Sensitivity to bias due to SLCO1B3 c.334T>G
SNP
There is no biologically plausible reason to expect prevalence of TT/TGSLCO1B3 c.334T>G genotype (estimated in Figure S4 at
31% in Caucasian Europeans) to differ between ABCG2
c.421C>A variant carriers (“treated”) and wt subjects
(“controls”). However, one could assume a range of different
imbalances in prevalence of TT/TG subjects occurring by chance. Table S1
illustrates scenarios in which a considerable imbalance occurred by
chance - prevalence of TT/TG (associated with higher MPA
AUC0-12) among ABCG2 c.421C>Avariant carriers (treated) is at the upper limit of the 95% prediction
interval (Figure S4) and is 40%, while in wt subjects (controls) it is
at the lower limit of the prediction interval and is 25%. It also
illustrates scenarios with an even greater imbalance with 2.5-fold
difference in prevalence of TT/TG in ABCG2 c.421 variant carriers
(50%) and wt controls (20%). Even if the effect of TT/TG is much
higher than estimated in Figure S2 (i.e., it is ROM=1.25, which should
be considered markedly higher than the pooled estimate, since it was
based on raw, unadjusted [reported] values) – the effect of the
variant ABCG2 c.421 allele would still be at least GMR=1.31 (vs.
the estimated 1.40).
Table S1 . Sensitivity analysis of the effect of ABCG2
c.421C>A variant allele on MPA AUCτ,ss(estimated in the main analysis as GMR=1.40) to account for hypothetical
bias arising from not accounting for the SLCO1B3
c.334T>G SNP. The effect of the TT/TG (vs. GG)SLCO1B3 c.334 genotype is estimated at ROM=1.135 (95%CI
0.949-1.361) (Figure S2) and prevalence of the TT/TG genotype is
estimated at 31% (Figure S4). Shown are bias-corrected effects (GMRs)
of the ABCG2 c.421C>A variant (vs. wt) assuming
considerable imbalance between variant carriers and wt controls in
prevalence of the SLCO1B3 c.334 TT/TG genotype, and assuming
TT/TG effect as estimated (i.e., 1.15) and higher, up to 1.25.