Evaluating marker-guided treatment selection strategies

© 2014, The International Biometric Society.A potential venue to improve healthcare efficiency is to effectively tailor individualized treatment strategies by incorporating patient level predictor information such as environmental exposure, biological, and genetic marker measurements. Many useful statistical methods for deriving individualized treatment rules (ITR) have become available in recent years. Prior to adopting any ITR in clinical practice, it is crucial to evaluate its value in improving patient outcomes. Existing methods for quantifying such values mainly consider either a single marker or semi-parametric methods that are subject to bias under model misspecification. In this article, we consider a general setting with multiple markers and propose a two-step robust method to derive ITRs and evaluate their values. We also propose procedures for comparing different ITRs, which can be used to quantify the incremental value of new markers in improving treatment selection. While working models are used in step I to approximate optimal ITRs, we add a layer of calibration to guard against model misspecification and further assess the value of the ITR non-parametrically, which ensures the validity of the inference. To account for the sampling variability of the estimated rules and their corresponding values, we propose a resampling procedure to provide valid confidence intervals for the value functions as well as for the incremental value of new markers for treatment selection. Our proposals are examined through extensive simulation studies and illustrated with the data from a clinical trial that studies the effects of two drug combinations on HIV-1 infected patients.

From clonal selection to immune networks: induction of silent idiotypes.

Journal Article

How well do ecosystem indicators communicate the effects of anthropogenic eutrophication?

Anthropogenic eutrophication affects the Mediterranean, Black, North and Baltic Seas to various extents. Responses to nutrient loading and methods of monitoring relevant indicators vary regionally, hindering interpretation of ecosystem state changes and preventing a straightforward pan-European assessment of eutrophication symptoms. Here we summarize responses to nutrient enrichment in Europe's seas, comparing existing time-series of selected pelagic (phytoplankton biomass and community composition, turbidity, N:P ratio) and benthic (macro flora and faunal communities, bottom oxygen condition) indicators based on their effectiveness in assessing eutrophication effects. Our results suggest that the Black Sea and Northern Adriatic appear to be recovering from eutrophication due to economic reorganization in the Black Sea catchment and nutrient abatement measures in the case of the Northern Adriatic. The Baltic is most strongly impacted by eutrophication due to its limited exchange and the prevalence of nutrient recycling. Eutrophication in the North Sea is primarily a coastal problem, but may be exacerbated by climatic changes. Indicator interpretation is strongly dependent on sea-specific knowledge of ecosystem characteristics, and no single indicator can be employed to adequately compare eutrophication state between European seas. Communicating eutrophication-related information to policy-makers could be facilitated through the use of consistent indicator selection and monitoring methodologies across European seas. This work is discussed in the context of the European Commission's recently published Marine Strategy Directive.

The effects of blood pressure lowering on development of cognitive impairment and dementia in patients without apparent prior cerebrovascular disease

BACKGROUND: Hypertension and cognitive impairment are prevalent in older people. It is known that hypertension is a direct risk factor for vascular dementia and recent studies have suggested hypertension also impacts upon prevalence of Alzheimer's disease. The question is therefore whether treatment of hypertension lowers the rate of cognitive decline. OBJECTIVES: To assess the effects of blood pressure lowering treatments for the prevention of dementia and cognitive decline in patients with hypertension but no history of cerebrovascular disease. SEARCH STRATEGY: The trials were identified through a search of CDCIG's Specialised Register, CENTRAL, MEDLINE, EMBASE, PsycINFO and CINAHL on 27 April 2005. SELECTION CRITERIA: Randomized, double-blind, placebo controlled trials in which pharmacological or non-pharmacological interventions to lower blood pressure were given for at least six months. DATA COLLECTION AND ANALYSIS: Two independent reviewers assessed trial quality and extracted data. The following outcomes were assessed: incidence of dementia, cognitive change from baseline, blood pressure level, incidence and severity of side effects and quality of life. MAIN RESULTS: Three trials including 12,091 hypertensive subjects were identified. Average age was 72.8 years. Participants were recruited from industrialised countries. Mean blood pressure at entry across the studies was 170/84 mmHg. All trials instituted a stepped care approach to hypertension treatment, starting with a calcium-channel blocker, a diuretic or an angiotensin receptor blocker. The combined result of the three trials reporting incidence of dementia indicated no significant difference between treatment and placebo (Odds Ratio (OR) = 0.89, 95% CI 0.69, 1.16). Blood pressure reduction resulted in a 11% relative risk reduction of dementia in patients with no prior cerebrovascular disease but this effect was not statistically significant (p = 0.38) and there was considerable heterogeneity between the trials. The combined results from the two trials reporting change in Mini Mental State Examination (MMSE) did not indicate a benefit from treatment (Weighted Mean Difference (WMD) = 0.10, 95% CI -0.03, 0.23). Both systolic and diastolic blood pressure levels were reduced significantly in the two trials assessing this outcome (WMD = -7.53, 95% CI -8.28, -6.77 for systolic blood pressure, WMD = -3.87, 95% CI -4.25, -3.50 for diastolic blood pressure).Two trials reported adverse effects requiring discontinuation of treatment and the combined results indicated a significant benefit from placebo (OR = 1.18, 95% CI 1.06, 1.30). When analysed separately, however, more patients on placebo in SCOPE were likely to discontinue treatment due to side effects; the converse was true in SHEP 1991. Quality of life data could not be analysed in the three studies. There was difficulty with the control group in this review as many of the control subjects received antihypertensive treatment because their blood pressures exceeded pre-set values. In most cases the study became a comparison between the study drug against a usual antihypertensive regimen. AUTHORS' CONCLUSIONS: There was no convincing evidence from the trials identified that blood pressure lowering prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent prior cerebrovascular disease. There were significant problems identified with analysing the data, however, due to the number of patients lost to follow-up and the number of placebo patients given active treatment. This introduced bias. More robust results may be obtained by analysing one year data to reduce differential drop-out or by conducting a meta-analysis using individual patient data.

