Familywise error control in multi-armed response-adaptive trials.

Response-adaptive designs allow the randomization probabilities to change during the course of a trial based on cumulated response data so that a greater proportion of patients can be allocated to the better performing treatments. A major concern over the use of response-adaptive designs in practice, particularly from a regulatory viewpoint, is controlling the type I error rate. In particular, we show that the naïve z-test can have an inflated type I error rate even after applying a Bonferroni correction. Simulation studies have often been used to demonstrate error control but do not provide a guarantee. In this article, we present adaptive testing procedures for normally distributed outcomes that ensure strong familywise error control by iteratively applying the conditional invariance principle. Our approach can be used for fully sequential and block randomized trials and for a large class of adaptive randomization rules found in the literature. We show there is a high price to pay in terms of power to guarantee familywise error control for randomization schemes with extreme allocation probabilities. However, for proposed Bayesian adaptive randomization schemes in the literature, our adaptive tests maintain or increase the power of the trial compared to the z-test. We illustrate our method using a three-armed trial in primary hypercholesterolemia.DSR and JMSW were funded by the Medical Research Council, grant code MC_UU_00002/6. DSR was also funded by the Biometrika Trust

The Newtonian Limit of Hermitian Gravity

We construct the gauge invariant potentials of Hermitian Gravity and derive the linearized equations of motion they obey. A comparison reveals a striking similarity to the Bardeen potentials of general relativity. We then consider the response to a point particle source, and discuss in what sense the solutions of Hermitian Gravity reduce to the Newtonian potentials. In a rather intriguing way, the Hermitian Gravity solutions exhibit a generalized reciprocity symmetry originally proposed by Born in the 1930s. Finally, we consider the trajectories of massive and massless particles under the influence of a potential. The theory correctly reproduces the Newtonian limit in three dimensions and the nonrelativistic acceleration equation. However, it differs from the light deflection calculated in linearized generalrelativity by 25%. While the specific complexification of general relativity by extension to Hermitian spaces performed here does not agree with experiment, it does possess useful properties for quantization and is well-behaved around singularities. Another form of complex general relativity may very well agree with experimental data.Comment: The published version in Gen. Rel. Grav. 24 pages, no figure

Gestation and the evolution of vertical stance bipedal humans

During mammalian gestation a change in maternal stance alters the velocities of maternal blood flows and results in a changed rate of delivery and distribution of nutrients required to form the bone and tissue in various parts of a developing foetus. The latter in turn results in change in the extent and position of tissue and bone formation in the foetus. It is shown that such changes would, over many generations, alter the physical characteristics of the ancestor offspring under conditions where the pregnant maternal ancestor normally exhibiting horizontal stance was constrained to adopt a vertical stance for all or most of the gestation period. This behaviour produced the physical characteristics seen in humans and other Hominidae primates, including the vertical stance and bipedalism of the former accompanied by increase in skull and brain size. The manner in which difficulties of giving birth as the change from horizontal stance to vertical stance proceeded from generation to generation, limited survival is discussed andreasons for the adoption of this behaviour are proposed. The induction of evolutionary change and the operation of natural selection through alterations in the characteristics of embryo/foetus of an animal, induced by physical, chemical, mechanical or behavioural means, is shown to be feasible. The changes are not related to the Lamarckian principle of inheritance of acquired characteristics as the changes described occurred before birth and are not related to any physical or mental characteristics already present in or acquired during the lifetime of the breeding pair

The impact of celestial pole offset modelling on VLBI UT1 Intensive results

Very Long Baseline Interferometry (VLBI) Intensive sessions are scheduled to provide operational Universal Time (UT1) determinations with low latency. UT1 estimates obtained from these observations heavily depend on the model of the celestial pole motion used during data processing. However, even the most accurate precession-nutation model, IAU 2000/2006, is not accurate enough to realize the full potential of VLBI observations. To achieve the highest possible accuracy in UT1 estimates, a celestial pole offset (CPO), which is the difference between the actual and modelled precession-nutation angles, should be applied. Three CPO models are currently available for users. In this paper, these models have been tested and the differences between UT1 estimates obtained with those models are investigated. It has been shown that neglecting CPO modelling during VLBI UT1 Intensive processing causes systematic errors in UT1 series of up to 20 microarcseconds. It has been also found that using different CPO models causes the differences in UT1 estimates reaching 10 microarcseconds. Obtained results are applicable to the satellite data processing as well.Comment: 8 pp., accepted for publication in Journal of Geodes

Piloting a parent and patient decision aid to support clinical trial decision making in childhood cancer

