Optimizing Y-chromosome microdeletion screening in Chinese male infertility patients: a large-scale multi-centre study on incidence

STUDY QUESTION: What is the optimal sperm concentration threshold for screening Y-chromosome microdeletions (YCMs) in male infertility patients? SUMMARY ANSWER: This study identified three clinically relevant screening thresholds: an receiver operating characteristic (ROC)-optimal cutoff at 0.45 million sperm/ml, a high-sensitivity cutoff at 8 million sperm/ml, and a cost-effective threshold at 1 million sperm/ml. WHAT IS KNOWN ALREADY: YCMs are the second most common genetic cause of male infertility, however, current screening thresholds remain controversial due to limited supporting evidence. STUDY DESIGN, SIZE, DURATION: This retrospective multi-centre cohort study included 6806 male patients who underwent fertility assessments and azoospermia factor (AZF) gene testing between September 2013 and January 2024. PARTICIPANTS/MATERIALS, SETTING, METHODS: ROC analysis was used to determine the AUC to show the effectiveness of sperm concentration for predicting AZF deletions. The sensitivity and specificity of different sperm concentration screening thresholds were measured. MAIN RESULTS AND THE ROLE OF CHANCE: The incidence of YCMs was found to be 12.71% in non-obstructive azoospermia patients, 13.35% in patients with sperm concentrations between 0 and 1 million/ml, and 3.56% in those between 1 and 5 million/ml. ROC analysis demonstrated that sperm concentration was a good predictor of AZF deletions (AUC: 0.75, 95% CI: 0.74-0.77). The optimal threshold of 0.45 million/ml yielded a sensitivity of 86.84%, specificity of 59.97%, positive predictive value (PPV) of 13.48%, and negative predictive value (NPV) of 98.45%. A threshold of 8 million/ml achieved maximum sensitivity of 100.00% and NPV of 100.00%, but with specificity of 30.32% and PPV of 9.34%. The model showed good calibration with a Brier score of 0.06 and a goodness-of-fit test P-value of 0.726. Cost-effectiveness analysis revealed that a threshold of 1 million/ml provided the lowest incremental cost-effectiveness ratio. LIMITATIONS, REASONS FOR CAUTION: Firstly, despite being the largest cohort study to date, our data primarily originated from eastern China, particularly the Zhejiang region. A nationwide multi-centre study could further validate our findings across different Chinese populations. Secondly, our cost-effectiveness analysis uses general gross domestics product-based willingness-to-pay thresholds, while disease-specific thresholds might be more appropriate and could be explored through nationwide surveys. Moreover, it is important to note that our cost-effectiveness findings are specifically based on the Chinese healthcare system and may not be directly applicable to other countries due to variations in healthcare systems, insurance coverage, and patient payment responsibilities across different regions globally. Another limitation of our cost-effectiveness analysis is that it may not fully capture the complex downstream implications of YCM detection in non-azoospermic men, where the primary impact relates to reproductive choices. Future studies should consider incorporating intergenerational effects and the potential costs of ART in subsequent generations when evaluating the true cost-effectiveness of YCM screening strategies. Thirdly, while we rigorously excluded cases with obstructive factors, the retrospective nature of our study might have introduced an inherent selection bias that could be addressed in future prospective studies. Fourthly, due to challenges in data collection, precise information on abstinence duration for some patients was unavailable and, therefore, not included in this article. We plan to further explore their potential impact on our conclusions in future prospective studies. WIDER IMPLICATIONS OF THE FINDINGS: This large-scale study provides comprehensive evidence for optimizing YCM screening strategies in male infertility evaluations. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by the Medical and Health Technology Program of Zhejiang Province (2025KY085), the Zhejiang Health Information Association Research Program (2024XHSZ-Z05), the Scientific Research Fund of Zhejiang Provincial Education Department (Y202249537), and the National Natural Science Foundation of China (82471638). There are no known competing interests. TRIAL REGISTRATION NUMBER: N/A.