OR32-02 Thyroid Cancer Polygenic Risk Score Improves Risk Stratification Of Thyroid Nodules When Added To Ultrasound Imaging
Authors: Pozdeyev Nikita , Dighe Manjiri , Barrio Martin , Raeburn Christopher , Smith Harry A , Fisher Matthew , Chavan Sameer , Rafaels Nicholas , Shortt Jonathan , Leu Michael , Clark Toshimasa , Marshall Carrie , Haugen Bryan R , Subramanian Devika , Crooks Kristy , Gignoux Christopher , Cohen Trevor A 
Published: October 2023

Abstract
Disclosure: N. Pozdeyev: None. M. Dighe: None. M. Barrio: None. C. Raeburn: None. H.A. Smith: None. M. Fisher: None. S. Chavan: None. N. Rafaels: None. J. Shortt: None. M. Leu: None. T. Clark: None. C. Marshall: None. B.R. Haugen: None. D. Subramanian: None. K. Crooks: None. C. Gignoux: None. T.A. Cohen: None.
Purpose. Evaluating thyroid nodules to rule out malignancy is a common clinical task. Image-based risk stratification schemas rely on the presence of high-risk thyroid nodule sonographic features and, therefore, are less suitable for the diagnosis of malignant thyroid nodules that have a benign appearance on the ultrasound. To mitigate the deficiency of thyroid nodule evaluation relying solely on the sonographic characteristics, we used thyroid cancer polygenic risk score (PRS) to complement deep learning analysis of ultrasound images. Methods. A supervised deep learning classifier of thyroid nodules was trained on 32,545 thyroid US images from 621 nodules and tested on an independent set of 232 nodules from patients genotyped on the Illumina's MEGAEX platform. The deep-learning thyroid nodule classifier was developed by fine-tuning a BiT-M ResNet-50x1 convolutional neural network (CNN) pre-trained on the ImageNet-21k dataset. A polygenic risk score (PRS) was calculated using thyroid cancer genome-wide association meta-analysis summary statistics from the Global Biobank Meta-analysis Initiative. The thyroid cancer PRS was defined as a weighted sum of five alleles with the strongest association with thyroid cancer. CNN predictions and PRS were combined into a meta-classifier using logistic regression with or without genetic ancestry and demographic covariates. Results. The CNN classifier achieved an area under the receiver operating characteristic curve (AUC) of 0.83 on the out-of-sample test set of 232 thyroid nodules. The CNN classifier incorrectly classified thyroid nodules without suspicious sonographic characteristics belonging to difficult-to-diagnose subtypes such as follicular thyroid cancer and follicular variant of papillary thyroid cancer. Combining predictions from the CNN classifier with PRS into a cross-validated classifier improved AUC to 0.868 (DeLong test, p = 0.05). Incorporating genetic ancestry in the form of five genetic principal components further improved AUC of the benign vs. malignant CNN + PRS thyroid nodule classifier to 0.885 (p = 0.007). Finally, when age, sex, and nodule dimensions were considered, the AUC of the meta-classifier increased to 0.915 (p = 2.3e-4). The meta-classifier including predictions from CNN, PRS, and genetic principal components showed a sensitivity of 0.95, specificity of 0.61, NPV of 0.97, and PPV of 0.5. This performance was superior to that of the clinical Thyroid Imaging Reporting and Data System (TI-RADS) as reported by radiologists in ultrasound reports. Conclusions. For the first time, we showed PRS provides an orthogonal thyroid cancer risk assessment complementary to the ultrasound image-based thyroid nodule risk evaluation. This proof-of-concept study opens an opportunity for developing next-generation schemas for thyroid nodule evaluation incorporating clinical, imaging, and genetic data.
Presentation: Sunday, June 18, 2023