An examination of effect estimation in factorial and standardly-tailored designs

Abstract

Background: Many clinical trials are designed to test an intervention arm against a control arm wherein all subjects are equally eligible for all interventional components. Factorial designs have extended this to test multiple intervention components and their interactions. A newer design referred to as a ;standardly-tailored' design, is a multicomponent interventional trial that applies individual interventional components to modify risk factors identified a priori and tests whether health outcomes differ between treatment arms. Standardly-tailored designs do not require that all subjects be eligible for every interventional component. Although standardly-tailored designs yield an estimate for the net effect of the multicomponent intervention, it has not yet been shown if they permit separate, unbiased estimation of individual component effects. The ability to estimate the most potent interventional components has direct bearing on conducting second stage translational research.

Purpose: We present statistical issues related to the estimation of individual component effects in trials of geriatric conditions using factorial and standardly-tailored designs. The medical community is interested in second stage translational research involving the transfer of results from a randomized clinical trial to a community setting. Before such research is undertaken, main effects and synergistic and or antagonistic interactions between them should be identified. Knowledge of the relative strength and direction of the effects of the individual components and their interactions facilitates the successful transfer of clinically significant findings and may potentially reduce the number of interventional components needed. Therefore the current inability of the standardly-tailored design to provide unbiased estimates of individual interventional components is a serious limitation in their applicability to second stage translational research.

Methods: We discuss estimation of individual component effects from the family of factorial designs and this limitation for standardly-tailored designs. We use the phrase ;factorial designs' to describe full-factorial designs and their derivatives including the fractional factorial, partial factorial, incomplete factorial and modified reciprocal designs. We suggest two potential directions for designing multicomponent interventions to facilitate unbiased estimates of individual interventional components.

Results: Full factorial designs and their variants are the most common multicomponent trial design described in the literature and differ meaningfully from standardly-tailored designs. Factorial and standardly-tailored designs result in similar estimates of net effect with different levels of precision. Unbiased estimation of individual component effects from a standardly-tailored design will require new methodology.

Limitations: Although clinically relevant in geriatrics, previous applications of standardly-tailored designs have not provided unbiased estimates of the effects of individual interventional components.

Discussion: Future directions to estimate individual component effects from standardly-tailored designs include applying D-optimal designs and creating independent linear combinations of risk factors analogous to factor analysis.

Conclusion: Methods are needed to extract unbiased estimates of the effects of individual interventional components from standardly-tailored designs.

Figure 1

Conceptual example of standardly-tailored design