Diagnostic characteristics of S100A8/A9 in a multicenter study of patients with acute right lower quadrant abdominal pain

Angela M. Mills, David S. Huckins, Heemun Kwok, Brigitte M. Baumann, Richard M. Ruddy, Richard Rothman, Jon W. Schrock, Frank Lovecchio, William I. Krief, Aaron Hexdall, Robert Caspari, Beth Cohen, Roger J. Lewis

Research output: Contribution to journalArticle

Abstract

Objectives: Over the past decade, clinicians have become increasingly reliant on computed tomography (CT) for the evaluation of patients with suspected acute appendicitis. To limit the radiation risks and costs of CT, investigators have searched for biomarkers to aid in diagnostic decision-making. We evaluated one such biomarker, calprotectin or S100A8/A9, and determined the diagnostic performance characteristics of a developmental biomarker assay in a multicenter investigation of patients presenting with acute right lower quadrant abdominal pain. Methods: This was a prospective, double-blinded, single-arm, multicenter investigation performed in 13 emergency departments (EDs) from August 2009 to April 2010 of patients presenting with acute right lower quadrant abdominal pain. Plasma samples were tested using the investigational S100A8/A9 assay. The primary outcome of acute appendicitis was determined by histopathology for patients undergoing appendectomy or 2-week telephone follow-up for patients discharged without surgery. The sensitivity, specificity, negative likelihood ratio (LR-), and positive likelihood ratio (LR+) of the biomarker assay were calculated using the prespecified cutoff value of 14 units. A post hoc stability study was performed to investigate the potential effect of time and courier transport on the measured value of the S100A8/A9 assay test results. Results: Of 1,052 enrolled patients, 848 met criteria for analysis. The median age was 24.5 years (interquartile range [IQR] = 16-38 years), 57% were female, and 50% were white. There was a 27.5% prevalence of acute appendicitis. The sensitivity and specificity for the investigational S100A8/A9 assay in diagnosing acute appendicitis were estimated to be 96% (95% confidence interval [CI] = 93% to 98%) and 16% (95% CI = 13% to 19%), respectively. The LR- ratio was 0.24 (95% CI = 0.12 to 0.47), and the LR+ was 1.14 (95% CI = 1.10 to 1.19). The post hoc stability study demonstrated that in the samples that were shipped, the estimated time coefficient was 7.6 × 10 -3 ± 2.0 × 10 -3 log units/hour, representing an average increase of 43% in the measured value over 48 hours; in the samples that were not shipped, the estimated time coefficient was 2.5 × 10 -3 ± 0.4 × 10 -3 log units/hour, representing a 13% increase on average in the measured value over 48 hours, which was the maximum delay allowed by the study protocol. Thus, adjusting the cutoff value of 14 units by the magnitude of systematic inflation observed in the stability study at 48 hours would result in a new cutoff value of 20 units and a "corrected" sensitivity and specificity of 91 and 28%, respectively. Conclusions: In patients presenting with acute right lower quadrant abdominal pain, we found the investigational enzyme-linked immunosorbent assay (ELISA) test for S100A8/A9 to perform with high sensitivity but very limited specificity. We found that shipping effect and delay in analysis resulted in a subsequent rise in test values, thereby increasing the sensitivity and decreasing the specificity of the test. Further investigation with hospital-based laboratory analyzers is the next critical step for determining the ultimate clinical utility of the ELISA test for S100A8/A9 in ED patients presenting with acute right lower quadrant abdominal pain.

Original languageEnglish (US)
Pages (from-to)48-55
Number of pages8
JournalAcademic Emergency Medicine
Volume19
Issue number1
DOIs
StatePublished - Jan 2012

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Abdominal Pain
Multicenter Studies
Appendicitis
Biomarkers
Confidence Intervals
Sensitivity and Specificity
Hospital Emergency Service
Enzyme-Linked Immunosorbent Assay
Tomography
Leukocyte L1 Antigen Complex
Hospital Laboratories
Appendectomy
Economic Inflation
Telephone
Decision Making
Research Personnel
Radiation
Costs and Cost Analysis

ASJC Scopus subject areas

  • Emergency Medicine

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Diagnostic characteristics of S100A8/A9 in a multicenter study of patients with acute right lower quadrant abdominal pain. / Mills, Angela M.; Huckins, David S.; Kwok, Heemun; Baumann, Brigitte M.; Ruddy, Richard M.; Rothman, Richard; Schrock, Jon W.; Lovecchio, Frank; Krief, William I.; Hexdall, Aaron; Caspari, Robert; Cohen, Beth; Lewis, Roger J.

