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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Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

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