Universally sloppy parameter sensitivities in systems biology models

Ryan N. Gutenkunst, Joshua J. Waterfall, Fergal P. Casey, Kevin S. Brown, Christopher R. Myers, James P. Sethna

Research output: Contribution to journalArticle

623 Scopus citations

Abstract

Quantitative computational models play an increasingly important role in modern biology. Such models typically involve many free parameters, and assigning their values is often a substantial obstacle to model development. Directly measuring in vivo biochemical parameters is difficult, and collectively fitting them to other experimental data often yields large parameter uncertainties. Nevertheless, in earlier work we showed in a growth-factor- signaling model that collective fitting could yield well-constrained predictions, even when it left individual parameters very poorly constrained. We also showed that the model had a "sloppy" spectrum of parameter sensitivities, with eigenvalues roughly evenly distributed over many decades. Here we use a collection of models from the literature to test whether such sloppy spectra are common in systems biology. Strikingly, we find that every model we examine has a sloppy spectrum of sensitivities. We also test several consequences of this sloppiness for building predictive models. In particular, sloppiness suggests that collective fits to even large amounts of ideal time-series data will often leave many parameters poorly constrained. Tests over our model collection are consistent with this suggestion. This difficulty with collective fits may seem to argue for direct parameter measurements, but sloppiness also implies that such measurements must be formidably precise and complete to usefully constrain many model predictions. We confirm this implication in our growth-factor-signaling model. Our results suggest that sloppy sensitivity spectra are universal in systems biology models. The prevalence of sloppiness highlights the power of collective fits and suggests that modelers should focus on predictions rather than on parameters.

Original languageEnglish (US)
Pages (from-to)1871-1878
Number of pages8
JournalPLoS computational biology
Volume3
Issue number10
DOIs
StatePublished - Oct 1 2007

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ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Ecology
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

Cite this

Gutenkunst, R. N., Waterfall, J. J., Casey, F. P., Brown, K. S., Myers, C. R., & Sethna, J. P. (2007). Universally sloppy parameter sensitivities in systems biology models. PLoS computational biology, 3(10), 1871-1878. https://doi.org/10.1371/journal.pcbi.0030189