title: Statistical approaches and software for clustering islet cell functional heterogeneity.
abstract: Worldwide efforts are underway to replace or repair lost or dysfunctional pancreatic β-cells to cure diabetes. However, it is unclear what the final product of these efforts should be, as β-cells are thought to be heterogeneous. To enable the analysis of β-cell heterogeneity in an unbiased and quantitative way, we developed model-free and model-based statistical clustering approaches, and created new software called TraceCluster. Using an example data set, we illustrate the utility of these approaches by clustering dynamic intracellular Ca(2+) responses to high glucose in ∼300 simultaneously imaged single islet cells. Using feature extraction from the Ca(2+) traces on this reference data set, we identified 2 distinct populations of cells with β-like responses to glucose. To the best of our knowledge, this report represents the first unbiased cluster-based analysis of human β-cell functional heterogeneity of simultaneous recordings. We hope that the approaches and tools described here will be helpful for those studying heterogeneity in primary islet cells, as well as excitable cells derived from embryonic stem cells or induced pluripotent cells.
authors.affiliation: a Wellcome Trust Center for Human Genetics, University of Oxford , Oxford , United Kingdom.|b Weatherall Institute of Molecular Medicine, University of Oxford , Oxford , United Kingdom.
authors.forename: Quin F
authors.initials: QF
authors.lastname: Wills
authors.affiliation: c Department of Cellular and Physiological Sciences , Life Sciences Center, University of British Columbia , Vancouver , Canada.
authors.forename: Tobias
authors.initials: T
authors.lastname: Boothe
authors.affiliation: c Department of Cellular and Physiological Sciences , Life Sciences Center, University of British Columbia , Vancouver , Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Asadi
authors.affiliation: d Department of Surgery , University of British Columbia , Vancouver , Canada.
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Ao
authors.affiliation: d Department of Surgery , University of British Columbia , Vancouver , Canada.
authors.forename: Garth L
authors.initials: GL
authors.lastname: Warnock
authors.affiliation: c Department of Cellular and Physiological Sciences , Life Sciences Center, University of British Columbia , Vancouver , Canada.|d Department of Surgery , University of British Columbia , Vancouver , Canada.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
authors.affiliation: c Department of Cellular and Physiological Sciences , Life Sciences Center, University of British Columbia , Vancouver , Canada.|d Department of Surgery , University of British Columbia , Vancouver , Canada.
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism; D012984:Software
chemical_list: D005947:Glucose; D002118:Calcium
keywords: calcium signals; insulin; oscillations