Combining markers with and without the limit of detection

Ting Dong, Catherine Chunling Liu, Emanuel F. Petricoin, Liansheng Larry Tang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


In this paper, we consider the combination of markers with and without the limit of detection (LOD). LOD is often encountered when measuring proteomic markers. Because of the limited detecting ability of an equipment or instrument, it is difficult to measure markers at a relatively low level. Suppose that after some monotonic transformation, the marker values approximately follow multivariate normal distributions. We propose to estimate distribution parameters while taking the LOD into account, and then combine markers using the results from the linear discriminant analysis. Our simulation results show that the ROC curve parameter estimates generated from the proposed method are much closer to the truth than simply using the linear discriminant analysis to combine markers without considering the LOD. In addition, we propose a procedure to select and combine a subset of markers when many candidate markers are available. The procedure based on the correlation among markers is different from a common understanding that a subset of the most accurate markers should be selected for the combination. The simulation studies show that the accuracy of a combined marker can be largely impacted by the correlation of marker measurements. Our methods are applied to a protein pathway dataset to combine proteomic biomarkers to distinguish cancer patients from non-cancer patients.

Original languageEnglish
Pages (from-to)1307-1320
Number of pages14
JournalStatistics in Medicine
Issue number8
StatePublished - 15 Apr 2014
Externally publishedYes


  • Diagnostic accuracy
  • Limit of detection
  • Linear discriminant analysis
  • ROC curve


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