Clinical Scorecard: Considerations on the Use of Test-Negative Design for Analyzing Mpox Risk Factors and Vaccine Efficacy

At a Glance

Key Highlights

• Test-negative design (TND) is commonly used for vaccine effectiveness studies and proposed for causal risk factor analysis during outbreaks.
• Mpox outbreak presents challenges for TND due to stigma affecting healthcare-seeking behavior and differential diagnoses not well captured in databases.
• Mpox diagnosis relies on PCR testing of symptomatic individuals; testing policies vary by country, influencing selection bias.

Guideline-Based Recommendations

Diagnosis

• Formal diagnosis by real-time PCR testing of skin lesions for orthopoxvirus or mpox virus.
• Testing primarily performed on individuals meeting mpox case definition with symptomatic presentation.

Management

• No proven specific treatment for mpox; vaccination relies on smallpox vaccine due to lack of mpox-specific vaccine.

Monitoring & Follow-up

• Surveillance through epidemiologic databases and electronic health records capturing tested symptomatic individuals.
• Monitoring test positivity rates which vary over outbreak phases (e.g., >60% early, ~20% later).

Risks

• Stigma surrounding mpox influences healthcare-seeking behavior, violating TND assumption of similar healthcare-seeking between cases and controls.
• Differential diagnoses with distinct clinical features may bias control selection in TND studies.
• Variability in testing policies across countries introduces selection bias.

Patient & Prescribing Data

Individuals presenting with mpox-like illness during outbreak surveillance.

Vaccination strategies rely on smallpox vaccine; no specific mpox vaccine or proven treatment available.

Clinical Best Practices

• Use caution when applying TND to mpox due to potential biases from differential healthcare-seeking and diagnosis.
• Ensure case and control groups have similar healthcare-seeking behavior to uphold TND assumptions.
• Consider local testing policies and stigma factors when interpreting TND study results in mpox.
• Incorporate detailed clinical and epidemiologic data to improve validity of TND analyses in mpox.

References

• World Health Organization mpox outbreak declaration
• Test-negative design overview and vaccine effectiveness studies
• Mpox diagnosis and differential diagnosis