Next-generation sequencing of pathogen quasispecies within a host yields data sets of tens to hundreds of unique sequences. However, the full data set often contains thousands of sequences, because many of those unique sequences have multiple identical copies. Data sets of this size represent a computational challenge for currently available Bayesian phylogenetic and phylodynamic methods. Through simulations, we explore how large data sets with duplicate sequences affect the speed and accuracy of phylogenetic and phylodynamic analysis within BEAST 2. We show that using unique sequences only leads to biases, and using a random subset of sequences yields imprecise parameter estimates. To overcome these shortcomings, we introduce PIQMEE, a BEAST 2 add-on that produces reliable parameter estimates from full data sets with increased computational efficiency as compared with the currently available methods within BEAST 2. The principle behind PIQMEE is to resolve the tree structure of the unique sequences only, while simultaneously estimating the branching times of the duplicate sequences. Distinguishing between unique and duplicate sequences allows our method to perform well even for very large data sets. Although the classic method converges poorly for data sets of 6,000 sequences when allowed to run for 7 days, our method converges in slightly more than 1 day. In fact, PIQMEE can handle data sets of around 21,000 sequences with 20 unique sequences in 14 days. Finally, we apply the method to a real, within-host HIV sequencing data set with several thousand sequences per patient.

中文翻译：

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PIQMEE：用于分析具有重复序列的大型数据集的贝叶斯系统动力学方法。


对宿主内病原体准种进行新一代测序可产生数十至数百个独特序列的数据集。然而，完整的数据集通常包含数千个序列，因为其中许多独特的序列具有多个相同的副本。这种大小的数据集对当前可用的贝叶斯系统发生和系统动力学方法来说是一个计算挑战。通过模拟，我们探索了具有重复序列的大型数据集如何影响 BEAST 2 中系统发育和系统动力学分析的速度和准确性。我们表明，使用唯一序列只会导致偏差，而使用随机序列子集会产生不精确的参数估计。为了克服这些缺点，我们引入了 PIQMEE，这是一个 BEAST 2 附加组件，与 BEAST 2 中当前可用的方法相比，它可以从完整的数据集中生成可靠的参数估计，并提高计算效率。PIQMEE 背后的原理是解析仅独特序列，同时估计重复序列的分支时间。区分唯一序列和重复序列使我们的方法即使对于非常大的数据集也能表现良好。尽管经典方法在允许运行 7 天时对于 6,000 个序列的数据集收敛性很差，但我们的方法在略多于 1 天的时间内收敛。事实上，PIQMEE 可以在 14 天内处理大约 21,000 个序列的数据集，其中包含 20 个独特序列。最后，我们将该方法应用于真实的宿主内 HIV 测序数据集，每个患者有数千个序列。