La découverte de nouveaux médicaments est un processus complexe qui implique de gros investissements et de longues phases de développement. Le coût des échecs est phénoménal et le taux de succès diminue depuis deux décennies, suggérant que le processus d'innovation-développement tel qu'il est pratiqué aujourd'hui n'est plus adapté aux défis actuels. Dans ce travail de thèse, nous proposons une nouvelle approche, dite descendante « Top-down » qui consiste à inverser le procédé traditionnel. Elle reposera essentiellement sur la conception et l'optimisation de modèles de prédiction, afin de mieux orienter les phases successives du développement et de prédire les résultats de chaque étape avec le maximum de précision. Cette démarche s'appuie sur la conception du modèle d'innovation thérapeutique et de toutes ses composantes, notamment le modèle physiopathologique (modèle simulant l'organisme et l'évolution naturelle de la maladie) le modèle thérapeutique (modèle simulant l'effet du médicament sur la maladie), et le modèle d'effet (modèle qui peut être prédit à partir des modèles précédents et qui permet de simuler l'impact du médicament sur la population traitée à partir de son effet sur chaque individu de la population. Le processus complet de notre stratégie comprend dix étapes : élaboration du modèle physiopathologique, calibration, validation, identification des cibles potentielles, activation du logiciel de modifications séquentielles des cibles, construction de la population virtuelle (réaliste ou non), obtention du modèle d'effet nécessaire pour calculer le nombre d'événements évités (NEE), calcul du NEE par cible, comparaison et choix de la “meilleure” cible / New drug discovery and development is a complex process which requires massive investments over protracted horizons. The cost of failed programs is significant in absolute dollar terms. Decreasing R&D productivity over the past 2 decades suggests that the traditional innovation model needs a radical rethink. The central purpose of this thesis work is to lay the theoretical foundations for a new "topdown" approach to new target identification construed as an alternative to the current bottomup approach based on high throughput screening. In essence, it will consist in the design and optimization of in silico models in order to guide the development of a new drug candidate by predicting the outcomes of each successive phase of the development process. This in silico framework brings together a physiopathological model (to simulate the natural evolution of the disease) with a therapeutic model (to simulate the effects of a drug candidate on disease evolution) and the effect model (to predict the impact of the drug candidate on a population of patients)

The migratory birds stop at different stopover sites during migration. The presence of resources in these stopover sites is essential to regain the energy of these birds. This thesis aims to compare the resource abundance and intake at the two stopover sites: Reda and Wisla river estuaries. How a bird's mass changes during its stay at an estuary is considered as a proxy for the resource abundance of a site. The comparison is made on different subsets, including those which has incomplete data, i.e. next day is not exactly one day after the previous capture. Multiple linear regression, Generalized additive model and Linear mixed effect model are used for analysis. Expectation maximization and an iterative predictive process are implemented to deal with incomplete data. We found that Reda has higher resource abundance and intake as compared to that of Wisla river estuary.

Indiana University-Purdue University Indianapolis (IUPUI) / Useful medical indices pose important roles in predicting medical outcomes. Medical indices, such as the well-known Body Mass Index (BMI), Charleson Comorbidity Index, etc., have been used extensively in research and clinical practice, for the quantification of risks in individual patients. However, the development of these indices is challenged; and primarily based on heuristic arguments. Statistically, most medical indices can be expressed as a function of a linear combination of individual variables and fitted by single-index model. Single-index model represents a way to retain latent nonlinear features of the data without the usual complications that come with increased dimensionality. In my dissertation, I propose a single-index model approach to analytically derive indices from observed data; the resulted index inherently correlates with specific health outcomes of interest. The first part of this dissertation discusses the derivation of an index function for the prediction of one outcome using longitudinal data. A cubic-spline estimation scheme for partially linear single-index mixed effect model is proposed to incorporate the within-subject correlations among outcome measures contributed by the same subject. A recursive algorithm based on the optimization of penalized least square estimation equation is derived and is shown to work well in both simulated data and derivation of a new body mass measure for the assessment of hypertension risk in children. The second part of this dissertation extends the single-index model to a multivariate setting. Specifically, a multivariate version of single-index model for longitudinal data is presented. An important feature of the proposed model is the accommodation of both correlations among multivariate outcomes and among the repeated measurements from the same subject via random effects that link the outcomes in a unified modeling structure. A new body mass index measure that simultaneously predicts systolic and diastolic blood pressure in children is illustrated. The final part of this dissertation shows existence, root-n strong consistency and asymptotic normality of the estimators in multivariate single-index model under suitable conditions. These asymptotic results are assessed in finite sample simulation and permit joint inference for all parameters.

