Abstract
Terrorism using radiological dirty bombs or improvised nuclear devices is recognized as a major threat to both public health and national security. In the event of a radiological or nuclear disaster, rapid and accurate biodosimetry of thousands of potentially affected individuals will be essential for effective medical management to occur. Currently, health care providers lack an accurate, high-throughput biodosimetric assay which is suitable for the triage of large numbers of radiation injury victims. Here, we describe the development of a biodosimetric assay based on the analysis of irradiated mice, ex vivo-irradiated human peripheral blood (PB) and humans treated with total body irradiation (TBI). Interestingly, a gene expression profile developed via analysis of murine PB radiation response alone was inaccurate in predicting human radiation injury. In contrast, generation of a gene expression profile which incorporated data from ex vivo irradiated human PB and human TBI patients yielded an 18-gene radiation classifier which was highly accurate at predicting human radiation status and discriminating medically relevant radiation dose levels in human samples. Although the patient population was relatively small, the accuracy of this classifier in discriminating radiation dose levels in human TBI patients was not substantially confounded by gender, diagnosis or prior exposure to chemotherapy. We have further incorporated genes from this human radiation signature into a rapid and high-throughput chemical ligation-dependent probe amplification assay (CLPA) which was able to discriminate radiation dose levels in a pilot study of ex vivo irradiated human blood and samples from human TBI patients. Our results illustrate the potential for translation of a human genetic signature for the diagnosis of human radiation exposure and suggest the basis for further testing of CLPA as a candidate biodosimetric assay.
Highlights
The possibility of a terrorist-mediated attack using a dirty bomb or an improvised nuclear device is considered a major threat to both national security and public health [1,2,3]
In independent studies of healthy adult people and patients treated with total body irradiation (TBI) as conditioning for hematopoietic cell transplantation, we showed that a human gene expression profile of radiation exposure was able to predict human radiation status with approximately 90% accuracy and that such signatures were not confounded by variables such as time from exposure, genotype or bacterial infection [13,14]
The predictor remained highly accurate at discriminating radiation dose levels in mice that were pre-treated with either E. coli-derived lipopolysaccharide (LPS), which mimics bacterial sepsis, or GCSF, which would be administered to many radiation victims (Figure 1B)
Summary
The possibility of a terrorist-mediated attack using a dirty bomb or an improvised nuclear device is considered a major threat to both national security and public health [1,2,3]. Substantial efforts have been made in the federal, state and private sectors to prepare for an effective medical response in the event of a radiation disaster in a U.S city [4,5]. [10,11] While these clinical algorithms can provide indication in some victims as to their radiation status and level of exposure, a high throughput, quantitative assay to predict radiation status and radiation dose levels in humans could be of substantial benefit in the triage of radiation mass casualties [7,9,11,12]. The successful development and validation of such an assay for human radiation injury would address a major gap in the capability of health care providers to assess and properly treat radiation victims
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