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While in many applications, a deeper understanding of the input-response behaviour is highly desirable, it is often hindered by the large number of molecular species and the complexity of the interactions. An approach that identifies key molecular species for a given input-response relationship and characterises dynamic properties of states is therefore highly desirable. We introduce the concept of index analysis; it is based on different time- and state-dependent quantities (indices) to identify important dynamic characteristics of molecular species. All indices are defined for a specific pair of input and response variables as well as for a specific magnitude of the input. In application to a large-scale kinetic model of the EGFR signalling cascade, we identified different phases of signal transduction, the peculiar role of Phosphatase3 during signal activation and Ras recycling during signal onset. In addition, we discuss the challenges and pitfalls of interpreting the relevance of molecular species based on knock-out simulation studies, and provide an alternative view on conflicting results on the importance of parallel EGFR downstream pathways. Beyond the applications in model interpretation, index analysis is envisioned to be a valuable tool in model reduction.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011777","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T18:35:14Z","timestamp":1707158114000},"page":"e1011777","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Index analysis: An approach to understand signal transduction with application to the EGFR signalling pathway"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9839-2433","authenticated-orcid":true,"given":"Jane","family":"Kn\u00f6chel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Kloft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5249-3914","authenticated-orcid":true,"given":"Wilhelm","family":"Huisinga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"issue":"4","key":"pcbi.1011777.ref001","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/nbt0402-370","article-title":"Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalised EGF receptors","volume":"20","author":"B Schoeberl","year":"2002","journal-title":"Nature Biotechnology"},{"issue":"77","key":"pcbi.1011777.ref002","doi-asserted-by":"crossref","first-page":"ra31","DOI":"10.1126\/scisignal.2000352","article-title":"Therapeutically Targeting ErbB3: A Key Node in Ligand-Induced Activation of the ErbB Receptor\u2013PI3K Axis","volume":"2","author":"B Schoeberl","year":"2009","journal-title":"Science Signaling"},{"key":"pcbi.1011777.ref003","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/clpt.2009.87","article-title":"A Comprehensive Model for the Humoral Coagulation Network in Humans","volume":"86","author":"T Wajima","year":"2009","journal-title":"Journal of Clinical Pharmacology and Therapeutics"},{"issue":"6","key":"pcbi.1011777.ref004","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1049\/iet-syb.2011.0015","article-title":"Sensitivity analysis approaches applied to systems biology models","volume":"5","author":"Z Zi","year":"2011","journal-title":"IET Systems Biology"},{"issue":"1","key":"pcbi.1011777.ref005","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s12918-017-0397-1","article-title":"A combined model reduction algorithm for controlled biochemical systems","volume":"11","author":"TJ Snowden","year":"2017","journal-title":"BMC Systems Biology"},{"issue":"2","key":"pcbi.1011777.ref006","doi-asserted-by":"crossref","DOI":"10.1021\/cr950223l","article-title":"Simplification of Mathematical Models of Chemical Reaction Systems","volume":"98","author":"MS Okino","year":"1998","journal-title":"Chemical Reviews"},{"issue":"1","key":"pcbi.1011777.ref007","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1049\/iet-syb:20070055","article-title":"Proper lumping in systems biology models","volume":"3","author":"A Dokoumetzidis","year":"2009","journal-title":"IET Systems Biology"},{"issue":"5-6","key":"pcbi.1011777.ref008","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1007\/s10928-005-0054-y","article-title":"Lumping in pharmacokinetics","volume":"32","author":"C Brochot","year":"2005","journal-title":"Journal of pharmacokinetics and pharmacodynamics"},{"issue":"2","key":"pcbi.1011777.ref009","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1063\/1.467811","article-title":"A general analysis of approximate nonlinear lumping in chemical kinetics. 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