. 2020 Jan 30;9(2):96–105. doi: 10.1002/psp4.12487

Table 1.

Model estimates for three models based on the weekly spaced data set

Model	Parameters	Estimate	SE, covariance step	RSE (%), covariance step	SE, bootstrapping	RSE (%), bootstrapping		Median (95% CI), bootstrapping
PO^a	k _eo	0.034		4.9		13.8		0.034 (0.026, 0.046)
	B ₁	−4.03	0.20		0.36			−4.09 (−4.90, −3.49)
	B ₂–B ₁	−4.33		4.9		13.8		−4.37 (−5.72, −3.39)
	Slope	20.0		12.1		14.3		20.4 (15.4, 26.5)
	CV% (slope)	78.9		12.4		15.0		78.0 (57.8, 101.3)
DTMM^b	B _1,0	−5.48	0.40		0.43		−5.54 (−6.53, −4.83)
	B _2,0–B _1,0	−1.58		15.5		15.8	−1.60 (−2.17, −1.19)
	B _1,1	1.35	0.22		0.19		1.33 (0.97,1.71)
	B _2,1–B _1,1	−9.86		7.7		18.5	−9.88 (−19.90, −8.53)
	B _1,2	0.394	0.33		0.38		0.352 (−0.454, 1.083)
	B _2,2–B _1,2	−0.0966 (fix)		NA		NA	NA
	Slope	18.8		12.4		13.2	19.1 (14.8, 24.9)
	CV% (slope)	21.1		28.7		23.7	20.4 (9.63, 29.95)
CTMM^c	Slope₀₁	0.053		21.6		23.4	0.053 (0.031, 0.077)
	Slope₁₀	32.14		50.1		40.8	36.60 (14.30, 75.19)
	Slope₀₂	0.014		39.3		35.6	0.013 (0.006, 0.024)
	Slope₂₀	8.94		41.3		23.0	9.87 (5.99, 14.88)
	Slope₁₂	0.1 × Slope₀₁		NA		NA	NA
	K ₁₀	0.115		44.6		45.5	0.141 (0.068, 0.368)
	K ₂₀	K₁₀		NA		NA	NA
	K ₂₁	0.01 × K₁₀		NA		NA	NA
	CV% (slope01)	86.0		35.9		68.3	87.8 (41.6, 199.8)
	CV% (slope10)	97.5		39.2		39.1	100.5 (71.7, 183.4)
	CV% (slope02)	146.3		17.6		18.4	139.3 (89.3, 189.8)
	CV% (slope20)	80.4		33.4		39.5	79.7 (19.2, 139.8)

Only the parameter estimates related to the adverse event analysis were included in the table. The parameter estimates related to the pharmacokinetics of vismodegib was included in Model S1 .

CI, confidence interval; Median (95% CI) bootstrapping, median and 95% CI from “percentile confidence intervals” (bootstrap_results.csv); NA, not applicable; RSE, relative standard error; SE, standard error.

^a K _eo is shown on a normal scale but was estimated in the log domain. The RSE% presented in “RSE (%) covariance step” or “RSE% bootstrapping” is the SE of the logged parameter *100 that is approximately equal to the RSE% of the parameter on the normal domain. $B_{m}$ , baseline of logit probability for AE ≥ m (m = 1, 2/3); coefficient of variation (CV%) (parameter), standard deviation of the interindividual variability for certain parameter that derived by “sqrt(omega)*100”; PO, proportional odds model; RSE% bootstrapping, relative standard error from bootstrapping that was derived by “(bootstrap SD/median)*100”, bootstrap SD is the standard deviation of parameter estimates that is “standard.errors”; RSE% for CV% are derived by RSE% for omega/2 for the RSE% from covariance step and bootstrapping; RSE (%) covariance step, relative standard error from nonlinear mixed‐effect modeling (NONMEM) covariance step; SE bootstrapping, “standard.errors” from bootstrapping results (bootstrap_results.csv) (same as SE covariance step, only apply to B1); SE covariance step, standard error from NONMEM covariance step (only apply to B1 as it can take either positive or negative value; RSE by SE/THETA is not a proper measure of uncertainty in this case); Slope, population mean increase in $Logit(P ({AE}_{i, j} \geq m))$ per unit increase in exposure. ^bSE covariance step and SE bootstrapping were only applied to B _1,0, B _1,1, B _1,2, as they can take either positive or negative value (same as B₁ for the PO model). $B_{m, k}$ , baseline of $Logit[P ({AE}_{i, j} \geq m)]$ , given the preceding grade $k$ ; B _2,2–B _1,2, the transition probability in logit scale from grade 2/3 to 1, which was fixed to the estimated value (−0.0966) with no change in the objective function values; DTMM, discrete‐time Markov model. ^cAll of the slope parameters and K ₁₀ are shown on normal scale but were estimated in the log domain. The RSE% presented in “RSE (%) covariance step” or “RSE% bootstrapping” are the SE of the logged parameter *100 that is approximately equal to the RSE% of the parameter on the normal domain. CTMM, continuous‐time Markov model; ${Slope}_{g 1 g 2}$ , slope for transition $g 1 g 2$ , with $g 1$ as the preceding grade and $g 2$ as the current grade; K _g1g2, baseline of ${KT}_{backward_g 1 g 2}$ without treatment ( ${KT}_{backward_g 1 g 2}$ , first‐order transfer rate constant from high to low grade ( $g 1 > g 2$ )).