Estimation of trend in state-space models: Asymptotic mean square error and rate of convergence

The focus of this paper is on trend estimation for a general state-space model $Y_t=\mu_t+\varepsilon_t$, where the $d$th difference of the trend $\{\mu_t\}$ is assumed to be i.i.d., and the error sequence $\{\varepsilon_t\}$ is assumed to be a mean zero stationary process. A fairly precise asymptotic expression of the mean square error is derived for the estimator obtained by penalizing the $d$th order differences. Optimal rate of convergence is obtained, and it is shown to be "asymptotically equivalent" to a nonparametric estimator of a fixed trend model of smoothness of order $d-0.5$. The results of this paper show that the optimal rate of convergence for the stochastic and nonstochastic cases are different. A criterion for selecting the penalty parameter and degree of difference $d$ is given, along with an application to the global temperature data, which shows that a longer term history has nonlinearities that are important to take into consideration.Comment: Published in at http://dx.doi.org/10.1214/08-AOS675 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

Structure-activity relationship analysis of cytotoxic cyanoguanidines: selection of CHS 828 as candidate drug

<p>Abstract</p> <p>Background</p> <p><it>N</it>-(6-(4-chlorophenoxy)hexyl)-<it>N</it>'-cyano-<it>N''</it>-4-pyridyl guanidine) (CHS 828) is the first candidate drug from a novel group of anti-tumour agents – the pyridyl cyanoguanidines, shown to be potent compounds interfering with cellular metabolism (inhibition of nicotinamide phosphoribosyl transferase) and NF-κB signalling. Substituted cyanoguanidines are also found in anti-hypertensive agents such as the potassium channel opener pinacidil (<it>N</it>-cyano-<it>N'</it>-(4-pyridyl)-<it>N''</it>-(1,2,2-trimethylpropyl)guanidine) and histamine-II receptor antagonists (e.g. cimetidine, <it>N</it>-cyano-<it>N'</it>-methyl-<it>N''</it>-[2-[[(5-methylimidazol-4-yl]methyl]thio]ethyl)guanidine). In animal studies, CHS 828 has shown very promising activity, and phase I and II studies resulted in further development of a with a water soluble prodrug.</p> <p>Findings</p> <p>To study the structural requirements for cyanoguanidine cytotoxicity a set of 19 analogues were synthesized. The cytotoxic effects were then studied in ten cell lines selected for different origins and mechanisms of resistance, using the fluorometric microculture cytotoxicity assay (FMCA). The compounds showed varying cytotoxic activity even though the dose-response curves for some analogues were very shallow. Pinacidil and cimetidine were found to be non-toxic in all ten cell lines. Starting with cyanoguanidine as the crucial core it was shown that 4-pyridyl substitution was more efficient than was 3-pyridyl substitution. The 4-pyridyl cyanoguanidine moiety should be linked by an alkyl chain, optimally a hexyl, heptyl or octyl chain, to a bulky end group. The exact composition of this end group did not seem to be of crucial importance; when the end group was a mono-substituted phenyl ring it was shown that the preferred position was 4-substitution, followed by 3- and, finally, 2-substitution as the least active. Whether the substituent was a chloro, nitro or methoxy substituent seemed to be of minor importance. Finally, the activity patterns in the ten cell lines were compared. Substances with similar structures correlated well, whilst substances with large differences in molecular structure demonstrated lower correlation coefficients.</p> <p>Conclusion</p> <p>According to this structure-activity relationship (SAR) study, CHS 828 meets the requirements for optimal cytotoxic activity for this class of compounds.</p

USFD at KBP 2011: Entity Linking, Slot Filling and Temporal Bounding

This paper describes the University of Sheffield's entry in the 2011 TAC KBP entity linking and slot filling tasks. We chose to participate in the monolingual entity linking task, the monolingual slot filling task and the temporal slot filling tasks. We set out to build a framework for experimentation with knowledge base population. This framework was created, and applied to multiple KBP tasks. We demonstrated that our proposed framework is effective and suitable for collaborative development efforts, as well as useful in a teaching environment. Finally we present results that, while very modest, provide improvements an order of magnitude greater than our 2010 attempt.Comment: Proc. Text Analysis Conference (2011

The epidemiology of medical emergency contacts outside hospitals in Norway - a prospective population based study

<p>Abstract</p> <p>Introduction</p> <p>There is a lack of epidemiological knowledge on medical emergencies outside hospitals in Norway. The aim of the present study was to obtain representative data on the epidemiology of medical emergencies classified as "red responses" in Norway.</p> <p>Method</p> <p>Three emergency medical dispatch centres (EMCCs) were chosen as catchment areas, covering 816 000 inhabitants. During a three month period in 2007 the EMCCs gathered information on every situation that was triaged as a red response, according to The Norwegian Index of Medical Emergencies (Index). Records from ground ambulances, air ambulances, and the primary care doctors were subsequently collected. International Classification of Primary Care - 2 symptom codes (ICPC-2) and The National Committee on Aeronautics (NACA) Score System were given retrospectively.</p> <p>Results</p> <p>Total incidence of red response situations was 5 105 during the three month period. 394 patients were involved in 138 accidents, and 181 situations were without patients, resulting in a total of 5 180 patients. The patients' age ranged from 0 to 107 years, with a median age of 57, and 55% were male. 90% of the red responses were medical problems with a large variation of symptoms, the remainder being accidents. 70% of the patients were in a non-life-threatening situation. Within the accident group, males accounted for 61%, and 35% were aged between 10 and 29 years, with a median age of 37 years. Few of the 39 chapters in the Index were used, A10 "Chest pain" was the most common one (22% of all situations). ICPC-2 symptom codes showed that cardiovascular, syncope/coma, respiratory and neurological problems were most common. 50% of all patients in a sever situation (NACA score 4-7) were > 70 years of age.</p> <p>Conclusions</p> <p>The results show that emergency medicine based on 816 000 Norwegians mainly consists of medical problems, where the majority of the patients have a non-life-threatening situation. More focus on the emergency system outside hospitals, including triage and dispatch, and how to best deal with "everyday" emergency problems is needed to secure knowledge based decisions for the future organization of the emergency system.</p

