Caveats regarding the test-negative design to study mpox risk factors and vaccine effectiveness

The test-negative design (TND) has been commonly used to study vaccine effectiveness (notably regarding COVID-19 and influenza vaccines) and recently has been proposed as a valid design to study causal risk factors of diseases during an outbreak. In April 2022, there was a worldwide outbreak of mpox (formerly called monkeypox) that resulted in an international public health emergency. The TND has been used in a few studies to investigate vaccine effectiveness and risk factors of mpox, using epidemiologic databases. However, several issues prevent such a study design from being valid for this purpose. Problems stem from stigma surrounding mpox, which affects a person's decision to seek health care. This poses a challenge to the similar health care-seeking behavior assumption that is central for test-negative studies. Further limitations include the differential diagnoses of mpox, which have notable differences from mpox that may be easily detected by clinicians or patients but are unlikely to be included in epidemiologic databases or electronic health records. Herein, the caveats regarding the use of the TND are discussed in the context of the mpox outbreak, as well as potential steps that may allow it to be used effectively.