In: Academic Emergency Medicine, Vol. 19, No. 1, 01.2012, p. 48-55.

Research output: Contribution to journalArticle

Mills, AM, Huckins, DS, Kwok, H, Baumann, BM, Ruddy, RM, Rothman, R, Schrock, JW, Lovecchio, F, Krief, WI, Hexdall, A, Caspari, R, Cohen, B & Lewis, RJ 2012, 'Diagnostic characteristics of S100A8/A9 in a multicenter study of patients with acute right lower quadrant abdominal pain', Academic Emergency Medicine, vol. 19, no. 1, pp. 48-55. https://doi.org/10.1111/j.1553-2712.2011.01259.x
Mills, Angela M. ; Huckins, David S. ; Kwok, Heemun ; Baumann, Brigitte M. ; Ruddy, Richard M. ; Rothman, Richard ; Schrock, Jon W. ; Lovecchio, Frank ; Krief, William I. ; Hexdall, Aaron ; Caspari, Robert ; Cohen, Beth ; Lewis, Roger J. / Diagnostic characteristics of S100A8/A9 in a multicenter study of patients with acute right lower quadrant abdominal pain. In: Academic Emergency Medicine. 2012 ; Vol. 19, No. 1. pp. 48-55.
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author = "Mills, {Angela M.} and Huckins, {David S.} and Heemun Kwok and Baumann, {Brigitte M.} and Ruddy, {Richard M.} and Richard Rothman and Schrock, {Jon W.} and Frank Lovecchio and Krief, {William I.} and Aaron Hexdall and Robert Caspari and Beth Cohen and Lewis, {Roger J.}",
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TY - JOUR

T1 - Diagnostic characteristics of S100A8/A9 in a multicenter study of patients with acute right lower quadrant abdominal pain

AU - Mills, Angela M.

AU - Huckins, David S.

AU - Kwok, Heemun

AU - Baumann, Brigitte M.

AU - Ruddy, Richard M.

AU - Rothman, Richard

AU - Schrock, Jon W.

AU - Lovecchio, Frank

AU - Krief, William I.

AU - Hexdall, Aaron

AU - Caspari, Robert

AU - Cohen, Beth

AU - Lewis, Roger J.

PY - 2012/1

Y1 - 2012/1

N2 - Objectives: Over the past decade, clinicians have become increasingly reliant on computed tomography (CT) for the evaluation of patients with suspected acute appendicitis. To limit the radiation risks and costs of CT, investigators have searched for biomarkers to aid in diagnostic decision-making. We evaluated one such biomarker, calprotectin or S100A8/A9, and determined the diagnostic performance characteristics of a developmental biomarker assay in a multicenter investigation of patients presenting with acute right lower quadrant abdominal pain. Methods: This was a prospective, double-blinded, single-arm, multicenter investigation performed in 13 emergency departments (EDs) from August 2009 to April 2010 of patients presenting with acute right lower quadrant abdominal pain. Plasma samples were tested using the investigational S100A8/A9 assay. The primary outcome of acute appendicitis was determined by histopathology for patients undergoing appendectomy or 2-week telephone follow-up for patients discharged without surgery. The sensitivity, specificity, negative likelihood ratio (LR-), and positive likelihood ratio (LR+) of the biomarker assay were calculated using the prespecified cutoff value of 14 units. A post hoc stability study was performed to investigate the potential effect of time and courier transport on the measured value of the S100A8/A9 assay test results. Results: Of 1,052 enrolled patients, 848 met criteria for analysis. The median age was 24.5 years (interquartile range [IQR] = 16-38 years), 57% were female, and 50% were white. There was a 27.5% prevalence of acute appendicitis. The sensitivity and specificity for the investigational S100A8/A9 assay in diagnosing acute appendicitis were estimated to be 96% (95% confidence interval [CI] = 93% to 98%) and 16% (95% CI = 13% to 19%), respectively. The LR- ratio was 0.24 (95% CI = 0.12 to 0.47), and the LR+ was 1.14 (95% CI = 1.10 to 1.19). The post hoc stability study demonstrated that in the samples that were shipped, the estimated time coefficient was 7.6 × 10 -3 ± 2.0 × 10 -3 log units/hour, representing an average increase of 43% in the measured value over 48 hours; in the samples that were not shipped, the estimated time coefficient was 2.5 × 10 -3 ± 0.4 × 10 -3 log units/hour, representing a 13% increase on average in the measured value over 48 hours, which was the maximum delay allowed by the study protocol. Thus, adjusting the cutoff value of 14 units by the magnitude of systematic inflation observed in the stability study at 48 hours would result in a new cutoff value of 20 units and a "corrected" sensitivity and specificity of 91 and 28%, respectively. Conclusions: In patients presenting with acute right lower quadrant abdominal pain, we found the investigational enzyme-linked immunosorbent assay (ELISA) test for S100A8/A9 to perform with high sensitivity but very limited specificity. We found that shipping effect and delay in analysis resulted in a subsequent rise in test values, thereby increasing the sensitivity and decreasing the specificity of the test. Further investigation with hospital-based laboratory analyzers is the next critical step for determining the ultimate clinical utility of the ELISA test for S100A8/A9 in ED patients presenting with acute right lower quadrant abdominal pain.

