Structured Abstract
Importance Tics are a common feature of early-onset neurodevelopmental disorders, characterized by involuntary and repetitive movements or sounds. Despite affecting up to 2% of young children and having a genetic contribution, the underlying causes remain poorly understood, likely due to the complex phenotypic and genetic heterogeneity among affected individuals.
Objective In this study, we leverage dense phenotype information from electronic health records to identify the disease features associated with tic disorders within the context of a clinical biobank. These disease features are then used to generate a phenotype risk score for tic disorder.
Design Using de-identified electronic health records from a tertiary care center, we extracted individuals with tic disorder diagnosis codes. We performed a phenome-wide association study to identify the features enriched in tic cases versus controls (N=1,406 and 7,030; respectively). These disease features were then used to generate a phenotype risk score for tic disorder, which was applied across an independent set of 90,051 individuals. A previously curated set of tic disorder cases from an electronic health record algorithm followed by clinician chart review was used to validate the tic disorder phenotype risk score.
Main Outcomes and Measures Phenotypic patterns associated with a tic disorder diagnosis in the electronic health record.
Results Our tic disorder phenome-wide association study revealed 69 significantly associated phenotypes, predominantly neuropsychiatric conditions, including obsessive compulsive disorder, attention-deficit hyperactivity disorder, autism, and anxiety. The phenotype risk score constructed from these 69 phenotypes in an independent population was significantly higher among clinician-validated tic cases versus non-cases.
Conclusions and Relevance Our findings provide support for the use of large-scale medical databases to better understand phenotypically complex diseases, such as tic disorders. The tic disorder phenotype risk score provides a quantitative measure of disease risk that can be leveraged for the assignment of individuals in case-control studies or for additional downstream analyses.
Question Can clinical features within the electronic medical records of patients with tic disorders be used to generate a quantitative risk score that can identify other individuals at high probability of tic disorders?
Findings In this phenome-wide association study using data from electronic health records, we identify the medical phenotypes associated with a tic disorder diagnosis. We then use the resulting 69 significantly associated phenotypes, which include several neuropsychiatric comorbidities, to generate a tic disorder phenotype risk score in an independent population and validate this score with clinician-validated tic cases.
Meaning The tic disorder phenotype risk score provides a computational method of evaluating and distilling the comorbidity patterns that characterize tic disorders (independent of tic diagnosis status) and may help improve downstream analyses by distinguishing between individuals that should be categorized as cases or controls for tic disorder population studies.
Competing Interest Statement
Conflicts of Interest and Funding: JMS is an unpaid member of the Scientific Advisory Board of the Tourette Association of America. JMS receives grant support from the TLC Foundation for Body-Focused Repetitive Behaviors. JMS, CAM, and LKD are supported by grants from the National Institute of Neurological Disorders and Stroke, NS105746 and NS102371. DAI receives funding from the Tourette Association of America, Vanderbilt Clinical and Translational Research Scholars (KL2TR002245), and Teva Branded Pharmaceutical Products, R&D, Inc.
Funding Statement
JMS receives grant support from the TLC Foundation for Body-Focused Repetitive Behaviors. JMS, CAM, and LKD are supported by grants from the National Institute of Neurological Disorders and Stroke, NS105746 and NS102371. DAI receives funding from the Tourette Association of America, Vanderbilt Clinical and Translational Research Scholars (KL2TR002245), and Teva Branded Pharmaceutical Products, R&D, Inc.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The project was approved by the Vanderbilt University Medical Center (VUMC) Institutional Review Board (IRB #160650).
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Data Availability
Because of patient confidentiality, individual-level data from BioVU and the Synthetic Derivative at Vanderbilt University Medical Center cannot be shared as it includes comprehensive electronic health record information. Data is available upon request and approval from Vanderbilt Institute for Clinical and Translational Research for researchers who meet the criteria for access to this confidential dataset. The phenotypes used to construct the tic disorder phenotype risk scores and the summary-level results are able to be shared and this information is included in the supplemental files of this manuscript.