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Sample Size Requirements for Pharmacogenetic Studies
No full text藥理遺傳研究將人體體質的差異納入藥理研究中，深入探討藥物與遺傳基因對藥效的影響性。藥理遺傳研究可依照是否採取隨機試驗步驟區分為觀察性藥理遺傳研究及試驗性藥理遺傳研究，本論文循序漸進介紹採用單一藥物只關心藥物反應與遺傳基因相關的病體－對照觀察性藥理遺傳研究，及延伸至使用多種藥物的試驗性藥理遺傳研究，萃取藥物反應與藥物試驗、遺傳基因與試驗－基因交互作用的相關訊息，運用由簡而繁的藥理遺傳研究設計勾勒出藥理遺傳研究個人化投藥目的藍圖；本論文針對每一種研究設計提出偵測相關訊息的分析方法並計算研究所需樣本數；此外，本研究不但採用群體為基礎的資料結構作為分析依據，更探討家庭為基礎的同胞對研究設計，給定相似的背景之下進行藥物、遺傳與藥效間的資料探勘步驟，以供研究人員處理族群混合的藥理遺傳研究方式。Pharmacogenetic studies investigate the inter-individual variability due to the genetic effect on drug response. Pharmacogenetic studies can be classified to experimental studies and observational studies with or without randomization. In this thesis, we aim to investigate the useful designs, from simple to delicate, in pharmacogenetic studies. In our framework, we use case-control study design to dissect the association between genetic effect and drug response when there is one drug treatment. Furthermore, when there are two or more treatment groups, we detect the effects of treatments, genotypes, and gene-treatment interaction on drug response under trial design. For each design we present the analysis methods for detecting association and the methods for calculation of required sample size. The family-based (sib pairs) design is especially discussed for the intention of setting up a robust design against population stratification.第一章 緒論 1
1.1 藥理遺傳研究 1
1.2 觀察性藥理遺傳研究 3
1.2.1 群體為基礎的病體(對藥物無反應)－對照(對藥物有反應)研究 4
1.2.2 家庭配對的病體(對藥物無反應)－同胞(對藥物有反應)研究 6
1.3 試驗性藥理遺傳研究 8
1.3.1 控制基因型的藥理遺傳試驗 9
1.3.2 未控制基因型的藥理遺傳試驗 10
1.3.2.1 使用兩種藥物，觀察兩種藥物療效差異及是否存在一個突變基因影響兩種藥物間藥效不一致的藥理遺傳試驗 11
1.3.2.2 使用多種藥物，觀察它們之間療效差異，存在單基因影響效應，並考慮試驗組與基因型交互作用效應的藥理遺傳試驗 12
1.3.2.3 使用多種藥物，觀察它們之間差異，存在多基因或其他影響因素影響藥物反應，多種交互作用的藥理遺傳試驗 13
1.4 樣本數計算之文獻回顧 14
1.5 研究動機與目的 17
第二章 研究方法 20
2.1 資料結構與符號定義 20
2.2 觀察性藥理遺傳研究之病體(對藥物無反應)－對照(對藥物有反應)研究 25
2.2.1 群體為基礎的病體(對藥物無反應)－對照(對藥物有反應)研究 25
2.2.2 家庭配對的病體(對藥物無反應)－同胞(對藥物有反應)研究 28
2.3 試驗性藥理遺傳研究之未控制基因型的藥理遺傳試驗 32
2.3.1 使用兩種藥物，觀察兩種藥物療效差異及是否存在一個突變基因影響兩種藥物間藥效不一致的藥理遺傳試驗 32
2.3.1.1 群體為基礎的藥理遺傳試驗 33
2.3.2 使用多種藥物，觀察它們之間療效差異，存在單基因影響效應，並考慮試驗組與基因型交互作用效應的藥理遺傳試驗 35
2.3.2.1 群體藥理遺傳試驗 35
2.3.2.2 同胞對藥理遺傳試驗 40
2.3.3 使用多種藥物，觀察它們之間差異，存在多基因或其他影響因素影響藥物反應，多種交互作用的藥理遺傳試驗 52
2.3.3.1 群體藥理遺傳試驗 52
2.3.3.2 同胞對藥理遺傳試驗 56
第三章 範例與模擬研究 60
3.1 觀察性藥理遺傳研究之病體(對藥物無反應)－對照(對藥物有反應)研究範例 60
3.1.1 群體為基礎的病體(對藥物無反應)－對照(對藥物有反應)研究範例 60
3.1.2 家庭配對病體(對藥物無反應)－同胞(對藥物有反應)研究範例 62
3.2 試驗性藥理遺傳研究之未控制基因型的藥理遺傳試驗範例 63
3.2.1 使用兩種藥物，觀察兩種藥物療效差異及是否存在一個突變基因影響兩種藥物間藥效不一致的群體藥理遺傳試驗範例 64
3.2.2 使用多種藥物，觀察它們之間療效差異，存在單基因影響效應，並考慮試驗組與基因型交互作用效應的群體藥理遺傳試驗範例 66
3.2.3 使用多種藥物，觀察它們之間差異，存在多基因或其他影響因素影響藥物反應，多種交互作用的藥理遺傳試驗模擬步驟 68
3.2.3.1 群體藥理遺傳試驗範例 71
3.2.3.2 同胞對藥理遺傳試驗範例 74
第四章 討論與建議 81
參考文獻 86
附錄I 群體資料結構雙標識基因聯合機率 88
