Explain immortal time bias in cohort studies and provide a remedy.

• A. Immortal time bias occurs when exposure status is misclassified due to recall.
• B. Immortal time bias occurs when participants die before initial assessment.
• C. Immortal time bias arises when a period during which the outcome cannot occur is incorrectly classified as exposed time; remedy: use time-varying exposure definitions or proper time-at-risk allocation in analysis.
• D. Immortal time bias is the same as confounding.

Answer: (C)

Immortal time bias happens when a period during which the outcome cannot occur is incorrectly counted as exposed time. In cohort studies, this tends to happen when people are classified as exposed from the start of follow-up even though they only become exposed later. Because they must survive until exposure starts to be classified as exposed, this creates artificial extra survival time in the exposed group, making the exposure look protective or more favorable than it really is.

A clear example is a study of a drug started after diagnosis. If you count all follow-up from diagnosis as exposed for anyone who ever gets the drug, you’re including the time before the drug was actually started in the exposed period. That “immortal” interval cannot experience the outcome while they’re unexposed, so it biases results toward better outcomes in the drug group.

The remedy is to handle exposure as a time-varying factor. Treat exposure status as changing when the person actually starts the drug, and allocate person-time accordingly—only the time after exposure begins should count as exposed. Using time-dependent Cox models or other analyses that respect the exact timing of exposure, or employing a design like a new-user or landmark approach, helps avoid this bias by aligning follow-up with when exposure can influence the outcome.

This bias is not simply recall bias or confounding. Misclassification due to recall refers to errors in how exposure is remembered or reported. Death before an initial assessment is a different issue related to study design and timing. Immortal time bias specifically centers on misallocating time-at-risk to the incorrect exposure category.