Expert View

Managing Clinical Heterogeneity: An Argument for Benefit-Based Action Limits

[+] Author and Article Information
Sudarshan Ramachandran

Department of Clinical Biochemistry,
University Hospitals of North Midlands/Faculty
of Health Sciences,
Staffordshire University,
Staffordshire ST4 6QG, UK;
College of Engineering,
Design & Physical Sciences,
Brunel University,
London UB8 3PH, UK;
Department of Clinical Biochemistry,
Heart of England Foundation Trust,
West Midlands B75 7RR, UK
e-mail: sud.ramachandran@heartofengland.nhs.uk

Carola S. König

College of Engineering,
Design & Physical Sciences,
Brunel University London,
Uxbridge UB8 3PH, UK

Geoffrey Hackett

Department of Urology,
Heart of England Foundation Trust,
West Midlands B75 7RR, UK

Mark Livingston

Department of Blood Sciences,
Walsall Healthcare NHS Trust,
Walsall WS2 9PS, UK

Richard C. Strange

Institute for Science and Technology in
Keele University,
Staffordshire ST4 7QB, UK

1Corresponding author.

2Present address: Professor, Department of Clinical Biochemistry, Heart of England NHS Foundation Trust, Good Hope Hospital, Rectory Road, Sutton Coldfield, West Midlands B75 7RR, UK.

Manuscript received December 19, 2017; final manuscript received March 8, 2018; published online April 12, 2018. Assoc. Editor: Tilo Winkler.

ASME J of Medical Diagnostics 1(3), 034701 (Apr 12, 2018) (7 pages) Paper No: JESMDT-17-2057; doi: 10.1115/1.4039561 History: Received December 19, 2017; Revised March 08, 2018

The use of reference ranges is well established in medical practice and research. Classically, a range would be derived from the local healthy population and matched in age, gender, and other characteristics to the patients under investigation. However, recruiting suitable controls is problematic and the derivation of the range by excluding 2.5% at each end of the distribution results in 5% of the values being arbitrarily discarded. Thus, the traditional reference range is derived using statistical and not clinical principles. While these considerations are recognized by clinicians, it is often not realized that the application of whole population derived reference ranges to complex pathologies that comprise patient subgroups may be problematic. Such subgroups may be identified by phenotypes including genetic etiology, variations in exposure to a causative agent, and tumor site. In this review, we provide examples of how subgroups can be identified in diverse pathologies and how better management can be achieved using evidence-based action limits rather than reference ranges. We give examples from our clinical experience of problems arising from using the wrong reference ranges for the clinical situation. Identifying subgroups will often enable clinicians to derive specific action limits for treatment that will lead to customized management and researchers a route into the study of complex pathologies.

Copyright © 2018 by ASME
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Grahic Jump Location
Fig. 1

An illustration of a normal (Gaussian) distribution and derived reference range

Grahic Jump Location
Fig. 5

Scheme depicting how immune surveillance could determine BCC presentation phenotypes

Grahic Jump Location
Fig. 4

Susceptibility, environmental and modifying factors leading to various BCC subgroups (1 − n) defined by presentation, each with specific causative mechanisms (1 − n)

Grahic Jump Location
Fig. 3

Management of a pathology as a heterogeneous entity

Grahic Jump Location
Fig. 2

Management of pathology viewed as a homogeneous entity



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