A resample-replace lasso procedure for combining high-dimensional markers with limit of detection

Jinjuan Wang, Yunpeng Zhao, Larry L. Tang, Claudius Mueller, Qizhai Li

Research output: Contribution to journalArticlepeer-review


In disease screening, a biomarker combination developed by combining multiple markers tends to have a higher sensitivity than an individual marker. Parametric methods for marker combination rely on the inverse of covariance matrices, which is often a non-trivial problem for high-dimensional data generated by modern high-throughput technologies. Additionally, another common problem in disease diagnosis is the existence of limit of detection (LOD) for an instrument–that is, when a biomarker's value falls below the limit, it cannot be observed and is assigned an NA value. To handle these two challenges in combining high-dimensional biomarkers with the presence of LOD, we propose a resample-replace lasso procedure. We first impute the values below LOD and then use the graphical lasso method to estimate the means and precision matrices for the high-dimensional biomarkers. The simulation results show that our method outperforms alternative methods such as either substitute NA values with LOD values or remove observations that have NA values. A real case analysis on a protein profiling study of glioblastoma patients on their survival status indicates that the biomarker combination obtained through the proposed method is more accurate in distinguishing between two groups.

Original languageEnglish (US)
Pages (from-to)4278-4293
Number of pages16
JournalJournal of Applied Statistics
Issue number16
StatePublished - 2022


  • Limit of detection (LOD)
  • area under the receiver operating characteristic curve (AUC)
  • graphical lasso
  • high-dimensional data
  • imputation
  • precision matrix

ASJC Scopus subject areas

  • Statistics and Probability
  • Statistics, Probability and Uncertainty


Dive into the research topics of 'A resample-replace lasso procedure for combining high-dimensional markers with limit of detection'. Together they form a unique fingerprint.

Cite this