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台灣和中國大陸於2010年六月正式簽署「經濟合作架構協議」（ECFA）。無疑地，這是兩岸交流有史以來規模最大、最具官方性質的制度性協商。在象徵意義上，意味著兩岸經濟整合邁入一個嶄新的階段。在實質意義上，透過早期收穫計畫的制度安排，使得兩岸之間的部分貨品和服務享有關稅調降的特殊待遇，對於台灣的整體經濟和部分產業具有立即性的影響。因此，本文旨在探討兩岸簽署ECFA前後，台灣民眾的統獨態度有無發生變化？在影響選民統獨態度因素中，有長期穩定與短期變動，也有感性與理性面向，選民對於兩岸簽訂ECFA的經濟效應評估又扮演了何種角色？最後，隨著兩岸經濟整合的腳步加速，理性層次的麵包效應又是否可能抵銷情感認同的作用？ 本研究使用2008年到2012年「台灣選舉與民主化調查」的定群追蹤資料（panel data），並以「固定與隨機效果並用法」（hybrid method of fixed and random effect model）來分析兩個時間點民眾統獨立場的動態變化。研究結果發現從08年到12年這段時間，民眾的統獨立場呈現往現狀/統一方向移動的趨勢，儘管變化的量不大，但在統計上卻是顯著的。在兩個時間點的動態架構中，選民對於ECFA經濟效益評估的態度變化，不僅與統獨立場的變遷模式與變化方向互相連動，在控制其他變數之後，ECFA經濟評估的態度變化對於統獨立場也有獨立性的影響效果。最後，當短期經濟利益和情感認同相互牴觸時，ECFA經濟的效果甚至會削弱感性認同的作用力。這意味在給定台灣人認同沒有改變的情況下，民眾仍有可能因為簽署ECFA的經濟因素而移動其統獨立場。因此，隨著兩岸經濟整合日益加深，影響個人統獨態度中理性層面利害考量的因素應該予以重視。 / The Taiwanese government has signed the ECFA with China in June 2010. Undoubtedly, ECFA is one of the largest and most official institutional negotiations in the history of cross-strait interactions and exchanges. Signing ECFA with China not only represents that cross-strait economic integration has entered into a new stage, through the arrangements of early harvest program, its impacts on Taiwan’s economy and industry are also immediate. Accordingly, this study aims to explore whether Taiwan people’s attitude toward the independence/unification changed or not after signing ECFA? How the economic inducement from China affect Taiwanese voters’ policy stances on independence/unification issue? Finally, as the accelerated pace of cross-strait economic integration, whether economic factors such as ECFA evaluation may offset the effects of emotional identity on the issue of independence/unification? By using individual panel data from ‘Taiwan Election and Democratization Study’ (TEDS), and taking advantage of hybrid method of fixed and random effect model, the empirical results show that respondents in 2012 are statistically significantly more inclined to maintain status quo or unification in comparison with their attitudes in 2008. Moreover, the attitudinal change of ECFA evaluation are not only systematically associated with the change of policy stance on independence/unification issue, it also reveals independent effect in the statistical model after controlling for other variables. Finally, although emotional affective identity is an important factor to determine public’s policy stances on the issue of Independence/Unification, its effects have begun to weaken especially when the economic interests are large and visible. The implication is that we shouldn’t underestimate the logic importance of political economy played in the trend of regional economic integration, and short-term economic fluctuations may have influence on long-term affective identity.

