Determination of confidence intervals of metabolic fluxes estimated from stable isotope measurements

Metabolic Engineering
Maciek R AntoniewiczGregory Stephanopoulos

Abstract

Metabolic fluxes, estimated from stable isotope studies, provide a key to quantifying physiology in fields ranging from metabolic engineering to the analysis of human metabolic diseases. A serious drawback of the flux estimation method in current use is that it does not produce confidence limits for the estimated fluxes. Without this information it is difficult to interpret flux results and expand the physiological significance of flux studies. To address this shortcoming we derived analytical expressions of flux sensitivities with respect to isotope measurements and measurement errors. These tools allow the determination of local statistical properties of fluxes and relative importance of measurements. Furthermore, we developed an efficient algorithm to determine accurate flux confidence intervals and demonstrated that confidence intervals obtained with this method closely approximate true flux uncertainty. In contrast, confidence intervals approximated from local estimates of standard deviations are inappropriate due to inherent system nonlinearities. We applied these methods to analyze the statistical significance and confidence of estimated gluconeogenesis fluxes from human studies with [U-13C]glucose as tracer and found tr...Continue Reading

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Citations

Mar 28, 2008·The Journal of Biological Chemistry·Hyuntae YooJoanne K Kelleher
Apr 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Joel F MoxleyGregory Stephanopoulos
May 5, 2009·Microbial Cell Factories·Lake-Ee QuekJens O Krömer
Sep 5, 2009·PloS One·Matthew L Rizk, James C Liao
Sep 18, 2009·The Journal of Biological Chemistry·Yasushi NoguchiGregory Stephanopoulos
Oct 29, 2009·Journal of the American Chemical Society·Kayvan R KeshariJohn Kurhanewicz
Nov 26, 2010·Microbial Cell Factories·Tae Hoon YangJun Sun
Dec 17, 2010·Genes & Development·Christian M Metallo, Matthew G Vander Heiden
Mar 19, 2011·Analytical Chemistry·Maciek R AntoniewiczGregory Stephanopoulos
Aug 19, 2011·BMC Systems Biology·Orr SrourYonina C Eldar
Aug 20, 2011·Genes & Development·Alexandra R GrassianJoan S Brugge
Sep 8, 2011·Plant Physiology·Thomas C R WilliamsR George Ratcliffe
Jan 15, 2013·Plant Physiology·Doug K Allen, Jamey D Young
Feb 28, 2013·The Plant Cell·Marek SzecowkaStéphanie Arrivault
Mar 1, 2012·Journal of Experimental Botany·John O'GradyJohn A Morgan
Feb 9, 2008·Annual Review of Plant Biology·Igor G L Libourel, Yair Shachar-Hill
Sep 18, 2010·Bioprocess and Biosystems Engineering·Olivier HenryAmine Kamen
Jul 7, 2011·Applied Microbiology and Biotechnology·Katharina Nöh, Wolfgang Wiechert
Feb 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Edouard MullarkyLewis C Cantley
Jul 31, 2013·Biotechnology and Bioengineering·Pierre MillardJean-Charles Portais
Dec 26, 2015·Metabolic Engineering·Lisa Maria DerschChristoph Wittmann
Nov 30, 2013·Metabolism: Clinical and Experimental·Robert A EgnatchikJamey D Young
Dec 5, 2012·Current Opinion in Biotechnology·Karsten Hiller, Christian M Metallo
Dec 19, 2012·Metabolic Engineering·Scott B Crown, Maciek R Antoniewicz
Jan 15, 2010·The Plant Journal : for Cell and Molecular Biology·Amy Marshall ColónJohn Morgan
Nov 13, 2012·Current Opinion in Biotechnology·Maciek R Antoniewicz
Oct 3, 2012·Metabolic Engineering·Ali R ZomorrodiCostas D Maranas
Aug 18, 2012·Metabolic Engineering·Taylor A MurphyJamey D Young
Dec 27, 2011·Metabolic Engineering·Jason L WaltherGregory Stephanopoulos
Jan 4, 2012·Pharmacology & Therapeutics·Teresa W-M FanAndrew N Lane
Oct 18, 2011·Metabolic Engineering·Robert W Leighty, Maciek R Antoniewicz
Sep 13, 2011·Metabolic Engineering·Jamey D YoungJohn A Morgan

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