Analysis and Synthesis of pHEMT Class-E Amplifiers with Shunt Inductor including ON-State Active-Device Resistance Effects

In this theoretical paper, the analysis of the effect that ON-state active-device resistance has on the performance of a Class-E tuned power amplifier using a shunt inductor topology is presented. The work is focused on the relatively unexplored area of design facilitation of Class-E tuned amplifiers where intrinsically low-output-capacitance monolithic microwave integrated circuit switching devices such as pseudomorphic high electron mobility transistors are used. In the paper, the switching voltage and current waveforms in the presence of ON-resistance are analyzed in order to provide insight into circuit properties such as RF output power, drain efficiency, and power-output capability. For a given amplifier specification, a design procedure is illustrated whereby it is possible to compute optimal circuit component values which account for prescribed switch resistance loss. Furthermore, insight into how ON-resistance affects transistor selection in terms of peak switch voltage and current requirements is described. Finally, a design example is given in order to validate the theoretical analysis against numerical simulation.

The near-edge structure in energy-loss spectroscopy: many-electron and magnetic effects in transition metal nitrides and carbides

We investigate the ability of the local density approximation (LDA) in density functional theory to predict the near-edge structure in electron energy-loss spectroscopy in the dipole approximation. We include screening of the core hole within the LDA using Slater's transition state theory. We find that anion K-edge threshold energies are systematically overestimated by 4.22 +/- 0.44 eV in twelve transition metal carbides and nitrides in the rock-salt (B1) structure. When we apply this 'universal' many-electron correction to energy-loss spectra calculated within the transition state approximation to LDA, we find quantitative agreement with experiment to within one or two eV for TiC, TiN and VN. We compare our calculations to a simpler approach using a projected Mulliken density which honours the dipole selection rule, in place of the dipole matrix element itself. We find remarkably close agreement between these two approaches. Finally, we show an anomaly in the near-edge structure in CrN to be due to magnetic structure. In particular, we find that the N K edge in fact probes the magnetic moments and alignments of ther sublattice.

Do protected areas mitigate the effects of fisheries-induced evolution on parental care behaviour of a recreationally-important teleost fish?

Human-induced selection on animals and plants has been highly influential throughout our history and resulted in both intentional benefits and unintended detriments. Fisheries-induced evolution (FIE) describes the unintended selection on wild fish populations by fishing that has resulted in the evolution of exploited populations. While the use of aquatic protected areas that exclude angling might be considered an evolutionarily-enlightened management approach to dealing with issues arising from FIE little is known about the effectiveness of this approach for maintaining the phenotypic diversity of traits in protected areas versus those outside of their boundaries. In species that exhibit parental care, including the largemouth bass (Micropterus salmoides), active nest guarding and aggression towards potential brood predators by males increases the survival of offspring. This aggression may render these individuals particularly vulnerable to capture via angling as a result of increased propensity to attack fishing lures near their nests. Relative levels of aggression by these males during the parental care period correlate with their vulnerability to angling year round. Inasmuch as this parental behavior is heritable, this selective removal of more aggressive individuals by anglers should drive population-average phenotypes towards lower levels of aggression. To assess the effectiveness of protected areas at mitigating FIE, I compared the nest guarding behaviours of wild, free-swimming male bass during the early nesting period for bass within and outside protected areas. I found that nesting males within long-standing fishing sanctuaries (>70 yrs) were more aggressive towards captive bluegill sunfish (Lepomis macrochirus) placed directly on their nests, and patrolled larger areas around their nests compared to bass outside of sanctuaries. Males within protected areas were more likely to strike at artificial fishing lures and more prone to capture during experimental angling events. Collectively, my findings suggest that recreational angling selects for individual bass with lower levels of parental care and aggression, and that the establishment of protected areas may mitigate potential FIE. The extent to which this phenomenon occurs in other species and systems likely depends on the reproductive strategies of the fishes being considered, their spatial ecology relative to sanctuary boundaries, and habitat quality within protected areas.

