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Principal Investigator: Ingo Helbig
Organization: CHILDREN'S HOSP OF PHILADELPHIA
Fiscal Year: 2024
Award: $697,071
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Over the last decade, there has been an exponential increase in identified genetic causes of neurodevelopmental
disorders and epilepsy. With more than 100 genes identified, understanding how phenotypes relate to specific
genetic variants is critical given the clinical complexity of developmental brain disorders. Given that treatment
and prognosis is dependent on understanding genotype-phenotype correlations, there is a critical need to better
assess clinical features in genetic epilepsies. However, phenotyping is a time-consuming, manual task with
limited throughput. To overcome this bottleneck, we have developed a novel approach, based on the Human
Phenotype Ontology (HPO) to capture and analyze longitudinal phenotypic data. In our preliminary data for
STXBP1- and SCN8A-related disorders, which we have reconstructed for >550 patient months, we identified
unique natural histories, outcomes, and distinct response patterns to specific treatment strategies. Natural history
and treatment response in pediatric epilepsies are deeply intertwined and often difficult to disentangle.
Accordingly, a comprehensive assessment of genetic epilepsies needs to account for two factors, subgroups
with common clinical trajectories as well as gene-specific treatment responses. Our suggested project therefore
has two aims. First, we plan to detect relevant subgroups in genetic epilepsies based on longitudinal clinical data
(Aim #1). We will reconstruct longitudinal trajectories and outcomes in the 15 most common genetic epilepsies
with 50-75 individuals per gene to delineate longitudinal seizure burden, seizures types, and developmental
milestones. Based on this, we will then identify subgroups defined by clinical features and global clinical
resemblance, as well as variant and gene groups. In addition (Aim #2), we will identify specific treatment
responses in genetic epilepsies using standardized phenotypes. We will combine reconstructed natural history
with treatment data to compare reduction in seizure frequencies and effect on maintaining seizure freedom
across >20 treatment strategies with the goal to identify the most effective treatment strategy when adjusting for
age and seizure type. Finally, we will also compare medication response across major variant classes and across
all genetic etiologies combined. Our team has previously pioneered computational phenotype analysis in the
epilepsies, positioning us uniquely to address these questions. Our analysis, mapping longitudinal clinical data
to a harmonized format will provide unprecedented granularity in deciphering the trajectory of genetic epilepsies,
informing clinical practice in these conditions. We hope that these results will provide a template for the analysis
of the limited clinical data in rare diseases in order to maximize treatment-relevant information, especially in
conditions with complex, longitudinal disease histories.
Terms: <Accounting><Address><Age><Age Factors><Anticonvulsant Agent><Anticonvulsant Drugs><Anticonvulsants><Anticonvulsive Agents><Anticonvulsive Drugs><Brain Diseases><Brain Disorders><Clinical><Clinical Data><Comparative Effectiveness Research><Complex><Computational toolkit><Consumption><Data><Data Analyses><Data Analysis><Dedications><Demographic Factors><Development><Diagnostic><Disease><Disorder><Drugs><Encephalon Diseases><Epilepsy><Epileptic Seizures><Epileptics><Freedom><Frequencies><Future><Gene variant><Genes><Genetic><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic propensity><Genotype><Goals><History><Human><Individual><Inherited Predisposition><Inherited Susceptibility><Intervention><Intervention Strategies><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Knowledge><Language><Liberty><Manuals><Maps><Measurement><Medication><Methods><Mission><Modern Man><NAV1.6><NINDS><NaCh6><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><Natural History><Nerve><Nervous System Diseases><Nervous System Disorder><Neurodevelopmental Disorder><Neurologic Disorders><Neurological Development Disorder><Neurological Disorders><Ontology><Operative Procedures><Operative Surgical Procedures><Orphan Disease><Outcome><Patients><Pattern><Pharmaceutical Preparations><Phenotype><Position><Positioning Attribute><Prognosis><Public Health><Rare Diseases><Rare Disorder><Recording of previous events><Research><SCN8A><SCN8A gene><Saint Jude><Saint Jude Children's Cancer Center><Saint Jude Children's Research Hospital><Seizure Disorder><Seizures><Sodium Channel Blockers><St. Jude><St. Jude Children's Cancer Center><St. Jude Children's Research Hospital><St. Jude Children's Research Hospital Comprehensive Cancer Center><St.Jude Children's Cancer Center><St.Jude Children's Research Hospital><St.Jude Children's Research Hospital Comprehensive Cancer Center><Standardization><Stratification><Subgroup><Surgical><Surgical Interventions><Surgical Procedure><Therapeutic><Time><Translating><Variant><Variation><ages><allele variant><allelic variant><analyzing longitudinal><childhood epilepsy><clinical care><clinical practice><cohort><compare treatment><computational toolbox><computational tools><computational toolset><computerized tools><data harmonization><data interpretation><developmental><dietary><drug/agent><effective therapy><effective treatment><epilepsia><epileptogenic><genetic etiology><genetic mechanism of disease><genetic variant><genetic vulnerability><genetically predisposed><genomic variant><harmonized data><histories><implantation><improved><interventional strategy><keto diet><ketogenic diet><longitudinal analysis><loss of function><neurodevelopmental disease><neurological disease><new approaches><novel approaches><novel strategies><novel strategy><orphan disorder><outcome prediction><oxcarbazepine><pediatric epilepsy><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><phenotypic data><programs><reconstruction><response><response to therapy><response to treatment><seizure drug><seizure medication><sodium channel, voltage gated, type VIII, alpha subunit><surgery><therapeutic response><therapy response><treatment and outcome><treatment choice><treatment comparison><treatment response><treatment responsiveness><treatment strategy>