SMARTp: A SMART design for nonsurgical treatments of chronic periodontitis with spatially referenced and nonrandomly missing skewed outcomes

Abstract

This paper proposes dynamic treatment regimes (DTRs) as effective individualized treatment strategies for managing chronic periodontitis. The proposed DTRs are studied via SMARTp—a two‐stage sequential multiple assignment randomized trial (SMART) design. For this design, we propose a statistical analysis plan and a novel cluster‐level sample size calculation method that factors in typical features of periodontal responses such as non‐Gaussianity, spatial clustering, and nonrandom missingness. Here, each patient is viewed as a cluster, and a tooth within a patient's mouth is viewed as an individual unit inside the cluster, with the tooth‐level covariance structure described by a conditionally autoregressive structure. To accommodate possible skewness and tail behavior, the tooth‐level clinical attachment level (CAL) response is assumed to be skew‐t, with the nonrandomly missing structure captured via a shared parameter model corresponding to the missingness indicator. The proposed method considers mean comparison for the regimes with or without sharing an initial treatment, where the expected values and corresponding variances or covariance for the sample means of a pair of DTRs are derived by the inverse probability weighting and method of moments. Simulation studies are conducted to investigate the finite‐sample performance of the proposed sample size formulas under a variety of outcome‐generating scenarios. An R package SMARTp implementing our sample size formula is available at the Comprehensive R Archive Network for free download.

Study design and primary outcome in randomized controlled trials in periodontology. A systematic review

“…Studies with adaptive design break the traditional “rigidity” of RCTs, opening to the possibility of adapting the study to initial results, leading to augmenting or reducing a certain intervention or modifying its frequency. Although these types of studies are becoming increasingly popular in medicine, particularly for cancer (Wang et al 2012; Kidwell, 2014), their application to periodontology is still limited (Xu et al 2020). We can speculate that this is due to investigators not being fully aware of these alternative study designs, to difficulties in obtaining approvals and funding with unconventional study designs or alternatively to authors deeming that adaptive or SMART design studies may not be appropriate in periodontal research.…”

A novel approach to assess dynamic treatment regimes embedded in a SMART with an ordinal outcome

“…[12][13][14] Methodological research on SMARTs has been on the rise in recent years, in accordance with the increasing prevalence of SMART or similar designs in practice, for example, in cancer, chronic periodontitis, health behavior change, and substance abuse, to mention a few. 7,[14][15][16] SMART designs involve randomization of individuals to available intervention options at an initial stage, followed by re-randomizations at each subsequent stage of some or all of the individuals to intervention options available at that stage. The re-randomizations and the set of intervention options at each stage may depend on information collected in prior stages such as how well the individual responded to the previous intervention(s).…”

“…Sequential multiple assignment randomized trial (SMART) is a special kind of clinical trial that provides high‐quality data for comparing or constructing DTRs; the data from such trials are less vulnerable to causal confounding than longitudinal observational data 12‐14 . Methodological research on SMARTs has been on the rise in recent years, in accordance with the increasing prevalence of SMART or similar designs in practice, for example, in cancer, chronic periodontitis, health behavior change, and substance abuse, to mention a few 7,14‐16 . SMART designs involve randomization of individuals to available intervention options at an initial stage, followed by re‐randomizations at each subsequent stage of some or all of the individuals to intervention options available at that stage.…”