Optimal adaptive two‐stage designs for phase II cancer clinical trials

In oncology, single‐arm two‐stage designs with binary endpoint are widely applied in phase II for the development of cytotoxic cancer therapies. Simon's optimal design with prefixed sample sizes in both stages minimizes the expected sample size under the null hypothesis and is one of the most popular designs. The search algorithms that are currently used to identify phase II designs showing prespecified characteristics are computationally intensive. For this reason, most authors impose restrictions on their search procedure. However, it remains unclear to what extent this approach influences the optimality of the resulting designs. This article describes an extension to fixed sample size phase II designs by allowing the sample size of stage two to depend on the number of responses observed in the first stage. Furthermore, we present a more efficient numerical algorithm that allows for an exhaustive search of designs. Comparisons between designs presented in the literature and the proposed optimal adaptive designs show that while the improvements are generally moderate, notable reductions in the average sample size can be achieved for specific parameter constellations when applying the new method and search strategy.     

Application of indicators for identifying climate change vulnerable areas in semi-arid regions of India

This paper aims at assess district-wise vulnerability index of the state of Karnataka State, which is predominantly is rainfed and is highly susceptible to climatic variability. Secondary data on relevant indicators were collected to prepare indices viz., crop production losses, exposure, sensitivity and adaptive capacity. Following normalization and using appropriate weights for indicators, these four indices were used for constructing vulnerability index, which can be used a rapid assessment method for prioritizing districts that need measures to moderate the detrimental impact of climate change. It has been observed that Climatic variability caused higher production losses in cereals, pulses and oilseeds in Davangere, Gulbarga and Raichur districts, respectively. Districts like Koppal, Raichur, Bijapur Gulbarga, Gadag, Bagalkote and Bellary were placed under extreme degree of exposure. As per the sensitivity index scores, Kolar district is the most sensitive. Further, Bengaluru (Urban), Dakshin Kannada and Kodagu are ranked first, second and third in terms of adaptive capacity in the state. Overall, vulnerability index scores indicate that Gulbarga, Koppal, Raichur, Bellary, Bagalkote, Bijapur and Belgaum are extremely vulnerable districts in the state. It was also estimated that around 70% of the cultivated area, which supports 60% and 67% of livestock and rural population of the state, respectively are facing ‘extreme to high’ level of vulnerability. The ranking based prioritization of the vulnerable areas calls for a holistic approach for each district or a group of districts to reduce their sensitivity, minimize exposure to rainfall variability through implementation of site-specific and leverage adaptive capacity through better health and education facilities, expansion of employment opportunities in other sectors or reducing over dependence on agriculture.     

FINE-SCALE GENETIC STRUCTURE OF A TURKEY OAK FOREST

Theoretical models and computer simulations of the genetic structure of a continuous population predict the existence of patches of highly inbred individuals when gene flow within the population is limited. A map of the three genotypes of a two-allele locus is expected to exhibit patches of homozygotes embedded in a matrix of heterozygotes, when gene flow is limited. A search for such patch structure was made on a 160 × 160 m plot within a continuous 60+ ha old-growth stand of Quercus laevis (turkey oak). Approximately 3400 trees were genotyped for 9 polymorphic loci using starch-gel electrophoresis, and the genetic structure was analyzed with spatial autocorrelation (both nominal and interval), hierarchical F statistics, and number-of-alleles-in-common. Adults (diameter at breast height > 0) and juveniles were analyzed separately but showed similar structure. While no distinct patch structure was found, a greater degree of relatedness was observed on a scale of 5 m–10 m than at greater distances, probably because of the limited acorn dispersal from maternal trees and a small amount of cloning by root sprouts. A computer simulation of a 10,000 tree forest breeding for 10,000 yr indicates that the effective neighborhood sizes (of randomly drawn seed- and pollen-donors) are both in excess of 440 individuals. The model thus cannot distinguish the observed data from panmictic mating.     

