Epi4K - Phenotyping and Clinical Informatics Core (U01)

Investigator: Daniel Lowenstein, MD
Sponsor: NIH National Institute of Neurological Disorders and Stroke

Location(s): United States


The primary goal of the Epi4K Center Without Walls is to increase understanding of the genetic basis of human epilepsy in order to improve the well-being of patients and family members living with these disorders. This improvement will come in the form of better diagnostics, treatments and cures. To accomplish this goal, Epi4K aims to analyze the genomes of a large number of well-phenotyped epilepsy patients and families collected by investigators from several major research groups. A critical aspect of this enterprise, and the main goal of the Epi4K Phenotyping and Clinical Informatics (PCI) Core described here, is to assemble, organize and validate the phenotypic information on all patients proposed for genomic analysis, and to insure that patients' DNA samples are available to the Epi4K Sequencing, Biostatistics and Bioinformatics (SBB) Core when needed. The availability of well-documented, high quality phenotype data is obviously crucial to the success of all four proposed projects in Epi4K, since the detection of meaningful phenotype:genotype associations will depend highly on phenotype validity. However, achieving this goal in Epi4K will require substantial effort for two main reasons. First, the diagnosis and classification of the epilepsies, including clinical characteristics such as seizure type, seizure semiology, therapeutic response, and additional features such as intellectual and neurological deficits, rests primarily on clinica observations, which are prone to subjectivity and often poorly described or interpreted. Second, Epi4K will assemble at least seven different cohorts of patients collected using varied phenotyping methodologies. To address these challenges, we will capitalize on the substantial experience of the PCI Core investigators, all of whom have devoted considerable portions of their careers to developing methods for accurately phenotyping epilepsy. In addition, through the work of the Epilepsy Phenome/Genome Project (EPGP), we have already created data review systems and a highly efficient informatics infrastructure that can be adapted to the needs of Epi4K. With these resources in hand, the PCI Core seeks to accomplish the following specific aims: 1) to establish standards for documentation of epilepsy phenotypes that can be used reliably across different sites for all subjects undergoing genetic analyses in Epi4K; 2) to design and implement an informatics infrastructure for an Epi4K Phenotype Data Repository and DNA Sample Tracking System; and 3) to validate the phenotype data associated with every DNA sample submitted for genome analyses. Epilepsy is one of the most common neurological disorders in humans, affecting up to 3% of the population. Although there is a strong genetic component for epilepsy, there are still only a few genes known. The Epi4K project will identify new genes and genetic pathways in epilepsy and will directly benefit individuals with epilepsy and their families through improved diagnostic, prognostic and recurrence risk information. Epi4K will also advance our understanding of the biological basis of epilepsy, which is essential for the development of new and effective treatments, as well as cures.