MODY probability calculator utility in individuals' selection for genetic testing: Its accuracy and performance

Area of Science:

• Endocrinology
• Genetics
• Diabetes Research

Background:

• Monogenic diabetes, including Maturity-Onset Diabetes of the Young (MODY), requires accurate genetic testing for diagnosis.
• The Exeter MODY Probability Calculator (MPC) was developed to assist clinicians in identifying individuals who would benefit most from genetic testing.
• Assessing the MPC's utility in diverse populations is crucial for its widespread clinical application.

Purpose of the Study:

• To evaluate the effectiveness of the Exeter MODY Probability Calculator in a Portuguese cohort of patients with early-onset monogenic diabetes.
• To determine the predictive values, accuracy, sensitivity, and specificity of the MPC within this specific population.

Main Methods:

• A retrospective analysis of 132 participants who underwent genetic testing for diabetes between 2015 and 2020.
• Genetic sequencing was performed, and MODY probabilities were calculated using the online MPC.
• Statistical analysis determined the calculator's performance metrics, including Positive Predictive Value (PPV) and Negative Predictive Value (NPV).

Main Results:

• The study included 73 individuals, identifying various MODY subtypes (GCK-MODY, HNF1A-MODY, HNF4A-MODY) and non-monogenic diabetes cases.
• The median MPC score was significantly higher in patients with monogenic diabetes (75.5%) compared to those without (24.2%).
• The MPC demonstrated a discriminative accuracy (Area Under the Curve) of 75%, with an optimal cut-off of 36% yielding a PPV of 74.4% and NPV of 73.5%.

Conclusions:

• The Exeter MODY Probability Calculator is a valuable tool for selecting individuals for genetic testing in highly pre-selected groups.
• An optimal cut-off of 36% showed good discrimination ability in the Portuguese cohort.
• Further research with geographical and population adjustments is recommended for broader implementation of the MPC.