Subpopulation Treatment Effect Pattern Plot (STEPP) analysis for continuous, binary, and count outcomes.
For the past few decades, randomized clinical trials have provided evidence for effective treatments by comparing several competing therapies. Their successes have led to numerous new therapies to combat many diseases. However, since their conclusions are based on the entire cohort in the trial, the treatment recommendation is for everyone, and may not be the best option for an individual. Medical research is now focusing more on providing personalized care for patients, which requires investigating how patient characteristics, including novel biomarkers, modify the effect of current treatment modalities. This is known as heterogeneity of treatment effects. A better understanding of the interaction between treatment and patient-specific prognostic factors will enable practitioners to expand the availability of tailored therapies, with the ultimate goal of improving patient outcomes. The Subpopulation Treatment Effect Pattern Plot (STEPP) approach was developed to allow researchers to investigate the heterogeneity of treatment effects on survival outcomes across values of a (continuously measured) covariate, such as a biomarker measurement.



Here, we extend the Subpopulation Treatment Effect Pattern Plot approach to continuous, binary, and count outcomes, which can be easily modeled using generalized linear models. With this extension of Subpopulation Treatment Effect Pattern Plot, these additional types of treatment effects within subpopulations defined with respect to a covariate of interest can be estimated, and the statistical significance of any observed heterogeneity of treatment effect can be assessed using permutation tests. The desirable feature that commonly used models are applied to well-defined patient subgroups to estimate treatment effects is retained in this extension.



We describe a simulation study to confirm that the proper Type I error rate is maintained when there is no treatment heterogeneity, and a power study to show that the statistics have power to detect treatment heterogeneity under alternative scenarios. As an illustration, we apply the methods to data from the Aspirin/Folate Polyp Prevention Study, a clinical trial evaluating the effect of oral aspirin, folic acid, or both as a chemoprevention agent against colorectal adenomas. The pre-existing R software package stepp has been extended to handle continuous, binary, and count data using Gaussian, Bernoulli, and Poisson models, and it is available on the Comprehensive R Archive Network.



The extension of the method and the availability of new software now permit STEPP to be applied to the full range of clinical trial end points.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA wyip@jimmy.harvard.edu.
Wai-Ki
WK
Yip
Carlo F. Dondena Centre for Research on Social Dynamics and Public Policy, Bocconi University, Milan, Italy.
Marco
M
Bonetti
Department of Mathematics and Statistics, University of Vermont, Burlington, VT, USA.
Bernard F
BF
Cole
Department of Statistical Science, University College London, London, UK.
William
W
Barcella
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA.
Xin Victoria
XV
Wang
Division of Oral Epidemiology, Department of Preventive and Restorative Dental Sciences and Division of Biostatistics, Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA, USA.
Ann
A
Lazar
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA.
Richard D
RD
Gelber
D000236:Adenoma / Q000517:prevention & control; D001241:Aspirin / Q000008:administration & dosage; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000517:prevention & control; D003627:Data Interpretation, Statistical; D005492:Folic Acid / Q000008:administration & dosage; D006801:Humans; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012306:Risk; D016019:Survival Analysis; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D005492:Folic Acid; D001241:Aspirin
Generalized linear model; Subpopulation Treatment Effect Pattern Plot (STEPP); randomized clinical trial; subgroup analysis