AB - Objectives: Over the past decade, clinicians have become increasingly reliant on computed tomography (CT) for the evaluation of patients with suspected acute appendicitis. To limit the radiation risks and costs of CT, investigators have searched for biomarkers to aid in diagnostic decision-making. We evaluated one such biomarker, calprotectin or S100A8/A9, and determined the diagnostic performance characteristics of a developmental biomarker assay in a multicenter investigation of patients presenting with acute right lower quadrant abdominal pain. Methods: This was a prospective, double-blinded, single-arm, multicenter investigation performed in 13 emergency departments (EDs) from August 2009 to April 2010 of patients presenting with acute right lower quadrant abdominal pain. Plasma samples were tested using the investigational S100A8/A9 assay. The primary outcome of acute appendicitis was determined by histopathology for patients undergoing appendectomy or 2-week telephone follow-up for patients discharged without surgery. The sensitivity, specificity, negative likelihood ratio (LR-), and positive likelihood ratio (LR+) of the biomarker assay were calculated using the prespecified cutoff value of 14 units. A post hoc stability study was performed to investigate the potential effect of time and courier transport on the measured value of the S100A8/A9 assay test results. Results: Of 1,052 enrolled patients, 848 met criteria for analysis. The median age was 24.5 years (interquartile range [IQR] = 16-38 years), 57% were female, and 50% were white. There was a 27.5% prevalence of acute appendicitis. The sensitivity and specificity for the investigational S100A8/A9 assay in diagnosing acute appendicitis were estimated to be 96% (95% confidence interval [CI] = 93% to 98%) and 16% (95% CI = 13% to 19%), respectively. The LR- ratio was 0.24 (95% CI = 0.12 to 0.47), and the LR+ was 1.14 (95% CI = 1.10 to 1.19). The post hoc stability study demonstrated that in the samples that were shipped, the estimated time coefficient was 7.6 × 10 -3 ± 2.0 × 10 -3 log units/hour, representing an average increase of 43% in the measured value over 48 hours; in the samples that were not shipped, the estimated time coefficient was 2.5 × 10 -3 ± 0.4 × 10 -3 log units/hour, representing a 13% increase on average in the measured value over 48 hours, which was the maximum delay allowed by the study protocol. Thus, adjusting the cutoff value of 14 units by the magnitude of systematic inflation observed in the stability study at 48 hours would result in a new cutoff value of 20 units and a "corrected" sensitivity and specificity of 91 and 28%, respectively. Conclusions: In patients presenting with acute right lower quadrant abdominal pain, we found the investigational enzyme-linked immunosorbent assay (ELISA) test for S100A8/A9 to perform with high sensitivity but very limited specificity. We found that shipping effect and delay in analysis resulted in a subsequent rise in test values, thereby increasing the sensitivity and decreasing the specificity of the test. Further investigation with hospital-based laboratory analyzers is the next critical step for determining the ultimate clinical utility of the ELISA test for S100A8/A9 in ED patients presenting with acute right lower quadrant abdominal pain.

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