Annals of Emergency Medicine
Volume 55, Issue 1 , Pages 62-70.e4, January 2010

Discovery and Validation of Urine Markers of Acute Pediatric Appendicitis Using High-Accuracy Mass Spectrometry

  • Alex Kentsis, MD, PhD

      Affiliations

    • Division of Emergency Medicine, Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA
    • Proteomics Center at Children's Hospital Boston, Boston, MA
    • ,
  • Yin Yin Lin, BS

      Affiliations

    • Proteomics Center at Children's Hospital Boston, Boston, MA
    • ,
  • Kyle Kurek, MD

      Affiliations

    • Proteomics Center at Children's Hospital Boston, Boston, MA
    • Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, MA
    • ,
  • Monica Calicchio, PhD

      Affiliations

    • Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, MA
    • ,
  • Yan Yan Wang, MD

      Affiliations

    • Proteomics Center at Children's Hospital Boston, Boston, MA
    • Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    • ,
  • Flavio Monigatti, PhD

      Affiliations

    • Proteomics Center at Children's Hospital Boston, Boston, MA
    • Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, MA
    • ,
  • Fabien Campagne, PhD

      Affiliations

    • 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
    • ,
  • Richard Lee, MD

      Affiliations

    • Proteomics Center at Children's Hospital Boston, Boston, MA
    • ,
  • Bruce Horwitz, MD, PhD

      Affiliations

    • Division of Emergency Medicine, Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA
    • Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    • ,
  • Hanno Steen, PhD

      Affiliations

    • Proteomics Center at Children's Hospital Boston, Boston, MA
    • Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, MA
    • ,
  • Richard Bachur, MD

      Affiliations

    • Division of Emergency Medicine, Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA
    • Corresponding Author InformationAddress for correspondence: Richard Bachur, MD, 300 Longwood Ave., Boston, MA 02115; 617-355-6624, fax 617-730-0335; or 617-919-2629, fax 617-730-0168

Received 7 January 2009; received in revised form 16 March 2009 and 29 March 2009; accepted 29 April 2009. published online 26 June 2009.

Study objective

Molecular definition of disease has been changing all aspects of medical practice, from diagnosis 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 with histologically 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 grade of 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), α-1-acid glycoprotein 1 (orosomucoid), and leucine-rich α-2-glycoprotein (LRG), with the receiver operating characteristic area under the curve and values 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 identified biomarkers may improve the diagnostic accuracy of clinical evaluations of appendicitis.

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 Supervising editors: Kelly D. Young, MD, MS; Steven M. Green, MD

 Author contributions: AK, HS, and RB were responsible for research design. AK, YYL, MC, YYW, RL, and BH conducted laboratory processing. AK, KK, FM, FC, and BH conducted data analysis. AK, HS, and RB wrote the article. RB takes responsibility for the paper as a whole. HS and RB contributed equally to the article.

 Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. Funded in part by the Frederick Lovejoy, Jr, MD Housestaff Research and Education grant, and by Children's Hospital Boston Houseofficer Development Award.

 Publication date: Available online June 25, 2009.

 Reprints not available from the authors.

 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.

PII: S0196-0644(09)00481-8

doi:10.1016/j.annemergmed.2009.04.020

Annals of Emergency Medicine
Volume 55, Issue 1 , Pages 62-70.e4, January 2010

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