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

This study assessed the feasibility of using the Milano-Torino staging (MiToS) system for conducting economic evaluation to measure health outcomes in amyotrophic lateral sclerosis (ALS). A Markov model was developed using the MiToS system and evaluated with a hypothetical treatment versus standard of care. Health utilities and transition probabilities were derived from the literature. Four-time horizons (1, 5, 10, and 20 years) were examined. Treatment effects of 20–35% relative risk reduction (RRR) of progressing to the next MiToS stage were assessed. Three patient distribution scenarios were tested: (1) all patients began in stage 0; (2) patient distribution based on real-world TONiC study; (3) distribution based on the PRO-ACT database. Health outcomes (quality-adjusted life-years [QALYs], life-years [LYs]) were reported with a 3% discount rate. A time horizon of 10 years fully captured treatment benefits: incremental QALYs were 0.28–0.60, 0.21–0.45, and 0.26–0.55 for scenarios 1–3, respectively; incremental LYs were 0.56–1.17, 0.46–0.97, and 0.53–1.11, respectively. MiToS-based staging can be used for conducting economic analyses in ALS. Estimated incremental QALY and LY gains were meaningful within the context of ALS, for hypothetical treatments with RRR of 20–35%.</p

TBSS results: areas of decreased fractional anisotropy (FA, red-yellow), and increased mean (MD, green) and radial diffusivity (radD, blue) in PLS patients with cognitive deficits (PLS-cd) <i>vs.</i> healthy controls are displayed on a FA template in the Montreal Neurological Institute space.

<p>FWE =  family wise error.</p

TBSS results: areas of decreased fractional anisotropy (FA, red-yellow) in PLS patients without cognitive impairment (PLS-cu) <i>vs.</i> healthy controls are displayed on a FA template in the Montreal Neurological Institute space.

<p>FWE =  family wise error.</p

TBSS results: areas of decreased fractional anisotropy (FA, red-yellow), and increased mean (MD, green) and radial diffusivity (radD, blue) in PLS patients with cognitive deficits (PLS-cd) <i>vs.</i> PLS patients without cognitive impairment (PLS-cu) are displayed on a FA template in the Montreal Neurological Institute space.

<p>FWE =  family wise error.</p

Sociodemographic and clinical features of the three study groups.

<p>Values are mean ± standard deviation [range] or number (%). P¹ =  differences between all groups; P² = differences between patient groups. *p<0.05 compared with healthy controls. Group differences in categorial variables (i.e., gender and onset type) were assessed using the Fisher Exact test. Continuous variables (i.e., age, WMH load, disease duration, ALSFRS-r, UMN score, and disease progression rate) were compared using the Kruskal-Wallis or the Mann-Whitney U-test. Disease progression rate = (48-ALSFRS-r score)/time from symptom onset. Abbreviations: ALSFRS-r =  ALS Functional Rating scale-revised; co =  cut-off; MMSE =  mini mental state examination; PLS-cd =  primary lateral sclerosis with cognitive deficits; PLS-cu =  cognitively unimpaired primary lateral sclerosis; UMN score =  upper motor neuron score; WMH =  white matter hyperintensity.</p

Neuropsychological and behavioral data of PLS patients.

<p>Scores are corrected for age, gender and education. P = differences between patient groups; values refer to the Mann-Whitney U-test. WCST, global score calculation = [N used cards-(completed categories*10)], higher scores mean worse performances <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082017#pone.0082017-Laiacona1" target="_blank">[23]</a>. Fluency indices calculation = for each letter (P, F, L) or category (animals, fruits, cars) a partial index was calculated in order to correct for motor disabilities as following: [(60-seconds for reading words previously reported in 1’)/N words previously reported in 1’]; the total semantic or phonemic index was obtained by averaging the 3 semantic or phonemic partial indices, respectively. Higher scores mean worse performances <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082017#pone.0082017-Abrahams1" target="_blank">[21]</a>. Abbreviations: BADA =  “Batteria per l'Analisi del Deficit Afasico”; co =  cut-off; FBI =  frontal behavioral battery; HDRS =  Hamilton depression rating scale; PLS-cd =  primary lateral sclerosis with cognitive deficits; PLS-cu =  cognitively unimpaired primary lateral sclerosis; WCST =  Wisconsin card sorting test.</p

Characteristics of European registers participating in the study.

<p>Characteristics of European registers participating in the study.</p

Demographics and clinical features of the Irish, Italian and French ALS population cohorts and the corresponding tertiary referral cohorts.

<p>Demographics and clinical features of the Irish, Italian and French ALS population cohorts and the corresponding tertiary referral cohorts.</p

Multicenter validation of [¹⁸F]-FDG PET and support-vector machine discriminant analysis in automatically classifying patients with amyotrophic lateral sclerosis versus controls

<p><i>Objective</i>: ¹⁸F-Fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) single-center studies using support vector machine (SVM) approach to differentiate amyotrophic lateral sclerosis (ALS) from controls have shown high overall accuracy on an individual patient basis using local <i>a priori</i> defined classifiers. The aim of the study was to validate the SVM accuracy on a multicentric level.</p> <p><i>Methods</i>: A previously defined Belgian (BE) group of 175 ALS patients (61.9 ± 12.2 years, 120M/55F) and 20 screened healthy controls (62.4 ± 6.4 years, 12M/8F) was used to classify another large dataset from Italy (IT), consisting of 195 patients (63.2 ± 11.6 years, 117M/78F) and 40 controls (62 ± 14.4 years; 29M/11F) free of any neurological and psychiatric disorder who underwent whole-body ¹⁸F-FDG PET-CT for lung cancer without any evidence of paraneoplastic symptoms. ¹⁸F-FDG within-center group comparisons based on statistical parametric mapping (SPM) were performed and SVM classifiers based on the local training sets were applied to differentiate ALS from controls from the other centers.</p> <p><i>Results</i>: SPM group analysis showed only minor differences between both ALS groups, indicating pattern consistency. SVM using BE data set as training, classified 183/193 ALS-IT correctly (accuracy of 94.8%). However, 35/40 CON-IT were misclassified as ALS (accuracy 12.5%). Furthermore, using IT data as training, ALS-BE could not be distinguished from CON-BE. Within-center SPM group analysis confirmed prefrontal hypometabolism in CON-IT versus CON-BE, indicating subclinical brain changes in patients undergoing oncological scanning.</p> <p><i>Conclusion</i>: This multicenter study confirms that the ¹⁸F-FDG ALS pattern is stable across centers. Furthermore, it highlights the importance of carefully selected controls, as subclinical frontal changes might be present in patients in an oncological setting.</p