Interpretable Machine Learning to Predict the Malignancy Risk of Follicular Thyroid Neoplasms in Extremely Unbalanced Data: Retrospective Cohort Study and Literature Review.

Background: Diagnosing and managing follicular thyroid neoplasms (FTNs) remains a significant challenge, as the malignancy risk cannot be determined until after diagnostic surgery. Objective: We aimed to use interpretable machine learning to predict the malignancy risk of FTNs preoperatively in a real-world setting. Methods: We conducted a retrospective cohort study at the Peking University Third Hospital in Beijing, China. Patients with postoperative pathological diagnoses of follicular thyroid adenoma (FTA) or follicular thyroid carcinoma (FTC) were included, excluding those without preoperative thyroid ultrasonography. We used 22 predictors involving demographic characteristics, thyroid sonography, and hormones to train 5 machine learning models: logistic regression, least absolute shrinkage and selection operator regression, random forest, extreme gradient boosting, and support vector machine. The optimal model was selected based on discrimination, calibration, interpretability, and parsimony. To address the highly imbalanced data (FTA:FTC ratio>5:1), model discrimination was assessed using both the area under the receiver operating characteristic curve and the area under the precision-recall curve (AUPRC). To interpret the model, we used Shapley Additive Explanations values and partial dependence and individual conditional expectation plots. Additionally, a systematic review was performed to synthesize existing evidence and validate the discrimination ability of the previously developed Thyroid Imaging Reporting and Data System for Follicular Neoplasm scoring criteria to differentiate between benign and malignant FTNs using our data. Results: The cohort included 1539 patients (mean age 47.98, SD 14.15 years; female: n=1126, 73.16%) with 1672 FTN tumors (FTA: n=1414; FTC: n=258; FTA:FTC ratio=5.5). The random forest model emerged as optimal, identifying mean thyroid-stimulating hormone (TSH) score, mean tumor diameter, mean TSH, TSH instability, and TSH measurement levels as the top 5 predictors in discriminating FTA from FTC, with the area under the receiver operating characteristic curve of 0.79 (95% CI 0.77-0.81) and AUPRC of 0.40 (95% CI 0.37-0.44). Malignancy risk increased nonlinearly with larger tumor diameters and higher TSH instability but decreased nonlinearly with higher mean TSH scores or mean TSH levels. FTCs with small sizes (mean diameter 2.88, SD 1.38 cm) were more likely to be misclassified as FTAs compared to larger ones (mean diameter 3.71, SD 1.36 cm). The systematic review of the 7 included studies revealed that (1) the FTA:FTC ratio varied from 0.6 to 4.0, lower than the natural distribution of 5.0; (2) no studies assessed prediction performance using AUPRC in unbalanced datasets; and (3) external validations of Thyroid Imaging Reporting and Data System for Follicular Neoplasm scoring criteria underperformed relative to the original study. Conclusions: Tumor size and TSH measurements were important in screening FTN malignancy risk preoperatively, but accurately predicting the risk of small-sized FTNs remains challenging. Future research should address the limitations posed by the extreme imbalance in FTA and FTC distributions in real-world data.