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Cores : Biostatistics and Study Design
NIH Collaboratory Cores and Working Groups


Biostatistics and Study Design

Chair: Elizabeth DeLong

NIH Representative: David Murray

Members: Chul Ahn, Bryan Comstock, Andrea Cook, Constantine Gatsonis, Dan Gillen, Roee Gutman, Patrick Heagerty, Jesse Hsu, Ken Kleinman, J. Richard Landis, Michael Leo, Qian Li, Joan Russo, Susan Shortreed, Liz Turner, William Vollmer, Jin Wang, Rui Wang, Song Zhang

Project Manager: Darcy Louzao

Pragmatic clinical trials, including cluster-randomized trials, present biostatistical and study design issues in addition to those typically encountered with traditional clinical trials. The Biostatistics and Study Design Core works with the NIH and Demonstration Project teams to create guidance and technical documents regarding study design and biostatistical issues relevant to pragmatic clinical trials.

For example, when randomizing clusters rather than individuals, several issues need attention. These include the trade-off between sample size and potential contamination, the intra-class correlation at different levels, varying cluster size, and the need for stratification or matching.

Additionally, special consideration must be given to handling informative missing follow-up data when using electronic health records as the basis for follow-up data collection. Individuals who are less healthy and have more chronic conditions will have more healthcare visits per year. If an intervention is effective in improving general health, then those who received the intervention would be more likely to have missing follow-up data compared with those who did not receive the intervention. Ignoring this missing data issue could lead to biased results, including concluding that the effective intervention is not effective.

Missing data, unequal cluster sizes, pair-matching vs stratification, and the intraclass correlation coefficient are some of the many topics being addressed by the Core, and the list will continue to grow as new challenges are faced.

The Core’s objectives include the following:

  • Work with Demonstration Projects to address gaps and limitations in their statistical plans and study designs during the planning phase

  • Understand which methods can be directly applied in a distributed data setting, which can potentially be modified for the distributed data setting, and which will require individual-level data

  • Document new statistical and methodological issues that arise and share knowledge through these case studies

  • Gather input on key methodological issues from NIH collaborators, investigators, and academic institutions

  • Identify areas in need of methods development and work to address these methodology challenges

  • Generate new knowledge by studying the application of statistical techniques (e.g., constrained randomization) in pragmatic and cluster-randomized trial designs



Andrea J. Cook, PhD, of the University of Washington and Group Health Research Institute
discusses biostatistics and study design challenges for pragmatic clinical trials.

Products and Publications

Cook AJ, et al. Clin Trials 2016

Li F, et al. Stat Med 2015

Small-Sample Robust Variance Correction for Generalized Estimating Equations for Use in Cluster-Randomized Trials

Frailty Models in Cluster-Randomized Trials

Unequal Cluster Sizes in Cluster-Randomized Clinical Trials 

Pair-Matching vs Stratification in Cluster-Randomized Trials 

The Intraclass Correlation Coefficient (ICC) 

Key Issues in Extracting Usable Data from Electronic Health Records for Pragmatic Clinical Trials 


12/2/2016: Grand Rounds Presentation: Lessons Learned from the NIH Collaboratory Biostatistics and Design Core (Video; Slides)

5/9/2016: Biostatistics and Study Design Core Presentation at Steering Committee Meeting

6/19/2015: Grand Rounds Presentation: Improving Pragmatic Clinical Trials: Lessons Learned from the NIH Collaboratory Biostatistics Core (Video; Slides)

4/24/2015: Grand Rounds Presentation: Analytic Challenges from the STOP CRC Trial: Pragmatic Solutions for Pragmatic Problems (Video; Slides)

8/19/2014: Biostatistics/Study Design Core Presentation at Steering Committee Meeting

2/25/2014: Biostatistics/Study Design Core Presentation at Steering Committee Meeting

4/19/2013: Grand Rounds Presentation: The NIH Health Care Systems Research Collaboratory's Biostatistics Core: Are We On the Right Track? (Video; Slides)

2/8/2013: Grand Rounds Presentation: Design and Analysis of Group-Randomized Trials (Video; Slides)


6/11/2015: Dr. Liz DeLong Discusses Lessons Learned in the Biostatistics and Study Design Core

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