Identifying Data-Driven Clinical Subgroups for Cervical Cancer Prevention With Machine Learning: Population-Based, External, and Diagnostic Validation Study

Background: Cervical cancer remains a major global health issue. Personalized, data-driven cervical cancer prevention (CCP) strategies tailored to phenotypic profiles may improve prevention and reduce disease burden. Objective: This study aimed to identify subgroups with differential cervical precancer or cancer risks using machine learning, validate subgroup predictions across datasets, and propose a computational phenomapping strategy to enhance global CCP efforts. Methods: We explored the data-driven CCP subgroups by applying unsupervised machine learning to a deeply phenotyped, population-based discovery cohort. We extracted CCP-specific risks of cervical intraepithelial neoplasia (CIN) and cervical cancer through weighted logistic regression analyses providing odds ratio (OR) estimates and 95% CIs. We trained a supervised machine learning model and developed pathways to classify individuals before evaluating its diagnostic validity and usability on an external cohort. Results: This study included 551,934 women (median age, 49 years) in the discovery cohort and 47,130 women (median age, 37 years) in the external cohort. Phenotyping identified 5 CCP subgroups, with CCP4 showing the highest carcinoma prevalence. CCP2-4 had significantly higher risks of CIN2+ (CCP2: OR 2.07 [95% CI: 2.03-2.12], CCP3: 3.88 [3.78-3.97], and CCP4: 4.47 [4.33-4.63]) and CIN3+ (CCP2: 2.10 [2.05-2.14], CCP3: 3.92 [3.82-4.02], and CCP4: 4.45 [4.31-4.61]) compared to CCP1 (P<.001), consistent with the direction of results observed in the external cohort. The proposed triple strategy was validated as clinically relevant, prioritizing high-risk subgroups (CCP3-4) for colposcopies and scaling human papillomavirus screening for CCP1-2. Conclusions: This study underscores the potential of leveraging machine learning algorithms and large-scale routine electronic health records to enhance CCP strategies. By identifying key determinants of CIN2+/CIN3+ risk and classifying 5 distinct subgroups, our study provides a robust, data-driven foundation for the proposed triple strategy. This approach prioritizes tailored prevention efforts for subgroups with varying risks, offering a novel and scalable tool to complement existing cervical cancer screening guidelines. Future work should focus on independent external and prospective validation to maximize the global impact of this strategy.