Anti-apoptotic effects of Z alpha-1 antitrypsin in human bronchial epithelial cells.

α1-antitrypsin (α1-AT) deficiency is a genetic disease which manifests as early-onset emphysema or liver disease. Although the majority of α1-AT is produced by the liver, it is also produced by bronchial epithelial cells, amongst others, in the lung. Herein, we investigate the effects of mutant Z α1-AT (ZAAT) expression on apoptosis in a human bronchial epithelial cell line (16HBE14o-) and delineate the mechanisms involved.

Control, M variant α1-AT (MAAT)- or ZAAT-expressing cells were assessed for apoptosis, caspase-3 activity, cell viability, phosphorylation of Bad, nuclear factor (NF)-κB activation and induced expression of a selection of pro- and anti-apoptotic genes.

Expression of ZAAT in 16HBE14o- cells, like MAAT, inhibited basal and agonist-induced apoptosis. ZAAT expression also inhibited caspase-3 activity by 57% compared with control cells (p = 0.05) and was a more potent inhibitor than MAAT. Whilst ZAAT had no effect on the activity of Bad, its expression activated NF-κB-dependent gene expression above control or MAAT-expressing cells. In 16HBE14o- cells but not HEK293 cells, ZAAT upregulated expression of cIAP-1, an upstream regulator of NF-κB. cIAP1 expression was increased in ZAAT versus MAAT bronchial biopsies.

The data suggest a novel mechanism by which ZAAT may promote human bronchial epithelial cell survival.

Perceiving and acting upon spaces in a VR rugby task: Expertise effects in affordance detection and task achievement

This study used a virtual simulated 3vs3 rugby task to investigate whether gaps opening in particular running channels promote different actions by the ball-carrier player and whether an effect of rugby expertise is verified. We manipulated emergent gaps in three different locations: gap1 in the participant’s own running channel, gap 2 in the 1st receiver's running channel, and gap3 in the 2nd receiver's running channel. Recreational, intermediate, professional and non-rugby players performed the task. They could i) run with the ball, ii) make a short pass, or iii) make a long pass. All actions were digitally recorded. Results revealed that the emergence of gaps in the defensive line with respect to the participant’s own position significantly influenced action selection. Namely, ‘run’ was most often the action performed in gap 1, ‘short pass’ in gap 2, and ‘long pass’ in gap 3 trials. Furthermore, a strong positive relationship between expertise and task achievement was found.

Late industrialization and the increased merit selection hypothesis - Ireland as a test case

The Irish case provides a particularly appropriate test of the increasing merit selection hypothesis deriving from the liberal theory of industrialization. This is so not only because the lateness and speed of economic change allows us to capture such change through a set of national surveys conducted in the past three decades, but also because such change was based on a sustained policy of increased openness to international competitive forces. The functional requirements of the economy and a rapid increase in the supply of those with higher educational qualifications provided an ideal context in which to observe the movement from ascription to achievement predicted by the liberal theory. However, while changes in the class structure and a rapid expansion of educational opportunity had significant consequences in terms of absolute mobility, there was no evidence of a significant shift towards meritocratic principles. At the same time as the service class increased their advantage over other classes in the pursuit of educational qualifications, the impact of educational qualifications on class destination diminished. Controlling for education, we find that the impact of class origin effects is substantial and shows little sign of diminishing over time. In our conclusion we discuss the implications of our findings in the context of the recent debate on meritocracy.

Numerical investigation of the effects of drill geometry on drilling induced delamination of carbon fiber reinforced composites

Drilling is a major process in the manufacturing of holes required for the assemblies of composite laminates in aerospace industry. Simulation of drilling process is an effective method in optimizing the drill geometry and process parameters in order to improve hole quality and to reduce the drill wear. In this research we have developed three-dimensional (3D) FE model for drilling CFRP. A 3D progressive intra-laminar failure model based on the Hashin's theory is considered. Also an inter-laminar delamination model which includes the onset and growth of delamination by using cohesive contact zone is developed. The developed model with inclusion of the improved delamination model and real drill geometry is used to make comparison between the step drill of different stage ratio and twist drill. Thrust force, torque and work piece stress distributions are estimated to decrease by the use of step drill with high stage ratio. The model indicates that delamination and other workpiece defects could be controlled by selection of suitable step drill geometry. Hence the 3D model could be used as a design tool for drill geometry for minimization of delamination in CFRP drilling. © 2013 Elsevier Ltd.

