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Abstract
Abstract
Among practitioners, the importance of inputs to a model output is commonly measured
via the computation of Sobol’ sensitivity indices. Various estimation strategies exist in the
literature, most of them requiring a very high number of model evaluations. Designing
methods that compete favorably both in terms of computational cost and accuracy is
therefore an issue of crucial importance. In this paper, an efficient replication-based
strategy is proposed to estimate the full set of first- and second-order Sobol’ indices. It
relies on a Sobol’ pick-freeze estimation scheme and requires only two replicated designs
based on randomized orthogonal arrays of strength two. The precision of this procedure is
assessed with bootstrap confidence intervals, presented for the first time in the replication
framework. Our developments are compared to known approaches and validated on
numerical test cases. A way to estimate the full set of first-, second-order but also total-
effect Sobol’ indices at a very competitive cost is also described, as a combination of our
procedure and the one introduced by Saltelli [1]. © 2018
Resumen
Entre los profesionales, la importancia de las entradas para un modelo de salida se mide
comúnmente mediante el cálculo de los índices de sensibilidad de Sobol. Existen varias
estrategias de estimación en la literatura, la mayoría de las cuales requieren un número
muy alto de evaluaciones de modelos. Diseñar métodos que compitan favorablemente
tanto en términos de costo computacional como de precisión es, por lo tanto, un tema de
importancia crucial. En este documento, se propone una estrategia eficiente basada en la
replicación para estimar el conjunto completo de índices de Sobol de primer y segundo
orden. Se basa en un esquema de estimación de congelación y selección de Sobol y solo
requiere dos diseños replicados basados en aleatoriosArreglos ortogonales de fuerza
dos. La precisión de este procedimiento se evalúa con intervalos de confianza de
arranque, presentados por primera vez en el marco de replicación. Nuestros desarrollos
se comparan con enfoques conocidos y se validan en casos de prueba
numéricos. También se describe una forma de estimar el conjunto completo de índices de
Sobol de primer orden, segundo y de efecto total a un costo muy competitivo, como una
combinación de nuestro procedimiento y el presentado por Saltelli [1]. © 2018
Abstract
Background and objectives: Epilepsy is the most common severe neurological disorder
worldwide. Approximately 40% of patients with focal epileptic seizures remain uncontrolled
with monotherapy or polytherapy with antiepileptic drugs (AED). Lacosamide has recently
been approved by the European Medicines Agency as monotherapy for the treatment of
focal seizures. The objective of this study was to estimate the cost-effectiveness of
lacosamide compared to zonisamide as a first-line treatment of focal epilepsy in patients
with epilepsy ≥ 16 years to inform clinical decision making in Greece. Methods: a discrete
event simulation model was adapted to reflect the treatment routes and the use of
resources within the Greek national health system, as specified by the clinical experts. The
model captures events that vary in time and patient characteristics. Clinical contributions
were obtained from pivotal trials and a network meta-analysis that compared lacosamide
with other AEDs. The model predicts disease progression and seizures, relevant and most
common adverse events, abstinence due to lack of efficacy or adverse events, and
mortality from specific epilepsy and all causes within a time horizon of 2 years. years. Unit
costs were recovered from published Greek sources. Health outcomes were measured as
quality adjusted life years (QALYs); The secondary result was the cost per attack avoided.
The robustness of the results was checked with univariate and probabilistic. Sensitivity
analysis. Results: The lacosamide treatment pathway was associated with higher costs (ie,
€ 1,064) and an additional 0,111 QALYs compared to zonisamide, which resulted in an
incremental cost-effectiveness ratio of € 8,938 for each AVAL gained. The sensitivity
analyzes showed that the results are more sensitive to the estimates of efficacy and utility.
Limitations: there are a number of limitations that stem from the process of adapting the
model and the lack of local evidence from the real world. Conclusions: Lacosamide is a
cost-effective option with a willingness to pay threshold of € 30,000 per QALY, which
represents a valuable option for monotherapy treatment for patients with focal epileptic
seizures in the Greek context. © 2019, © 2019 Informs UK Limited, under the name of
Taylor & Francis Group.
Resumen