Cyclotide–membrane interactions: Defining factors of membrane binding, depletion and disruption

AbstractThe cyclotide family of plant-derived peptides is defined by a cyclic backbone and three disulfide bonds locked into a cyclic cystine knot. They display a diverse range of biological activities, many of which have been linked to an ability to target biological membranes. In the current work, we show that membrane binding and disrupting properties of prototypic cyclotides are dependent on lipid composition, using neutral (zwitterionic) membranes with or without cholesterol and/or anionic lipids. Cycloviolacin O2 (cyO2) caused potent membrane disruption, and showed selectivity towards anionic membranes, whereas kalata B1 and kalata B2 cyclotides were significantly less lytic towards all tested model membranes. To investigate the role of the charged amino acids of cyO2 in the membrane selectivity, these were neutralized using chemical modifications. In contrast to previous studies on the cytotoxic and antimicrobial effects of these derivatives, the Glu6 methyl ester of cyO2 was more potent than the native peptide. However, using membranes of Escherichia coli lipids gave the opposite result: the activity of the native peptide increased 50-fold. By using a combination of ellipsometry and LC-MS, we demonstrated that this unusual membrane specificity is due to native cyO2 extracting preferentially phosphatidylethanolamine-lipids from the membrane, i.e., PE-C16:0/cyC17:0 and PE-C16:0/C18:1

Targeting Net Zero Energy at Marine Corps Air Station Miramar: Assessment and Recommendations

In 2008, the Department of Defense (DoD) and Department of Energy (DOE) defined a joint initiative to address military energy use by identifying specific actions to reduce energy demand and increase use of renewable energy on DoD installations. A Task Force comprised of representatives from the Office of the Secretary of Defense (OSD), the four military Services, DOE’s Federal Energy Management Program (FEMP), and the National Renewable Energy Laboratory (NREL) was established. In light of DoD priorities, early attention was given to the possibility of net zero energy military installations (NZEI), that is, installations that would meet their energy needs with local renewable resources. Marine Corps Air Station (MCAS) The Task Force selected Miramar to be the prototype installation for net zero energy assessment and planning. This selection was based on Miramar’s strong history of energy advocacy and extensive track record of successful energy projects

A geometric model of tube categories

We give a geometric model for a tube category in terms of homotopy classes of oriented arcs in an annulus with marked points on its boundary. In particular, we interpret the dimensions of extension groups of degree 1 between indecomposable objects in terms of negative geometric intersection numbers between corresponding arcs, giving a geometric interpretation of the description of an extension group in the cluster category of a tube as a symmetrized version of the extension group in the tube. We show that a similar result holds for finite dimensional representations of the linearly oriented quiver of type A-double-infinity.Comment: 15 pages, 7 figures. Discussion of maximal rigid objects and triangulations at end of Section 3. Minor correction

Optimized adaptive enrichment designs

Based on a Bayesian decision theoretic approach, we optimize frequentist single- and adaptive two-stage trial designs for the development of targeted therapies, where in addition to an overall population, a pre-defined subgroup is investigated. In such settings, the losses and gains of decisions can be quantified by utility functions that account for the preferences of different stakeholders. In particular, we optimize expected utilities from the perspectives both of a commercial sponsor, maximizing the net present value, and also of the society, maximizing cost-adjusted expected health benefits of a new treatment for a specific population. We consider single-stage and adaptive two-stage designs with partial enrichment, where the proportion of patients recruited from the subgroup is a design parameter. For the adaptive designs, we use a dynamic programming approach to derive optimal adaptation rules. The proposed designs are compared to trials which are non-enriched (i.e. the proportion of patients in the subgroup corresponds to the prevalence in the underlying population). We show that partial enrichment designs can substantially improve the expected utilities. Furthermore, adaptive partial enrichment designs are more robust than single-stage designs and retain high expected utilities even if the expected utilities are evaluated under a different prior than the one used in the optimization. In addition, we find that trials optimized for the sponsor utility function have smaller sample sizes compared to trials optimized under the societal view and may include the overall population (with patients from the complement of the subgroup) even if there is substantial evidence that the therapy is only effective in the subgroup

Emergence of particle clusters in a one-dimensional model: connection to condensation processes

We discuss a simple model of particles hopping in one dimension with attractive interactions. Taking a hydrodynamic limit in which the interaction strength increases with the system size, we observe the formation of multiple clusters of particles, each containing a finite fraction of the all the particles in the system. These clusters are correlated in space, and the system has a self-similar (fractal) structure. These results are related to condensation phenomena in mass transport models and to a recent mathematical analysis of the hydrodynamic limit in a related model.Comment: 16 page