3.6 Assessment of the diagnostic performance of biomarkers
Univariate ROC curves were generated for each metabolite at each
timepoint, and univariate AUROC was calculated to assess the diagnostic
performance of each individual metabolite. All AUROC values for early
plasma markers were summarized in Figure 7A for C57BL/6 mice
and Figure S8A for FVB/N mice. All AUROC values for early urine
markers were summarized in Figure 8A for C57BL/6 mice andFigure S9A for FVB/N mice. Metabolites were ranked from highest
to lowest univariate AUROC values. Multivariate ROCs were generated to
assess the aggregate diagnostic performance of a combination of
metabolites, ranging from a combination of the top two highest ranked
metabolites to the top 10 and top 15 ranked metabolites for plasma
(Figure 7, S8 ) and urine (Figure 8, S9 ), respectively.
An AUROC value ≥ 0.7 is generally considered to be acceptable. When
discriminating saline vs. cisplatin treated C57BL/6 mice, plasma
creatinine had an AUROC of 0.719 at day 1. Nine plasma metabolites had
an AUROC ≥ 0.7 when discriminating saline vs. cisplatin-treated C57BL/6
mice on day 1 (creatine; 0.729, equol 4-sulfate; 0.736,
L-acetylcarnitine; 0.944, L-carnitine; 0.944, LysoPC(20:3); 0.875,
phenylalanine; 0.917, taurocholic acid; 0.708, trigonelline; 0.785, and
tryptophan; 0.826). Eight of the nine metabolites with AUROC ≥ 0.7 on
day 1 outperformed plasma creatinine, with the exception of taurocholic
acid. In FVB/N mice, plasma creatinine had an AUROC of 0.562 at day 1.
Five plasma metabolites in FVB/N mice had an AUROC ≥ 0.7 at day 1
(creatine; 0.773, pyrocatechol sulfate; 0.828, taurine; 0.719,
taurocholic acid; 0.891, and trigonelline; 0.891). All 5 metabolites
with AUROC ≥ 0.7 on day 1 outperformed plasma creatinine on day 1.
Multivariate ROCs generated for C57BL/6 plasma samples at day 1 revealed
a maximum AUROC of 0.877, which was achieved in the ROC curve modeled
using the top three ranked metabolites: L-acetylcarnitine,
phenylalanine, and LysoPC(20:3) (Figure 7B ). The maximum
multivariate AUROC achieved in C57BL/6 urine was 0.545 on day 1, but
reached AUROC values of 1 in all combinations of the top two to top 15
metabolites on day 2 (Figure 8B, 8C ). In FVB/N plasma, a peak
AUROC of 0.656 was obtained at day 1, whereas AUROC values of ≥ 0.991
were observed on day 2 for all combinations of metabolites
(Figure S8B, S8C ). In day 1 FVB/N urine samples, the highest
multivariate AUROC value of 0.940 was produced via the combination of
all 15 early urine metabolites (Figure S9B ). Diagnostic
performance was further improved in day 2 FVB/N urine, with all
metabolite combinations yielding an AUROC ≥ 0.953 (Figure S9C ).