Classical detection theory and the cryo-EM particle selection problem.

Particle selection is an essential but tedious step in the determination of macromolecular structures by single particle reconstruction. This paper presents an automatic, multi-reference particle detection scheme that is based on the classical matched filter principle. It makes use of a pre-whitening filter to standardize the noise, a reduced representation of the references by means of principal component analysis, and a statistic for distinguishing particles from image artifacts. Standardizing the noise allows the noise-induced false-positive frequency to be estimated, and also allows the distribution of the discrimination statistic to be calculated a priori. The method is demonstrated with an annotated dataset of cryo-EM images.