Objective: Families of a child with cancer can find the decision to enrol in a clinical trial challenging and often misunderstand key concepts that underpin trials. We pilot tested “Delta,” an online and booklet decision aid for parents with a child with cancer, and adolescents with cancer, deciding whether or not to enrol in a clinical trial. Methods: We developed Delta in accordance with the International Patient Decision Aid Standards. We conducted a pre-post pilot with parents with a child, and adolescents, who had enrolled in a paediatric phase III clinical trial for newly diagnosed acute lymphoblastic leukaemia. Parents (n = 37) and adolescents (n = 3) completed a questionnaire before and after using Delta (either the website or booklet, based on their preference). Results: Twenty-three parents (62.2%) and three adolescents (100%) reviewed the Delta website. Parents rated Delta as highly acceptable in regard to being clearly presented, informative, easy to read, useful, visually appealing, and easy to use. All participants reported that they would recommend Delta to others and that it would have been useful when making their decision. Parents' subjective (Mdiff=10.8, SDdiff = 15.69, P <.001) and objective (OR = 2.25, 95% CI, 1.66-3.04; P <.001) clinical trial knowledge increased significantly after reviewing Delta. Conclusions: To our knowledge, Delta is the first reported decision aid, available online and as a booklet, for parents and adolescents deciding whether or not to enrol in a paediatric oncology clinical trial. Our study suggests that Delta is acceptable, feasible, and potentially useful

The Frequency of Visually Induced Gamma-Band Oscillations Depends on the Size of Early Human Visual Cortex

The structural and functional architecture of the human brain is characterized by considerable variability, which has consequences for visual perception. However, the neurophysiological events mediating the relationship between interindividual differences in cortical surface area and visual perception have, until now, remained unknown. Here, we show that the retinotopically defined surface areas of central V1 and V2 are correlated with the peak frequency of visually induced oscillations in the gamma band, as measured with magnetoencephalography. Gamma-band oscillations are thought to play an important role in visual processing. We propose that individual differences in macroscopic gamma frequency may be attributed to interindividual variability in the microscopic architecture of visual cortex

Testing special relativity with geodetic VLBI

Geodetic Very Long Baseline Interferometry (VLBI) measures the group delay in the barycentric reference frame. As the Earth is orbiting around the Solar system barycentre with the velocity $V$ of 30 km/s, VLBI proves to be a handy tool to detect the subtle effects of the special and general relativity theory with a magnitude of $(V/\textrm{c})^2$. The theoretical correction for the second order terms reaches up to 300~ps, and it is implemented in the geodetic VLBI group delay model. The total contribution of the second order terms splits into two effects - the variation of the Earth scale, and the deflection of the apparent position of the radio source. The Robertson-Mansouri-Sexl (RMS) generalization of the Lorenz transformation is used for many modern tests of the special relativity theory. We develop an alteration of the RMS formalism to probe the Lorenz invariance with the geodetic VLBI data. The kinematic approach implies three parameters (as a function of the moving reference frame velocity) and the standard Einstein synchronisation. A generalised relativistic model of geodetic VLBI data includes all three parameters that could be estimated. Though, since the modern laboratory Michelson-Morley and Kennedy-Thorndike experiments are more accurate than VLBI technique, the presented equations may be used to test the VLBI group delay model itself.Comment: Proceedings of the IAG 2017 Scientific Meeting, Kobe, Japa

Milling plant and soil material in plastic tubes over-estimates carbon and under-estimates nitrogen concentrations

Peer reviewedPostprin

Zero-shot language transfer for cross-lingual sentence retrieval using bidirectional attention model

We present a neural architecture for cross-lingual mate sentence retrieval which encodes sentences in a joint multilingual space and learns to distinguish true translation pairs from semantically related sentences across languages. The proposed model combines a recurrent sequence encoder with a bidirectional attention layer and an intra-sentence attention mechanism. This way the final fixed-size sentence representations in each training sentence pair depend on the selection of contextualized token representations from the other sentence. The representations of both sentences are then combined using the bilinear product function to predict the relevance score. We show that, coupled with a shared multilingual word embedding space, the proposed model strongly outperforms unsupervised cross-lingual ranking functions, and that further boosts can be achieved by combining the two approaches. Most importantly, we demonstrate the model's effectiveness in zero-shot language transfer settings: our multilingual framework boosts cross-lingual sentence retrieval performance for unseen language pairs without any training examples. This enables robust cross-lingual sentence retrieval also for pairs of resource-lean languages, without any parallel data