The limit of plausibility for predictors of response: application to biventricular pacing.

Objectives We sought a method for any reader to quantify the limit, imposed by variability, to sustainably observable R2 between any baseline predictor and response marker. We then apply this to echocardiographic measurements of mechanical dyssynchrony and response. Background Can mechanical dyssynchrony markers strongly predict ventricular remodeling by biventricular pacing (cardiac resynchronization therapy)? Methods First, we established the mathematical depression of observable R2 arising from: 1) spontaneous variability of response markers; and 2) test–retest variability of dyssynchrony measurements. Second, we contrasted published R2 values between externally monitored randomized controlled trials and highly skilled single-center studies (HSSCSs). Results Inherent variability of response markers causes a contraction factor in R2 of 0.48 (change in left ventricular ejection fraction [ΔLVEF]), 0.50 (change in end-systolic volume [ΔESV]), and 0.40 (change in end-diastolic volume [ΔEDV]). Simultaneously, inherent variability of mechanical dyssynchrony markers causes a contraction factor of between 0.16 and 0.92 (average, 0.6). Therefore the combined contraction factor, that is, limit on sustainably observable R2 between mechanical dyssynchrony markers and response, is ∼0.29 (ΔLVEF), ∼0.24 (ΔESV), and ∼0.30 (ΔEDV). Many R2 values published in HSSCSs exceeded these mathematical limits; none in externally monitored trials did so. Overall, HSSCSs overestimate R2 by 5- to 20-fold (p = 0.002). Absence of bias-resistance features in study design (formal enrollment and blinded measurements) was associated with more overstatement of R2. Conclusions Reports of R2 > 0.2 in response prediction arose exclusively from studies without formally documented enrollment and blinding. The HSSCS approach overestimates R2 values, frequently breaching the mathematical ceiling on sustainably observable R2, which is far below 1.0, and can easily be calculated by readers using formulas presented here. Community awareness of this low ceiling may help resist future claims. Reliable individualized response prediction, using methods originally designed for group-mean effects, may never be possible because it has 2 currently unavailable and perhaps impossible prerequisites: 1) excellent blinded test–retest reproducibility of dyssynchrony; and 2) response markers reproducible over time within nonintervened individuals. Dispassionate evaluation, and improvement, of test–retest reproducibility is required before any further claims of strong prediction. Prediction studies should be designed to resist bias.