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Geometric least squares means ratios for the analysis of Plasmodium falciparum in vitro susceptibility to antimalarial drugs.

Vaillant M, Olliaro P - Malar. J. (2007)

Bottom Line: GLSMRs were more conservative than ANOVA and resulted in lower levels of statistical significance.The three analyses yielded generally consistent results.The random effects GLSMRs with adjustment for multiple comparisons and 90%CIs require only assumptions on the mixed model to be applied.

View Article: PubMed Central - HTML - PubMed

Affiliation: Clinical Epidemiology and Public Health Unit, Centre for Health Studies, Centre de Recherche Publique (CRP)-Santé, Luxembourg. michel.vaillant@crp-sante.lu

ABSTRACT

Background: The susceptibility of microbes such as Plasmodium falciparum to drugs is measured in vitro as the concentration of the drug achieving 50% of maximum effect (IC50); values from a population are summarized as geometric means. For antimalarial drugs, as well as for antibiotics, assessing changes in microbe susceptibility over time under drug pressure would help inform treatment policy decisions, but no standard statistical method exists as yet.

Methods: A mixed model was generated on loge-transformed IC50 values and calculated geometric least squares means (GLSM) with 90% confidence intervals (CIs). In order to compare IC50s between years, GLSM ratios (GLSMR) with 90%CIs were calculated and, when both limits of the 90%CIs were below or above 100%, the difference was considered statistically significant. Results were compared to those obtained from ANOVA and a generalized linear model (GLM).

Results: GLSMRs were more conservative than ANOVA and resulted in lower levels of statistical significance. The GLSMRs approach allowed for random effect and adjustment for multiple comparisons. GLM was limited in the number of year-to-year comparisons by the need for a single reference year. The three analyses yielded generally consistent results.

Conclusion: A robust analytical method can palliate inherent limitations of in vitro sensitivity testing. The random effects GLSMRs with adjustment for multiple comparisons and 90%CIs require only assumptions on the mixed model to be applied. Results are easy to display graphically and to interpret. The GLMSRs should be considered as an option for monitoring changes in drug susceptibility of P. falciparum malaria and other microbes.

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Related in: MedlinePlus

Geometric Least Squares Means Ratios of the IC50s to quinine (QN), chloroquine (CQ), monodesethylamodiaquine (MdAQ), and artemisinin (ART). The legend indicates the reference year for the ratio. The x-axis indicates the year tested in the ratio. A logarithmic scale was applied for QN.
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Figure 2: Geometric Least Squares Means Ratios of the IC50s to quinine (QN), chloroquine (CQ), monodesethylamodiaquine (MdAQ), and artemisinin (ART). The legend indicates the reference year for the ratio. The x-axis indicates the year tested in the ratio. A logarithmic scale was applied for QN.

Mentions: GLSMR (Table 4) of CQ IC50s showed no significant differences, consistent with a stable response to CQ over the study period (Figure 2). For MdAQ, there were statistically significant increases between 1997 and 2000–2004. From 2000 to 2004, there was a decrease in IC50s which was significant between 2000 and 2004, 2001 and 2004, as well as 2002 and 2004. QN showed an increase between 1997 and 2001 and 2001–2002, and a significant decrease between 2002–2004. For ART, no statistically significant changes were found (Figure 2).


Geometric least squares means ratios for the analysis of Plasmodium falciparum in vitro susceptibility to antimalarial drugs.

Vaillant M, Olliaro P - Malar. J. (2007)

Geometric Least Squares Means Ratios of the IC50s to quinine (QN), chloroquine (CQ), monodesethylamodiaquine (MdAQ), and artemisinin (ART). The legend indicates the reference year for the ratio. The x-axis indicates the year tested in the ratio. A logarithmic scale was applied for QN.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2235875&req=5

Figure 2: Geometric Least Squares Means Ratios of the IC50s to quinine (QN), chloroquine (CQ), monodesethylamodiaquine (MdAQ), and artemisinin (ART). The legend indicates the reference year for the ratio. The x-axis indicates the year tested in the ratio. A logarithmic scale was applied for QN.
Mentions: GLSMR (Table 4) of CQ IC50s showed no significant differences, consistent with a stable response to CQ over the study period (Figure 2). For MdAQ, there were statistically significant increases between 1997 and 2000–2004. From 2000 to 2004, there was a decrease in IC50s which was significant between 2000 and 2004, 2001 and 2004, as well as 2002 and 2004. QN showed an increase between 1997 and 2001 and 2001–2002, and a significant decrease between 2002–2004. For ART, no statistically significant changes were found (Figure 2).

Bottom Line: GLSMRs were more conservative than ANOVA and resulted in lower levels of statistical significance.The three analyses yielded generally consistent results.The random effects GLSMRs with adjustment for multiple comparisons and 90%CIs require only assumptions on the mixed model to be applied.

View Article: PubMed Central - HTML - PubMed

Affiliation: Clinical Epidemiology and Public Health Unit, Centre for Health Studies, Centre de Recherche Publique (CRP)-Santé, Luxembourg. michel.vaillant@crp-sante.lu

ABSTRACT

Background: The susceptibility of microbes such as Plasmodium falciparum to drugs is measured in vitro as the concentration of the drug achieving 50% of maximum effect (IC50); values from a population are summarized as geometric means. For antimalarial drugs, as well as for antibiotics, assessing changes in microbe susceptibility over time under drug pressure would help inform treatment policy decisions, but no standard statistical method exists as yet.

Methods: A mixed model was generated on loge-transformed IC50 values and calculated geometric least squares means (GLSM) with 90% confidence intervals (CIs). In order to compare IC50s between years, GLSM ratios (GLSMR) with 90%CIs were calculated and, when both limits of the 90%CIs were below or above 100%, the difference was considered statistically significant. Results were compared to those obtained from ANOVA and a generalized linear model (GLM).

Results: GLSMRs were more conservative than ANOVA and resulted in lower levels of statistical significance. The GLSMRs approach allowed for random effect and adjustment for multiple comparisons. GLM was limited in the number of year-to-year comparisons by the need for a single reference year. The three analyses yielded generally consistent results.

Conclusion: A robust analytical method can palliate inherent limitations of in vitro sensitivity testing. The random effects GLSMRs with adjustment for multiple comparisons and 90%CIs require only assumptions on the mixed model to be applied. Results are easy to display graphically and to interpret. The GLMSRs should be considered as an option for monitoring changes in drug susceptibility of P. falciparum malaria and other microbes.

Show MeSH
Related in: MedlinePlus