A Prediction Algorithm for Drug Response in Patients with Mesial Temporal Lobe Epilepsy Based on Clinical and Genetic Information

<div><p>Mesial temporal lobe epilepsy is the most common form of adult epilepsy in surgical series. Currently, the only characteristic used to predict poor response to clinical treatment in this syndrome is the presence of hippocampal sclerosis. Single nucleotide polymorphisms (SNPs) located in genes encoding drug transporter and metabolism proteins could influence response to therapy. Therefore, we aimed to evaluate whether combining information from clinical variables as well as SNPs in candidate genes could improve the accuracy of predicting response to drug therapy in patients with mesial temporal lobe epilepsy. For this, we divided 237 patients into two groups: 75 responsive and 162 refractory to antiepileptic drug therapy. We genotyped 119 SNPs in <i>ABCB1</i>, <i>ABCC2</i>, <i>CYP1A1</i>, <i>CYP1A2</i>, <i>CYP1B1</i>, <i>CYP2C9</i>, <i>CYP2C19</i>, <i>CYP2D6</i>, <i>CYP2E1</i>, <i>CYP3A4</i>, and <i>CYP3A5</i> genes. We used 98 additional SNPs to evaluate population stratification. We assessed a first scenario using only clinical variables and a second one including SNP information. The random forests algorithm combined with leave-one-out cross-validation was used to identify the best predictive model in each scenario and compared their accuracies using the area under the curve statistic. Additionally, we built a variable importance plot to present the set of most relevant predictors on the best model. The selected best model included the presence of hippocampal sclerosis and 56 SNPs. Furthermore, including SNPs in the model improved accuracy from 0.4568 to 0.8177. Our findings suggest that adding genetic information provided by SNPs, located on drug transport and metabolism genes, can improve the accuracy for predicting which patients with mesial temporal lobe epilepsy are likely to be refractory to drug treatment, making it possible to identify patients who may benefit from epilepsy surgery sooner.</p></div

Percentage that each AED appears in monotherapy or polytherapy in the responsive and refractory patients.

<p>Percentage that each AED appears in monotherapy or polytherapy in the responsive and refractory patients.</p

Fst values from the sample for all five chromosomes combined and separated.

<p>The table also includes the percentage of genetic variation between and within groups.</p

Chromosome location of candidate genes and SNPtag map.

<p>a) genes are indicated by the grey vertical bars and distribution of SNPs used in the population structure are indicated by the red vertical bars; b) linkage disequilibrium estimates are presented in terms of pairwise r² values. Values of r² > 80 indicate linkage disequilibrium.</p

ROC curve showing the true positive rate (sensitivity), in function of false positive rate (1-specificity).

<p>The blue line indicates the prediction scenario using only clinical variables (hippocampal sclerosis, age of onset epilepsy, febrile seizures, and gender). The red line indicates the second scenario using the clinical variables plus SNPs. The dark green line indicates the scenario using only SNP genotypes. The area under the curve (AUC) values is showed for the three scenarios. The diagonal dashed line indicates a non-informative prediction (AUC = 0.5).</p

<i>ABCC2</i> mRNA relative quantification.

<p>The boxplots include dots for each sample, showing the relative quantification of ABCC2 mRNA, in terms of 2^-ΔΔCT (y-axis), between hippocampal tissue from refractory MTLE patients and control autopsies.</p

Descriptive statistics of the two groups of patients with MTLE.

<p>Descriptive statistics of the two groups of patients with MTLE.</p

Variable importance plot.

<p>Each point represents the mean decreased accuracy estimate (y-axis), for each clinical variable and SNP genotype selected by the model (x-axis). Letter codes (AB and BB), after SNP name, indicate heterozygote and the alternative homozygote allele for each SNP, respectively.</p

ROI subgroups analysis.

<p>Axial view of significant areas in the comparison of B&O versus controls. Areas described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182735#pone.0182735.t004" target="_blank">Table 4</a>. p-values in red scale colorbar, α = 0.017 (Bonferroni correction).</p

Primary exploratory analysis.

<p>Primary exploratory analysis.</p