Does host‐plant diversity explain species richness in insects? A test using Coccidae (Hemiptera)

1. The megadiverse herbivores and their host plants are a major component of biodiversity, and their interactions have been hypothesised to drive the diversification of both. 2. If plant diversity influences the diversity of insects, there is an expectation that insect species richness will be strongly correlated with host‐plant species richness. This should be observable at two levels (i) more diverse host‐plant groups should harbour more species of insects, and (ii) the species richness of a group of insects should correlate with the richness of the host groups it uses. However, such a correlation is also consistent with a hypothesis of random host use, in which insects encounter and use hosts in proportion to the diversity of host plants. Neither of these expectations has been widely tested. 3. These expectations were tested using data from a species‐rich group of insects – the Coccidae (Hemiptera). 4. Significant positive correlations were found between the species richness of coccid clades (genera) and the species richness of the host‐plant family or families upon which the clades occur. On a global scale, more closely related plant families have more similar communities of coccid genera but the correlation is weak. 5. Random host use could not be rejected for many coccids but randomisation tests and similarity of coccid communities on closely related plant families show that there is non‐random host use in some taxa. Overall, our results support the idea that plant diversity is a driver of species richness of herbivorous insects, probably via escape‐and‐radiate or oscillation‐type processes.     

Calculating Free Energies Using a Scaled-Force Molecular Dynamics Algorithm

We propose and test a family of methods to calculate the free energy along a generalized coordinate, , based on computing the force acting on this coordinate. First, we derive a formula that connects the free energy in unconstrained simulations with the force of constraint that can be readily calculated numerically. Then, we consider two methods, which improve the efficiency of the free energy calculation by yielding uniform or nearly uniform sampling of . Both rely on modifying the force acting on . In one method, this force is replaced by a force with zero mean and is advanced quasistatically. In the second method, the force is augmented adaptively by a biasing force. We provide formulas for calculating the free energy of the unmodified system from the forces acting in these modified, non-Hamiltonian systems. Using conformational transitions in 1,2-dichloroethane as a test case, we show that both methods perform very well.     

Advanced control of dissolved oxygen concentration in fed batch cultures during recombinant protein production

Design and experimental validation of advanced pO₂ controllers for fermentation processes operated in the fed-batch mode are described. In most situations, the presented controllers are able to keep the pO₂ in fermentations for recombinant protein productions exactly on the desired value. The controllers are based on the gain-scheduling approach to parameter-adaptive proportional-integral controllers. In order to cope with the most often appearing distortions, the basic gain-scheduling feedback controller was complemented with a feedforward control component. This feedforward/feedback controller significantly improved pO₂ control. By means of numerical simulations, the controller behavior was tested and its parameters were determined. Validation runs were performed with three Escherichia coli strains producing different recombinant proteins. It is finally shown that the new controller leads to significant improvements in the signal-to-noise ratio of other key process variables and, thus, to a higher process quality.     

After the deluge: mitochondrial DNA indicates Miocene radiation and Pliocene adaptation of tree and giant weta (Orthoptera: Anostostomatidae)

Aim New Zealand broke away from the margins of Gondwana c. 75 Ma. Since then, New Zealand taxa derived from the Gondwanan biota are thought to have been exposed first to a subtropical climate on a low lying terrain, then severe land reduction during the Oligocene marine transgression, followed by much cooler climates of the Pliocene and Pleistocene, at which time mountain ranges emerged. The biological consequence of New Zealand's geological and climatic history is not well understood, in particular the extent to which the Oligocene acted as a biological bottleneck remains unresolved. Methods We used mitochondrial cytochrome oxidase I and 12S DNA sequences to examine the extent of diversity and inferred timing of speciation of New Zealand weta (Anostostomatidae), a group of Orthoptera with a Gondwanan distribution generally thought to be ancient inhabitants of New Zealand. Main conclusions We hypothesize that at least three distinct groups of weta survived the Oligocene marine transgression and radiated subsequently. Speciation followed during the Miocene and radiation into new habitats occurred during the Pliocene when mountain building created novel environments. Patterns of genetic diversity within species reflect, in some instances, geographical subdivision in the Pliocene, and in other cases, Pleistocene range changes resulting from climate change.