在全球化的趨勢之下，國際分工不可避免地成為跨國公司運作的趨勢。2013年2月，OECD發布《處理稅基侵蝕及利潤移轉》的報告表示，跨國公司利潤移轉策略的採取被認為是稅基侵蝕的主要原因。基於BEPS已經成為各國非常重視的議題，世界各國也為了保全稅基及防杜利潤移出，紛紛訂出反制措施。這些反制措施是否能遏制利潤不當的移動，是一個值得重視議題。惟目前學術文獻上並未有一篇全面盤點這些反制措施及地主國租稅制度對利潤移轉的影響。 故本篇研究以2005年至2012年台灣電子工業作為研究對象，利用橫斷面及時間序列的追蹤資料 (panel data) 之隨機模型做估計，探討台灣跨國公司之電子業海外子公司的利潤移轉是否會受到租稅規避行為的影響。結果顯示，利潤移轉會受到以下四種國際租稅規避工具所影響，分別是地主國是否有移轉訂價的規範、是否有預先移轉訂價規範、是否有反資本弱化條款以及地主國是否為租稅天堂。

The thesis presents a two pronged approach for predicting aerodynamics of air- foils/wings in the vicinity of the ground. The first approach is effectively a model for ground effect studies, employing an inexpensive Discrete Vortex Method for the 2D pre- dictions and the well known Numerical lifting line theory for the 3D predictions. The second one pertains to the dynamic ground effect analysis which employs the state of the art moving mesh methodology based time accurate CFD. In that sense, the thesis deals with two ends of spectrum in the ground effect analysis; one, a model to be used in the concept design phase and the other an advanced CFD tool for analysis. The proposed model for ground effect studies is based on the well known Discrete Vortex Method (DVM). An important aspect of this method is that it employs what is referred to as the Generalized Kutta Joukowski Theorem (GKJ), meant for interaction problems with multiple vortices, for predicting the lift (and drag) within a potential flow framework. After ascertaining the correctness of using the GKJ theorem for lift prediction for airfoils in ground effect, a modified DVM is presented as a model for ground effect predictions. As per this model, knowing the free stream lift and drag (either from an ex- periment or from a RANS computation) the aerodynamics of the section in ground effect can be predicted. The model is effectively built by constraining the DVM to produce the reference lift/drag in the free stream. The accuracy of the model, particularly for the more relevant high lift sections used during take-off and landing, is systematically estab- lished for a number of test cases. Knowing the sectional ground effect, the extension to 3D analysis is very simple and this is achieved through the well known Numerical Lifting Line theory. The efficacy of the proposed method for the 3D applications is demonstrated using a high lift wing in ground effect. It is worth noting that the proposed model predicts the lift and drag very accurately, practically at no computational cost as compared to modern RANS based CFD tools requiring over 40 or 50 million volumes at a high computational cost and intense human intervention for generating the grids for every ground clearance. The other aspect of the thesis pertains to what is referred to as the Dynamic Ground Effect. Normally the CFD computations mimic the ground effect experiments in simulat- ing the ground effect. These simulations do not maintain geometric similarity with the actual landing or take-off sequence of the aircrafts and this can only be achieved when the simulations are dynamic. Dynamics is also important in case of combat aircrafts (particularly their naval versions) with an aggressive landing and take-off. The dynamic ground effect simulations also provides a framework for simulating varied gust conditions. This dynamic simulation of the ground effect is accomplished using a novel sinking grid methodology, which allows the grids to sink in the ground as the aircraft approaches the ground along the glide path. These simulations make use of the state of the art, time accurate moving grid methods and therefore can be computationally expensive. Never- theless, the utility of such computations in terms of their ability to produce continuous data has been highlighted in the thesis. In that sense, these dynamic computations will be cheaper as compared to the static simulations to produce data at the same level of resolution.

