Table 4.

Possible analytical approaches for estimating the effect of a post-infusion exposure/covariate on TTE endpoints.

	Approach 1	Approach 2	Approach 3
	Naïve ever/never	Landmark	Exposure as TVC
Analytic cohort	All patients	Those who are still event-free and under observation by the landmark time	All patients
Time origin	Infusion	Landmark time	Infusion
Exposure group	Defined by ever having the exposure using information obtained post-infusion	Defined by ever having the exposure by the landmark time	Time-varying; a person moves to the exposure group at the time the exposure occurs
Analysis method	When competing risks absent: KM Cox PH model	When competing risks absent: KM Cox PH model	When competing risks absent: Extended KM Extended Cox PH model w. TVC
	When competing risks present: CIF csH model Fine and Gray model	When competing risks present: CIF csH model Fine and Gray model	When competing risks present: csH model w. TVC Fine and Gray model w. TVC
Estimate of the exposure effect	Biased estimate of the effect on the risk of outcome after the infusion due to immortal person-time bias;	Unbiased estimate of the effect of exposure pre-landmark on the risk of outcome after the landmark conditional on being event-free and censoring-free at the landmark	Unbiased estimate of the effect on the risk of outcome after the infusion
	The immortal person-time refers to the time between infusion and the occurrence of exposure, among the patients who eventually get exposed.
Notes	Should be avoided.	Choice of landmark time can complicate the interpretation of the estimated exposure effect if there are too many additional individuals with a post-landmark exposure, or too-many excluded individuals who failed or were censored before the landmark time.	More complex analytically but most appropriate for exposure effect of interest.
	Bias increases with increasing risk of events shortly after infusion	May be acceptable given its simplicity, if the exposure occurs in a short time window with few intercurrent events	Advantages include allowing the exposure status to change more than one time (e.g., from unexposed to exposed and then unexposed again), and being able to evaluate the exposure effects within a given time interval (e.g., BCR within 6 months) by considering a patient exposed only if the exposure occurs within 6 months and not counting any exposure afterwards.
			Caution is needed, for extended KM method due to its problematic causal interpretation (41), and for Fine and Gray model w. TVC because some TVCs are not measurable after competing risks occurred (43).