Feasibility assessment of using the MiToS staging system for conducting economic evaluation in amyotrophic lateral sclerosis

Figures & data

Figure 1. MiToS-based model structure.

The Markov model represents the six stages of ALS disease progression according to MiToS staging. As indicated by the arrows in the model, at each cycle, each person with ALS has a probability of remaining in the same stage or transitioning to any of the later stages.

Abbreviations. ALS, amyotrophic lateral sclerosis, MiToS, Milano-Torino staging.

Table 1. EQ-5D-5 L scores for MiToS stages (Moore et al. [23]).

	EQ-5D-5 L utility, mean (95% CI)
Stage 0	0.71 (0.69–0.73)
Stage 1	0.48 (0.44–0.51)
Stage 2	0.36 (0.31–0.42)
Stage 3	0.33 (0.23–0.43)
Stage 4	0.25 (0.07–0.42)

Abbreviations. CI, confidence interval; EQ-5D-5 L, EuroQol 5-dimension 5-level; MiToS, Milano-Torino staging.

Table 2. Transition probability matrix for standard of care (Thakore et al. [14]).

	Stage 0	Stage 1	Stage 2	Stage 3	Stage 4	Dead
Stage 0	0.714	0.232	0.040	0.006	0.001	0.007
Stage 1	0.094	0.605	0.199	0.042	0.010	0.050
Stage 2	0.013	0.164	0.435	0.177	0.066	0.145
Stage 3	0.001	0.025	0.126	0.330	0.269	0.249
Stage 4	0	0.002	0.018	0.101	0.574	0.305
Dead	0	0	0	0	0	1

Table 3. Patient distributions in the three scenarios.

	Patients starting in each MiToS stage (%)
	0	1	2	3	4	Source
Scenario
1	100	0	0	0	0	Assumption
2	50.59	33.28	12.69	3.03	0.84	Real-world cohort [23]
3	80.3	18.3	1.3	0.1	0	Pooled dataset [14]

Abbreviations. MiToS, Milano-Torino staging.

Table 4. Model input values for base case, one-way analysis sensitivity and probabilistic sensitivity analyses.

	Base case value	95% CI	Standard error	Distribution	Min	Max	Source
Transition probabilities (Thakore et al.)*							[14]
stage 0 to stage 1	0.232	(0.216, 0.248)	0.008	beta	0.216	0.248
stage 0 to stage 2	0.040	(0.032, 0.048)	0.004	beta	0.032	0.048
stage 0 to stage 3	0.006	(0.003, 0.009)	0.002	beta	0.003	0.009
stage 0 to stage 4	0.001	(0.000, 0.002)	0.001	beta	0.000	0.002
stage 0 to stage 5	0.007	(0.004, 0.010)	0.002	beta	0.004	0.010
stage 1 to stage 2	0.199	(0.167, 0.231)	0.016	beta	0.167	0.231
stage 1 to stage 3	0.042	(0.026, 0.058)	0.008	beta	0.026	0.058
stage 1 to stage 4	0.010	(0.002, 0.018)	0.004	beta	0.002	0.018
stage 1 to stage 5	0.050	(0.032, 0.068)	0.009	beta	0.032	0.068
stage 2 to stage 3	0.177	(0.060, 0.294)	0.060	beta	0.060	0.294
stage 2 to stage 4	0.066	(−0.010, 0.142)	0.039	beta	−0.010	0.142
stage 2 to stage 5	0.145	(0.037, 0.253)	0.055	beta	0.037	0.253
stage 3 to stage 4	0.269	(−0.233, 0.771)	0.256	beta	−0.233	0.771
stage 3 to stage 5	0.249	(−0.240, 0.738)	0.250	beta	−0.240	0.738
stage 4 to stage 5	0.305	(0.244, 0.366)	0.031	beta	0.244	0.366
Utilities (Moore et al.)**							[23]
utility in stage 0	0.71	(0.69, 0.73)	0.01	beta	0.69	0.73
utility in stage 1	0.48	(0.44, 0.51)	0.02	beta	0.44	0.51
utility in stage 2	0.36	(0.31, 0.42)	0.03	beta	0.31	0.42
utility in stage 3	0.33	(0.23, 0.43)	0.05	beta	0.23	0.43
utility in stage 4	0.25	(0.07, 0.42)	0.09	beta	0.07	0.42
Treatment effect***							Assumption
RR for progression reduction	0.80		0.08	log normal	0.88	0.64
	0.75		0.075	log normal
	0.70		0.07	log normal
	0.65		0.065	log normal
Discount rates							Assumption
discount rates effects	3%				1%	5%
Patient Distribution Scenarios							Assumption
Scenario 1-Hypothetical
Stage 0	100%
Stage 1	0
Stage 2	0
Stage 3	0
Stage 4	0
Stage 5	0
Scenario 2-RWE (Moore et al.)							[23]
Stage 0	50.59%
Stage 1	33.28%
Stage 2	12.27%
Stage 3	3.03%
Stage 4	0.84%
Stage 5	0.00%
Scenario 3-RWE (Thakore et al.)							[14]
Stage 0	80.3%
Stage 1	18.30%
Stage 2	1.30%
Stage 3	0.10%
Stage 4	0.00%
Stage 5	0.00%

Note: *standard error (SE) calculated from the proportion ($\mathit{P}$) and sample size ($\mathit{n})$ except for stage 4 to 5 because $\mathit{n}=0$ (SE assumed to be 10% of the point estimate, $\mathit{P}$). 95% CI calculated using $\mathit{P}$and estimated SE.

