Two-stage re-estimation adaptive design: a simulation study

  Background: adaptive clinical trial design has been proposed as a promising new approach to improve the drug discovery process. Among the many options available, adaptive sample size re-estimation is of great interest mainly because of its ability to avoid a large ‘up-front’ commitment of resources. In this simulation study, we investigate the statistical properties of two-stage sample size re-estimation designs in terms of type I error control, study power and sample size, in comparison with the fixed-sample study. Methods: we simulated a balanced two-arm trial aimed at comparing two means of normally distributed data, using the inverse normal method to combine the results of each stage, and considering scenarios jointly defined by the following factors: the sample size re-estimation method, the information fraction, the type of group sequential boundaries and the use of futility stopping. Calculations were performed using the statistical software SAS™ (version 9.2). Results: under the null hypothesis, any type of adaptive design considered maintained the prefixed type I error rate, but futility stopping was required to avoid the unwanted increase in sample size. When deviating from the null hypothesis, the gain in power usually achieved with the adaptive design and its performance in terms of sample size were influenced by the specific design options considered. Conclusions: we show that adaptive designs incorporating futility stopping, a sufficiently high information fraction (50-70%) and the conditional power method for sample size re-estimation have good statistical properties, which include a gain in power when trial results are less favourable than anticipated.&nbsp

Two-stage re-estimation adaptive design: a simulation study

Background: adaptive clinical trial design has been proposed as a promising new approach to improve the drug discovery process. Among the many options available, adaptive sample size re-estimation is of great interest mainly because of its ability to avoid a large ‘up-front’ commitment of resources. In this simulation study, we investigate the statistical properties of two-stage sample size re-estimation designs in terms of type I error control, study power and sample size, in comparison with the fixed-sample study. Methods: we simulated a balanced two-arm trial aimed at comparing two means of normally distributed data, using the inverse normal method to combine the results of each stage, and considering scenarios jointly defined by the following factors: the sample size re-estimation method, the information fraction, the type of group sequential boundaries and the use of futility stopping. Calculations were performed using the statistical software SAS™ (version 9.2). Results: under the null hypothesis, any type of adaptive design considered maintained the prefixed type I error rate, but futility stopping was required to avoid the unwanted increase in sample size. When deviating from the null hypothesis, the gain in power usually achieved with the adaptive design and its performance in terms of sample size were influenced by the specific design options considered. Conclusions: we show that adaptive designs incorporating futility stopping, a sufficiently high information fraction (50-70%) and the conditional power method for sample size re-estimation have good statistical properties, which include a gain in power when trial results are less favourable than anticipated.&nbsp

Operating Hydrogen-Based Energy Storage Systems in Wind Farms for Smooth Power Injection: A Penalty Fees Aware Model Predictive Control

Smooth power injection is one of the possible services that modern wind farms could provide in the not-so-far future, for which energy storage is required. Indeed, this is one among the three possible operations identified by the International Energy Agency (IEA)-Hydrogen Implementing Agreement (HIA) within the Task 24 final report, that may promote their integration into the main grid, in particular when paired to hydrogen-based energy storages. In general, energy storage can mitigate the inherent unpredictability of wind generation, providing that they are deployed with appropriate control algorithms. On the contrary, in the case of no storage, wind farm operations would be strongly affected, as well as their economic performances since the penalty fees wind farm owners/operators incur in case of mismatches between the contracted power and that actually delivered. This paper proposes a Model Predictive Control (MPC) algorithm that operates a Hydrogen-based Energy Storage System (HESS), consisting of one electrolyzer, one fuel cell and one tank, paired to a wind farm committed to smooth power injection into the grid. The MPC relies on Mixed-Logic Dynamic (MLD) models of the electrolyzer and the fuel cell in order to leverage their advanced features and handles appropriate cost functions in order to account for the operating costs, the potential value of hydrogen as a fuel and the penalty fee mechanism that may negatively affect the expected profits generated by the injection of smooth power. Numerical simulations are conducted by considering wind generation profiles from a real wind farm in the center-south of Italy and spot prices according to the corresponding market zone. The results show the impact of each cost term on the performances of the controller and how they can be effectively combined in order to achieve some reasonable trade-off. In particular, it is highlighted that a static choice of the corresponding weights can lead to not very effective handling of the effects given by the combination of the system conditions with the various exogenous’, while a dynamic choice may suit the purpose instead. Moreover, the simulations show that the developed models and the set-up mathematical program can be fruitfully leveraged for inferring indications on the devices’ sizing.publishedVersio

