Bayesian versus frequentist statistical inference for investi gating a one-off cancer cluster reported to a health department

Background The problem of silent multiple comparisons is one of the most difficult statistical problems faced by scientists. It is a particular problem for investigating a one-off cancer cluster reported to a health department because any one of hundreds, or possibly thousands, of neighbourhoods, schools, or workplaces could have reported a cluster, which could have been for any one of several types of cancer or any one of several time periods. Methods This paper contrasts the frequentist approach with a Bayesian approach for dealing with silent multiple comparisons in the context of a one-off cluster reported to a health department. Two published cluster investigations were re-analysed using the Dunn-Sidak method to adjust frequentist p-values and confidence intervals for silent multiple comparisons. Bayesian methods were based on the Gamma distribution. Results Bayesian analysis with non-informative priors produced results similar to the frequentist analysis, and suggested that both clusters represented a statistical excess. In the frequentist framework, the statistical significance of both clusters was extremely sensitive to the number of silent multiple comparisons, which can only ever be a subjective "guesstimate". The Bayesian approach is also subjective: whether there is an apparent statistical excess depends on the specified prior. Conclusion In cluster investigations, the frequentist approach is just as subjective as the Bayesian approach, but the Bayesian approach is less ambitious in that it treats the analysis as a synthesis of data and personal judgements (possibly poor ones), rather than objective reality. Bayesian analysis is (arguably) a useful tool to support complicated decision-making, because it makes the uncertainty associated with silent multiple comparisons explicit.

Validation Gating for Non-Linear Non-Gaussian Target Tracking

This paper develops a general theory of validation gating for non-linear non-Gaussian mod- els. Validation gates are used in target tracking to cull very unlikely measurement-to-track associa- tions, before remaining association ambiguities are handled by a more comprehensive (and expensive) data association scheme. The essential property of a gate is to accept a high percentage of correct associ- ations, thus maximising track accuracy, but provide a su±ciently tight bound to minimise the number of ambiguous associations. For linear Gaussian systems, the ellipsoidal vali- dation gate is standard, and possesses the statistical property whereby a given threshold will accept a cer- tain percentage of true associations. This property does not hold for non-linear non-Gaussian models. As a system departs from linear-Gaussian, the ellip- soid gate tends to reject a higher than expected pro- portion of correct associations and permit an excess of false ones. In this paper, the concept of the ellip- soidal gate is extended to permit correct statistics for the non-linear non-Gaussian case. The new gate is demonstrated by a bearing-only tracking example.

Gene Silencing in Arabidopsis Spreads from the Root to the Shoot, through a Gating Barrier, by Template-Dependent, Nonvascular, Cell-to-Cell Movement

Upward long-distance mobile silencing has been shown to be phloem mediated in several different solanaceous species. We show that the Arabidopsis (Arabidopsis thaliana) seedling grafting system and a counterpart inducible system generate upwardly spreading long-distance silencing that travels not in the phloem but by template-dependent reiterated short-distance cell-to-cell spread through the cells of the central stele. Examining the movement of the silencing front revealed a largely unrecognized zone of tissue, below the apical meristem, that is resistant to the silencing signal and that may provide a gating or protective barrier against small RNA signals. Using a range of auxin and actin transport inhibitors revealed that, in this zone, alteration of vesicular transport together with cytoskeleton dynamics prevented or retarded the spread of the silencing signal. This suggests that small RNAs are transported from cell to cell via plasmodesmata rather than diffusing from their source in the phloem.

Primary and secondary neural networks of auditory prepulse inhibition: a functional magnetic resonance imaging study of sensorimotor gating of the human acoustic startle response

Feedforward inhibition deficits have been consistently demonstrated in a range of neuropsychiatric conditions using prepulse inhibition (PPI) of the acoustic startle eye-blink reflex when assessing sensorimotor gating. While PPI can be recorded in acutely decerebrated rats, behavioural, pharmacological and psychophysiological studies suggest the involvement of a complex neural network extending from brainstem nuclei to higher order cortical areas. The current functional magnetic resonance imaging study investigated the neural network underlying PPI and its association with electromyographically (EMG) recorded PPI of the acoustic startle eye-blink reflex in 16 healthy volunteers. A sparse imaging design was employed to model signal changes in blood oxygenation level-dependent (BOLD) responses to acoustic startle probes that were preceded by a prepulse at 120 ms or 480 ms stimulus onset asynchrony or without prepulse. Sensorimotor gating was EMG confirmed for the 120-ms prepulse condition, while startle responses in the 480-ms prepulse condition did not differ from startle alone. Multiple regression analysis of BOLD contrasts identified activation in pons, thalamus, caudate nuclei, left angular gyrus and bilaterally in anterior cingulate, associated with EMGrecorded sensorimotor gating. Planned contrasts confirmed increased pons activation for startle alone vs 120-ms prepulse condition, while increased anterior superior frontal gyrus activation was confirmed for the reverse contrast. Our findings are consistent with a primary pontine circuitry of sensorimotor gating that interconnects with inferior parietal, superior temporal, frontal and prefrontal cortices via thalamus and striatum. PPI processes in the prefrontal, frontal and superior temporal cortex were functionally distinct from sensorimotor gating.

