The pharmaceutical industry is currently facing an industry wide problem of high attrition rates for new compounds and rising development costs. As a result of this, there is an emphasis on making the development process more ecient. By learning more about new compounds in the early stages of development, the aim is to stop ineective compounds earlier and improve dose selection for compounds that progress to phase III. One approach to this is to use adaptive designs. The focus of this thesis is on response adaptive designs within phase IIb dose-finding studies. We explore adapting the subject allocations based on accrued data, with the intention of focusing the allocation on the interesting parts of the curve and/or the best dose for phase III. In this thesis we have used simulation studies to assess the operational characteristics of a number of response adaptive designs. We found that there were consistent gains to be made by adapting when we were relatively cautious in our method of adaptation. That is, the adaptive method has the opportunity to alter the subject allocation when there is a clear signal in the data, but maintains roughly equal allocation when there is a lot of variability in the data. When we used adaptive designs that were geared to randomising subjects to a few doses, the results were more varied. In some cases the adaptation led to gains in efficacy whilst in others it was detrimental. One of the key aims of a phase IIb dose-finding study is to identify a dose to take forward into phase III. In the final chapter, we show that the way in which we choose the dose for phase III affects the expected gain, and so begin to consider how we can optimise the decision making process.

The management of genomic diversity is important within breeding programs and is primarily achieved through controlling the rate of inbreeding. A failure to adequately manage the rate of inbreeding will result in an increased risk of the expression of lethal recessive mutations, inbreeding depression and losses in genetic variance, thereby restricting long-term genetic progress. Each research chapter within this thesis used real data collected from a commercial pig breeding operation to examine a key area of research regarding the management of genomic diversity. The first research chapter examined the selection outcomes from the practical application of Optimal Contributions (OC). These outcomes were examined to determine their alignment with the current theories regarding selection, particularly as to the extent by which selection decisions were influenced by estimated Mendelian sampling terms. This assessment was conducted for the initial selection of individuals as parents, which parents went on to provide a long-term contribution and the magnitude of these contributions. OC was shown to have shifted breeding decisions more closely in alignment with the estimated Mendelian sampling terms. The second research chapter used genomic data to assess the adequacy of the pedigree-based approach for managing diversity during selection. This approach assumes the infinitesimal model with all loci neutral and no impact from selection per se on heterozygosity. Using genomic information, the observed loss of heterozygosity at each marker was compared to the loss of heterozygosity expected from the pedigree-based relationships. Regional disparities between the observed and expected losses in heterozygosity were detected, which were potentially attributable to selection. Runs of homozygosity and the pairwise linkage disequilibrium between markers were also examined within these regions. Regions showing disparity were found to contain well validated quantitative trait loci for important traits. The third research chapter sought to provide a genomic solution to the shortcomings of the pedigree-based approach for quantifying relatedness, identified above. A methodology was devised for tracing identity by descent (IBD) at each allelic position over five ancestral generations, following phasing and imputation of the genomic data. A comparison was made between the inbreeding expected from the pedigree relationships and that observed from the identity by descent of genomic information. In the population studied it was not currently feasible to derive a relationship matrix based exclusively on observed IBD. The fourth research chapter used imputed genomic information to identify haplotypes which had a putative lethal recessive effect. Haplotypes which were never observed in the homozygous form, either in the population or in the offspring produced between carriers, were classified as candidate haplotypes. The top candidates on each chromosome were then examined for a reduction in the total number born when two carriers were mated together. A total of six putative lethal recessive haplotypes were detected relating to at least four putative lethal recessive mutations, where one homozygote was absent and the size of the reduction in litter size matched that expected for a lethal recessive effect. The research chapters contained within this thesis demonstrate the important role that genomics can have in managing inbreeding in addition to generating genetic gain. Genomics is able to provide a more accurate prediction of the Mendelian sampling term, better quantify the relatedness between individuals and detect lethal recessive effects.

Tato práce je zaměřena na zhodnocení alternativního systému zdanění na principu rovné daně. Pro svoji práci jsem zvolila podrobnější zkoumání konkrétní příjmové situace poplatníků v případě zavedení rovné daně a zhodnocení přínosů rovné daně převážně v souvislosti s příjmy. Součástí této práce jsou také příklady z několika států, kde rovná daň byla již zavedena.

