# Imprecision in tuberculosis infection outcomes: implications for non-inferiority vaccine trials

## TL;DR

This paper shows that using imperfect tests for tuberculosis infection in vaccine trials can lead to incorrect conclusions about a vaccine's effectiveness.

## Contribution

The study reveals how flaws in test accuracy can bias non-inferiority vaccine trial results, especially in low infection risk settings.

## Key findings

- With 95% sensitivity and specificity, false non-inferiority declarations reached 96.8% in low-risk scenarios.
- Type I error and power were accurate only when tests had 100% sensitivity and specificity.
- The risk of falsely declaring non-inferiority decreases as cumulative infection risk increases.

## Abstract

Randomized trials comparing new vaccines against tuberculosis for use in neonates and infants, for whom Bacille Calmette–Guérin vaccination is established practice, are using tuberculosis infection as the primary endpoint in a non-inferiority design. Markers of tuberculosis infection have imperfect sensitivity and specificity. Flaws in the non-inferiority trial design typically bias towards non-inferiority, which may result in falsely declaring non-inferiority.

We conducted a statistical simulation study to assess the impact of imperfect markers of tuberculosis infection on the interpretation of tuberculosis vaccine trials testing a non-inferiority hypothesis of an infection primary outcome in a two-arm randomized comparison. Data were generated in three 2-year cumulative risk of tuberculosis infection scenarios (2%, 5%, and 8%). The specificity of tests of tuberculosis infection was assumed to range from 100% to 85%, while the sensitivity was assumed to range from 100% to 64%. Log-binomial regression was used to estimate the relative risk of tuberculosis infection.

With 100% sensitivity and specificity, type I error and power were both approximately equal to the expected values (2.5% and 80%, respectively) in all three cumulative tuberculosis risk scenarios. With modest deviations from perfect sensitivity and specificity (95% for both), the risk of falsely declaring non-inferiority was 96.8%, 53.2%, and 27.8% in the 2%, 5%, and 8% cumulative tuberculosis risk infection scenarios, respectively.

Tuberculosis vaccine non-inferiority trials using an infection primary outcome must be designed and interpreted accounting for the specificity of the tools used to measure infection, otherwise they risk declaring non-inferiority by default.