附錄II 同胞對資料結構雙標識基因聯合機率 89
附錄III 單基因群體資料結構模擬程式 105
附錄IV 單基因同胞對資料結構模擬程式 107
附錄V Schlesselman (1974) 病體－對照樣本數公式推導 110
附錄VI Schlesselman (1982) 配對病體－對照樣本數公式推導 112
附錄VII Greenland (1985) 樣本數公式推導 114
附錄VIII Elston et al. (1999) 樣本數公式推導 116
附錄 IX Gauderman (2002)樣本數公式推導 11
Apply nonlinear optical microscopy to biodegradable materials and cancer diagnosis
No full text多光子顯微術使用近紅光作為激發光源、具有描掃深度深、可激發所有可見光波段的螢光及二倍頻訊號的優點使樣品不需染色; 自動光學切片使樣品不需切片並可沿深度掃瞄得到三維影像,是一種低侵入性生物三維造影技術。是非常有力的工具。我們可以把應用於生物可分解性的材料及正常與癌症組織的初步診斷。
第一部分 :生物可降解性的材料
組織工程為組織修復及器官複製帶來新希望，其所用的材料為生物可降解性。在此篇論文中，我們先嘗試使用多光子顯微術來觀測這些材料的非線性光學特性，作用未來鷹架與細胞間的交互作用的對照組。結果發現以上所掃瞄的生物可分解的薄膜的光譜多偏向藍光，膠原蛋白鷹架在水中會降解而使得二倍頻訊號降低等。
第二部分: 正常與癌症組織的初步診斷
鼻咽部位於鼻部與咽部90 度交會的隱密地帶。鼻咽癌乃東南華人特有之癌症。傳統診斷方式是組織病理切片, 製作需費時2 小時~1 天及需要醫生的長期經驗來判斷。於是我們利用多光子顯微術的優點，希望能藉此快迅區分出鼻咽組織中的正常細胞與癌細胞。並可做到傳統病理染切片染色難做到的定量分析。
實驗結果對於NPC 沒有區分出正常細胞及癌細胞，原因在於鼻咽部細胞種
類眾多，特別的是NPC 癌細胞會與正常細胞夾雜。
另一種對國人健康造成威脅是腎臟癌(Renal cell carcinoma)，我們可以使用二倍頻對自體螢光的指數及強度分佈圖等來區分正常腎組織及癌症腎組織。Multiphoton microscopy, which uses near infrared light as excitation light source,has deeper penetration depth, and automatic optical sectioning ability. It is a minimally
invasive bioimaging technique and can capable visible autofluorescences excitation. Thespecimens used for multiphoton microscopy need not be sliced and dyed, and the imagesobtained clearly displays cell morphology, collagen, and elastins. In this thesis, we apply
multiphoton and second harmonic generation microscopy to biodegradable materialimaging and to cancer diagnosis.
Part I: Biodegradable scaffolds and films
Tissue engineering brings new hope for tissue recovery and organ replication. One important aspect of tissue engineering is utilizing suitable biodegradable material as a scaffold. We observed in these biomaterial’s nonlinear optical properties. We found that most biodegradable materials emit blue light. Therefore, if the cell’s autofluorescence is weak, green or red fluorescence protein should be chosen to transfect
the cells.
Part II：Preliminary diagnosis of Normal and cancerous tissue
Nasopharynx is the concealed region where the pharynx and the nose intersect each other perpendicularly. Nasopharyngeal carcinoma(NPC) is a type of cancer peculiar to southeaster Chinese. The traditional method of diagnosing nasopharyngeal carcinoma is with histology, which can be time consuming to prepare.
We attempted to utilize multiphoton and second harmonic generation microscopy to distinguish normal nasopharyngeal cell from nasopharyngeal carcinomatous cell. We
find that multiphoton microscopy cannot effectively make the distinction. The reason is that naspharyngeal cells are numerous, and the cancer cells of NPC are mixed with the normal cells.
