Toxicology Volume 183, February 2003, Pages 39-56

Identification of an abnormal beryllium lymphocyte proliferation test

Edward L. Fromea, Lee S. Newmanb, Donna L. Craglec , Shirley P. Colyerc and Paul F. Wambach d

aComputer Science and Mathematics Division, Oak Ridge National Laboratory, Oak Ridge, TN 37830,USA
b National Jewish Medical and Research Center, Denver, CO, USA
c Center for Epidemiologic Research, Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA
d U.S. Department of Energy, Germantown, MD, USA


The potential hazards from exposure to beryllium or beryllium compounds in the workplace were first reported in the 1930s. The tritiated thymidine beryllium lymphocyte proliferation test (BeLPT) is an in vitro blood test that is widely used to screen beryllium exposed workers in the nuclear industry for sensitivity to beryllium. The clinical significance of the BeLPT was described and a standard protocol was developed in the late 1980s. Cell proliferation is measured by the incorporation of tritiated thymidine into dividing cells on two culture dates and using three concentrations of beryllium sulfate. Results are expressed as a `stimulation index' (SI) which is the ratio of the amount of tritiated thymidine (measured by beta counts) in the simulated cells divided by the counts for the unstimulated cells on the same culture day. Several statistical methods for use in the routine analysis of the BeLPT were proposed in the early 1990s. The least absolute values (LAV) method was recommended for routine analysis of the BeLPT. This report further evaluates the LAV method using new data, and proposes a new method for identification of an abnormal or borderline test. This new statistical–biological positive (SBP) method reflects the clinical judgment that: (i) at least two SIs show a `positive' response to beryllium; and (ii) that the maximum of the six SIs must exceed a cut-point that is determined from a reference data set of normal individuals whose blood has been tested by the same method in the same serum. The new data is from the Y-12 National Security Complex in Oak Ridge (Y-12) and consists of 1080 workers and 33 non-exposed control BeLPTs (all tested in the same serum). Graphical results are presented to explain the statistical method, and the new SBP method is applied to the Y-12 group. The true positive rate and specificity of the new method were estimated to be 86% and 97%, respectively. An electronic notebook that is accessible via the Internet was used in this work and contains background information and details not included in the paper.

Article Outline

1. Introduction
2. Materials and methods
2.1. Beryllium lymphocyte proliferation test
2.2. Statistical analysis of the BeLPT
2.3. Identification of abnormal BeLPTS using the SBP method
2.4. Receiver operating characteristic (ROC)curve
3. Results
3.1. Graphical results for mitrogen control BeLPT data
3.2. Graphical results for beryllium workers and non-exposed BeLPTs
3.3. Identification of abnormal BeLPTs using the SBP method
3.4. Identification of cases and ROC curve analysis
4. Discussion
Appendix A. Least absolute values analysis for BeLPT

ACKNOWLEDGMENTS. This research was supported by the Offices of Occupational Medicine, Environment, Safety and Health, U. S. Department of Energy under contract DE-AC05-00OR22725 with UT-Battele, LLC. The authors thank ORISE, Center for Epidemiologic Research for help with data collection and Carole Holbrook, ORNL, Computer Science and Mathematics Division staff for assistance in preparing this report.

The work has been authored by a contractor of the U.S. Government. Accordingly, the U.S. Government retains a nonexclusive, royalty-free license to publish or reproduce the published form of this work, or to allow others to do so for U. S. Government purposes.