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Fool's gold: Why imperfect reference tests are undermining the evaluation of novel diagnostics: a reevaluation of 5 diagnostic tests for leptospirosis.

Publication ,  Journal Article
Limmathurotsakul, D; Turner, EL; Wuthiekanun, V; Thaipadungpanit, J; Suputtamongkol, Y; Chierakul, W; Smythe, LD; Day, NPJ; Cooper, B; Peacock, SJ
Published in: Clin Infect Dis
August 2012

BACKGROUND: We observed that some patients with clinical leptospirosis supported by positive results of rapid tests were negative for leptospirosis on the basis of our diagnostic gold standard, which involves isolation of Leptospira species from blood culture and/or a positive result of a microscopic agglutination test (MAT). We hypothesized that our reference standard was imperfect and used statistical modeling to investigate this hypothesis. METHODS: Data for 1652 patients with suspected leptospirosis recruited during three observational studies and one randomized control trial that described the application of culture, MAT, immunofluorescence assay (IFA), lateral flow (LF) and/or PCR targeting the 16S rRNA gene were reevaluated using Bayesian latent class models and random-effects meta-analysis. RESULTS: The estimated sensitivities of culture alone, MAT alone, and culture plus MAT (for which the result was considered positive if one or both tests had a positive result) were 10.5% (95% credible interval [CrI], 2.7%-27.5%), 49.8% (95% CrI, 37.6%-60.8%), and 55.5% (95% CrI, 42.9%-67.7%), respectively. These low sensitivities were present across all 4 studies. The estimated specificity of MAT alone (and of culture plus MAT) was 98.8% (95% CrI, 92.8%-100.0%). The estimated sensitivities and specificities of PCR (52.7% [95% CrI, 45.2%-60.6%] and 97.2% [95% CrI, 92.0%-99.8%], respectively), lateral flow test (85.6% [95% CrI, 77.5%-93.2%] and 96.2% [95% CrI, 87.7%-99.8%], respectively), and immunofluorescence assay (45.5% [95% CrI, 33.3%-60.9%] and 96.8% [95% CrI, 92.8%-99.8%], respectively) were considerably different from estimates in which culture plus MAT was considered a perfect gold standard test. CONCLUSIONS: Our findings show that culture plus MAT is an imperfect gold standard against which to compare alterative tests for the diagnosis of leptospirosis. Rapid point-of-care tests for this infection would bring an important improvement in patient care, but their future evaluation will require careful consideration of the reference test(s) used and the inclusion of appropriate statistical models.

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Published In

Clin Infect Dis

DOI

EISSN

1537-6591

Publication Date

August 2012

Volume

55

Issue

3

Start / End Page

322 / 331

Location

United States

Related Subject Headings

  • Young Adult
  • Reference Standards
  • Randomized Controlled Trials as Topic
  • Models, Statistical
  • Microscopy
  • Microbiology
  • Leptospirosis
  • Leptospira
  • Humans
  • Diagnostic Tests, Routine
 

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Limmathurotsakul, D., Turner, E. L., Wuthiekanun, V., Thaipadungpanit, J., Suputtamongkol, Y., Chierakul, W., … Peacock, S. J. (2012). Fool's gold: Why imperfect reference tests are undermining the evaluation of novel diagnostics: a reevaluation of 5 diagnostic tests for leptospirosis. Clin Infect Dis, 55(3), 322–331. https://doi.org/10.1093/cid/cis403
Limmathurotsakul, Direk, Elizabeth L. Turner, Vanaporn Wuthiekanun, Janjira Thaipadungpanit, Yupin Suputtamongkol, Wirongrong Chierakul, Lee D. Smythe, Nicholas P. J. Day, Ben Cooper, and Sharon J. Peacock. “Fool's gold: Why imperfect reference tests are undermining the evaluation of novel diagnostics: a reevaluation of 5 diagnostic tests for leptospirosis.Clin Infect Dis 55, no. 3 (August 2012): 322–31. https://doi.org/10.1093/cid/cis403.
Limmathurotsakul D, Turner EL, Wuthiekanun V, Thaipadungpanit J, Suputtamongkol Y, Chierakul W, et al. Fool's gold: Why imperfect reference tests are undermining the evaluation of novel diagnostics: a reevaluation of 5 diagnostic tests for leptospirosis. Clin Infect Dis. 2012 Aug;55(3):322–31.
Limmathurotsakul, Direk, et al. “Fool's gold: Why imperfect reference tests are undermining the evaluation of novel diagnostics: a reevaluation of 5 diagnostic tests for leptospirosis.Clin Infect Dis, vol. 55, no. 3, Aug. 2012, pp. 322–31. Pubmed, doi:10.1093/cid/cis403.
Limmathurotsakul D, Turner EL, Wuthiekanun V, Thaipadungpanit J, Suputtamongkol Y, Chierakul W, Smythe LD, Day NPJ, Cooper B, Peacock SJ. Fool's gold: Why imperfect reference tests are undermining the evaluation of novel diagnostics: a reevaluation of 5 diagnostic tests for leptospirosis. Clin Infect Dis. 2012 Aug;55(3):322–331.
Journal cover image

Published In

Clin Infect Dis

DOI

EISSN

1537-6591

Publication Date

August 2012

Volume

55

Issue

3

Start / End Page

322 / 331

Location

United States

Related Subject Headings

  • Young Adult
  • Reference Standards
  • Randomized Controlled Trials as Topic
  • Models, Statistical
  • Microscopy
  • Microbiology
  • Leptospirosis
  • Leptospira
  • Humans
  • Diagnostic Tests, Routine