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研究生: 張鈞傑
Chun-Chieh Chang
論文名稱: 深度學習系統應用於子宮內膜癌微衛星不穩定與組織學分級預測
Application of deep learning systems to predict microsatellite instability and histological grade in endometrial cancer
指導教授: 王靖維
Ching-Wei Wang
口試委員: 王靖維
Ching-Wei Wang
趙載光
Tai-Kuang Chao
許維君
Wei-Chun Hsu
許昕
Hsin Hsiu
鄭智嘉
Chih-Chia Cheng
學位類別: 碩士
Master
系所名稱: 應用科技學院 - 醫學工程研究所
Graduate Institute of Biomedical Engineering
論文出版年: 2023
畢業學年度: 111
語文別: 中文
論文頁數: 65
中文關鍵詞: 子宮內膜癌弱監督式學習深度學習微衛星不穩定全景域影像組織病理學
外文關鍵詞: Endometrial cancer, Weakly supervised learning, Whole slide image, Deep learning, Microsatellite instability, Morphology
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  • 子宮內膜癌是女性生殖系統中常見的惡性腫瘤之一,且其發病率在過去幾十年中呈現上升的趨勢。而如何將子宮內膜癌在組織病理學上有效分出其分級以及在分子分型的分類上來辨識出其微衛星不穩定 (MSI) 狀態就成為了重要的課題。
    本研究使用了癌症基因族譜 (TCGA) 與台灣台北國防醫學中心三軍總醫院所提供被診斷為子宮內膜癌之患者的全景域玻片影像 (WSI)。其中在 TCGA 資料集內,共有 529 位子宮內膜癌患者,並利用Polymerase Chain Reaction(PCR) 和 Next­Generation Sequencing(NGS) 兩種技術來進行 MSI 狀態的標註。在台灣台北國防醫學中心三軍總醫院資料集內,共有 225 位子宮內膜癌患者,並利用免疫組織化學 (Immunohistochemistry,IHC) 之四種 MMR 酶 (MLH1,MSH2,MSH6,PMS2)的缺失數量來進行 MSI 狀態的標註。並依照患者的組織學分級進行組別劃分,分別為判斷組織學分級的 ((G1,G2),(G3,Serous carcinoma)),以及判斷 MSI 狀態的(G1,G2)、(G3)、(G1,G2,G3)。
    本研究中藉由蘇木精­伊紅染色 (Hematoxylin and eosin, H&E) 影像,結合深度學習提出一個用於子宮內膜癌組織學分級和 MSI 狀態的預測系統。並與其他先進的深度學習方法進行比較,其中包括:CLAM,TOAD 和 MIL RNN。而在 NGS 技
    術所標註的 TCGA 資料集有良好的結果。在 G1,G2 組別中,Accuarcy 為 0.887、Precision 為 0.875、F1­score 為 0.925、Sensitivity 為 0.980、MSS 為 0.823。在 G3組別中,Accuarcy 為 0.836、Precision 為 0.813、F1­score 為 0.871、Sensitivity 為 0.938、MSS 為 0.814。證明了透過此方法能輔助預測患者在 NGS 之標註下的 MSI狀態。


    Endometrial cancer is one of the common malignant tumors in the female reproductive system, and its incidence has shown an upward trend in the past few decades. How to effectively classify endometrial cancer into histopathological grades and identify its microsatellite instability (MSI) status in terms of molecular typing has become an important issue.
    This study used The Cancer Genome Atlas Program (TCGA) and the National Defense Medical Center, Tri­Service General Hospital in Taipei, Taiwan, with whole slide images (WSI) of patients diagnosed with endometrial cancer. Among them, in the TCGA
    data set, there are 529 patients with endometrial cancer, and the two technologies of Polymerase Chain Reaction (PCR) and Next­Generation Sequencing (NGS) are used to mark the MSI status. In Taiwan National Defense Medical Center, Tri­Service General Hospital dataset, there are 225 patients with endometrial cancer, and the deletion of four MMR enzymes (MLH1, MSH2, MSH6, PMS2) in immunohistochemistry (IHC) was used to determine the MSI status. According to the histological grade of the patients, the groups are divided into ((G1, G2), (G3, Serous carcinoma)) for judging the histological grade, and (G1, G2), (G3), (G1,G2,G3) for judging the MSI status.
    In this study, hematoxylin­eosin (H&E) staining images combined with deep learning proposed a prediction system for endometrial cancer histological grading and MSI status. And compared with other advanced deep learning methods, including: CLAM, TOAD and MIL RNN. However, the TCGA dataset marked by NGS technology has good results. In the G1 and G2 groups, Accuarcy is 0.887, Precision is 0.875, F1­score is 0.925, Sensitivity is 0.980, and MSS is 0.823. In the G3 group, Accuarcy was 0.836, Precision was 0.813, F1­score was 0.871, Sensitivity was 0.938, and MSS was 0.814. It is proved that this method can assist in predicting the MSI status of patients under NGS labeling.

    摘要 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II 致謝 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III 目錄 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV 圖目錄 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V 表目錄 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI 第一章 緒論 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.1 研究動機 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.2 研究目標 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.3 論文貢獻 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.4 論文架構 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 第二章 研究背景. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1 樣本製備及染色方法 . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.2 醫學影像應用深度學習之文獻 . . . . . . . . . . . . . . . . . . . . . . 4 2.2.1 弱監督式學習 (Weakly supervised learning) . . . . . . . . . . . 5 2.2.2 分割 (Segmentation) . . . . . . . . . . . . . . . . . . . . . . . . 6 2.2.3 分類 (Classification) 及預測 . . . . . . . . . . . . . . . . . . . . 7 第三章 研究方法. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.1 腫瘤組織分割模型 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.2 AI 訓練策略: 分類預測模型與最佳模型選擇 . . . . . . . . . . . . . . 15 3.2.1 分類預測模型 . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.2.2 最佳模型選擇 . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.3 決策推理策略:分割圖像選擇與最終決策 . . . . . . . . . . . . . . . 21 第四章 實驗設計與結果 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.1 實驗資料集介紹 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.2 實驗設備及設置介紹 . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.3 實驗結果 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.3.1 量化分析方法 . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.3.2 TCGA NGS dataset 之 MSI 量化分析結果 . . . . . . . . . . . . 31 4.3.3 TCGA PCR dataset 之 MSI 量化分析結果 . . . . . . . . . . . . 34 4.3.4 NDMC dataset 之 MSI 量化分析結果 . . . . . . . . . . . . . . 37 4.3.5 TCGA 與 NDMC dataset 之組織學分級量化分析結果 . . . . . 40 4.3.6 腫瘤組織分割結果 . . . . . . . . . . . . . . . . . . . . . . . . 42 第五章 結論與未來展望 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 5.1 結論 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 5.2 未來發展 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 參考文獻 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

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