3.4.2. Hierarchy of reference standards

Studies evaluating the performance of IGRAs are hampered by the lack of a gold standard to distinguish the presence or absence of TB infection. Since diagnostic accuracy for TB infection could not be directly assessed, a hierarchy of reference standards was developed and agreed beforehand with the systematic reviewers, to evaluate the role of IGRAs, depending on the individual topic (i.e. not all systematic reviews necessarily used the hierarchy). Primary outcomes were predefined for each systematic review as relevant; for example, the predictive value of IGRAs for development of active TB, the sensitivity of IGRAs in individuals with cultureconfirmed active TB (as a surrogate reference standard for TB infection), and the correlation between IGRA and TST results. In addition to primary outcomes, specific characteristics of IGRAs that could influence their overall utility were evaluated where relevant; for example, the proportion of indeterminate IGRA results (i.e. not able to be interpreted, either due to a high IFN-γ response in the negative control or a low IFN-γ response in the positive control), the impact of HIV-related immunosuppression (i.e. CD4+ cell count) on test performance where available and correlation of IGRA results with an exposure gradient (typically used in contact and outbreak investigations).

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