title: Bias due to composite reference standards in diagnostic accuracy studies.
abstract: Composite reference standards (CRSs) have been advocated in diagnostic accuracy studies in the absence of a perfect reference standard. The rationale is that combining results of multiple imperfect tests leads to a more accurate reference than any one test in isolation. Focusing on a CRS that classifies subjects as disease positive if at least one component test is positive, we derive algebraic expressions for sensitivity and specificity of this CRS, sensitivity and specificity of a new (index) test compared with this CRS, as well as the CRS-based prevalence. We use as a motivating example the problem of evaluating a new test for Chlamydia trachomatis, an asymptomatic disease for which no gold-standard test exists. As the number of component tests increases, sensitivity of this CRS increases at the expense specificity, unless all tests have perfect specificity. Therefore, such a CRS can lead to significantly biased accuracy estimates of the index test. The bias depends on disease prevalence and accuracy of the CRS. Further, conditional dependence between the CRS and index test can lead to over-estimation of index test accuracy estimates. This commonly-used CRS combines results from multiple imperfect tests in a way that ignores information and therefore is not guaranteed to improve over a single imperfect reference unless each component test has perfect specificity, and the CRS is conditionally independent of the index test. When these conditions are not met, as in the case of C. trachomatis testing, more realistic statistical models should be researched instead of relying on such CRSs.
authors.affiliation: Division of Clinical Epidemiology, McGill University Health Centre, Montreal, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Schiller
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van Smeden
authors.affiliation: Division of STD Prevention, Centers for Disease Control, Atlanta, GA 30329-4027, U.S.A.
authors.forename: Alula
authors.initials: A
authors.lastname: Hadgu
authors.affiliation: Division of Infectious Diseases, McGill University Health Centre, Montreal, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Libman
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.
authors.forename: Johannes B
authors.initials: JB
authors.lastname: Reitsma
authors.affiliation: Division of Clinical Epidemiology, McGill University Health Centre, Montreal, Canada.
authors.forename: Nandini
authors.initials: N
authors.lastname: Dendukuri
mesh_terms: D015982:Bias; D002690:Chlamydia Infections / Q000175:diagnosis; D002692:Chlamydia trachomatis; D003933:Diagnosis; D003955:Diagnostic Tests, Routine / Q000592:standards* / Q000706:statistics & numerical data; D006801:Humans; D015233:Models, Statistical; D012015:Reference Standards; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
keywords: composite; conditional dependence; imperfect reference; sensitivity; specificity