctive Chronolog is capable of expressing dynamic behaviour as well as uncertainty, two notions that are very common in a variety of real systems. We present the minimal temporal model semantics and the fixpoint semantics for the new programming language and demonstrate their equivalence. We also show how proof procedures developed for disjunctive logic programs can be easily extended to apply to Disjunctive Chronolog programs. Manolis Gergatsoulis, Ph.D.: He received his B.Sc. in Physics in 1983, the M.Sc. and the Ph.D. degrees in Computer Science in 1986 and 1995 respectively all from the University of Athens, Greece. Since 1996 he is a Research Associate in the Institute of Informatics and Telecommunications, NCSR ‘Demokritos’, Athens. His research interests include logic and temporal programming, program transformations and synthesis, as well as theory of programming languages. Panagiotis Rondogiannis, Ph.D.: He received his B.Sc. from the Department of Computer Engineering and Informatics, University of Patras, Greece, in 1989, and his M.Sc. and Ph.D. from the Department of Computer Science, University of Victoria, Canada, in 1991 and 1994 respectively. From 1995 to 1996 he served in the Greek army. From 1996 to 1997 he was a visiting professor in the Department of Computer Science, University of Ioannina, Greece, and since 1997 he is a Lecturer in the same Department. In January 2000 he was elected Assistant Professor in the Department of Informatics at the University of Athens. His research interests include functional, logic and temporal programming, as well as theory of programming languages. Themis Panayiotopoulos, Ph.D.: He received his Diploma on Electrical Engineering from the Department of Electrical Engineering, National Technical Univesity of Athens, in 1984, and his Ph.D. on Artificial Intelligence from the above mentioned department in 1989. From 1991 to 1994 he was a visiting professor at the Department of Mathematics, University of the Aegean, Samos, Greece and a Research Associate at the Institute of Informatics and Telecommunications of “Democritos” National Research Center. Since 1995 he is an Assistant Prof. at the Department of Computer Science, University of Piraeus. His research interests include temporal programming, logic programming, expert systems and intelligent agent architectures.     

Radiocarbon apportionment of fossil versus biofuel combustion sources of polycyclic aromatic hydrocarbons in the Stockholm metropolitan area

Source-diagnostic markers and the isotopic composition of polycyclic aromatic hydrocarbons (PAHs) were examined in surface sediments from the greater Stockholm waterways to deduce the contribution from biomass sources to the environmental PAH load. The summed concentration of 20 PAHs ranged from 0.8 to 45.1 microg/g (dry weight) and exhibited a steep decline with increasing distance from the city center evidencing that sources within the metropolitan area of Stockholm dominate its PAH burden. Several diagnostic PAH ratios indicated an overwhelming predominance of pyrogenic sources over the petrogenic ones, while retene and 1,7-dimethylphenanthrene were unable to correctly evaluate the contribution from biomass combustion. The stable carbon isotope composition (delta13C) of individual PAHs ranged from -24.8 to -27.0% but also was proved inefficient to discriminate between different types of fuels due to the overlapping signals in various sources. The delta14C values of PAHs ranged between -550.4 and -934.1%, indicating a clear predominance of fossil fuel sources. By using an isotopic mass balance approach, we estimated that on average 17+/-9% of PAHs derived from biomass combustion. This radiocarbon apportionment, in conjunction with detailed energy statistics for the Stockholm region, revealed that the ambient PAH burden is roughly similar, per unit energy produced, from fossil fuels and biofuels. Societies' shifting energy policies toward a larger reliance on biofuels may thus not lead to further deterioration of air quality and respiratory ailments for the urban population.     

A semantic grid infrastructure enabling integrated access and analysis of multilevel biomedical data in support of postgenomic clinical trials on cancer.

This paper reports on original results of the Advancing Clinico-Genomic Trials on Cancer integrated project focusing on the design and development of a European biomedical grid infrastructure in support of multicentric, postgenomic clinical trials (CTs) on cancer. Postgenomic CTs use multilevel clinical and genomic data and advanced computational analysis and visualization tools to test hypothesis in trying to identify the molecular reasons for a disease and the stratification of patients in terms of treatment. This paper provides a presentation of the needs of users involved in postgenomic CTs, and presents such needs in the form of scenarios, which drive the requirements engineering phase of the project. Subsequently, the initial architecture specified by the project is presented, and its services are classified and discussed. A key set of such services are those used for wrapping heterogeneous clinical trial management systems and other public biological databases. Also, the main technological challenge, i.e. the design and development of semantically rich grid services is discussed. In achieving such an objective, extensive use of ontologies and metadata are required. The Master Ontology on Cancer, developed by the project, is presented, and our approach to develop the required metadata registries, which provide semantically rich information about available data and computational services, is provided. Finally, a short discussion of the work lying ahead is included.     

Wave propagation in a restricted class of orthotropic inhomogeneous half-planes

This work presents closed-form solutions for free-field motions in a certain type of orthotropic, continuously inhomogeneous half-planes that include both incident and reflected waves from the traction-free horizontal surface. A state of plane strain holds and both pressure and vertically polarized shear waves are considered. The methodology is restricted to media with orthotropic material characteristics that vary quadratically with respect to the depth coordinate. The method of solution is a hybrid approach based on the plane wave decomposition technique, augmented by appropriate functional transformation relations for the displacement vector. The existence of a unique analytical solution as superposition of incident P- or SV-waves and the corresponding reflected P- and SV-waves is proved under certain restrictions on the incident wave direction. Finally, a numerical study reveals the influence of material inhomogeneity and orthotropy on the displacement free-field motion.