title: Could the clinical interpretability of subgroups detected using clustering methods be improved by using a novel two-stage approach?
abstract: BACKGROUND
  Recognition of homogeneous subgroups of patients can usefully improve prediction of their outcomes and the targeting of treatment. There are a number of research approaches that have been used to recognise homogeneity in such subgroups and to test their implications. One approach is to use statistical clustering techniques, such as Cluster Analysis or Latent Class Analysis, to detect latent relationships between patient characteristics. Influential patient characteristics can come from diverse domains of health, such as pain, activity limitation, physical impairment, social role participation, psychological factors, biomarkers and imaging. However, such 'whole person' research may result in data-driven subgroups that are complex, difficult to interpret and challenging to recognise clinically. This paper describes a novel approach to applying statistical clustering techniques that may improve the clinical interpretability of derived subgroups and reduce sample size requirements.
  
  
  METHODS
  This approach involves clustering in two sequential stages. The first stage involves clustering within health domains and therefore requires creating as many clustering models as there are health domains in the available data. This first stage produces scoring patterns within each domain. The second stage involves clustering using the scoring patterns from each health domain (from the first stage) to identify subgroups across all domains. We illustrate this using chest pain data from the baseline presentation of 580 patients.
  
  
  RESULTS
  The new two-stage clustering resulted in two subgroups that approximated the classic textbook descriptions of musculoskeletal chest pain and atypical angina chest pain. The traditional single-stage clustering resulted in five clusters that were also clinically recognisable but displayed less distinct differences.
  
  
  CONCLUSIONS
  In this paper, a new approach to using clustering techniques to identify clinically useful subgroups of patients is suggested. Research designs, statistical methods and outcome metrics suitable for performing that testing are also described. This approach has potential benefits but requires broad testing, in multiple patient samples, to determine its clinical value. The usefulness of the approach is likely to be context-specific, depending on the characteristics of the available data and the research question being asked of it.
authors.affiliation: Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Campusvej 55, Odense, M 5230 Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Kent
authors.affiliation: Nordic Institute of Chiropractic and Clinical Biomechanics, Odense, Denmark.
authors.forename: Mette Jensen
authors.initials: MJ
authors.lastname: Stochkendahl
authors.affiliation: Nordic Institute of Chiropractic and Clinical Biomechanics, Odense, Denmark.
authors.forename: Henrik Wulff
authors.initials: HW
authors.lastname: Christensen
authors.affiliation: Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Campusvej 55, Odense, M 5230 Denmark ; Nordic Institute of Chiropractic and Clinical Biomechanics, Odense, Denmark.
authors.forename: Alice
authors.initials: A
authors.lastname: Kongsted
keywords: Chest pain; Clustering; Latent class analysis; Low back pain; Stratified health care; Subgroups