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Stratified medicine methodology framework

The MRC Framework for the Development, Design and Analysis of Stratified Medicine Research

Aims of the Framework

  • present a pathway for stratified medicine research that starts with the end in mind and covers stratum discovery and verification, leading towards early clinical assessment. 
  • identify critical questions when designing studies, and draw attention to potential design pitfalls and sources of bias.
  • describe methodological approaches and resources to inform study design and analysis, drawing on appropriate guidance and case studies.
  • enable investigators working at different phases of the stratified medicine pipeline to integrate their work.

The framework summarises the state of the art, and will provide guidance for researchers to consider the fundamental principles of stratified medicine methodology.

Themes covered by the Framework:

Theme 1: Framing the Question/Defining the Population

  • start with the end in mind
  • team composition
  • reviewing existing evidence
  • defining the study population
  • defining outcome(s)
  • mechanistic plausibility

Theme 2: Designing Stratum Discovery Studies; selecting variables, defining response and powering

  • marker discovery – selecting variables to measure
  • defining effect size and calculating sample size
  • use of retrospective data and secondary analysis
  • anticipating adherence Issues
  • planning for verification

Theme 3: Assay Design; managing complexity and variability

  • pre-analytic variation
  • operator and centre variability in assay design and development
  • dissecting mechanistic variation from measurement variation; assay accuracy and variability
  • meta-data and transparency on data cleaning/processing
  • advances in technology

Theme 4: Defining Strata; data integration, linkage to existing knowledge, linkage to outcome

  • strata defined by multiple marker profiles
  • setting cut-offs
  • interpret new associations and effects with caution

Theme 5: Stratum Verification

  • discovery and verification; differences in design
  • verifying a stratum intended for clinical use
  • verifying markers/strata using retrospective versus prospective data

Theme 6: Progression Toward Clinical Utility

  • population effects
  • re-framing the question
  • patient involvement
  • changing practice

For all queries regarding the MRC Framework for Stratified Medicine Research Methodology please contact:

Dr Samuel Rowley
Programme Manager – Methodology and Clinical Research
Samuel.Rowley@mrc.ukri.org

Dr Richard Evans
Programme Manager for Precision and Experimental Medicine
Richard.evans@mrc.ukri.org