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Introduction: Ankylosing spondylitis (AS) is a chronic progressive inflammatory disease of the spine and its affiliated tissues. AS mainly affects the axial bone, sacroiliac joint, hip joint, spinal facet, and adjacent ligaments. We used machine learning (ML) methods to construct diagnostic models based on blood routine examination, liver function test, and kidney function test of patients with AS. This method will help clinicians enhance diagnostic efficiency and allow patients to receive systematic treatment as soon as possible. Methods: We consecutively screened 348 patients with AS through complete blood routine examination, liver function test, and kidney function test at the First Affiliated Hospital of Guangxi Medical University according to the modified New York criteria (diagnostic criteria for AS). By using random sampling, the patients were randomly divided into training and validation cohorts. The training cohort included 258 patients with AS and 247 patients without AS, and the validation cohort included 90 patients with AS and 113 patients without AS. We used three ML methods (LASSO, random forest, and support vector machine recursive feature elimination) to screen feature variables and then took the intersection to obtain the prediction model. In addition, we used the prediction model on the validation cohort. Results: Seven factors—erythrocyte sedimentation rate (ESR), red blood cell count (RBC), mean platelet volume (MPV), albumin (ALB), aspartate aminotransferase (AST), and creatinine (Cr)—were selected to construct a nomogram diagnostic model through ML. In the training cohort, the C value and area under the curve (AUC) value of this nomogram was 0.878 and 0.8779462, respectively. The C value and AUC value of the nomogram in the validation cohort was 0.823 and 0.8232055, respectively. Calibration curves in the training and validation cohorts showed satisfactory agreement between nomogram predictions and actual probabilities. The decision curve analysis showed that the nonadherence nomogram was clinically useful when intervention was decided at the nonadherence possibility threshold of 1%. Conclusion: Our ML model can satisfactorily predict patients with AS. This nomogram can help orthopedic surgeons devise more personalized and rational clinical strategies. Plain Language Summary: AS is a chronic progressive inflammatory disease of the spine and its affiliated tissues. AS starts gradually, and its early symptoms are mild. Some hospitals lack HLA-B27 and related imaging instruments to assist in the diagnosis of AS. There are relatively few studies on liver function and kidney function of patients with AS. We used ML methods to construct diagnostic models. Our model can satisfactorily predict patients with AS. This diagnostic model can help orthopedic surgeons devise more personalized and rational clinical strategies. [ABSTRACT FROM AUTHOR]