SUPPLEMENTARY MATERIAL
Statistical analyses
The distribution of the quantitative variables analysed deviated significantly from normality (Shapiro-Wilk test P < 0.05),
thus they were described by median (IQR). The presence of statistically significant differences in terms of QTc distributions
before vs. during TKI therapy were tested by the Wilcoxon Signed Rank Test for paired samples. Differences in terms of
quantitative variables distribution as function of categorical outcomes were tested by the Wilcoxon Rank-Sum test or by
the Kruskal-Wallis test as appropriate. The McNemar test was applied to compare the distributions of categorical variables
before vs. during TKI therapy. Differences in terms of categorical variables distributions between binary outcomes were
evaluated by the Fisher’s exact test. The impact of quantitative and categorical variables on the probability of binary
outcomes was tested by stepwise logistic regression. Calcium and potassium levels, age, gender, co-medications and the
presence of relevant cardiovascular diseases and/or diabetes mellitus were tested as potentially informative variables in
the analysis since they are known to influence the QTc interval and the risk of developing drug induced LQTS.26 Both
baseline and on therapy calcium and potassium levels were discretized into three levels (hypo-, normo- and hyper-)
according to lab-specific normality ranges and analysed as categorical variables. Ethnicity, time-lapse between baseline
ECG and start of TKI treatment, tumor type and recruitment center were considered potential confounders when
evaluating multivariate models. The significance threshold was set to P-value < 0.05, all tests were two-tailed. The
statistical software R version 3.0.1 was used for all statistical analyses (http://www.r-project.org/).
Supplementary Table 1 Impact of predictors and confounders on baseline QTc interval
Variable
N
Statistic
P-value
rho or
median QTc (IQR)
Age (years)
363
0.01
0.8532
Gender
0.0266
Male
215
399 (385-414)
Female
148
404 (392-417)
Co-medication
0.0349
No
329
400 (387-414)
Yes
34
409 (398-424)
CVD
0.0792
No
326
400 (388-415)
Yes
37
408 (396-429)
DM
0.628
No
320
401 (389-415)
Yes
43
401 (384-415)
Baseline Ca2+
0.5699
Hypocalciemie
22
409 (385-418)
Normocalciemie
193
400 (388-411)
Hypercalciemie
10
391 (383-411)
Baseline K+
0.0276
Hypokaliemie
3
416 (376-431)
Normokaliemie
255
401 (389-415)
Hyperkaliemie
41
391 (381-408)
Abbreviations: CVD, cardiovascular disease; DM, diabetes mellitus; Ca2+, calcium; K+,
potassium; n, number of patients
Supplementary Table 2 Impact of predictors and confounders on outcome measures
∆QTc
Yes
∆QTc≥ 30 ms
No
Transition to high risk (QTc≥470ms)
Yes
No
CTCAE grading scale
Increased
Variable
N
Median (IQR)
P-value
Median (IQR) or N
(%)
60 (53-70)
Median (IQR) or N
(%)
60 (51-66)
P-value
Median (IQR) or N
(%)
66 (60-76)
Median (IQR) or N
(%)
60 (51-66)
P-value
Median (IQR) or N
(%)
62 (59-72)
Unchanged/
decreased Median
(IQR) or N (%)
P-value
Age (years)
363
0
0.9519
0.1263
0.0072
60 (51-67)
0.0263
Gender
Male
215
12 (-3-28)
0.1774
47 (61.8)
168 (58.5)
0.6940
14 (70)
201 (58.6)
0.3578
22 (66.7)
193 (58.5)
0.4582
Female
148
10 (-4-24)
29 (38.2)
119 (41.5)
6 (30)
142 (41.4)
11 (33.3)
137 (41.5)
Co-medication
No
329
12 (-3-25)
0.7915
65 (85.5)
264 (92.0)
0.1181
15 (75)
314 (91.6)
0.0296
27 (81.8)
302 (91.5)
0.1066
Yes
34
9 (-3-34)
11 (14.5)
23 (8.0)
5 (25)
29 (8.4)
6 (18.2)
28 (8.5)
CVD
No
326
11 (-3-26)
0.7729
68 (89.5)
258 (89.9)
1
16 (80)
310 (90.4)
0.1343
28 (84.9)
298 (90.3)
0.3598
Yes
37
12 (-4-24)
8 (10.5)
29 (10.1)
4 (20)
33 (9.6)
5 (15.1)
32 (9.7)
DM
No
320
11 (-3-25)
0.7651
65 (85.5)
255 (88.9)
0.4275
19 (95)
301 (87.8)
0.4893
30 (90.9)
290 (87.9)
0.7816
Yes
43
11 (-1-30)
11(14.5)
32 (11.1)
1 (5)
42 (12.2)
3 (9.1)
40 (12.1)
Ca2+
Normo/hyper
169
10 (-3-24)
0.9434
30 (71.4)
139 (70.6)
1
8 (80)
161 (70.3)
0.7277
13 (61.9)
156 (71.6)
0.4510
Hypo
70
14 (-5-23)
12 (28.6)
58 (29.4)
2 (20)
68 (29.7)
8 (38.1)
62 (28.4)
K+
Normo/hyper
304
11 (-3-24)
0.2419
60 (92.3)
244 (96.1)
0.1992
16 (88.9)
288 (95.6)
0.2042
23 (79.3)
281 (96.9)
0.0009
Hypo
15
21 (3-42)
5 (7.7)
10 (3.9)
2 (11.1)
13 (4.3)
6 (20.7)
9 (3.1)
2+
+
Abbreviations: CVD, cardiovascular disease; DM, diabetes mellitus; Ca , calcium; K , potassium; N, number of patients; IQR, interquartile range; ∆QTc, difference between QTc interval during treatment with a tyrosine kinase inhibitor and
QTc interval at baseline measurement; CTCAE, common terminology criteria for adverse events