Machine Learning for Classification and Genome Annotations

这项题为“用于分类和基因组注释的机器学习”的提案建立在我之前由NSERC资助的题为“生物信息学中的计算智能和应用”的研究项目的基础上。它有两个组成部分：1)自调整进化神经网络及其在计算生物学中的应用计算生物学中的许多问题都涉及分类，例如将细胞样本分类为恶性(癌症)或良性(正常)。对于这样的任务，可以开发和使用神经网络。神经网络为机器学习提供了一个很好的通用框架，包括分类、图像分割和理解。虽然神经网络领域目前是一个热门的研究领域，在图像处理和计算机视觉方面取得了许多成功，但对单个层或节点的激活函数的学习却相对较少关注。为此，我们提出了一种进化深度神经网络EvoDNN，它使用进化算法来进化深度异质前馈神经网络。目前大多数前馈神经网络采用用户定义的同质激活函数，而EvoDNN则创建了异质多层网络，其中每个神经元的激活函数不是由用户静态定义的，而是在进化过程中动态优化的。EvoDNN提供的一个优点是激活函数不需要是可微的。这一功能为用户提供了使用哪些激活功能的很大程度的灵活性。2)用于半自动基因组注释的机器学习方法(SAGA)本提案的第二个主题涉及基因组注释领域中的机器学习。半自动基因组注释(SAGA)方法被广泛用于了解基因组活动和基因调控。这些方法将一组基于测序的表观基因组活性分析(例如组蛋白修饰和转录因子结合的芯片序列测量)作为输入，并输出为每个基因组位置分配染色质状态标签的基因组注释。现有的SAGA方法有几个由离散注释框架引起的局限性：这种注释不能容易地表示基因组元件的不同强度，并且它们不能容易地表示同时显示多种类型活动的组合元件。为了弥补这些局限性，我们提出了一种标注策略，它在每个位置输出染色质状态特征的矢量，而不是单个离散标签。连续建模在其他领域中很常见，例如在文本文档的主题建模中。我们提出了一种使用非负卡尔曼滤波状态空间模型来有效地标注具有染色质状态特征的基因组的方法--表观基因组-SSM。我们打算证明，来自表观基因组SSM的染色质状态特征对于几个下游应用比连续和离散的替代方案更有用。

This proposal entitled "Machine Learning for Classification and Genome Annotations" builds on my previous research program funded by NSERC entitled "Computational Intelligence and Applications in Bioinformatics". It has 2 components: 1) Self-adjusting Evolutionary Neural Networks and Applications in Computational Biology Many problems in Computational Biology involve classification, such as classifying cell samples into malignant (cancer) or benign (normal). For such tasks, Neural Networks can be developed and employed. Neural Networks offer a great general framework for machine learning, including classification, image segmentation and understanding. While the neural network field is currently a hot research area, with many successes in image processing and computer vision, relatively little attention has been paid to the learning of activation functions for individual layers or nodes. For this purpose, we propose EvoDNN, an evolutionary deep neural network that employs an evolutionary algorithm to evolve deep heterogeneous feed-forward neural networks. While the majority of current feed-forward neural networks employ user defined homogeneous activation functions, EvoDNN creates heterogeneous multi-layer networks where each neuron's activation function is not statically defined by the user, but dynamically optimized during evolution. One advantage offered by EvoDNN is that the activation functions do not need to be differentiable. This feature gives users a great degree of flexibility over which activation functions to employ. 2) Machine Learning Methods for Semi Automated Genome Annotation (SAGA) A second topic of this proposal is related to machine learning in the area of genome annotation. Semi automated genome annotation (SAGA) methods are widely used to understand genome activity and gene regulation. These methods take as input a set of sequencing based assays of epigenomic activity (such as ChIP-seq measurements of histone modification and transcription factor binding), and output an annotation of the genome that assigns a chromatin state label to each genomic position. Existing SAGA methods have several limitations caused by the discrete annotation framework: such annotations cannot easily represent varying strengths of genomic elements, and they cannot easily represent combinatorial elements that simultaneously exhibit multiple types of activity. To remedy these limitations, we propose an annotation strategy that instead outputs a vector of chromatin state features at each position rather than a single discrete label. Continuous modeling is common in other fields, such as in topic modeling of text documents. We propose a method, epigenome-ssm, that uses a nonnegative Kalman filter state space model to efficiently annotate the genome with chromatin state features. We intend to show that chromatin state features from epigenome-ssm are more useful for several downstream applications than both continuous and discrete alternatives.