Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Wellcome Trust Centre for Human Genetics University of Oxford, Oxford, UK.
Bioinformatics. 2019 Jan 1;35(1):28-35. doi: 10.1093/bioinformatics/bty498.
MOTIVATION: Pseudotime estimation from single-cell gene expression data allows the recovery of temporal information from otherwise static profiles of individual cells. Conventional pseudotime inference methods emphasize an unsupervised transcriptome-wide approach and use retrospective analysis to evaluate the behaviour of individual genes. However, the resulting trajectories can only be understood in terms of abstract geometric structures and not in terms of interpretable models of gene behaviour. RESULTS: Here we introduce an orthogonal Bayesian approach termed 'Ouija' that learns pseudotimes from a small set of marker genes that might ordinarily be used to retrospectively confirm the accuracy of unsupervised pseudotime algorithms. Crucially, we model these genes in terms of switch-like or transient behaviour along the trajectory, allowing us to understand why the pseudotimes have been inferred and learn informative parameters about the behaviour of each gene. Since each gene is associated with a switch or peak time the genes are effectively ordered along with the cells, allowing each part of the trajectory to be understood in terms of the behaviour of certain genes. We demonstrate that this small panel of marker genes can recover pseudotimes that are consistent with those obtained using the entire transcriptome. Furthermore, we show that our method can detect differences in the regulation timings between two genes and identify 'metastable' states-discrete cell types along the continuous trajectories-that recapitulate known cell types. AVAILABILITY AND IMPLEMENTATION: An open source implementation is available as an R package at http://www.github.com/kieranrcampbell/ouija and as a Python/TensorFlow package at http://www.github.com/kieranrcampbell/ouijaflow. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
动机:从单细胞基因表达数据中估计伪时间允许从个体细胞的静态剖面中恢复时间信息。传统的伪时间推断方法强调无监督的转录组范围方法,并使用回顾性分析来评估单个基因的行为。然而,由此产生的轨迹只能根据抽象的几何结构来理解,而不能根据基因行为的可解释模型来理解。
结果:在这里,我们引入了一种称为“ Ouija”的正交贝叶斯方法,该方法从一小部分标记基因中学习伪时间,这些标记基因通常用于回顾性地确认无监督伪时间算法的准确性。至关重要的是,我们根据轨迹上的开关样或瞬态行为来对这些基因进行建模,从而使我们能够理解为什么推断出伪时间,并了解每个基因行为的有用参数。由于每个基因都与沿轨迹的开关或峰值时间相关联,因此基因实际上与细胞一起排序,从而可以根据某些基因的行为来理解轨迹的各个部分。我们证明,这一小部分标记基因可以恢复与使用整个转录组获得的伪时间一致的伪时间。此外,我们表明,我们的方法可以检测两个基因之间的调控时间差异,并识别出沿连续轨迹的“亚稳态”状态-离散细胞类型,这些类型再现了已知的细胞类型。
可用性和实现:一个开源实现可作为 R 包在 http://www.github.com/kieranrcampbell/ouija 获得,并作为 Python/TensorFlow 包在 http://www.github.com/kieranrcampbell/ouijaflow 获得。
补充信息:补充数据可在生物信息学在线获得。
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