A three-groups model for high-throughput survival screens

Biometrics
Benjamin A ShabySteven Finkbeiner

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive deterioration of motor neurons in the cortex and spinal cord. Using an automated robotic microscope platform that enables the longitudinal tracking of thousands of single neurons, we examine the effects a large library of compounds on modulating the survival of primary neurons expressing a mutation known to cause ALS. The goal of our analysis is to identify the few potentially beneficial compounds among the many assayed, the vast majority of which do not extend neuronal survival. This resembles the large-scale simultaneous inference scenario familiar from microarray analysis, but transferred to the survival analysis setting due to the novel experimental setup. We apply a three-component mixture model to censored survival times of thousands of individual neurons subjected to hundreds of different compounds. The shrinkage induced by our model significantly improves performance in simulations relative to performing treatment-wise survival analysis and subsequent multiple testing adjustment. Our analysis identified compounds that provide insight into potential novel therapeutic strategies for ALS.

References

Mar 3, 1994·The New England Journal of Medicine·S A Lipton, P A Rosenberg
Nov 17, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Eric P WinerMark R Somerfield
Jan 27, 2007·The Cochrane Database of Systematic Reviews·R G MillerD H Moore
Jan 15, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sami J BarmadaSteven Finkbeiner
Jan 9, 2014·Journal of the Royal Society of Medicine·Dirk BäumerMartin R Turner

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Citations

Jun 11, 2019·Expert Opinion on Drug Discovery·Jeremy W LinsleySteven Finkbeiner

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