Continuous-time systems are usually modelled by differential equations arising from physical laws. However, the use of these models in practice requires discretisation. In this thesis we consider sampled-data models for linear and nonlinear systems. We study some of the issues involved in the sampling process, such as the accuracy of the sampled-data models, the artifacts produced by the particular sampling scheme, and the relations to the underlying continuous-time system. We review, extend and present new results, making extensive use of the delta operator which allows a clearer connection between a sampled-data model and the underlying continuous-time system. In the first part of the thesis we consider sampled-data models for linear systems. In this case exact discrete-time representations can be obtained. These models depend, not only on the continuous-time system, but also on the artifacts involved in the sampling process, namely, the sample and hold devices. In particular, these devices play a key role in determining the sampling zeros of the discrete-time model. We consider robustness issues associated with the use of discrete-time models for continuous-time system identification from sampled data. We show that, by using restricted bandwidth frequency domain maximum likelihood estimation, the identification results are robust to (possible) under-modelling due to the sampling process. Sampled-data models provide a powerful tool also for continuous-time optimal control problems, where the presence of constraints can make the explicit solution impossible to find. We show how this solution can be arbitrarily approximated by an associated sampled-data problem using fast sampling rates. We also show that there is a natural convergence of the singular structure of the optimal control problem from discrete- to continuous-time, as the sampling period goes to zero. In Part II we consider sampled-data models for nonlinear systems. In this case we can only obtain approximate sampled-data models. These discrete-time models are simple and accurate in a well defined sense. For deterministic systems, an insightful observation is that the proposed model contains sampling zero dynamics. Moreover, these correspond to the same dynamics associated with the asymptotic sampling zeros in the linear case. The topics and results presented in the thesis are believed to give important insights into the use of sampled-data models to represent linear and nonlinear continuous-time systems. / PhD Doctorate

<p>This thesis consists of three self-contained essays in the fields of banking and portfolio choice.</p><p>Banking and Optimal Reserves in an Equilibrium Model:</p><p>I address the question of reserves in banking, particularly the fact that reserves are substantially larger than the stipulated reserve requirements by Bank of International Settlements. My contribution is to show that when the underlying values of borrowers are correlated, banks should hold positive reserves, regardless of the regulation. I use a derived distribution for debt portfolios to show that intermediation in a debt market will outperform direct lending, even if intermediaries are allowed to default. The model used is a generalization of Williamson (1986), with Costly State Verification as asymmetric information. By using a factor model for the value of entrepreneurs' projects, I introduce a positive probability for banks to default. It is shown that, in equilibrium, banks choose to hold capital reserves that are almost large enough to eliminate the expected auditing cost for their depositors. The reason is that auditing does not provide any utility and hence, the cake to be split between banks and depositors is enlarged by reserves as an insurance against bad outcomes. It is also shown that the more correlation there is in the debt portfolio, the larger is the optimal reserve level. This could explain why small regional banks in Sweden often have more than twice the reserve level of their nation-wide competitors.</p><p>Optimal Rebalancing of Portfolio Weights under Time-varying Return Volatility:</p><p>This paper considers horizon effects on portfolio weights under time varying and forecastable return volatility. The return volatility is modeled as a GARCH-M, which is sufficiently general to encompass both constant and time varying means. The analysis confirms earlier results, namely that there are no horizon effects when the stochastic process, which governs asset returns, has a constant mean. However, when time varying and forecastable volatility is included in the mean equation, there are horizon effects. I show three features to be of importance for the horizon effect: First, the size of the parameter on conditional volatility in the mean equation and second, persistence in conditional volatility. Third, the asymmetry in volatility has some effect. In addition, the parameter of relative risk aversion is important. For low levels of risk aversion, only very small effects on portfolio weights are present; when the level of risk aversion increases, so does the effects on portfolio weights. Portfolio weights increase for the first 2-3 years when the investment horizon is increased; the total effect slightly exceeds 10%.</p><p>Can Parameter Uncertainty Help Solve the Home Bias Puzzle?</p><p>A well-known puzzle in international finance is the equity home bias. This paper illustrates a mechanism where exchange rate estimation risk causes equity home bias. Estimation risk is introduced into a standard mean-variance portfolio framework by having return time series with different lengths. We argue that the exchange rate return history, which is a part of the local currency return on a foreign investment, is likely to be substantially shorter than the available return histories of equity indices due to, for example, exchange rate regime shifts. To econometrically deal with return histories of different lengths we utilize a framework devised by Stambaugh (1997). The impact of estimation risk on an optimal portfolio is tested with data from Sweden and the U.S. Our results suggest that explicitly accounting for estimation risk causes the domestic investor to increase his fraction of domestic assets. While the introduction of exchange rate estimation risk is not powerful enough to explain the whole home bias observed in data, the results of this paper illustrate a mechanism that is often overlooked in discussions of international portfolio diversification.</p>

