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GENERAL MEDICINE/ORIGINAL RESEARCH

Discovery and Validation of Urine Markers of Acute Pediatric Appendicitis Using High-Accuracy Mass Spectrometry
Alex Kentsis, MD, PhD Yin Yin Lin, BS Kyle Kurek, MD Monica Calicchio, PhD Yan Yan Wang, MD Flavio Monigatti, PhD Fabien Campagne, PhD Richard Lee, MD Bruce Horwitz, MD, PhD Hanno Steen, PhD Richard Bachur, MD
From the Division of EmergencyMedicine, Department of Medicine, Children’s Hospital Boston, Harvard Medical School, Boston, MA (Kentsis, Horwitz, Bachur); the Proteomics Center at Children’s Hospital Boston, Boston, MA (Kentsis, Lin, Kurek, Wang, Monigatti, Lee, Steen); the Department of Pathology, Children’s Hospital Boston, Harvard Medical School, Boston, MA (Kurek, Calicchio, Monigatti, Steen); the Department of Pathology,Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (Wang, Horwitz); and the Department of Physiology and Biophysics and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY (Campagne).

Study objective: Molecular definition of disease has been changing all aspects of medical practice, fromdiagnosis and screening to understanding and treatment. Acute appendicitis is among many human conditions that are complicated by the heterogeneity of clinical presentation and shortage of diagnostic markers. Here, we sought to profile the urine of patients with appendicitis, with the goal of identifying new diagnostic markers. Methods: Candidate markers were identified from the urine of children withhistologically proven appendicitis by using high-accuracy mass spectrometry proteome profiling. These systemic and local markers were used to assess the probability of appendicitis in a blinded, prospective study of children being evaluated for acute abdominal pain in our emergency department. Tests of performance of the markers were evaluated against the pathologic diagnosis and histologic gradeof appendicitis. Results: Test performance of 57 identified candidate markers was studied in 67 patients, with median age of 11 years, 37% of whom had appendicitis. Several exhibited favorable diagnostic performance, including calgranulin A (S100-A8), -1-acid glycoprotein 1 (orosomucoid), and leucine-rich -2-glycoprotein (LRG), with the receiver operating characteristic area under the curve andvalues of 0.84 (95% confidence interval [CI] 0.72 to 0.95), 0.84 (95% CI 0.72 to 0.95), and 0.97 (95% CI 0.93 to 1.0), respectively. LRG was enriched in diseased appendices, and its abundance correlated with severity of appendicitis. Conclusion: High-accuracy mass spectrometry urine proteome profiling allowed identification of diagnostic markers of acute appendicitis. Usage of LRG and other identifiedbiomarkers may improve the diagnostic accuracy of clinical evaluations of appendicitis. [Ann Emerg Med. 2010;55:62-70.] Please see page 63 for the Editor’s Capsule Summary of this article.
Provide feedback on this article at the journal’s Web site, www.annemergmed.com. 0196-0644/$-see front matter Copyright © 2009 by the American College of Emergency Physicians. doi:10.1016/j.annemergmed.2009.04.020INTRODUCTION
Appendicitis is among many human diseases for which the diagnosis is complicated by the heterogeneity of its clinical presentation and shortage of diagnostic markers. As such, it remains the most common surgical emergency of children, with initial diagnostic accuracy additionally challenged because of nonspecific but similar symptoms of many other childhood conditions.1 Delays inaccurate diagnosis lead to increased 62 Annals of Emergency Medicine

mortality, morbidity, and costs associated with the complications of appendicitis.2-4 The use of high-resolution computed tomography (CT) to identify appendiceal inflammation was hoped to improve both the diagnosis and treatment of acute appendicitis. Though variable, these improvements have been modest, with rates of...