Project: Rational antiepileptic drug selection by combining gene network and ICT analysis

Acronym	RAISE-GENIC (Reference Number: ERAPERMED2018-134)
Duration	01/03/2019 - 28/02/2022
Project Topic	Epilepsy is one of the most frequent chronic neurological disorders with a major impact on quality of life. Currently, less than 50% of patients become seizure free with the first antiepileptic drug (AED). The identification of factors allowing the selection of the AED with the best chance of success in individual patients (precision medicine) would revolutionise epilepsy treatment. We aim to achieve this by two data-integrative (big-data) strategies. The first approach consists of the identification of the gene networks that are activated upon exposure to two classical first-line AEDs (carbamazepine and valproate) as well as two newer first-line AEDs (lacosamide and levetiracetam) in glutamatergic and GABA-ergic neurons derived from induced pluripotent stem cells. In a cohort of 1382 patients with available exome sequencing data we will then estimate each patient’s AED-network properties by mapping the individual’s functional variants to the respective genes. The graph theoretical parameters of each individual’s network will then be tested as predictors for AED response using machine learning approaches. The second approach integrates detailed clinical information and biomarkers such as raw EEG, MRI and exome data of the same cohort to similarly develop a decision support tool for predicting the AED with the highest likelihood of success. We will optimize the decision support tool by integrating both approaches, compare them to the individual strategies and identify the parameters ultimately needed for a reliable prediction of AED response. Subsequently, we will select 100 independent patients from an available database with information on treatment outcome, assess the predictive parameters (e.g. perform exome sequencing and EEG) and evaluate if the predicted best AED corresponds with the observed most effective drug. Based on these results we will prepare a prospective multicentre randomized controlled trial with industry support.
Network	ERA PerMed
Call	1st Joint Transnational Call for Proposals (2018)

Project partner

Number	Name	Role	Country
1	University of Calgary	Coordinator	Canada
2	University of Calgary	Partner	Canada
3	Goethe University Frankfurt a. M.	Partner	Germany
4	Goethe University Frankfurt a. M.	Partner	Germany
5	University of Eastern Finland	Partner	Finland
6	Université Libre de Bruxelles	Partner	Belgium