Kidney cancer (Renal cell carcinoma) is another cancer that threatens the health of Chinese people. In this case, we were able to use an index of second-harmonic generation
to autofluorescence and an intensity distribution diagram to distinguish the normal kidney tissue from cancerous kidney tissue.目錄…………………………………………………………I
致謝…………………………………………………………Ⅲ
英文摘要……………………………………………………Ⅳ
中文摘要……………………………………………………Ⅴ
圖表目錄……………………………………………………Ⅵ
1 緒論1
1.1 組織工程與生物可分解性材料簡介1
1.2 癌症研究的重要性2
2 傳統醫學檢驗方法7
2.1 非光學診斷法7
2.2 光學顯微術與組織切片8
3 非線性光學顯微術13
3.1 單光子與雙光子吸收15
3.2 倍頻產生的機制19
4 多光子顯微術儀器23
4.1 顯微鏡之前的光處理23
4.2 顯微系統與光子資訊處理25
5 生物可分解性材料的非線性光訊號
5.1 材料選擇27
5.2 材料的非線性光學反應28
6 區分鼻咽癌組織與正常組織
6.1 鼻咽及鼻咽癌簡介39
6.2 實驗方式與結果討論40
7 腎細胞上皮癌組織與正常腎上皮組織之
非線性顯微影像
7.1 腎及腎細胞上皮癌簡介47
7.2 光訊號飽和測試48
7.3 量化分析及圖表比較50
7.4 傳統H.E.染片結果62
7.5 結果解釋62
8 結論64
附錄:上皮組織65
參考文獻6
Seismic Velocity Anomalies beneath the Tatun Volcano Group, Northern Taiwan
No full text 臺灣北部大屯火山群（Tatun Volcano Group, 簡稱TVG）地表地熱現象明顯，根據經驗定義很可能是活火山。大屯火山群臨近臺灣的首都臺北，如果大屯火山群有活動，對臺灣勢必有重大衝擊，因此學者們都希望能確認大屯火山群的活動性，以及底下有無岩漿庫存在。 地球物理學家研究火山區域常會利用區域地震層析法（local seismic tomography），得到地底下震波速度快慢的分佈，推測地下構造的物理特性。然而大屯火山群的地震主要都發生在淺部地殼，利用區域地震層析法無法得到清楚的深部資訊，因此本研究改利用遠距大型地震產生的地震波到時（the arrival time of tele-earthquakes）去觀察地下速度構造，如果震波穿過低速帶，就會有到時延遲的現象。 本研究使用大屯火山觀測站提供的2014年地震波形資料，利用交差相關函數（cross-correlation function）幫助判斷各個測站收到的地震波到時的相對時間，並以最小平方法得到理論到時，比較各個測站收到的地震波到時有無延遲現象以及延遲時間，去判斷該測站收到的震波在傳遞路程中是否受到其他物質影響造成震波到時延遲的現象，以尋找低速帶位置，並進一步利用有延遲現象的波傳路徑尋找波線交集，確認低速帶的位置與深度。 研究結果顯示：從地球對面來的地震（如；智利），以八煙測站為中心，八煙測站與附近測站（如：大油坑測站）收到的地震波到時皆有延遲的現象，顯示低速帶存在該區域下方。而透過其他方向來的地震，利用到時延遲的波線做交集，亦顯示了交集位置位在八煙測站偏西下方，在八煙與大油坑區域，深度約10 km。顯然在八煙、大油坑與附近區域下方存在一個低速帶，可能暗示著有部份融熔物質存在。 The Tatun Volcano Group (TVG) is situated in northern Taiwan, where hydrothermal activity is prevailing. According to the empirical definition of active volcano, TVG can be categorized as composed of active volcanoes. Therefore, scientists are eager to know whether there is a magma chamber beneath the TVG. Since earthquakes occurred in this area are too shallow to get a good local seismic tomography, it’s difficult to estimate possible velocity anomaly of magma chamber and/or hydrothermal system. Instead, we use natural seismic waves generated by large earthquakes worldwide to image the possible velocity anomaly beneath TVG. We systematically compare the differences of first arrival times from tele-seismic earthquakes in 2014 for finding any low-velocity zone within the crust. The waveform data was obtained from Taiwan Volcano Observatory – Tatun (TVO). If the seismic waves pass the low-velocity zone, the arrival-time will be delayed. We used cross-correlation function to get first-arrival times from those earthquake records, and calculated theoretical arrival times through least squares method. Then, we compared “observed” arrival times and “calculated” arrival times for examining possible delay as seismic waves passing through the low-velocity zones beneath TVG if there is any. The results show that arrival times of some of the tele-earthquakes occurred on the other side of the Earth appear to have significant delay, particularly for those recorded at Station Ba-Yan (BY) and near by. In addition, we drew the ray-paths of those earthquake waves with arrival-time delay, and tried to find the intersection of ray-paths. The obtained “crossing area” is under BY and Da-You-Keng (DYK) area, about 10 km deep. This may imply the existence of possible low-velocity zones, which is likely an indication of partial melting materials, existing beneath Stations BY and DYK
Use of transoesophageal echocardiography during cardiac arrest in patients undergoing elective non-cardiac surgery.