BepiColombo’s geodesy and relativity experiments from an extended mission

The Mercury Orbiter Radio science Experiment (MORE) of the ESA-JAXA BepiColombo mission to Mercury consists of ground and onboard instrumentation enabling a highly stable, multi-frequency radio link at X and Ka band (8.4 and 32.5 GHz). Range rate measurements obtained from this advanced radio link will be unaffected by plasma noise and are expected to attain accuracies of 3 micron/s (at 1000 seconds integration time) at nearly all elongation angles. Thanks to a novel wideband ranging system, based on a 24 Mcps pseudo-noise modulation, the spacecraft range will be measured to an accuracy 20 cm (two-way). The MORE investigation will greatly benefit from a direct measurement of the vectorial non-gravitational accelerations by means of the Italian Spring Accelerometer (ISA). The high quality radio-metric observables will provide a precise reconstruction of the spacecraft orbit and an accurate estimation of the gravity field and rotational state of the planet. Thanks to the dedicated onboard instrumentation, MORE is expected to improve significantly the already outstanding MESSENGER results, limited by plasma noise and the difficulty of modeling non-gravitational accelerations. In addition, BepiColombo will carry out tests of general relativity by reconstructing the orbit of the planet and the propagation of photons in the solar gravitational field. Indeed, since the orbit of Mercury is affected more than any other planets by relativistic effects, the relativity experiment aims at improving the determination of several Post-Newtonian (PN) parameters. Further physical parameters such as the rate of change of the gravitational constant G and the oblateness factor J2 of the Sun will be estimated as well. Several numerical simulations of the MORE experiment have been carried out over the past years. In this work we present a new set of simulations under the latest mission scenario and instrument performances, as obtained from ground tests of the instrumentation. Our simulation setup solves simultaneously for gravity harmonic coefficients, rotational state elements and relativistic PN parameters. The paper reports on the results obtained under the nominal, one year, mission duration, and shows the improvements attained by an extended mission of one or two years. Indeed, the pericenter of BepiColombo’s planetary orbiter will drift from 15 degree N to 13, 41, 70 degree S respectively in one, two and three years. In addition the pericenter altitude will decrease from 480 to 250 km in three years. This will allow a more comprehensive and homogeneous reconstruction of the gravity field and rotational state of Mercury. We show also that an extended mission would be greatly beneficial also to the relativity experiment

Quantitative analysis of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in patients with low-grade gliomas

Methylation of the MGMT promoter is supposed to be a predictive and prognostic factor in glioblastoma. Whether MGMT promoter methylation correlates with tumor response to temozolomide in low-grade gliomas is less clear. Therefore, we analyzed MGMT promoter methylation by a quantitative methylation-specific PCR in 22 patients with histologically verified low-grade gliomas (WHO grade II) who were treated with temozolomide (TMZ) for tumor progression. Objective tumor response, toxicity, and LOH of microsatellite markers on chromosomes 1p and 19q were analyzed. Histological classification revealed ten oligodendrogliomas, seven oligoastrocytomas, and five astrocytomas. All patients were treated with TMZ 200mg/m2 on days 1-5 in a 4week cycle. The median progression-free survival was 32months. Combined LOH 1p and 19q was found in 14 patients; one patient had LOH 1p alone and one patient LOH 19q alone. The LOH status could not be determined in two patients and was normal in the remaining four. LOH 1p and/or 19q correlated with longer time to progression but not with radiological response to TMZ. MGMT promoter methylation was detectable in 20 patients by conventional PCR and quantitative analysis revealed the methylation status was between 12 and 100%. The volumetric response to chemotherapy analyzed by MRI and time to progression correlated with the level of MGMT promoter methylation. Therefore, our retrospective case series suggests that quantitative methylation-specific PCR of the MGMT promoter predicts radiological response to chemotherapy with TMZ in WHO grade II glioma

Parametric and nonparametric two-sample tests for feature screening in class comparison: a simulation study

Background. The identification of a location-, scale- and shape-sensitive test to detect differentially expressed features between two comparison groups represents a key point in high dimensional studies. The most commonly used tests refer to differences in location, but general distributional discrepancies might be important to reveal differential biological processes.                                                         Methods. A simulation study was conducted to compare the performance of a set of two-sample tests, i.e. Student's t, Welch's t, Wilcoxon-Mann-Whitney, Podgor-Gastwirth PG2, Cucconi, Kolmogorov-Smirnov (KS), Cramer-von Mises (CvM), Anderson-Darling (AD) and Zhang tests (ZK, ZC and ZA) which were investigated under different distributional patterns. We applied the same tests to a real data example.                   Results. AD, CvM, ZA and ZC tests proved to be the most sensitive tests in mixture distribution patterns, while still maintaining a high power in normal distribution patterns. At best, the AD test showed a loss in power of ~ 2% in the comparison of two normal distributions, but a gain of ~ 32% with mixture distributions respect to the parametric tests. Accordingly, the AD test detected the greatest number of differentially expressed features in the real data application.   Conclusion. The tests for the general two-sample problem introduce a more general concept of 'differential expression', thus overcoming the limitations of the other tests restricted to specific moments of the feature distributions. In particular, the AD test should be considered as a powerful alternative to the parametric tests for feature screening in order to keep as many discriminative features as possible for the class prediction analysis

Fattori protettivi per lo stress lavorativo degli insegnanti: programmi psicoeducativi basati sull’autoefficacia e sulla speranza per rafforzare le risorse personali