This work is devoted to the theoretical and numerical aspects of shape optimization. The first part (chapter I to IV) deals with optimization problems under convexity constraint or constant width constraint. We give several new results related to Newton's problem and Meissner's conjecture. The second part (chapter V to VII) deals with the numerical study of shape optimization problems where many shapes or phases are involved. Some new numerical methods are introduced to study optimal configurations of famous problems : Kelvin's problem and Caffarelli's conjecture. The last part (chapter VIII and IX) is devoted to optimal transportation problems and irrigation problems. More precisely, we introduce a general framework, where different kind of cost functions are allowed. This seems relevant in some problems presenting congestion effects as for instance traffic on a highway, crowds moving in domains with obstacles. In the last chapter we give preliminary results related to the numerical approximation of optimal irrigation networks.

<p>Syftet med föreliggande studie var att få en större förståelse för några personers tankar och reflektioner om vad en optimal parrelation innebär. Följande frågeställningar var i fokus: Vilka aspekter kan knytas till en optimal parrelation? På vilket sätt styr olika omvärldsfaktorer? En semistrukturerad intervjuform användes och urvalet bestod av fem personer i åldrarna 30-45 år. Resultatet visade att tilliten hade en avgörande roll för välbefinnandet i en optimal parrelation. Den optimala parrelationens negativa sidor påpekades också, till fördel för den reella relationen. Vänner och intressen visade sig ha en stor betydelse för den egna parrelationens välbefinnande. Det framkom att könsrollerna försvårade den jämlika relationens utveckling, men även hur gränsöverskridande könsroller uppfattades av samhället. Det individualiserade samhället betraktades utifrån två aspekter; dels det positiva med att forma traditioner som passade den egna parrelationen, dels det negativa med denna traditionsfrihet som ansågs kunna resultera i en framtida traditionslöshet. I diskussionen lyftes följande mönster fram för problematisering: den optimala parrelationens aspekter och omvärldsfaktorernas betydelse i enlighet med Bronfenbrenners bioekologiska modell.</p>

No description available.

The combined effects of food availability and predation risk on fish foraging behavior have been investigated via both laboratory and field experiments, primarily in temperate, freshwater systems and during daylight hours. In contrast, relatively little attention has been directed towards fish foraging decisions along subtropical shorelines, which serve as nursery grounds for a variety of economically important fishes, as well as at night, when many species emerge from refuges to feed. The mangrove-seagrass ecotone and adjacent seagrass beds constitute nocturnal feeding grounds for fish secondary-tertiary consumers. In subtropical Biscayne Bay, Florida (USA), I investigated the influences of food and risk on nocturnal seagrass use by gray snapper (Lutjanus griseus), bluestriped grunt (Haemulon sciurus), great barracuda (Sphyraena barracuda), and seabream (Archosargus rhomboidalis) along a distance gradient, spanning from the mangrove fringe to 120 m from shore. This was accomplished by conducting a series of integrated field and laboratory studies, including: (1) nocturnal seine sampling to determine fish abundance patterns in relation to the mangrove-seagrass interface; (2) fish stomach content analysis to reveal feeding habits and trophic relationships; and (3) diel field tethering experiments to explore nearshore gradients in predation pressure. With these data I tested a priori predictions of fish distributions relative to food and predation risk that were generated from foraging theory: (1) fishes will be distributed across the distance gradient in proportion to their food supply (i.e., ideal free distribution, IFD); or (2) fishes will avoid high risk areas such that their abundances will be lower than predicted by food resources in high-risk habitats (i.e., food-risk trade-off). Results revealed that fish assemblage composition differed by season and distance from shore, with the zone nearest the mangroves generally harboring the lowest densities of late-stage juvenile fishes. Stomach content analysis demonstrated that gray snapper fed on a variety of small fishes and crustaceans, while bluestriped grunt fed primarily on caridean shrimp. Seabream fed almost exclusively on vegetation and great barracuda was almost entirely piscivorous; however, seasonal shifts in diet and feeding habits were evident. Seasonal shifts in major food resource use generally did not correspond with changes in relative abundance of food supply. Seasonal trophic niche breadth differences were evident for gray snapper, great barracuda and bluestriped grunt, while niche breadth was equivalent between seasons for seabream. Based on seasonal food supply in the environment, niche breadth values did not match basic foraging theory predictions, which state niche breadth should expand as preferred food resources become scarce. Tethering experiments indicated that predation rates were highest nearest the mangrove edge and decreased with increasing distance from shore. Moreover, predation pressure at night was nearly twice as high compared to the day. Testing these data against my predictions from foraging theory, I found that none of the fishes examined (gray snapper, seabream and bluestriped grunt) were distributed according to IFD. Seabream and gray snapper avoided foraging close to the mangrove-edge, where their food was most abundant, but risk was highest. Bluestriped grunt appeared to forage randomly across the distance gradient despite spatial variation in food and predation risk. Overall, results suggest that: (1) spatial patterns of utilization of seagrass habitat adjacent to the mangrove-seagrass ecotone differs by species, life-stage and season; (2) Seasonal shifts in diet were not correlated with changes in relative abundance of food supply; (3) trophic niche breadth of late juveniles did not expand with declines in their food resources; (4) the mangrove-seagrass ecotone appears to serve as a hunting corridor for predators targeting juvenile fishes moving about the mangroves; and (5) two of the three species examined appeared to give up food in return for safety by avoiding foraging near the mangroves, despite high food availability.

