Subgroup Analysis

Reviewed and revised 26 August 2015

OVERVIEW

  • Subgroup analysis involves assessing an association between an intervention (or other factor) and a subset of the patients that were exposed
  • Subgroup analysis can be decided upon a priori or performed post hoc

OBSERVATIONAL STUDIES

  • identification of associations within particular subgroups is the usual method of investigation in observational studies

RANDOMISED CONTROL TRIALS

  • an RCT provides a comparison of the test subjects and the controls
  • when there is particular interest in the results of treatment in a certain section of trial participants, a subgroup analysis is performed
  • subgroups are examined to see if they are liable to a greater benefit or risk from treatment
  • subgroup analysis is often unreliable due to problems of multiplicity and small numbers of patients studied
  • inferences based on comparisons between subgroups in RCTs must be approached more cautiously than those based on the main comparison

PROBLEMS

  • false positive or false negative effects
  • chance differences in observed effects
  • lack of power to perform the analysis
  • floor or ceiling effects
  • issues relating to multiple statistical testing (if enough subroup analyses are performed one will eventually be postive by chance alone!)
  • over-reporting and under-reporting
  • Industry funded randomised controlled trials, in the absence of statistically significant primary outcomes, are more likely to report subgroup analyses than non-industry funded trials

CREDIBILITY OF A SUBGROUP ANALYSIS FINDING

The result is more credible when the claim meets the following:

  • comes from a within-study comparison
  • has a significant interaction
  • is unequivocally specified a priori
  • is one of a small number of hypotheses tested
  • presents a large difference of effects
  • is supported by the external evidence, and
  • has compelling biological rationale

CONCLUSION

  •  subgroup analysis results derived from a sound clinical trial are not necessarily valid
  • do not accept the validity of subgroup analysis results without due consideration
  • subgroup analyses are generally considered hypothesis generating rather than practice changing

References and Links

  • Cook DI, Gebski VJ, Keech AC. Subgroup analysis in clinical trials. Med J Aust. 2004 Mar 15;180(6):289-91. PMID: 15012568.
  • Guillemin F. Primer: the fallacy of subgroup analysis. Nat Clin Pract Rheumatol. 2007 Jul;3(7):407-13. PMID: 17599075.
  • Rothwell PM. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet. 2005 Jan  8-14;365(9454):176-86. PMID: 15639301.
  • Sun X et al. The influence of study characteristics on reporting of subgroup analyses in randomised controlled trials: systematic review. BMJ. 2011 Mar 28;342:d1569. PMC6173170.
  • Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ. 2010 Mar 30;340:c117. PMID: 20354011.
  • Study to Prospectively Evaluate Reamed Intramedullary Nails in Tibial Fractures (SPRINT) Investigators. Is a subgroup claim believable? A user’s guide to subgroup analyses in the surgical literature. J Bone Joint Surg Am. 2011 Feb 2;93(3):e8. PMC3028449.
  • Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA. 1991 Jul 3;266(1):93-8. PMID: 2046134.

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