Relative Effects of Gamete Compatibility and Hydrodynamics on Fertilization in the Green Sea Urchin Strongylocentrotus droebachiensis

Intraspecific variation in gamete compatibility among male/female pairs causes variation in the concentration of sperm required to achieve equivalent fertilization levels. Gamete compatibility is therefore potentially an important factor controlling mating success. Many broadcast-spawning marine invertebrates, however, also live in a dynamic environment where hydrodynamic conditions can affect the concentration of sperm reaching eggs during spawning. Thus flow conditions may moderate the effects of gamete compatibility on fertilization. Using the green sea urchin Strongylocentrotus droebachiensis as a model system, we assessed the relative effects of gamete compatibility (the concentration of sperm required to fertilize 50% of the eggs in specific male/female pairs; F50) and the root-mean-square of total velocity (urms; 0.01-0.11 m s(-1)) on fertilization in four locations near a spawning female (water column, wake eddy, substratum, and aboral surface) in both unidirectional and oscillatory flows. Percent fertilization decreased significantly with increasing urms at all locations and both flow regimes. However, although gamete compatibility varied by almost 1.5 orders of magnitude, it was not a significant predictor of fertilization for most combinations of position and flow. The notable exception was a significant effect of gamete compatibility on fertilization on the aboral surface under unidirectional flow. Our results suggest that selection on variation in gamete compatibility may be strongest in eggs fertilized on the aboral surface of sea urchins and that hydrodynamic conditions may add environmental noise to selection outcomes.

Proactive Relay Selection with Joint Impact of Hardware Impairment and Co-channel Interference

In this paper, we investigate the end-to-end performance of dual-hop proactive decode-and-forward relaying networks with Nth best relay selection in the presence of two practical deleterious effects: i) hardware impairment and ii) cochannel interference. In particular, we derive new exact and asymptotic closed-form expressions for the outage probability and average channel capacity of Nth best partial and opportunistic relay selection schemes over Rayleigh fading channels. Insightful discussions are provided. It is shown that, when the system cannot select the best relay for cooperation, the partial relay selection scheme outperforms the opportunistic method under the impact of the same co-channel interference (CCI). In addition, without CCI but under the effect of hardware impairment, it is shown that both selection strategies have the same asymptotic channel capacity. Monte Carlo simulations are presented to corroborate our analysis.

Plan Selection for Probabilistic BDI Agents

When an agent wants to fulfill its desires about the world, the agent usually has multiple plans to choose from and these plans have different pre-conditions and additional effects in addition to achieving its goals. Therefore, for further reasoning and interaction with the world, a plan selection strategy (usually based on plan cost estimation) is mandatory for an autonomous agent. This demand becomes even more critical when uncertainty on the observation of the world is taken into account, since in this case, we consider not only the costs of different plans, but also their chances of success estimated according to the agent's beliefs. In addition, when multiple goals are considered together, different plans achieving the goals can be conflicting on their preconditions (contexts) or the required resources. Hence a plan selection strategy should be able to choose a subset of plans that fulfills the maximum number of goals while maintaining context consistency and resource-tolerance among the chosen plans. To address the above two issues, in this paper we first propose several principles that a plan selection strategy should satisfy, and then we present selection strategies that stem from the principles, depending on whether a plan cost is taken into account. In addition, we also show that our selection strategy can partially recover intention revision.

Differential evolution combined with clonal selection for dynamic economic dispatch

Dynamic economic load dispatch (DELD) is one of the most important steps in power system operation. Various optimisation algorithms for solving the problem have been developed; however, due to the non-convex characteristics and large dimensionality of the problem, it is necessary to explore new methods to further improve the dispatch results and minimise the costs. This article proposes a hybrid differential evolution (DE) algorithm, namely clonal selection-based differential evolution (CSDE), to solve the problem. CSDE is an artificial intelligence technique that can be applied to complex optimisation problems which are for example nonlinear, large scale, non-convex and discontinuous. This hybrid algorithm combines the clonal selection algorithm (CSA) as the local search technique to update the best individual in the population, which enhances the diversity of the solutions and prevents premature convergence in DE. Furthermore, we investigate four mutation operations which are used in CSA as the hyper-mutation operations. Finally, an efficient solution repair method is designed for DELD to satisfy the complicated equality and inequality constraints of the power system to guarantee the feasibility of the solutions. Two benchmark power systems are used to evaluate the performance of the proposed method. The experimental results show that the proposed CSDE/best/1 approach significantly outperforms nine other variants of CSDE and DE, as well as most other published methods, in terms of the quality of the solution and the convergence characteristics.