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Machine Learning Strategy That Leverages Large Data sets to Boost Statistical Power in Small-Scale Experiments.

ABSTRACT: Machine learning methods have proven invaluable for increasing the sensitivity of peptide detection in proteomics experiments. Most modern tools, such as Percolator and PeptideProphet, use semisupervised algorithms to learn models directly from the data sets that they analyze. Although these methods are effective for many proteomics experiments, we suspected that they may be suboptimal for experiments of smaller scale. In this work, we found that the power and consistency of Percolator results were reduced as the size of the experiment was decreased. As an alternative, we propose a different operating mode for Percolator: learn a model with Percolator from a large data set and use the learned model to evaluate the small-scale experiment. We call this a "static modeling" approach, in contrast to Percolator's usual "dynamic model" that is trained anew for each data set. We applied this static modeling approach to two settings: small, gel-based experiments and single-cell proteomics. In both cases, static models increased the yield of detected peptides and eliminated the model-induced variability of the standard dynamic approach. These results suggest that static models are a powerful tool for bringing the full benefits of Percolator and other semisupervised algorithms to small-scale experiments.

SUBMITTER: Fondrie WE

PROVIDER: S-EPMC8455073 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:MotivationChIP-seq technology enables investigators to study genome-wide binding of transcription factors and mapping of epigenomic marks. Although the availability of basic analysis tools for ChIP-seq data is rapidly increasing, there has not been much progress on the related design issues. A challenging question for designing a ChIP-seq experiment is how deeply should the ChIP and the control samples be sequenced? The answer depends on multiple factors some of which can be set by the experimenter based on pilot/preliminary data. The sequencing depth of a ChIP-seq experiment is one of the key factors that determine whether all the underlying targets (e.g. binding locations or epigenomic profiles) can be identified with a targeted power.ResultsWe developed a statistical framework named CSSP (ChIP-seq Statistical Power) for power calculations in ChIP-seq experiments by considering a local Poisson model, which is commonly adopted by many peak callers. Evaluations with simulations and data-driven computational experiments demonstrate that this framework can reliably estimate the power of a ChIP-seq experiment at different sequencing depths based on pilot data. Furthermore, it provides an analytical approach for calculating the required depth for a targeted power while controlling the false discovery rate at a user-specified level. Hence, our results enable researchers to use their own or publicly available data for determining required sequencing depths of their ChIP-seq experiments and potentially make better use of the multiplexing functionality of the sequencers. Evaluation of power for multiple public ChIP-seq datasets indicate that, currently, typical ChIP-seq studies are powered well for detecting large fold changes of ChIP enrichment over the control sample, but they have considerably less power for detecting smaller fold changes.AvailabilityAvailable at www.stat.wisc.edu/~zuo/CSSP.Contactkeles@stat.wisc.eduSupplementary informationSupplementary data are available at Bioinformatics online.

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Machine Learning Strategy That Leverages Large Data sets to Boost Statistical Power in Small-Scale Experiments.

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