This study analysed the intricacies of trade flows imbibed in the EU-SA TDCA. It assessed the trade creation and trade diversion effects of this bilateral trade agreement – using the top 10 selected commodity exports. This follows the report on the Harmonised System (HS) at the 2-digit codes. A Gravity Model Approach on bilateral trade flows is grounded on panel data models for the period 2000-2017 between South Africa as exporter country and the twenty EU countries (EU-20) as importer country-block out of the twenty-eight countries (EU-28). The study reports that the EU-SA TDCA enhanced significant trade expansion and trade creation effects. Mixed results for GDPs and GDPPKs for both South Africa and the EU countries were reported, but the overall results showed that the bilateral agreement do affect South African commodity exports more negatively, albeit with few positive effects from the EU countries in particular. Besides, ICTSA does have a negative effect on commodity exports, while the South African REER has the positive effect on export models. Lastly, the distance as a proxy of transportation costs negatively affects South Africa’s exports, while common colonial relationship and English as common official language have both a positive effect on exports. The findings imply that trade policies should focus on adequate telecommunication tools, alongside fair trade practices allowing South Africa to integrate with the global market, promote economic growth as well as enhance competitive advantage in most sectoral trades. / Business Management / M. Com. (Business Management (International Business and Finance))

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人類慾望無窮而資源有限，所以如何將資源做最有效的使用一直是經濟學所追求的課題。有關效率的規範分析中，巴瑞圖最適（Pareto optimality）為接受度最高的準則。基於巴瑞圖效率的觀點，不論是營利組織或非營利組織其經營之基本理念皆是希望以最少的投入獲得最大的產出，因此衡量投入與產出間之相對表現即為效率的評估。非營利組織及公共部門因為有許多產出、投入不易量化，故其效率不易評定。此一情況一直到DEA（Data Envelopment Analysis；資料包絡分析法）發展才逐漸改善。另外，有關DEA的運用幾乎都集中在個別決策單位的效率衡量，將之應用在衡量總體經濟的表現上非常少見。所以論文第肆章是按傳統方式以DEA衡量我國地方政府的效率並分析造成效率差異的原因，第參章則將DEA的概念應用於經濟成長上，探討使經濟成長達到極大化之租稅負擔及租稅結構。又效率的追求為經濟學的主軸，但中央政府的效率目標與地方政府並不相同，由於目標不同，因此彼此所訂的租稅政策亦不相同。本文第伍章試圖提出一理論模型說明中央政府在面對異質地區的垂直外部性下如何有效率的訂定其租稅政策。 / The human desires are infinite but resources are scarce. Using resources effectively is the topic of the economics. In efficient analyses, the Pareto optimality is the highest criterion to accept. Based on Pareto efficiency, the basic idea is to obtain the most outputs by the least inputs. Therefore the efficiency measurement is to calculate the relative performance of inputs and outputs. The nonprofit organization and the public agencies have many outputs and inputs not easy to be quantified; hence, their efficiency is not easy to evaluate. This phenomenon doesn’t improve until DEA (Data Envelopment Analysis) was developed. However, the application of DEA concentrates nearly on the efficiency measurement of individual policy-making unit; the application is be rarely used in measuring the performance of the macro-economy. Chapter 4 of this dissertation measures and explains the variation in cost efficiency of the local governments in Taiwan area. Chapter 3 deals with the application the DEA to economic growth, estimating a combination of the tax burden(the ratio of tax revenue to GDP）and the tax structure(the ratio of indirect taxes to direct taxes)which would maximize the rate of growth of GDP of Taiwan. Efficiency is the core of economics, but the national government’s efficient goal is not as same as the local government’s. Because their goals are not consistent, thus the tax policies are different. Chapter 5 attempts to propose a theoretical model to explain how a national or federal government decides its tax policy in the vertical externalities happening in heterogeneous states.