Preventing Heterotopic Ossification in Combat Casualties—Which Models Are Best Suited for Clinical Use?

• Published in: Clinical orthopaedics and related research 2015-09, Vol.473 (9), p.2807-2813
• Main Authors: Alfieri, Keith A., Potter, Benjamin K., Davis, Thomas A., Wagner, Matthew B., Elster, Eric A., Forsberg, Jonathan A.
• Format: Article
• Language: English
• Subjects: Area Under Curve; Biopsy; Conservative Orthopedics; Debridement; Decision Support Techniques; Gene Expression Profiling; Gene Expression Regulation; Genetic Markers; Humans; Logistic Models; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Military Medicine; Neural Networks (Computer); Orthopedics; Ossification, Heterotopic - diagnosis; Ossification, Heterotopic - etiology; Ossification, Heterotopic - genetics; Ossification, Heterotopic - prevention & control; Predictive Value of Tests; Risk Assessment; Risk Factors; RNA, Messenger - metabolism; ROC Curve; Sports Medicine; Surgery; Surgical Orthopedics; Symposium: Research Advances After a Decade of War; Time Factors; Trauma; Treatment Outcome; Wound Healing; Wounds and Injuries - complications; Wounds and Injuries - diagnosis; Wounds and Injuries - surgery
• ISSN: 0009-921X; 1528-1132; 1528-1132
• DOI: 10.1007/s11999-015-4302-1

Background To prevent symptomatic heterotopic ossification (HO) and guide primary prophylaxis in patients with combat wounds, physicians require risk stratification methods that can be used early in the postinjury period. There are no validated models to help guide clinicians in the treatment for this common and potentially disabling condition. Questions/purposes We developed three prognostic models designed to estimate the likelihood of wound-specific HO formation and compared them using receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) to determine (1) which model is most accurate; and (2) which technique is best suited for clinical use. Methods We obtained muscle biopsies from 87 combat wounds during the first débridement in the United States, all of which were evaluated radiographically for development of HO at a minimum of 2 months postinjury. The criterion for determining the presence of HO was the ability to see radiographic evidence of ectopic bone formation within the zone of injury. We then quantified relative gene expression from 190 wound healing, osteogenic, and vascular genes. Using these data, we developed an Artificial Neural Network, Random Forest, and a Least Absolute Shrinkage and Selection Operator (LASSO) Logistic Regression model designed to estimate the likelihood of eventual wound-specific HO formation. HO was defined as any HO visible on the plain film within the zone of injury. We compared the models accuracy using area under the ROC curve (area under the curve [AUC]) as well as DCA to determine which model, if any, was better suited for clinical use. In general, the AUC compares models based solely on accuracy, whereas DCA compares their clinical utility after weighing the consequences of under- or overtreatment of a particular disorder. Results Both the Artificial Neural Network and the LASSO logistic regression models were relatively accurate with AUCs of 0.78 (95% confidence interval [CI], 0.72–0.83) and 0.75 (95% CI, 0.71–0.78), respectively. The Random Forest model returned an AUC of only 0.53 (95% CI, 0.48–0.59), marginally better than chance alone. Using DCA, the Artificial Neural Network model demonstrated the highest net benefit over the broadest range of threshold probabilities, indicating that it is perhaps better suited for clinical use than the LASSO logistic regression model. Specifically, if only patients with greater than 25% risk of developing HO received prophylaxis, for ev