title: Recognizing and analyzing variability in amyloid formation kinetics: Simulation and statistical methods.
abstract: We examine the phenomenon of variability in the kinetics of amyloid formation and detail methods for its simulation, identification and analysis. Simulated data, reflecting intrinsic variability, were produced using rate constants, randomly sampled from a pre-defined distribution, as parameters in an irreversible nucleation-growth kinetic model. Simulated kinetic traces were reduced in complexity through description in terms of three characteristic parameters. Practical methods for assessing convergence of the reduced parameter distributions were introduced and a bootstrap procedure was applied to determine convergence for different levels of intrinsic variation. Statistical methods for assessing the significance of shifts in parameter distributions, relating to either change in parameter mean or distribution shape, were tested. Robust methods for analyzing and interpreting kinetic data possessing significant intrinsic variance will allow greater scrutiny of the effects of anti-amyloid compounds in drug trials.
authors.affiliation: Research School of Chemistry, Australian National University, Acton ACT 2601, Australia; Institute for Protein Research, Osaka University, 3-1- Yamada-oka, Suita, Osaka 565-0871 Japan. Electronic address: damien.hall@anu.edu.au.
authors.forename: Damien
authors.initials: D
authors.lastname: Hall
authors.affiliation: Research School of Chemistry, Australian National University, Acton ACT 2601, Australia.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Institute for Protein Research, Osaka University, 3-1- Yamada-oka, Suita, Osaka 565-0871 Japan.
authors.forename: Masatomo
authors.initials: M
authors.lastname: So
authors.affiliation: Institute for Protein Research, Osaka University, 3-1- Yamada-oka, Suita, Osaka 565-0871 Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Centro de Investigaciones Biológicas, CSIC, 28006 Madrid, Spain.
authors.forename: Germán
authors.initials: G
authors.lastname: Rivas
authors.affiliation: Research School of Chemistry, Australian National University, Acton ACT 2601, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Carver
authors.affiliation: Institute for Protein Research, Osaka University, 3-1- Yamada-oka, Suita, Osaka 565-0871 Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Goto
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D003198:Computer Simulation; D006801:Humans; D008956:Models, Chemical; D066329:Protein Aggregates
chemical_list: D000682:Amyloid; D066329:Protein Aggregates
keywords: Aggregation assay; Amyloid; Anti-amyloid drug screening; Statistical significance