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Nonlinear Mixed-Effects Modelling of In Vitro Drug Susceptibility and Molecular Correlates of Multidrug Resistant Plasmodium falciparum

Simpson, Julie A., Jamsen, Kris M., Anderson, Tim J.C., Zaloumis, Sophie, Nair, Shalini, Woodrow, Charles, White, Nicholas J., Nosten, Francois and Price, Ric N. (2013). Nonlinear Mixed-Effects Modelling of In Vitro Drug Susceptibility and Molecular Correlates of Multidrug Resistant Plasmodium falciparum. PLoS One,8(7):e69505-1-e69505-9.

Document type: Journal Article
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IRMA ID bsmithxPUB200
NHMRC Grant No. 1025319
1035261
Title Nonlinear Mixed-Effects Modelling of In Vitro Drug Susceptibility and Molecular Correlates of Multidrug Resistant Plasmodium falciparum
Author Simpson, Julie A.
Jamsen, Kris M.
Anderson, Tim J.C.
Zaloumis, Sophie
Nair, Shalini
Woodrow, Charles
White, Nicholas J.
Nosten, Francois
Price, Ric N.
Journal Name PLoS One
Publication Date 2013
Volume Number 8
Issue Number 7
ISSN 1932-6203   (check CDU catalogue  open catalogue search in new window)
Scopus ID 2-s2.0-84880796644
Start Page e69505-1
End Page e69505-9
Total Pages 9
Place of Publication United States of America
Publisher Public Library of Science
HERDC Category C1 - Journal Article (DIISR)
Abstract The analysis of in vitro anti-malarial drug susceptibility testing is vulnerable to the effects of different statistical approaches and selection biases. These confounding factors were assessed with respect to pfmdr1 gene mutation and amplification in 490 clinical isolates. Two statistical approaches for estimating the drug concentration associated with 50% effect (EC50) were compared: the commonly used standard two-stage (STS) method, and nonlinear mixed-effects modelling. The in vitro concentration-effect relationships for, chloroquine, mefloquine, lumefantrine and artesunate, were derived from clinical isolates obtained from patients on the western border of Thailand. All isolates were genotyped for polymorphisms in the pfmdr1 gene. The EC50 estimates were similar for the two statistical approaches but 15–28% of isolates in the STS method had a high coefficient of variation (>15%) for individual estimates of EC50 and these isolates had EC50 values that were 32 to 66% higher than isolates derived with more precision. In total 41% (202/490) of isolates had amplification of pfmdr1 and single nucleotide polymorphisms were found in 50 (10%). Pfmdr1 amplification was associated with an increase in EC50 for mefloquine (139% relative increase in EC50 for 2 copies, 188% for 3+ copies), lumefantrine (82% and 75% for 2 and 3+ copies respectively) and artesunate (63% and 127% for 2 and 3+ copies respectively). In contrast pfmdr1 mutation at codons 86 or 1042 were associated with an increase in chloroquine EC50 (44–48%). Sample size calculations showed that to demonstrate an EC50 shift of 50% or more with 80% power if the prevalence was 10% would require 430 isolates and 245 isolates if the prevalence was 20%. In conclusion, although nonlinear mixed-effects modelling did not demonstrate any major advantage for determining estimates of anti-malarial drug susceptibility, the method includes all isolates, thereby, potentially improving confirmation of candidate molecular markers of anti-malarial drug susceptibility.

DOI http://dx.doi.org/10.1371/journal.pone.0069505   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)
Additional Notes This is an Open Access article distributed under the terms of the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Description for Link Link to CC Attribution 4.0 License
URL https://creativecommons.org/licenses/by/4.0/au/legalcode


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