Note: **standard error calculated from reported mean and 95% CI

Note: ***standard error was assumed to be 10% of the mean

$\mathit{SE}=\sqrt{\frac{\mathit{P}\left[1-\mathit{P}\right]}{n}}$ [27]

$95\mathrm{\%}\mathit{CI}=\mathit{P}\pm 1\cdot 96\times \mathit{SE}$ [27]

$95\mathrm{\%}\mathit{CI}=\mathrm{mean}\pm 1\cdot 96\times \mathit{SE}$

UB $95\mathrm{\%}\mathit{CI}=\mathrm{mean}+1\cdot 96\times \mathit{SE}$

SE $=(\mathrm{UB}95\mathrm{\%}\mathit{CI}-\mathrm{mean})/1\cdot 96$ or SE $=(\mathrm{mean}-\mathrm{LB}95\mathrm{\%}\mathit{CI})/1\cdot 96$ [28]

Table 5. QALY and LY for a range of hypothetical treatment effects versus standard of care: patient distribution based on a pooled dataset (scenario 3).

	QALY		Incremental QALY	LY		Incremental LY
RR	Treatment	SoC	Treatment vs SoC	Treatment	SoC	Treatment vs SoC
1-year horizon
0.80	0.59	0.58	0.01	0.97	0.96	0.01
0.75	0.60	0.58	0.02	0.97	0.96	0.01
0.70	0.60	0.58	0.02	0.97	0.96	0.01
0.65	0.61	0.58	0.03	0.97	0.96	0.01
5-year horizon
0.80	1.39	1.16	0.22	2.76	2.33	0.42
0.75	1.45	1.16	0.29	2.88	2.33	0.54
0.70	1.52	1.16	0.36	3.00	2.33	0.67
0.65	1.60	1.16	0.44	3.14	2.33	0.80
10-year horizon
0.80	1.43	1.18	0.26	2.90	2.37	0.53
0.75	1.52	1.18	0.34	3.07	2.37	0.70
0.70	1.61	1.18	0.44	3.26	2.37	0.89
0.65	1.72	1.18	0.55	3.48	2.37	1.11
20-year horizon
0.80	1.43	1.18	0.26	2.90	2.37	0.53
0.75	1.52	1.18	0.34	3.07	2.37	0.70
0.70	1.62	1.18	0.44	3.27	2.37	0.90
0.65	1.73	1.18	0.55	3.50	2.37	1.12

In scenario 3, the initial patient distribution was based on a pooled dataset [14]. A relative risk of 0.80 corresponds to a relative risk reduction of 20%, etc.

Abbreviations. LY, life-year; QALY, quality-adjusted life-year; RR, relative risk; SoC, standard of care.

Figure 2. Incremental QALYs and LYs for a range of hypothetical treatment effects versus standard of care over a 10-year horizon, for 3 scenarios of patient distribution.

The bar graphs show the incremental QALYs (solid bars) and LYs (clear bars) gained with hypothetical treatment effects in three different patient scenarios. In scenario 1, all patients begin at MiToS stage 0; in scenario 2, the initial distribution of patients across MiToS stages was based on a real-world cohort [23]; in scenario 3, the initial distribution of patients was based on a pooled dataset [14]. A relative risk of 0.80 corresponds to a relative risk reduction of 20%, etc. In all scenarios, the pattern of results was similar, with incremental gains in QALYs and LYs increasing as the hypothetical treatment effect increases. Abbreviations. LY, life-year; QALY, quality-adjusted life-year.

Table 6. QALY for a treatment with hypothetical RR of 0.65 versus standard of care for each MiToS stage: patient distribution based on a pooled dataset (scenario 3).

	QALY		Incremental QALY
	Treatment	SoC	Treatment vs SoC
1-year horizon
Stage 0	0.46	0.41	0.05
Stage 1	0.12	0.13	−0.01
Stage 2	0.02	0.03	−0.01
Stage 3	0.00	0.01	0.00
Stage 4	0.00	0.00	0.00
Total	0.61	0.58	0.03
5-year horizon
Stage 0	0.80	0.56	0.24
Stage 1	0.46	0.33	0.13
Stage 2	0.19	0.15	0.05
Stage 3	0.08	0.06	0.02
Stage 4	0.07	0.07	0.00
Total	1.60	1.16	0.44
10-year horizon
Stage 0	0.81	0.56	0.25
Stage 1	0.49	0.33	0.16
Stage 2	0.22	0.15	0.07
Stage 3	0.10	0.07	0.03
Stage 4	0.10	0.07	0.03
Total	1.72	1.18	0.55
20-year horizon
Stage 0	0.81	0.56	0.25
Stage 1	0.49	0.33	0.16
Stage 2	0.22	0.15	0.07
Stage 3	0.10	0.07	0.03
Stage 4	0.10	0.07	0.03
Total	1.73	1.18	0.55

In scenario 3, the initial patient distribution was based on a pooled dataset [14]. A RR of 0.65 corresponds to a RRR of 35%.

Abbreviations. MiToS, Milano-Torino staging; QALY, quality-adjusted life-year; RR, relative risk; RRR, relative risk reduction; SoC, standard of care.

Figure 3. Tornado diagram from one-way sensitivity: incremental QALYs of hypothetical treatment effect versus standard of care over a 10-year horizon, for scenario 3 of patient distribution.

Abbreviations. QALY, quality-adjusted life-year; RR, relative risk; TP, transition probability.

Figure 4. Histogram from probabilistic sensitivity analyses: QALYs of hypothetical treatment effect and standard of care over a 10-year horizon, for scenario 3 of patient distribution.

Abbreviations. QALY, quality-adjusted life-year; SoC, standard of care.

Figure 5. Markov trace for standard of care: overall survival (a) and individual stages (b).

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Data availability statement

All data generated or analyzed during this study are included in this published article and its supplementary information files.