title: Inference of spatiotemporal effects on cellular state transitions from time-lapse microscopy.
abstract: BACKGROUND
  Time-lapse microscopy allows to monitor cell state transitions in a spatiotemporal context. Combined with single cell tracking and appropriate cell state markers, transition events can be observed within the genealogical relationship of a proliferating population. However, to infer the correlations between the spatiotemporal context and cell state transitions, statistical analysis with an appropriately large number of samples is required.
  
  
  RESULTS
  Here, we present a method to infer spatiotemporal features predictive of the state transition events observed in time-lapse microscopy data. We first formulate a generative model, simulate different scenarios, such as time-dependent or local cell density-dependent transitions, and illustrate how to estimate univariate transition rates. Second, we formulate the problem in a machine-learning language using regularized linear models. This allows for a multivariate analysis and to disentangle indirect dependencies via feature selection. We find that our method can accurately recover the relevant features and reconstruct the underlying interaction kernels if a critical number of samples is available. Finally, we explicitly use the tree structure of the data to validate if the estimated model is sufficient to explain correlated transition events of sister cells.
  
  
  CONCLUSIONS
  Using synthetic cellular genealogies, we prove that our method is able to correctly identify features predictive of state transitions and we moreover validate the chosen model. Our approach allows to estimate the number of cellular genealogies required for the proposed spatiotemporal statistical analysis, and we thus provide an important tool for the experimental design of challenging single cell time-lapse microscopy assays.
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany. michael.strasser@helmholtz-muenchen.de.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Strasser
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany. justin.feigelman@helmholtz-muenchen.de.|Department of Mathematics, Technische Universität München, Boltzmannstr. 3, Garching, 85747, Germany. justin.feigelman@helmholtz-muenchen.de.
authors.forename: Justin
authors.initials: J
authors.lastname: Feigelman
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany. fabian.theis@helmholtz-muenchen.de.|Department of Mathematics, Technische Universität München, Boltzmannstr. 3, Garching, 85747, Germany. fabian.theis@helmholtz-muenchen.de.
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany. carsten.marr@helmholtz-muenchen.de.
authors.forename: Carsten
authors.initials: C
authors.lastname: Marr
mesh_terms: D002450:Cell Communication; D002452:Cell Count; D002454:Cell Differentiation; D002468:Cell Physiological Phenomena; D003198:Computer Simulation; D016014:Linear Models; D008954:Models, Biological; D015999:Multivariate Analysis; D059010:Single-Cell Analysis; D059008:Time-Lapse Imaging