From a Viewpoint of Causal Graph

학위논문(석사) -- 서울대학교대학원 : 데이터사이언스대학원 데이터사이언스학과, 2024. 2. 이상학.Studies aimed at estimating the causal effects of interventions, treatments, or events occurring in the middle of time-series data have been attempted in various fields. Among such studies, Synthetic Control Methods (SCMs), initially introduced by Abadie et al. (2010), have been applied in various empirical research cases (Abadie et al. 2010, 2015; Doudchenko and Imbens 2016) to estimate causal effects of treatments on outcomes. Recently, to address weaknesses of vanilla SCM, some extensions such as penalized SCMs (Abadie and LHour 2021) and combination of matching and SCM (Kellogg et al. 2021), which select control units close to the treated unit by additional information, have also introduced. However, these studies have not considered casual structures. In particular, they imply the strong assumption that the coefficients of each covariate with respect to the outcome variable are the same for all control units and the treated unit, which means that the causal relationships of every unit are homogeneous. Unfortunately, in practice, it is common for distinct entities or domains to have different causal relationships (Glymour et al. 2019; Saggioro et al. 2020; Huang et al. 2020). Therefore, errors may be inherent in the estimation of synthetic control if the SCMs are applied without considering causal relationships and subsequently lead to misunderstanding of causal effects. In this paper, we explore the issues of the SCMs from the viewpoint of causal graph by using linear Structural Equation Models (SEM) (Pearl 2000). We demonstrate the assumptions implied by the SCMs and empirically confirm the issues that arise when these assumptions are not satisfied. We propose a method called Causal Structurally Regularized Synthetic Control, abbreviated as CSRSC. By leveraging information on causal structures, CSRSC distinguishes between heterogeneous and homogeneous control units and then assigns greater weights to control units with causal structures similar to that of the treated unit. Through this process, CSRSC construct a causally comparable synthetic control incorporating homogeneous control units.시간의 흐름에 따라 관측되는 데이터의 중간에 발생한 중재, 처치 또는 사건이 어떠한 변수에 미치는 인과효과를 측정하고자 하는 연구는 다양한 분야에서 시도되어 왔다. 이러한 연구 중 Abadie와 Gardeazabal에 의해 처음 소개된 통제집단합성법(Synthetic Control Methods)(Abadie et al. 2010)은, 관측된 시계열 데이터를 토대로 인과 효과를 측정하는 도구로서 다양한 실증 연구 사례에 활용되었다(Abadie et al. 2015; Tirunillai and Tellis 2017). 최근에는, 큰 수의 통제집단이 존재하는 상황에서 통제집단합성법이 겪게 되는 내삽 편향 또는 중복해로 인한 취약점을 보완하고자,처치집단과 통제집단의 특성 차이를 고려하는 벌점화 통제집단합성법(Abadie and LHour 2021), 매칭 통제집단합성법(Kellogg et al. 2021) 등이 등장했다. 그러나, 앞선 연구들은 통제집단과 처치집단 간의 인과구조적 유사성은 고려하지 않았다. 특히, 통제집단합성법의 선형 모델은 각 공변량이 종속변수에 대하여 갖는 선형계수가 통제집단과 처치집단에서 동일하다는 가정을 내포하고 있는데,이것은 모든 집단의 인과관계가 동일하다는 것을 의미한다. 그러나,현실에서는 서로 다른 개체가 서로 다른 양상의 인과관계를 갖는 경우가 많다(Glymouret al. 2019; Saggioro et al. 2020; Huang et al. 2020). 때문에 집단 간 인과관계의 차이를 고려하지 않고 통제집단합성법을 그대로 사용할 경우, 합성통제집단의 추정에 오차가 생길 수 있으며,잘못된 인과 효과 해석으로 이어질 수 있다. 본 논문에서는 통제집단합성법을 선형 인과구조적 모델(linearStructuralEquationModels)(Pearl 2000) 관점에서 해석함으로써,해당 방법론이 내재하고 있는 인과적 전제들을 확인하고, 그러한 전제가 충족되지 않았을 때에 발생하는 문제를 살펴보고 실험을 통해 확인한다. 나아가,이러한 문제 상황에서도 비교 가능한 합성통제집단을 생성하는 기법인 CSRSC: 인과구조로 정규화한 통제집단합성법(Causal Structurally Regularized Synthetic Control)을 제시한다. CSRSC는 인과구조 정보를 활용하여 처치집단의 인과구조와 동질적 인과구조를 가진 통제집단에 가중치를 부여하도록 유도함으로써, 이질적 인과구조를 가진 통제집단이 존재할 때에도 안정적으로 동질적 통제집단을 선택하고 그들에게 더 높은 가중치를 부여하여, 인과적으로 비교 가능한 합성통제집단의 생성을 가능케 한다.Abstract i 1 Introduction 1 2 Preliminaries 4 2.1 Linear Structural Equation Models 4 2.2 Causal Discovery 7 2.2.1 NOTEARS 7 2.2.2 DYNOTEARS 9 2.3 Synthetic Control Methods 11 3 Limitation of Synthetic Control Methods 14 3.1 Formulating SCMs into Linear SEMs 14 3.2 When does synthetic control work correctly? 16 3.3 When does synthetic control work incorrectly? 17 3.4 Experiment for the Three Cases 22 3.4.1 Synthetic Data 23 3.4.2 RMSPE/C-RMSPE 25 3.4.3 Results 27 4 Regularized Synthetic Control by Causal Structure 33 4.1 Method 33 5 Experiment 36 5.1 Experimental Setting 36 5.2 Empirical Results 37 6 Discussion and Conclusions 42 6.1 Discussion 42 6.2 Conclusions 43 Bibliography 45 Abstract in Korean 48석