This thesis consists of three self-contained essays in the fields of banking and portfolio choice. Banking and Optimal Reserves in an Equilibrium Model: I address the question of reserves in banking, particularly the fact that reserves are substantially larger than the stipulated reserve requirements by Bank of International Settlements. My contribution is to show that when the underlying values of borrowers are correlated, banks should hold positive reserves, regardless of the regulation. I use a derived distribution for debt portfolios to show that intermediation in a debt market will outperform direct lending, even if intermediaries are allowed to default. The model used is a generalization of Williamson (1986), with Costly State Verification as asymmetric information. By using a factor model for the value of entrepreneurs' projects, I introduce a positive probability for banks to default. It is shown that, in equilibrium, banks choose to hold capital reserves that are almost large enough to eliminate the expected auditing cost for their depositors. The reason is that auditing does not provide any utility and hence, the cake to be split between banks and depositors is enlarged by reserves as an insurance against bad outcomes. It is also shown that the more correlation there is in the debt portfolio, the larger is the optimal reserve level. This could explain why small regional banks in Sweden often have more than twice the reserve level of their nation-wide competitors. Optimal Rebalancing of Portfolio Weights under Time-varying Return Volatility: This paper considers horizon effects on portfolio weights under time varying and forecastable return volatility. The return volatility is modeled as a GARCH-M, which is sufficiently general to encompass both constant and time varying means. The analysis confirms earlier results, namely that there are no horizon effects when the stochastic process, which governs asset returns, has a constant mean. However, when time varying and forecastable volatility is included in the mean equation, there are horizon effects. I show three features to be of importance for the horizon effect: First, the size of the parameter on conditional volatility in the mean equation and second, persistence in conditional volatility. Third, the asymmetry in volatility has some effect. In addition, the parameter of relative risk aversion is important. For low levels of risk aversion, only very small effects on portfolio weights are present; when the level of risk aversion increases, so does the effects on portfolio weights. Portfolio weights increase for the first 2-3 years when the investment horizon is increased; the total effect slightly exceeds 10%. Can Parameter Uncertainty Help Solve the Home Bias Puzzle? A well-known puzzle in international finance is the equity home bias. This paper illustrates a mechanism where exchange rate estimation risk causes equity home bias. Estimation risk is introduced into a standard mean-variance portfolio framework by having return time series with different lengths. We argue that the exchange rate return history, which is a part of the local currency return on a foreign investment, is likely to be substantially shorter than the available return histories of equity indices due to, for example, exchange rate regime shifts. To econometrically deal with return histories of different lengths we utilize a framework devised by Stambaugh (1997). The impact of estimation risk on an optimal portfolio is tested with data from Sweden and the U.S. Our results suggest that explicitly accounting for estimation risk causes the domestic investor to increase his fraction of domestic assets. While the introduction of exchange rate estimation risk is not powerful enough to explain the whole home bias observed in data, the results of this paper illustrate a mechanism that is often overlooked in discussions of international portfolio diversification.