Background: Prostate cancer is one of the most common malignant tumors and poses a substantial threat to human health. The PSA test is commonly used in prostate cancer screening, however its high rate of false-positive results causes unnecessary mental suffering, expensive examination costs, physical injury and other adverse consequences. Therefore, there is an urgent need to find a convenient, cost-effective and non-invasive diagnostic method to reduce the false-positive rate of PSA. This study aimed to assess the diagnostic value of YiDiXie™-SS in PSA-positive patients. Patients and methods: The study finally included 465 subjects with positive PSA test (prostate cancer group, n=292; BPH group, n=173). Remaining serum samples from the subjects were collected and tested with YiDiXie™ all-cancer detection kit. The sensitivity and specificity of YiDiXie™-SS were evaluated respectively. Results: The sensitivity of YiDiXie™-SS for the malignant group was 100% (95% CI: 98.7% - 100%; 292/292), with a false negative rate of 0 (95% CI: 0 - 1.3%; 0/292). The specificity of YiDiXie™-SS for the benign group was 57.2% (95% CI: 49.8% - 64.4%; 99/173), with a false positive rate of 42.8% (95% CI: 35.6% - 50.2%; 74/173). This means that YiDiXie™-SS reduces the false positive rate by 57.2% (95% CI: 49.8% - 64.4%; 99/173) with essentially no increase in malignancy leakage. Conclusion: YiDiXie™-SS significantly reduces the false-positive rate of PSA-positive patients without increasing the number of underdiagnosed malignant tumors. YiDiXie™-SS has vital diagnostic value in PSA-positive patients, and is expected to solve the problem of "high false-positive rate of PSA". Clinical trial number: ChiCTR2200066840. Key words: Prostate cancer, PSA, False-positive, YiDiXie™-SS

The authors have declared no competing interest.

This work was supported by Shenzhen High-level Hospital Construction Fund, Clinical Research Project of Peking University Shenzhen Hospital (LCYJ2020002, LCYJ2020015, LCYJ2020020, LCYJ2017001).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of Peking University Shenzhen Hospital gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are contained in the manuscript.