Data analysis
As a measure of exposure, (i ) C D-1 ratio of
atomoxetine was defined as the main outcome measure of interest, as well
as (ii ) unadjusted serum concentration, (iii ) daily dose,
and (iv ) risk of having undetectable serum concentration of
atomoxetine. For outcome measures (i-iii ), linear mixed model
analyses (using random intercept and the restricted maximum likelihood
model) were used to allow for inclusion of multiple samples per patient
with age, sex and blood sampling time as covariate, if not otherwise
described. The C D-1 ratios and absolute
concentrations of atomoxetine were ln-transformed prior to analysis in
order to ensure normal distribution of the data. Furthermore, several
sensitivity analyses were performed to estimate the robustness when
estimating the effects of CYP2D6/2C19 genotype subgroups,
including limiting inclusion of serum samples solely to those withdrawn
4-8 hours post dose. To calculate the risk of having undetectable serum
samples, a mixed logistic regression model allowing inclusion of all
serum samples per patients was used with risk of having undetectable
serum samples as reference. The other proportions (i.e., male sex,
samples with available sampling time, samples with dose, undetectable
serum samples, patients with at least one undetectable serum sample andCYP2D6/2C19 genotype subgroups) were compared using Fisher’s
exact test.
All statistical analyses were performed in SPSS, version 25.0 (IBM
SPSS Statistics, Armonk, NY, USA). GraphPad version 4 was used for
graphical presentations (GraphPad Software, San Diego, CA). In figure 1,
linear mixed model was used as described above but with no covariates
and with Sidak-adjusted p-values. For the other analyses, the
comparison-wise alpha was set at 0.05 and no multiplicity adjustments
were made. The estimated means are given with either standard error (SE)
or 95% confidence intervals (CI).