Disrupted sensory gating in pathological gambling

Background Some neurochemical evidence as well as recent studies on molecular genetics suggest that pathologic gambling may be related to dysregulated dopamine neurotransmission. Methods The current study examined sensory (motor) gating in pathologic gamblers as a putative measure of endogenous brain dopamine activity with prepulse inhibition of the acoustic startle eye-blink response and the auditory P300 event-related potential. Seventeen pathologic gamblers and 21 age- and gender-matched healthy control subjects were assessed. Both prepulse inhibition measures were recorded under passive listening and two-tone prepulse discrimination conditions. Results Compared to the control group, pathologic gamblers exhibited disrupted sensory (motor) gating on all measures of prepulse inhibition. Sensory motor gating deficits of eye-blink responses were most profound at 120-millisecond prepulse lead intervals in the passive listening task and at 240-millisecond prepulse lead intervals in the two-tone prepulse discrimination task. Sensory gating of P300 was also impaired in pathologic gamblers, particularly at 500-millisecond lead intervals, when performing the discrimination task on the prepulse. Conclusions In the context of preclinical studies on the disruptive effects of dopamine agonists on prepulse inhibition, our findings suggest increased endogenous brain dopamine activity in pathologic gambling in line with previous neurobiological findings.

Measurement of ventilation and cardiac related impedance changes with electrical impedance tomography

Introduction Electrical impedance tomography (EIT) has been shown to be able to distinguish both ventilation and perfusion. With adequate filtering the regional distributions of both ventilation and perfusion and their relationships could be analysed. Several methods of separation have been suggested previously, including breath holding, electrocardiograph (ECG) gating and frequency filtering. Many of these methods require interventions inappropriate in a clinical setting. This study therefore aims to extend a previously reported frequency filtering technique to a spontaneously breathing cohort and assess the regional distributions of ventilation and perfusion and their relationship. Methods Ten healthy adults were measured during a breath hold and while spontaneously breathing in supine, prone, left and right lateral positions. EIT data were analysed with and without filtering at the respiratory and heart rate. Profiles of ventilation, perfusion and ventilation/perfusion related impedance change were generated and regions of ventilation and pulmonary perfusion were identified and compared. Results Analysis of the filtration technique demonstrated its ability to separate the ventilation and cardiac related impedance signals without negative impact. It was, therefore, deemed suitable for use in this spontaneously breathing cohort. Regional distributions of ventilation, perfusion and the combined ΔZV/ΔZQ were calculated along the gravity axis and anatomically in each position. Along the gravity axis, gravity dependence was seen only in the lateral positions in ventilation distribution, with the dependent lung being better ventilated regardless of position. This gravity dependence was not seen in perfusion. When looking anatomically, differences were only apparent in the lateral positions. The lateral position ventilation distributions showed a difference in the left lung, with the right lung maintaining a similar distribution in both lateral positions. This is likely caused by more pronounced anatomical changes in the left lung when changing positions. Conclusions The modified filtration technique was demonstrated to be effective in separating the ventilation and perfusion signals in spontaneously breathing subjects. Gravity dependence was seen only in ventilation distribution in the left lung in lateral positions, suggesting gravity based shifts in anatomical structures. Gravity dependence was not seen in any perfusion distributions.

Half metallicity in finite-length zigzag single walled carbon nanotube : A first-principle prediction

We predict here from first-principle calculations that finite-length (n,0) single walled carbon nanotubes (SWCNTs) with H-termination at the open ends displaying antiferromagnetic coupling when n is greater than 6. An opposite local gating effect of the spin states, i.e., half metallicity, is found under the influence of an external electric field along the direction of tube axis. Remarkably, boron doping of unpassivated SWCNTs at both zigzag edges is found to favor a ferromagnetic ground state, with the B-doped tubes displaying half-metallic behavior even in the absence of an electric field. Aside of the intrinsic interest of these results, an important avenue for development of CNT-based spintronic is suggested.

