title: How to Determine the Accuracy of an Alternative Diagnostic Test when It Is Actually Better than the Reference Tests: A Re-Evaluation of Diagnostic Tests for Scrub Typhus Using Bayesian LCMs.
abstract: BACKGROUND
  The indirect immunofluorescence assay (IFA) is considered a reference test for scrub typhus. Recently, the Scrub Typhus Infection Criteria (STIC; a combination of culture, PCR assays and IFA IgM) were proposed as a reference standard for evaluating alternative diagnostic tests. Here, we use Bayesian latent class models (LCMs) to estimate the true accuracy of each diagnostic test, and of STIC, for diagnosing scrub typhus.
  
  
  RESULTS
  Data from 161 patients with undifferentiated fever were re-evaluated using Bayesian LCMs. Every patient was evaluated for the presence of an eschar, and tested with blood culture for Orientia tsutsugamushi, three different PCR assays, IFA IgM, and the Panbio IgM immunochromatographic test (ICT). True sensitivity and specificity of culture (24.4% and 100%), 56kDa PCR assay (56.8% and 98.4%), 47kDa PCR assay (63.2% and 96.1%), groEL PCR assay (71.4% and 93.0%), IFA IgM (70.0% and 83.8%), PanBio IgM ICT (72.8% and 96.8%), presence of eschar (42.7% and 98.9%) and STIC (90.5% and 82.5%) estimated by Bayesian LCM were considerably different from those obtained when using STIC as a reference standard. The IgM ICT had comparable sensitivity and significantly higher specificity compared to IFA (p=0.34 and p<0.001, respectively).
  
  
  CONCLUSIONS
  The low specificity of STIC was caused by the low specificity of IFA IgM. Neither STIC nor IFA IgM can be used as reference standards against which to evaluate alternative diagnostic tests. Further evaluation of new diagnostic tests should be done with a carefully selected set of diagnostic tests and appropriate statistical models.
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Cherry
authors.initials: C
authors.lastname: Lim
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Paris
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Blacksell
authors.affiliation: Chiang Rai Prachanukroh Hospital, Chiang Rai, Thailand.
authors.forename: Achara
authors.initials: A
authors.lastname: Laongnualpanich
authors.affiliation: Chiang Rai Prachanukroh Hospital, Chiang Rai, Thailand.
authors.forename: Pacharee
authors.initials: P
authors.lastname: Kantipong
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Wirongrong
authors.initials: W
authors.lastname: Chierakul
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Vanaporn
authors.initials: V
authors.lastname: Wuthiekanun
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Ben S
authors.initials: BS
authors.lastname: Cooper
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Direk
authors.initials: D
authors.lastname: Limmathurotsakul
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001499:Bayes Theorem; D003955:Diagnostic Tests, Routine / Q000592:standards*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007075:Immunoglobulin M / Q000032:analysis; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012612:Scrub Typhus / Q000175:diagnosis*; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D007075:Immunoglobulin M