Mainstreaming Genetic Testing for Monogenic Diabetes: A Feasibility, Outcome, and Validation Study
Health Services and Implementation
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
Monogenic diabetes (MGD), including Maturity-Onset Diabetes of the Young (MODY), is under-diagnosed. Genetic testing enables accurate diagnosis and genotype-based treatment, which if mainstreamed, would allow timely optimisation of diabetes care. Despite significant progress in genetic testing, various barriers impede access to MGD genetic testing, including lack of awareness, and long wait times associated with genetics clinic referrals. We aimed to explore the feasibility and outcomes of mainstreaming MGD testing within diabetes clinics, circumventing the long wait times associated with referrals to genetics clinics. To facilitate wider implementation of genetic testing, we aimed to develop a decision tree for patient selection for testing and evaluated the performance of the criteria in an independent validation cohort in predicting MGD diagnosis.
Methods:
Seventy-two adult participants were prospectively identified by endocrinologists based on a priori criteria, recruited from diabetes clinics, and underwent multigene panel testing for MGD. Clinical, demographic, and psychosocial data were collected. The psychosocial questionnaire was constructed by combining two validated questionnaires, the 24-item Genetic Counselling Outcome Scale (GCOS-24) and the 6-item Satisfaction with Decision (SWD) Scale, aiming to assess potential psychosocial stress associated with testing in the mainstreaming setting. Multigene panel testing was undertaken at Exeter Laboratory, which is a Clinical Laboratory Improvement Amendments (CLIA)-certified diagnostic laboratory in the UK. The genetic results were returned to each patient via endocrinologist in a routine follow-up clinic. Patients were referred for clinical genetics follow-up if a causative variant or a variant of uncertain significance (VUS) was identified. A posteriori criteria were developed based on the findings and validated in an independent cohort of 3166 adult and paediatric patients with suspected MGD. This study was approved by St Vincent’s Hospital Human Research Ethics Committee (2019ETH00149) and registered with the ANZCTR (ACTRN12620001123932).
Results:
A priori criteria achieved MGD diagnostic yield of 21.4%. Multivariable analysis identified younger age at diagnosis (p=0.04), but not lower body mass index (p=0.18) or positive family history (p=0.35), as independent predictors of MGD. Validation of a posteriori criteria yielded positive predictive value 22.7% and negative predictive value 86.5%, in predicting MGD, with sensitivity 79.8% and specificity 32.3%. Patient satisfaction and empowerment were high. Sixty-percent of endocrinologists reported modifying patient management. Lack of clinical guidelines for testing, access and cost of testing were identified barriers to mainstreaming MGD testing.
Conclusion:
Integrating MGD testing into routine diabetes care is feasible with support and can influence treatment decisions. A posteriori criteria achieved high predictive performance and can be used to guide future patient selection for MGD testing, facilitating wider implementation of mainstreaming MGD testing.
Monogenic diabetes (MGD), including Maturity-Onset Diabetes of the Young (MODY), is under-diagnosed. Genetic testing enables accurate diagnosis and genotype-based treatment, which if mainstreamed, would allow timely optimisation of diabetes care. Despite significant progress in genetic testing, various barriers impede access to MGD genetic testing, including lack of awareness, and long wait times associated with genetics clinic referrals. We aimed to explore the feasibility and outcomes of mainstreaming MGD testing within diabetes clinics, circumventing the long wait times associated with referrals to genetics clinics. To facilitate wider implementation of genetic testing, we aimed to develop a decision tree for patient selection for testing and evaluated the performance of the criteria in an independent validation cohort in predicting MGD diagnosis.
Methods:
Seventy-two adult participants were prospectively identified by endocrinologists based on a priori criteria, recruited from diabetes clinics, and underwent multigene panel testing for MGD. Clinical, demographic, and psychosocial data were collected. The psychosocial questionnaire was constructed by combining two validated questionnaires, the 24-item Genetic Counselling Outcome Scale (GCOS-24) and the 6-item Satisfaction with Decision (SWD) Scale, aiming to assess potential psychosocial stress associated with testing in the mainstreaming setting. Multigene panel testing was undertaken at Exeter Laboratory, which is a Clinical Laboratory Improvement Amendments (CLIA)-certified diagnostic laboratory in the UK. The genetic results were returned to each patient via endocrinologist in a routine follow-up clinic. Patients were referred for clinical genetics follow-up if a causative variant or a variant of uncertain significance (VUS) was identified. A posteriori criteria were developed based on the findings and validated in an independent cohort of 3166 adult and paediatric patients with suspected MGD. This study was approved by St Vincent’s Hospital Human Research Ethics Committee (2019ETH00149) and registered with the ANZCTR (ACTRN12620001123932).
Results:
A priori criteria achieved MGD diagnostic yield of 21.4%. Multivariable analysis identified younger age at diagnosis (p=0.04), but not lower body mass index (p=0.18) or positive family history (p=0.35), as independent predictors of MGD. Validation of a posteriori criteria yielded positive predictive value 22.7% and negative predictive value 86.5%, in predicting MGD, with sensitivity 79.8% and specificity 32.3%. Patient satisfaction and empowerment were high. Sixty-percent of endocrinologists reported modifying patient management. Lack of clinical guidelines for testing, access and cost of testing were identified barriers to mainstreaming MGD testing.
Conclusion:
Integrating MGD testing into routine diabetes care is feasible with support and can influence treatment decisions. A posteriori criteria achieved high predictive performance and can be used to guide future patient selection for MGD testing, facilitating wider implementation of mainstreaming MGD testing.