지방의회의 행정통제에 관한 연구 : 인천시의회의 질문권 행사를 중심으로

학위논문(석사)--서울대학교 행정대학원 :행정학과 행정학전공,2000.Maste

속격 및 명사 병치 구성에 관한 연구: 한국어와 불어를 중심으로

This article aims to give an explanation to the fact that French genitive constructions N1 de N2 can be translated in Korean sometimes as genitive construction N2 ui Nl, sometimes as noun parallel construction (henceforth NPC) N2 N1. We suppose that in Korean NPCs are formed by one of the following processes: (i) derivation from genitive construction by incorporation of N2 onto N1, (ii) lexical composition, (iii) phonetic deletion of the Case-marker ui. In Korean NPCs, N2 is in most cases an internal argument of N1. And in general, the incorporated element should be an internal argument of the incorporating element. So we propose that NPC can be formed from genitive construction when N2 is an internal argument of N1 and is incorporated onto ít. It follows that the Korean counterpart of French genitive constructions will be NPC if the incorporation in question takes place, and otherwise it will be a genitive construction as in French. As for (ii), we presume that in Korean, lexical composition can derive the form N2 N1 too. But as lexical composition often depends on cultural needs and is not a productive and systematic process, there are not many Korean exemples of lexical composition which translate French genitive constructions. Finally we suppose that in Korean the genitive marker ui can be phonetically invisible just like nominative or accusative markers. If so, the third form of NPC will be obtained. But this third possibility is permitted only in colloquial Korean

