{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T21:38:48Z","timestamp":1766180328561},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"20","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Motivation: Our recent work introduced a generic method to construct the design space of biochemical systems: a representation of the relationships between system parameters, environmental variables and phenotypic behavior. In design space, the qualitatively distinct phenotypes of a biochemical system can be identified, counted, analyzed and compared. Boundaries in design space indicate a transition between phenotypic behaviors and can be used to measure a system's tolerance to large changes in parameters. Moreover, the relative size and arrangement of such phenotypic regions can suggest or confirm global properties of the system.<\/jats:p><jats:p>Results: Our work here demonstrates that the construction and analysis of design space can be automated. We present a formal description of design space and a detailed explanation of its construction. We also extend the notion to include variable kinetic orders. We describe algorithms that automate common steps of design space construction and analysis, introduce new analyses that are made possible by such automation and discuss challenges of implementation and scaling. In the end, we demonstrate the techniques using software we have created.<\/jats:p><jats:p>Availability: The Design Space Toolbox for MATLAB is freely available at http:\/\/www.bme.ucdavis.edu\/savageaulab\/<\/jats:p><jats:p>Contact: \u00a0masavageau@ucdavis.edu<\/jats:p>","DOI":"10.1093\/bioinformatics\/btq479","type":"journal-article","created":{"date-parts":[[2010,9,8]],"date-time":"2010-09-08T02:49:56Z","timestamp":1283914196000},"page":"2601-2609","source":"Crossref","is-referenced-by-count":24,"title":["Automated construction and analysis of the design space for biochemical systems"],"prefix":"10.1093","volume":"26","author":[{"given":"Rick A.","family":"Fasani","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University of California, Davis, CA 95616, USA"}]},{"given":"Michael A.","family":"Savageau","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of California, Davis, CA 95616, USA"}]}],"member":"286","published-online":{"date-parts":[[2010,9,7]]},"reference":[{"key":"2023012507540767300_B1","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0092-8674(03)00346-5","article-title":"Development of genetic circuitry exhibiting toggle switch or oscillatory behavior in Escherichia coli","volume":"113","author":"Atkinson","year":"2003","journal-title":"Cell"},{"key":"2023012507540767300_B2","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/BF02293050","article-title":"A pivoting algorithm for convex hulls and vertex enumeration of arrangements and polyhedra","volume":"8","author":"Avis","year":"1992","journal-title":"Discrete Comput. Geom."},{"key":"2023012507540767300_B3","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0925-7721(96)00023-5","article-title":"How good are convex hull algorithms?","volume":"7","author":"Avis","year":"1997","journal-title":"Comput. Geom."},{"key":"2023012507540767300_B4","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511804441","volume-title":"Convex Optimization.","author":"Boyd","year":"2004"},{"key":"2023012507540767300_B5","doi-asserted-by":"crossref","first-page":"e1000319","DOI":"10.1371\/journal.pcbi.1000319","article-title":"Quantifying global tolerance of biochemical systems: design implications for moiety-transfer cycles","volume":"5","author":"Coelho","year":"2009","journal-title":"PLoS Comput. Biol."},{"key":"2023012507540767300_B6","volume-title":"Linear Programming and Extensions.","author":"Dantzig","year":"1963"},{"key":"2023012507540767300_B7","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1006\/jmbi.1995.0257","article-title":"Subunit structure of regulator proteins influences the design of gene circuitry: analysis of perfectly coupled and completely uncoupled circuits","volume":"248","author":"Hlavacek","year":"1995","journal-title":"J. Mol. Biol."},{"key":"2023012507540767300_B8","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1006\/jmbi.1996.0011","article-title":"Rules for coupled expression of regulator and effector genes in inducible circuits","volume":"255","author":"Hlavacek","year":"1996","journal-title":"J. Mol. Biol."},{"key":"2023012507540767300_B9","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/35057062","article-title":"Initial sequencing and analysis of the human genome","volume":"409","author":"Lander","year":"2001","journal-title":"Nature"},{"key":"2023012507540767300_B10","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1145\/1576702.1576737","article-title":"Isolating real roots of real polynomials","volume-title":"Proceedings of the 2009 International Symposium on Symbolic and Algebraic Computation.","author":"Mehlhorn","year":"2009"},{"key":"2023012507540767300_B11","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nrg2626","article-title":"Sequencing technologies - the next generation","volume":"11","author":"Metzker","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"2023012507540767300_B12","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.jsc.2008.04.016","article-title":"Subdivision methods for solving polynomial equations","volume":"44","author":"Mourrain","year":"2009","journal-title":"J. Symbolic Comput."