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Natural language processing and expert follow-up establishes tachycardia association with CDKL5 deficiency disorder
Alina Ivaniuk1,2, Christian M Boßelmann1,2, Xiaoming Zhang1,2
1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
Insights
CDKL5 deficiency disorder (CDD) is linked to tachycardia, including supraventricular tachycardia (SVT). This study used HPO analysis to identify novel cardiovascular associations in CDD patients.
Area of Science:
- Genetics
- Neurology
- Cardiology
Background:
- CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental condition.
- Cardiovascular comorbidities are recognized in CDD but poorly characterized in patient cohorts.
- Animal models suggest cardiac involvement, necessitating human data.
Purpose of the Study:
- To investigate cardiovascular comorbidities in individuals with CDKL5 deficiency disorder.
- To identify novel phenotype associations using a large dataset of medical records.
- To explore the relationship between tachycardia and other symptoms in CDD.
Main Methods:
- Utilized natural language processing to extract Human Phenotype Ontology (HPO) terms from 30,512 medical encounters of 38 individuals with genetically confirmed CDD.
- Compared CDD patients with 190 matched controls with non-genetic epilepsy.
- Conducted HPO association testing and manual chart review.
Main Results:
- Confirmed known CDD phenotypes and identified a significant association between CDD and tachycardia (OR 4.2).
- Discovered a 99.6-fold enrichment of supraventricular tachycardia (SVT) in CDD, identifying two new cases of fetal/neonatal onset SVT.
- Found tachycardia in CDD was associated with other autonomic symptoms (OR 5.63).
Conclusions:
- CDKL5 deficiency disorder is associated with tachycardia, potentially including early-onset SVT.
- Semiautomated genotype-phenotype analysis with matched controls is an effective method for identifying novel phenotype associations.
- Further prospective studies are recommended for validation.
Purpose:
CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy with multisystemic comorbidities. Cardiovascular involvement in CDD was shown in animal models but is yet poorly described in CDD cohorts.
Methods:
We identified 38 individuals with genetically confirmed CDD through the Cleveland Clinic CDD specialty clinic and matched 190 individuals with non-genetic epilepsy to them as a comparison group. Natural language processing was applied to yield Human Phenotype Ontology (HPO) terms from medical records. We conducted HPO association testing and manual chart review to explore cardiovascular comorbidities associated with CDD.
Results:
We extracted 243,541 HPO terms from 30,512 medical encounters. Phenome-wide analysis confirmed well-established CDD phenotypes and identified association of tachycardia with CDD (Odds ratio 4.2, 95% confidence interval (CI) 1.75-9.93, P adj < .001). We found a 99.6-fold enrichment of supraventricular tachycardia (SVT) in CDD encounter notes (P adj < .001), which led to identification of 2 cases of fetal/neonatal onset SVT previously undescribed in CDD. Tachycardia in CDD individuals was associated with the presence of other autonomic symptoms (Odds ratio 5.63, 95% CI 1.08-40.3, P = .038).
Conclusion:
CDD is associated with tachycardia, potentially including early-onset SVT. Alongside prospective validation studies, semiautomated genotype-phenotype analysis with matched controls is a scalable, rapid, and efficient approach for validating known and identifying novel phenotype associations.
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