Thresholding of cryo-EM density maps by false discovery rate control
Thresholding of cryo-EM density maps by false discovery rate control
复制标题
通过错误发现率控制对冷冻电镜密度图进行阈值化
作者：
Maximilian Beckers;A. Jakobi;C. Sachse
冷冻电镜现在通常可以从分离和原位观察的大分子生成接近原子分辨率和中间分辨率的图。由于最高分辨率外壳中的信号较差并且需要选择密度分析的阈值，解释这些图仍然是一项具有挑战性的任务。为了促进这一过程，我们开发了一个统计框架，用于通过多重假设检验和错误发现率 (FDR) 控制来生成置信图。通过这种方式，3D 置信图包含以 EM 密度值的局部检测率形式从背景噪声中分离出来的信号。我们证明，置信图和基于 FDR 的阈值可用于解释近原子分辨率的单粒子结构以及由次断层图平均确定的较低分辨率图。由于噪声最小化，置信图代表了解释分子结构的保守方法。同时，它们提供了相对于背景噪声的检测误差，该误差与密度相关，并且在构象灵活性和结构中结合分子和离子的占用率较低的情况下特别有利于解释较弱的冷冻电镜密度。
Cryo-EM now commonly generates close-to-atomic resolution as well as intermediate resolution maps from macromolecules observed in isolation and in situ. Interpreting these maps remains a challenging task due to poor signal in the highest resolution shells and the necessity to select a threshold for density analysis. In order to facilitate this process, we developed a statistical framework for the generation of confidence maps by multiple hypothesis testing and false discovery rate (FDR) control. In this way, 3D confidence maps contain separated signal from background noise in the form of local detection rates of EM density values. We demonstrate that confidence maps and FDR-based thresholding can be used for the interpretation of near-atomic resolution single-particle structures as well as lower resolution maps determined by subtomogram averaging. Confidence maps represent a conservative way of interpreting molecular structures due to minimized noise. At the same time they provide a detection error with respect to background noise, which is associated with the density and particularly beneficial for the interpretation of weaker cryo-EM densities in cases of conformational flexibility and lower occupancy of bound molecules and ions to the structure.
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