소음에 의한 와우 손상의 약리학적 치료

학위논문(박사)--아주대학교 일반대학원 :의생명학과,2014. 2Acknowledgement i ABSTRACT iii TABLE OF CONTENTS vi LIST OF FIGURES x LIST OF TABLES xii I. INTRODUCTION 1 A. Noise-induced hearing loss 1 1. Definition 1 2. Characteristics 1 3. Pathophysiology 2 B. Preventive methods 6 1. Hearing protective devices 6 2. Pharmacological treatment 6 C. Pravastatin 7 D. Methylene blue 8 E. Cysteinyl leukotriene receptor antagonist 9 II. MATERIALS AND METHODS 11 A. Experimental groups 11 1. Pravastatin experiment 11 2. Methylene blue experiment 11 3. Cysteinyl leukotriene receptor antagonist experiment 12 B. Experimental procedures 12 1. Noise exposure 12 2. Auditory Brainstem Response (ABR) analysis 13 3. Immunohistochemistry 13 4. Surface preparation 14 5. Electron microscopy 16 6. Tissue homogenization and Western blotting 17 7. Measurement of serum cholesterol content 17 8. Rac1 activity assay 17 9. Cell culture and viability 18 10. Intracellular ATP assay 19 11. Mitochondrial complex IV activity assay 19 12. Total RNA extraction and RT-PCR 20 13. Determination of cysteinyl leukotriene concentration in cochlear homogenates 21 14. Gene expression profiling and data analysis 21 15. Statistical analysis 23 III. RESULTS 25 A. Pravastatin attenuates noise-induced cochlear injury 25 1. Administration of pravastatin before noise exposure attenuated noise-induced threshold shift 25 2. Pravastatin pretreatment reduced hair cell loss after acoustic overstimulation 26 3. Pravastatin pretreatment attenuated reactive oxygen species (ROS) generation in the cochlea after acoustic overstimulation 32 4. Protective effect of pravastatin is associated with decreased Rac1 activity in vivo 33 B. Methylene blue alleviates oxidative stress and preserves synaptic structures 37 1. Administration of methylene blue before noise exposure attenuated noise-induced threshold shift 37 2. MB pretreatment reduced hair cell loss after acoustic overstimulation 38 3. MB pretreatment attenuated both ROS and RNS generation in the cochlea after acoustic overstimulation 42 4. MB treatment selectively ameliorated impaired mitochondrial electron transport chain (ETC) in inner ear cell line and in vivo 46 5. NT-3 was upregulated in noise-exposed cochlea by MB pretreatment 48 6. Improved mitochondrial function and upregulation of NT-3 by MB protected cochlear efferent and afferent synaptic structures from acoustic overexposure 51 C. Cysteinyl leukotriene signaling affects noise exposed cochleae 54 1. Leukotriene receptor gene expression in normal cochlear tissue of mice 54 2. Induction of LT signaling in the noise exposed mouse cochlea 54 3. Temporal and spatial expression pattern of CysLT1 receptor after noise exposure 58 4. Noise exposure increased concentration of cochlear CysLTs 58 5. Blockade of CysLT signaling using montelukast attenuated noise induced threshold shift 61 6. Montelukast reduced hair cell loss after acoustic overstimulation 64 7. Montelukast affected gene expression patterns after acoustic overstimulation 67 8. Inhibition of MMP-3 after noise exposure attenuated cochlear injury 67 IV. Discussion 73 V. Conclusion 87 References 88 국문요약 99DoctoralNoise-induced hearing loss (NIHL) has become one of the most common occupational disease in both developing and developed countries and is also the major contributing factor of age-related hearing loss. NIHL is uniquely preventable sensorineural hearing loss and researchers have investigated additional preventive strategy based on the discovered pathogenesis of NIHL. The pathogenetic mechanisms of NIHL are considered as multifactorial such as glutamate excitotoxicity, ischemia-reperfusion injury, ATP depletion and reactive oxygen species (ROS) formation. Among them, I determined that blockade of ROS formation is one of the most efficient targets of prevention using an animal model of NIHL. Firstly I reported that noise exposure induced superoxide formation through the activation of NADPH oxidase complex and inhibition of complex formation by pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which is a rate-limiting enzyme of cholesterol synthesis, before noise exposure protected against cochlear injury in BALB/c mice. Noise exposure produced both compound threshold shift (CTS) and permanent threshold shift (PTS) over 40 dB at 16 and 32 kHz. Pretreatment with pravastatin (25 mg/kg) for 5 days significantly decreased both CTS and PTS. Pravastatin also reduced hair cell death after noise exposure in the cochlea which was identified by surface preparation and scanning electron microscopy (SEM). It also reduced the formation of noise-induced 4-hydroxynonenal (4-HNE), a byproduct of lipid peroxidation. Activation of Rac1, one of the subunits of the NADPH oxidase complex was inhibited by the administration of pravastatin due to its pleiotropic effect. Secondly, I also showed that methylene blue (MB) pretreatment for 4 consecutive days significantly decreased both CTS and PTS after exposure to intense broad band noise for 3 h. MB reduced outer hair cell (OHC) death in the cochlea that was identified by surface preparation and SEM, and it also reduced ROS and RNS formation after noise exposure. MB significantly protected against rotenone- and antimycin A-induced cell death, and also reversed ATP generation in vitro. Furthermore, MB effectively attenuated noise-induced impairment of complex IV activity. MB also increased the neurotrophin-3 (NT-3) level which could affect synaptic connections between hair cells and spiral ganglion neurons in the noise-exposed cochlea. MB promoted the conservation of both efferent and afferent nerve terminals on the OHC and inner hair cells. Finally, I found the expression of cysteinyl leukotriene type 1 receptor (CysLT1) were increased at 3 days after noise exposure, but not in control mice. Enhanced CysLT1 expression was mainly occurred in the spiral ligament and the organ of Corti. Expression pattern of upstream enzyme 5-lipoxygenase was similar to CysLT1. Consistent with these results, elevated cysteinyl leukotrienes (CysLTs) concentration was also accompanied, as compared to control mice. Posttreatment of leukotriene receptor antagonist (LTRA), montelukast (10 mg/kg) for 4 consecutive days significantly decreased not CTS but PTS. Montelukast also reduced hair cell death after noise exposure in the cochlea which was identified by surface preparation and SEM. Taken together, pharmacological management using pravastatin, MB and montelukast will be helpful for providing novel strategies for the prevention of NIHL and other hearing loss-related diseases possibly related to oxidative stress or leukotriene signaling