Teaching at school is subject to stress and tension, which in some cases can lead to pathological conditions and can also lead to the abandonment of the same profession. In literature, the work of the teacher is often associated with stress, so much so that it is often indicated as one of the jobs most exposed to this phenomenon. As a matter of fact, there are many different sources of stress. For example, teaching unmotivated students, dealing with educational changes, and unsatisfactory working conditions. Persistence over time can lead to a strong personal exhaustion and also to the perception of a decline in one's working abilities accompanied by high levels of fatigue and negative attitudes towards one's work. Starting from some personal resources such as self-efficacy and hope, this study analyses the correlation between these resources and stress in a sample of 95 primary and lower secondary school teachers and then proposes a possible psychoeducational intervention.Fare formazione a livello scolastico può essere fonte di stress e tensione che in alcuni casi può sfociare in situazioni patologiche e portare all’abbandono della professione stessa. In letteratura il lavoro dell’insegnante è spesso accumunato allo stress tanto che viene indicato come uno dei lavori maggiormente esposti a tale fenomeno. Le fonti di stress sono molteplici. Ad esempio insegnare a studenti non motivati, far fronte al cambiamento educativo e condizioni di lavoro insoddisfacenti. Il perdurare nel tempo di queste situazioni può portare a un forte esaurimento personale e anche la percezione di un declino delle proprie capacità lavorative, accompagnati da alti livelli di stanchezza e atteggiamenti negativi nei confronti del proprio lavoro. Il presente studio, partendo da alcune risorse personali come l’autoefficacia e la speranza, analizza, su in campione di 95 insegnanti di una scuola primaria e secondaria di 1° grado, la correlazione tra queste risorse rispetto allo stress, al fine di proporre un possibile intervento di tipo psicoeducativo di supporto

A temperature-dependent physiologically based model for the invasive apple snail Pomacea canaliculata

In order to set priorities in management of costly and ecosystem-damaging species, policymakers and managers need accurate predictions not only about where a specific invader may establish but also about its potential abundance at different geographical scales. This is because density or biomass per unit area of an invasive species is a key predictor of the magnitude of environmental and economic impact in the invaded habitat. Here, we present a physiologically based demographic model describing and explaining the population dynamics of a widespread freshwater invader, the golden apple snail Pomacea canaliculata, which is causing severe environmental and economic impacts in invaded wetlands and rice fields in Southeastern Asia and has also been introduced to North America and Europe. The model is based on bio-demographic functions for mortality, development and fecundity rates that are driven by water temperature for the aquatic stages (juveniles and adults) and by air temperature for the aerial egg masses. Our model has been validated against data on the current distribution in South America and Japan, and produced consistent and realistic patterns of reproduction, growth, maturation and mortality under different scenarios in accordance to what is known from real P. canaliculata populations in different regions and climates. The model further shows that P. canaliculata will use two different reproductive strategies (semelparity and iteroparity) within the potential area of establishment, a plasticity that may explain the high invasiveness of this species across a wide range of habitats with different climates. Our results also suggest that densities, and thus the magnitude of environmental and agricultural damage, will be largely different in locations with distinct climatic regimes within the potential area of establishment. We suggest that physiologically based demographic modelling of invasive species will become a valuable tool for invasive species managers

Biometrics measurements in Red foxes (Vulpes vulpes) in the Picentini area. Discussion and conclusions

Techniques for assigning individual to age-classes and/or distinguish between sexes are necessary to understand population dynamics and behavioral interactions of Red foxes (Vulpes vulpes). Many studies have focused on separating juveniles from adults; age of captured live pups can be estimated from morphological changes, hind foot (HF) length, zygomatic (Z) width and body weight1. Methods that avoid capturing the animals would be particularly useful, but none is available. In this paper biometric differences between young adults and adults subjects and between sexes are investigated. Lower canine length (LCL), lower canine width (LCW), condilo-basal (CB) and scapular length resulted smaller than female adults, whereas male young adults had withers height, occipito-coccygeal (OC), ear length, and upper canine width (UCW) smaller than male adults. Almost all the parameters included in this study confirmed sexual dimorphism and some of the differences already present in young adults gained significance (from P<0.05 to P<0.01) in the adult foxes. In particular bodyweight, OC length, withers height, ear length, upper canine length and LCL, scapular and mandibular length, and inter-carnassial (IC) and Z width were significantly greater in male than in female adult foxes (P<0.01). Nasal-occipitalis (NO) length, total length, UCW and LCW, and upper dentition (UD) were significantly greater in male than in female adult foxes, as well (P<0.05). The low number of subjects included in each category, strictly due to hunting season, did not allow estimating an accurate range for the biometrics measurements performed and probably biased recordings, producing some contradictory results. Fox size varies geographically, thus mean adults measurements should be determined for each area in which they have to be applied1. HF method has been demonstrated to be an accurate method for assessing age of pups1; our data suggest that it might be as efficient in young adults, at least in female subjects. On the other hand, our results confirm the sexual dimorphism in the canine region to be higher than in the carnassial region (data not shown in our results)