A comparison of methods to generate adaptive reference ranges in longitudinal monitoring

PLoS One. 2021 Feb 19;16(2):e0247338. doi: 10.1371/journal.pone.0247338. eCollection 2021.

Abstract

In a clinical setting, biomarkers are typically measured and evaluated as biological indicators of a physiological state. Population based reference ranges, known as 'static' or 'normal' reference ranges, are often used as a tool to classify a biomarker value for an individual as typical or atypical. However, these ranges may not be informative to a particular individual when considering changes in a biomarker over time since each observation is assessed in isolation and against the same reference limits. To allow early detection of unusual physiological changes, adaptation of static reference ranges is required that incorporates within-individual variability of biomarkers arising from longitudinal monitoring in addition to between-individual variability. To overcome this issue, methods for generating individualised reference ranges are proposed within a Bayesian framework which adapts successively whenever a new measurement is recorded for the individual. This new Bayesian approach also allows the within-individual variability to differ for each individual, compared to other less flexible approaches. However, the Bayesian approach usually comes with a high computational cost, especially for individuals with a large number of observations, that diminishes its applicability. This difficulty suggests that a computational approximation may be required. Thus, methods for generating individualised adaptive ranges by the use of a time-efficient approximate Expectation-Maximisation (EM) algorithm will be presented which relies only on a few sufficient statistics at the individual level.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Bayes Theorem
  • Biomarkers / analysis*
  • Humans
  • Reference Standards
  • Reference Values

Substances

  • Biomarkers

Grants and funding

D. Roshan received funding jointly through Global Oncology Services Ltd. under the directorship of Prof. Frank Sullivan, and the CÚRAM Research Centre for Medical Devices (http://www.curamdevices.ie) under financial support from Science Foundation Ireland (https://www.sfi.ie/), co-funded under the European Regional Development Fund under Grant Number 13/RC/2073. J. Ferguson is supported by the Grant EIA-20170017 awarded by the HRB, Ireland. A. Simpkin is supported by Science Foundation Ireland under Grant Number 19/FFP/7002. W. Wyns is supported by Science Foundation Ireland Research Professorship Award RSF 1413. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.