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Complications of intraoperative transesophageal echocardiography in adult cardiac surgical patients- Experiences of two institutions in Taiwan
No full textFactors affecting arsenic mobilization for arsenic-contaminated groundwater in Blackfoot disease endemic region in Taiwan
No full text地下水中砷的汙染，在世界各地皆造成嚴重的人體危害，而導致地下水中砷濃度升高的因素，仍有待探討。台灣等許多國家的研究發現，砷汙染案例多位於農業用地，然而農業行為中肥料的施用對地下水中砷移動性的影響，尚未明確。本研究的主要目的有二，一為調查台灣烏腳病疫區與非烏腳病疫區間微生物族群的差異；二為研究烏腳病疫區土壤樣品中，肥料的施用與微生物，對於砷由底泥釋放至地下水之影響。本研究分別使用烏腳病疫區與非烏腳病疫區之底泥，添加無機氮肥與磷肥後，並培養於好氧與厭氧環境2及4個月。研究結果顯示，經過2個月的培養，烏腳病疫區與非烏腳病疫區之樣品，顯示相當不同的微生物群相。當添加25與100 mg/L磷肥並培養於厭氧環境4個月，人工地下水中的砷濃度明顯的增加，其中三價砷的濃度由66.4 ± 4.6 μg/L (未添加磷肥的未滅菌樣品) 上升至 81.6 ± 8.6 (添加25 mg/L磷肥的未滅菌樣品) 及110.5 ± 6.0 μg/L (添加100 mg/L 磷肥的未滅菌樣品)。相反的，添加氮肥的樣品並未顯示出砷移動性的增加。本研究同時也發現，在高砷濃度的磷肥樣品中，鐵、錳、鉀、納、鈣與鎂的濃度也相對增加，說明上述元素極有可能參與砷的釋出反應。除此之外，透過微生物群相的分析，本研究發現隨著人工地下水樣品中砷濃度的上升，優勢物種由α-Proteobacteria 轉變成β-及γ-Proteobacteria。本研究提供直接的證據，顯示磷肥與微生物的存在皆可調控烏腳病疫區中的砷由底泥釋出至地下水，故本研究建議，農業上肥料的施用行為須顧及其導致地下水砷汙染之潛在可能。Arsenic (As) contamination of groundwater is a worldwide public health concern. Arsenic affected areas in Taiwan were reported mostly in farmland, yet the factors of arsenic mobilization in aquifer remain uncharacterized. This study investigated microbial communities between sediments from the blackfoot disease (BFD) and non-BFD endemic area. The results showed that after 2 months incubation, the microbial community showed significantly different in the BFD and non-BFD endemic area. In addition, the effects of fertilizers and microorganisms on arsenic mobilization in the sediments of the BFD endemic area were examined. Microcosm experiments were performed amending with inorganic nitrogenous or phosphorus fertilizers for 2 and 4 months under aerobic and anaerobic conditions. The results showed that microcosms amended with 25 and 100 mg/L phosphorus fertilizers (dipotassium phosphate) showed significant increases in arsenic concentrations in aqueous phases, with an arsenite (As(III)) concentration increase from 66.4 ± 4.6 μg/L (original non-sterilized sediments) to 81.6 ± 8.6 (25 mg/L dipotassium phosphate, non-sterilized sediments) and 110.5 ± 6.0 μg/L (100 mg/L dipotassium phosphate, non-sterilized sediments) under anaerobic condition. However, the addition of nitrogenous fertilizers (ammonium sulfate) showed little effect on the arsenic mobility. Moreover, concentrations of iron, manganese, potassium, sodium, calcium, and magnesium were increased in the aqueous amended with dipotassium phosphate, suggesting that multiple metal elements may take part in the arsenic release process. Furthermore, microbial analysis indicated that the dominant microbial phylum was shifted from α-Proteobacteria to β- and γ-Proteobacteria when the As(III) was increased and phosphate was added in the aquifer. Our results provide evidence that both phosphorus fertilizers and microorganisms can mediate the release of sedimentary arsenic to groundwater in the BFD region, suggesting that agricultural activity such as usage of fertilizers should be taken into consideration
Immediate Extubation In the Operating Room After Cardiac Operations with Thoracotomy and Sternotomy
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