Review Question - QID 103897

Lead-time bias occurs when an increased ability to detect disease increases the survival time after diagnosis without changing the course of the disease.

Despite the fact that randomized controlled trials (RCTs) are considered the gold standard in determining clinical efficacy, they are not completely immune to bias. Lead-time biases are especially problematic in RCTs that are investigating the efficacy of new diagnostic procedures. The hope of new diagnostic procedures is that detecting disease earlier will improve prognosis. The potential for lead time bias clouds this picture, as the detection of disease before it becomes symptomatic will result in an apparent prolongation of survival after diagnosis, even if early detection has no impact on natural history of disease.

Rothman formally defines the period of the lead-time. In the course of any disease, the first event to occur is the biologic onset of disease, e.g. when the very first cell becomes malignant. At this point the disease is asymptomatic, which is why diagnostic procedures performed during this time are considered screening tests. Eventually the disease will manifest with symptoms. The period between a positive screening and the onset of symptoms is the lead time. Rothman cautions that one should not count lead-time towards the survival time because it does not represent any real benefit in and of itself. In the absence of any benefit from early treatment of the disease the lead-time is simply a period during which the patient is aware of his disease, but the date of his death is unchanged. If early detection cannot postpone his death than an increased lead-time is not only unhelpful, but possibly psychologically detrimental.

Gordis expands on the concept of lead-time bias further. Increasing lead-time seem to cause increases in survival, but the patient is not any better off because death has not truly been delayed. Furthermore, lead-time bias can affect the results of trials whose outcomes are not mortality. The same bias can occur when investigating morbidity, recurrence of disease, quality of life, or patient satisfaction.

Illustration A depicts the natural progression of disease from biologic onset of breast cancer to death. The difference between the apparent lengths of survival between MRI and conventional mammography is the lead-time bias.

Incorrect Answers:
Answer 1: The sample size and randomization procedure in this study protect it from selection bias.
Answer 2: Incorrect diagnosis of breast cancer cases by either method could lead to misclassification bias, but in the absence of other information can neither be suspected nor assumed more problematic than lead-time bias.
Answer 4: As this study is prospective and the exposure and outcome are determined clinically, recall bias would not be expected.
Answer 5: RCTs, including this one, are still susceptible to certain types of bias.