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研究生: 蘇子竣
Su, Zi-Jun
論文名稱: 使用偽階層式標籤以改進治療性肽的功能分類
Improving identification of functional therapeutic peptides by pseudo hierarchical labeling
指導教授: 張天豪
Chang, Tien-Hao
學位類別: 碩士
Master
系所名稱: 電機資訊學院 - 電機工程學系
Department of Electrical Engineering
論文出版年: 2024
畢業學年度: 112
語文別: 中文
論文頁數: 60
中文關鍵詞: 偽標籤階層式標籤多標籤深度學習治療性肽
外文關鍵詞: Pseudo label, Hierarchical label, Multi-label, Deep learning, Therapeutic peptide
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  • 治療性肽(therapeutic peptide)指的是具有醫療功能的短序列蛋白質,而使用到治療性肽的療程就被稱之為胜肽療法(peptide therapy)。胜肽療法因為比起傳統療法來說具有對人體低毒性、容易被人體分解、高選擇性等等多種好處,已是現代生醫領域中的不可忽視的研究重點之一。
    治療性肽的功能非常多樣,現今已被證實的功能就包括了抗微生物、抗寄生蟲、抗腫瘤、抗真菌、抗病毒、抗細菌等多種反應目標,足以顯示其種類之廣泛,且一條肽鍊可同時具備多種反應對象,如抗葛蘭氏陽性菌肽常常同時具有抗葛蘭氏陰性菌的能力,精準辨認治療性肽的功能是胜肽療法中一個重要的課題。
    傳統上一般透過生物實驗的方式來驗證肽鏈的功能,但生物實驗較為昂貴且耗時,在機器學習技術蓬勃發展的今日,許多研究都嘗試了比較快速的傳統機器學習或深度學習來建構肽鏈的分類模型,也得到了不錯的表現,證實了透過機器學習方法來分類治療性肽是可行的。
    在蒐集並整理相關研究後,發現多數研究方法是獨立對每種治療性肽進行分類,較少考慮胜肽種類之間是否具備關聯性。即使有,多數也僅視為同一層級的胜肽群使用。但實際上,例如抗菌肽我們可以依照其對象進一步細分為抗葛蘭氏陽性菌和抗葛蘭氏陰性菌兩種類。若以階層式方式設計,不僅可以讓模型學習不同層級問題的知識,還可以簡化問題並幫助模型學習。
    本研究建立了一個階層式的卷積神經網路分類器。首先模型將學習如何判斷肽鏈是否具有治療功能的高層級知識,此時分類標準為假定的治療性肽,故稱之為偽標籤,後續再進一步去學習分辨特定的治療功能,例如抗腫瘤或抗病毒,最後再混合前面兩層級所學出來的特徵以強化分類表現。在與相關研究比較中,本研究所提出的模型在多種治療性肽的馬修斯相關係數得到了更好的表現。

    Therapeutic peptides are short protein sequences that have the ability to fight off illnesses. The term "therapeutic peptides" is derived from the concept of "peptide therapies," which refers to treatments utilizing these peptides. Compared to traditional treatments, peptide therapies offer many benefits, such as low toxicity, easier metabolism by the human body, and high selectivity. These advantages make peptide therapies indispensable in medical developments.
    Before any peptide is deployed for practical usage, we must first verify its targets and mechanisms. Many kinds of therapeutic peptides have been discovered, including anti-microbial peptides, anti-parasite peptides, anti-cancer peptides, anti-fungal peptides, anti-virus peptides, and anti-bacterial peptides. Additionally, a peptide sequence can have multiple reactions toward various target cells. For example, a peptide that is effective against Gram-positive bacteria is likely to also have an effect on Gram-negative bacteria. Therefore, efficiently classifying these peptides' functions is critical.
    Traditionally, we use biological experiments to test peptide sequences, but these experiments are costly and inefficient. Nowadays, many researchers have introduced computational methods into peptide classification, and the results indicate that these computational approaches can yield incredible results.
    After collecting and organizing relative works, it was found that most research methods classify each type of therapeutic peptide independently, with little consideration of potential relationships between different peptide types. Even in cases where such relationships are considered, such as in methods like MLBP, they are often treated as belonging to the same hierarchical level. In practice, however, anti-bacterial peptides can be further subdivided based on their targets into categories like anti-Gram-positive and anti-Gram-negative peptides. Designing a hierarchical approach allows the model to learn knowledge at different levels of granularity, simplifying the problem and aiding in model learning.
    This study establishes a hierarchical convolutional neural network classifier. Initially, the model learns high-level knowledge to determine whether a peptide sequence has therapeutic functions, using a pseudo label since the classification criterion does not encompass all real therapeutic peptides. Subsequently, it delves deeper to learn specific therapeutic functions, such as anti-cancer or anti-viral properties. Finally, the features learned at these two levels are combined to enhance classification performance. Compared with related studies, the proposed model achieves better Matthews Correlation Coefficient (MCC) performance across various therapeutic peptides.

    第一章 緒論 1 第二章 相關研究 3 第2.1節 治療性肽 3 第2.2節 多肽分類研究 4 第2.2.1節 Ampfun 4 第2.2.2節 IAMP-2L 5 第2.2.3節 IAMP-RAAC 6 第2.2.4節 Pep-CNN 7 第2.2.5節 MLBP 8 第2.3節 單肽分類研究 9 第2.3.1節 Shen 9 第2.4節 深度學習架構 11 第2.4.1節 卷積層( Convolution Layer ) 11 第2.4.2節 平均池化層( Average Pooling Layer ) 12 第2.4.3節 自適應平均池化層( Adaptive Average Pooling Layer ) 13 第2.4.4節 全連接層( Fully Connected Layer ) 13 第2.4.5節 Deep Residue Network( ResNet ) 13 第2.4.6節 Densely Connected Convolution Network( DenseNet ) 14 第2.4.7節 Squeeze and Excitation Network( SENet ) 15 第三章 研究方法 17 第3.1節 資料集 17 第3.2節 資料前處理 18 第3.2.1節 資料充填與截斷 18 第3.2.2節 偽多標籤資料集 18 第3.3節 資料編碼 19 第3.3.1節 序列編碼( Sequence Encoding) 19 第3.3.2節 標籤設計( Labeling ) 20 第3.4節 模型架構 20 第3.4.1節 特徵抽取部件( Feature extractor component ) 21 第3.4.2節 特徵融合部件( Embedding mixer component ) 23 第3.4.3節 分類部件( Classifier component ) 24 第3.4.4節 組合模型 25 第3.5節 模型訓練與驗證流程 25 第3.5.1節 訓練與驗證資料集 26 第3.5.2節 模型訓練流程 26 第3.5.3節 交叉驗證 28 第四章 研究結果 29 第4.1節 效能評估標準 29 第4.2節 與現行其他方法的比較 30 第4.3節 模型與訓練消融實驗 31 第4.3.1節 特徵混合部件的重要性 32 第4.3.2節 訓練方法的重要性 33 第五章 討論 36 第5.1節 治療性肽對於結果之影響 36 第5.1.1節 胜肽關聯性對於結果之影響 36 第5.1.2節 胜肽資料集大小對於結果之影響 38 第5.2節 模型視覺化 40 第六章 結論 43 第6.1節 結論 43 第6.2節 未來展望 43 參考資料 44

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