Missing value imputation in proximity extension assay-based targeted proteomics data

PLoS One. 2020 Dec 14;15(12):e0243487. doi: 10.1371/journal.pone.0243487. eCollection 2020.

Abstract

Targeted proteomics utilizing antibody-based proximity extension assays provides sensitive and highly specific quantifications of plasma protein levels. Multivariate analysis of this data is hampered by frequent missing values (random or left censored), calling for imputation approaches. While appropriate missing-value imputation methods exist, benchmarks of their performance in targeted proteomics data are lacking. Here, we assessed the performance of two methods for imputation of values missing completely at random, the previously top-benchmarked 'missForest' and the recently published 'GSimp' method. Evaluation was accomplished by comparing imputed with remeasured relative concentrations of 91 inflammation related circulating proteins in 86 samples from a cohort of 645 patients with venous thromboembolism. The median Pearson correlation between imputed and remeasured protein expression values was 69.0% for missForest and 71.6% for GSimp (p = 5.8e-4). Imputation with missForest resulted in stronger reduction of variance compared to GSimp (median relative variance of 25.3% vs. 68.6%, p = 2.4e-16) and undesired larger bias in downstream analyses. Irrespective of the imputation method used, the 91 imputed proteins revealed large variations in imputation accuracy, driven by differences in signal to noise ratio and information overlap between proteins. In summary, GSimp outperformed missForest, while both methods show good overall imputation accuracy with large variations between proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Algorithms
  • Bias
  • Blood Proteins / analysis
  • Blood Proteins / standards
  • Female
  • Humans
  • Interleukin-6 / blood
  • Interleukin-6 / standards
  • Limit of Detection
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Proteomics / methods*
  • Proteomics / standards
  • Quality Control
  • Venous Thromboembolism / metabolism
  • Venous Thromboembolism / pathology

Substances

  • Blood Proteins
  • Interleukin-6

Grants and funding

The GMP-VTE project, on which this study is based, was funded by the German Federal Ministry of Education and Research (BMBF 01EO1003), internal funds of the Clinical Epidemiology, Center for Thrombosis 676 and Hemostasis Mainz and a grant from Bayer AG. The funder (Bayer AG) provided support in the form of salaries for authors M.S. and K.L., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.