Five-level current-source inverters with buck-boost and inductive-current balancing capabilities

This paper presents new five-level current-source inverters (CSIs) with voltage/current buck-boost capability, unlike existing five-level CSIs where only voltage-boost operation is supported. The proposed inverters attain self-inductive-current-balancing per switching cycle at their dc front ends without having to include additional balancing hardware or complex control manipulation. The inverters can conveniently be controlled by using the well-established phase-shifted carrier modulation scheme with only two additional linear references and a mapping logic table needed. Existing modulators can therefore be conveniently retrofitted for controlling the presented inverters. By appropriately coordinating the inverter gating signals, their implementations can be realized by using the least number of components without degrading performance. These enhanced features of the inverters have already been verified in simulation and experimentally using a scaled-down laboratory platform.

Topological design and modulation strategy for buck-boost three-level inverters

To date, designed topologies for DC-AC inversion with both voltage-buck and boost capabilities are mainly focused on two-level circuitries with extensions to three-level possibilities left nearly unexplored. Contributing to this area of research, this paper presents the design of a number of viable buck-boost three-level inverters that can also support bidirectional power conversion. The proposed front-end circuitry is developed from the Cuk-derived buck-boost two-level inverter, and by using the "alternative phase opposition disposition" (APOD) modulation scheme, the buck-boost three-level inverters can perform distinct five-level line voltage and three-level phase voltage switching by simply controlling the active switches located in the designed voltage boost section of the circuits. As a cost saving option, one active switch can further be removed from the voltage-boost section of the circuits by simply re-routing the gating commands of the remaining switches without influencing the ac output voltage amplitude. To verify the validity of the proposed inverters, Matlab/PLECS simulations were performed before a laboratory prototype was implemented for experimental testing.

Topological design and modulation strategy for buck-boost three-level inverters

To date, designed topologies for DC-AC inversion with both voltage buck and boost capabilities are mainly focused on two-level circuitries with extensions to three-level possibilities left nearly unexplored. Contributing to this area of research, this paper presents the design of a number of viable buck-boost three-level inverters that can also support bidirectional power conversion. The proposed front-end circuitry is developed from the Cuk-derived buck-boost two-level inverter, and by using the ldquoalternative phase opposition dispositionrdquo modulation scheme, the buck-boost three-level inverters can perform distinct five-level line voltage and three-level phase voltage switching by simply controlling the active switches located in the designed voltage boost section of the circuits. As a cost saving option, one active switch can further be removed from the voltage boost section of the circuits by simply rerouting the gating commands of the remaining switches without influencing the AC output voltage amplitude. To verify the validity of the proposed inverters, MATLAB/PLECS simulations were performed before a laboratory prototype was implemented for experimental testing.

Performance evaluation of three-level Z-source inverters under semiconductor-failure conditions

This paper evaluates and proposes various compensation methods for three-level Z-source inverters under semiconductor-failure conditions. Unlike the fault-tolerant techniques used in traditional three-level inverters, where either an extra phase-leg or collective switching states are used, the proposed methods for three-level Z-source inverters simply reconfigure their relevant gating signals so as to ride-through the failed semiconductor conditions smoothly without any significant decrease in their ac-output quality and amplitude. These features are partly attributed to the inherent boost characteristics of a Z-source inverter, in addition to its usual voltage-buck operation. By focusing on specific types of three-level Z-source inverters, it can also be shown that, for the dual Z-source inverters, a unique feature accompanying it is its extra ability to force common-mode voltage to zero even under semiconductor-failure conditions. For verifying these described performance features, PLECS simulation and experimental testing were performed with some results captured and shown in a later section for visual confirmation.

4DCT radiotherapy for NSCLC: A review of planning methods

Purpose To establish whether the use of a passive or active technique of planning target volume (PTV) definition and treatment methods for non-small cell lung cancer (NSCLC) deliver the most effective results. This literature review assesses the advantages and disadvantages in recent studies of each, while assessing the validity of the two approaches for planning and treatment. Methods A systematic review of literature focusing on the planning and treatment of radiation therapy to NSCLC tumours. Different approaches which have been published in recent articles are subjected to critical appraisal in order to determine their relative efficacy. Results Free-breathing (FB) is the optimal method to perform planning scans for patients and departments, as it involves no significant increase in cost, workload or education. Maximum intensity projection (MIP) is the fastest form of delineation, however it is noted to be less accurate than the ten-phase overlap approach for computed tomography (CT). Although gating has proven to reduce margins and facilitate sparing of organs at risk, treatment times can be longer and planning time can be as much as 15 times higher for intensity modulated radiation therapy (IMRT). This raises issues with patient comfort and stabilisation, impacting on the chance of geometric miss. Stereotactic treatments can take up to 3 hours to treat, along with increases in planning and treatment, as well as the additional hardware, software and training required. Conclusion Four-dimensional computed tomography (4DCT) is superior to 3DCT, with the passive FB approach for PTV delineation and treatment optimal. Departments should use a combination of MIP with visual confirmation ensuring coverage for stage 1 disease. Stages 2-3 should be delineated using ten-phases overlaid. Stereotactic and gated treatments for early stage disease should be used accordingly; FB-IMRT is optimal for latter stage disease.