},{"key":"2023012507540767300_B13","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1137\/S0036144595288554","article-title":"Solving a polynomial equation: some history and recent progress","volume":"39","author":"Pan","year":"1997","journal-title":"SIAM Rev."},{"key":"2023012507540767300_B14","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1145\/384101.384136","article-title":"Univariate polynomials: nearly optimal algorithms for factorization and rootfinding","volume-title":"Proceedings of the 2001 International Symposium on Symbolic and Algebraic Computation.","author":"Pan","year":"2001"},{"key":"2023012507540767300_B15","doi-asserted-by":"crossref","first-page":"5463","DOI":"10.1073\/pnas.74.12.5463","article-title":"DNA sequencing with chain-terminating inhibitors","volume":"74","author":"Sanger","year":"1977","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012507540767300_B16","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/S0003-9861(71)80021-8","article-title":"Concepts relating the behavior of biochemical systems to their underlying molecular properties","volume":"145","author":"Savageau","year":"1971","journal-title":"Arch. Biochem. Biophys."},{"key":"2023012507540767300_B17","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/229542a0","article-title":"Parameter sensitivity as a criterion for evaluating and comparing the performance of biochemical systems","volume":"229","author":"Savageau","year":"1971","journal-title":"Nature"},{"key":"2023012507540767300_B18","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/252546a0","article-title":"Comparison of classical and autogenous systems of regulation in inducible operons","volume":"252","author":"Savageau","year":"1974","journal-title":"Nature"},{"key":"2023012507540767300_B19","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/BF01741242","article-title":"Optimal design of feedback control by inhibition","volume":"5","author":"Savageau","year":"1975","journal-title":"J. Mol. Evol."},{"key":"2023012507540767300_B20","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1063\/1.1349892","article-title":"Design principles for elementary gene circuits: elements, methods, and examples","volume":"11","author":"Savageau","year":"2001","journal-title":"Chaos"},{"key":"2023012507540767300_B21","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0025-5564(02)00113-X","article-title":"Alternative designs for a genetic switch: analysis of switching times using the piecewise power-law representation","volume":"180","author":"Savageau","year":"2002","journal-title":"Math. Biosci."},{"key":"2023012507540767300_B22","volume-title":"Biochemical Systems Analysis: A Study of Function and Design in Molecular Biology.","author":"Savageau","year":"2009"},{"key":"2023012507540767300_B23","doi-asserted-by":"crossref","first-page":"3914","DOI":"10.1016\/j.febslet.2009.10.073","article-title":"Qualitatively distinct phenotypes in the design space of biochemical systems","volume":"583","author":"Savageau","year":"2009","journal-title":"FEBS Lett."},{"key":"2023012507540767300_B24","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/0025-5564(87)90035-6","article-title":"Recasting nonlinear differential equations as S-systems: a canonical nonlinear form","volume":"87","author":"Savageau","year":"1987","journal-title":"Math. Biosci."},{"key":"2023012507540767300_B25","doi-asserted-by":"crossref","first-page":"6435","DOI":"10.1073\/pnas.0809869106","article-title":"Phenotypes and tolerances in the design space of biochemical systems","volume":"106","author":"Savageau","year":"2009","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023012507540767300_B26","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/nbt1486","article-title":"Next-generation DNA sequencing","volume":"26","author":"Shendure","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"2023012507540767300_B27","doi-asserted-by":"crossref","DOI":"10.1007\/978-0-387-74388-2","volume-title":"Linear Programming: Foundations and Extensions.","author":"Vanderbei","year":"2008"},{"key":"2023012507540767300_B28","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1126\/science.1058040","article-title":"The sequence of the human genome","volume":"291","author":"Venter","year":"2001","journal-title":"Science"},{"key":"2023012507540767300_B29","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/S0377-0427(02)00731-8","article-title":"Finding all solutions of nonlinear equations using the dual simplex method","volume":"152","author":"Yamamura","year":"2003","journal-title":"J. Comput. Appl. Math."},{"key":"2023012507540767300_B30","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.amc.2009.05.017","article-title":"LP narrowing: a new strategy for finding all solutions of nonlinear equations","volume":"215","author":"Yamamura","year":"2009","journal-title":"Appl. Math. Comput."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/26\/20\/2601\/48851710\/bioinformatics_26_20_2601.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/26\/20\/2601\/48851710\/bioinformatics_26_20_2601.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,3]],"date-time":"2023-06-03T06:27:38Z","timestamp":1685773658000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/26\/20\/2601\/194331"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,9,7]]},"references-count":30,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2010,10,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btq479","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2010,10,15]]},"published":{"date-parts":[[2010,9,7]]}}}