A comparison of factors influencing perceived risk by French and Australian cyclists and drivers

Differences in the levels of risk perceived by cyclists and car drivers may contribute to the dangers in their interactions. Levels of perceived risk have been shown to vary according to personal and environmental factors and between countries. Cycling rates in France are higher than in Australia, particularly among women. This study investigated whether cultural differences between France and Australia are reflected in perceived risks for experienced adult cyclists and drivers in the two countries. In online surveys, regular cyclists (France 336, Australia 444) and drivers (France 92, Australia 151) were asked to rate the level of risk in six situations: failure to yield; going through a red light; not signalling when turning; swerving; tail-gating; and not checking traffic. The effects of type of interacting vehicle and participant type on perceived risk were similar in France and Australia. However, the influence of responsibility for the risky behaviour differed according to participant type, type of situation and nationality. When the bicycle rider committed the road rule violation, Australian cyclists and drivers gave higher risk ratings than French cyclists and drivers. In both countries, cyclists rated themselves significantly higher than drivers on the perceived control and overconfidence subscales of the perceived skill measure. The French cyclists rated themselves higher than Australian cyclists on these scales, which could be responsible for overall lower perceived risk levels when interacting with a bike. Australian cyclists rated themselves significantly lower than drivers on the incompetence subscale but French cyclists rated themselves higher than drivers. In both countries incompetence scores were positively related to levels of perceived risk. Weekly time was associated with perceived risk in Australia but not in France. Frequency of traffic violations was not associated with perceived risk in either country. In conclusion, levels of perceived risk differed between drivers and cyclists in both countries and were influenced by type of interacting vehicle, experience and perceived skill. However, some differences between the results from the two countries merit further investigation to shed light on potential improvements in safety and cycling participation.

Neurodevelopmental animal models of schizophrenia: Effects on prepulse inhibition

Epidemiological studies have shown increased incidence of schizophrenia in patients subjected to different forms of pre- or perinatal stress. However, as the onset of schizophrenic illness does not usually occur until adolescence or early adulthood, it is not yet fully understood how disruption of early brain development may ultimately lead to malfunction years later. In order to elucidate a possible role for neurodevelopmental factors in the pathogenesis of schizophrenia and to highlight potential new treatments, animal models are needed. Prepulse inhibition (PPI) is a model of sensorimotor gating mechanisms in the brain. It is disrupted in schizophrenia patients and the disruption can be reversed with atypical antipsychotics. It has been widely used in animal studies to explore central mechanisms possibly involved in schizophrenia. There has been a recent surge of behavioural and neurochemical animal studies on neurodevelopmental models, particularly on the effects of postweaning isolation, maternal separation and neonatal lesions of the hippocampus. In these models, long lasting alterations in behaviour and/or molecular changes in specific brain regions are observed, comparable to those seen in schizophrenia. The aim of this article is to critically review the available literature on such neurodevelopmental animal models with special focus on the effects on PPI and brain regions that are putatively involved in regulation of PPI.

Mice lacking the serotonin Htr2B receptor gene present an antipsychotic-sensitive schizophrenic-like phenotype

Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a population-specific serotonin 2B (5-HT2B) receptor stop codon (ie, HTR2B Q20*) was reported to segregate with severely impulsive individuals, whereas 5-HT2B mutant (Htr2B−/−) mice also showed high impulsivity. Interestingly, in the same cohort, early-onset schizophrenia was more prevalent in HTR2B Q*20 carriers. However, the putative role of 5-HT2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT2B receptors in mice subjected to a comprehensive series of behavioral test screenings for schizophrenic-like symptoms and investigated relevant dopaminergic and glutamatergic neurochemical alterations in the cortex and the striatum. Domains related to the positive, negative, and cognitive symptom clusters of schizophrenia were affected in Htr2B−/− mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions, and in learning and memory processes. In addition, Htr2B−/− mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT2B receptors induced a region-selective decrease of dopamine and glutamate concentrations in the dorsal striatum. Importantly, selected schizophrenic-like phenotypes and endophenotypes were rescued by chronic haloperidol treatment. We report herein that 5-HT2B receptor deficiency confers a wide spectrum of antipsychotic-sensitive schizophrenic-like behavioral and psychopharmacological phenotypes in mice and provide first evidence for a role of 5-HT2B receptors in the neurobiology of psychotic disorders