ORIGINAL ARTICLE
Beryllium BioBank: 2. Lymphocyte Proliferation Testing Philip Harber, MD, MPH, Jing Su, MS, and Gabriela Alongi, BS
Objective: To incrementally improve the use of beryllium lymphocyte proliferation test (LPT) results. Methods: Beryllium BioBank data were analyzed for 532 subjects in three groups: beryllium-exposed, sensitized, or chronic beryllium disease. Predictor variables were LPT stimulation index (SI) at the date of the earliest available data and at the study entry date. Results: Cross-sectionally, LPT SI magnitude does not distinguish among the three groups. The likelihood of progression from sensitization to disease is associated with the absolute value of SI, but LPT SI interpreted by traditional cut point criteria was not predictive. Conclusions: Updating the criteria for interpreting beryllium LPT data should be considered. Prediction of progression to chronic beryllium disease may be improved by changing the cut point for interpretation or by using the SI as a continuous variable.
E
xposure to beryllium produces chronic beryllium disease (CBD), a serious disease that may lead to respiratory morbidity and even death. The disease develops sequentially—individuals who are beryllium-exposed may develop allergic sensitization and be considered beryllium-sensitized (BeS). Some of the latter may progress to develop the pulmonary disease known as CBD, a disorder characterized by granulomatous and lymphocytic inflammatory response of the lung.1 Published evidence indicates that treatment of early CBD with immunosuppressant medications (eg, prednisone) may reduce the likelihood of developing serious or fatal disease.1–5 Development of immunologic sensitization to beryllium is considered to be a necessary precursor to developing CBD. The beryllium lymphocyte proliferation test (LPT) measures the immunologic responsiveness of a person’s lymphocytes to beryllium. Lymphocyte proliferation test serves several purposes: (1) It is frequently incorporated in screening programs of exposed workers to identify patients with beryllium sensitization who may then be referred for more in-depth diagnostic testing including bronchoscopy and biopsy to determine whether they have CBD. (2) Clinicians may use LPT results to help determine whether a specific patient’s pulmonary abnormalities are related to beryllium exposure. (3) LPT results may influence the decision about whether a worker may be placed in a job with potential beryllium exposure. (4) In the United States, many current and former Department of Energy (DOE) employees or contractor employees are eligible to receive compensation and medical surveillance testing benefits on the basis of LPT results under the auspices of the Department of Labor Energy Employees Occupational Illness Compensation Act. (5) LPT may serve as a form of biologic monitoring for hazard surveillance. Development of positive test results among new workers who have had no previous exposure suggests that exposure controls may be inadequate.6
From the Community, Environment, and Policy Division, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson. The Beryllium BioBank was developed with funding from the US Department of Energy. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.joem.org). The authors declare no conflicts of interest. Address correspondence to: Philip Harber, MD, MPH, University of Arizona, 1656 E. Mabel St, Room 112, Tucson, AZ 85724 ([email protected]). C 2014 by American College of Occupational and Environmental Copyright Medicine DOI: 10.1097/JOM.0000000000000199
Several characteristics of the LPT are desirable for these purposes. The test is minimally invasive, requiring only a sample of blood. Because the test measures immunologic reactivity, it is inherently biologically logical that it should play a role in the detection of CBD. Several laboratories in the United States perform this routinely using standardized methodology, and automated testing makes the cost reasonable. The test is performed by placing the patient’s cells into a series of tubes. Different concentrations of beryllium are added to several of the tubes (“stimulated”). Another tube has nothing added (“unstimulated”). An antigen such as tetanus toxoid or phytohemagglutinin to which most persons respond is added to another tube (“positive control”). The extent of cell proliferation is measured in each of the tubes by measuring the uptake of radiolabeled thymidine, which is incorporated in newly synthesized DNA. The stimulation index (SI) is the ratio of radioactive counts in the stimulated tube to counts in the unstimulated tube. This is generally measured at two different times (eg, at 5 and 7 days) for each of the tubes. Therefore, several individual SIs from the same blood specimen are calculated on the basis of the concentration of beryllium added and the day measured. During the formative years of testing, experts defined criteria to facilitate the classification of results as positive or negative. The experts chose criteria to limit the number of false-positive tests. To be considered positive, the highest SI from the blood sample must be greater than a criterion value chosen to limit false-positive results to less than 5%. Several recommendations for applying LPT results to clinical decision making have been widely used. To classify an individual is having beryllium sensitization (BeS), he/she should have at least two positive LPT results or one positive and one borderline from different dates. Several factors contribute to variability of LPTs. Studies have demonstrated differences among laboratories testing the same specimen.7 As with most biologic tests, results for a specific person may vary over time. The testing depends upon living cells shipped to one of the reference laboratories, and therefore transportation issues may affect the degree of cell viability. In addition, on some occasions the “positive control,” which is expected to show cell proliferation simulation, does not respond or the total number of radioactive counts in all cells is too low to calculate a stable value. Therefore, results may be considered borderline or indeterminate as well as positive or negative. The LPT evidence of immunologic sensitization is frequently the basis for concluding that pulmonary abnormalities may be related to beryllium. This article considers four issues: (1) Does the LPT help distinguish BeS from CBD? (2) Can the LPT predict who will develop CBD in the future and therefore guide the frequency of future examinations? (3) What is the potential utility of a single LPT result? (4) What interpretation criteria might be alternatives to the current approach?
METHODS This article reports the analyses of LPT data derived from the Beryllium BioBank, a program sponsored by the US DOE to develop a tissue and clinical data resource for future research. Recruitment processes and a description of eligibility criteria are described elsewhere.8 Persons classified as probable CBD and definite CBD were combined into a single class (CBD) for this analysis.
JOEM r Volume 56, Number 8, August 2014 Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
857
JOEM r Volume 56, Number 8, August 2014
Harber et al
Additional clarification of classification terminology is included in an online supplement (http://links.lww.com/JOM/A158). At the time of enrollment, each subject had a detailed standardized interview and agreed to inclusion of his/her deidentified clinical data and biologic specimens in the central repository. This date is considered the time of interview (TI). Nearly all subjects had clinical data available from visits before the TI. The date of the first available data for each subject is the first time (TF) date. Persons with BeS at TF were classified as either a progressor or a nonprogressor on the basis of their classification at TI (ie, progressors had changed from BeS to CBD between TF and TI). Please see more detailed description elsewhere. Subjects could be classified as having sensitization (BeS) at the time of the first LPT record included in the database because they may have had testing performed before results were incorporated in the available records. For blood beryllium LPT results, each record includes the highest and second-highest stimulation indices (SI1, SI2). Statistical analyses were conducted using the SI as a continuous (absolute) variable and dichotomous classification as positive/negative using a cut point of 3.0, representing the most frequently used interpretation method. Analyses were conducted separately using the highest SI (SI1), the second highest (SI2), and the sum of SI1 and SI2. The record for each test also included indication of whether cells in a tube with a positive control agent (eg, phytohemagglutinin, concanavalin A lectin, or tetanus toxoid) reacted. Analyses were performed for the LPT data for BeS and CBD groups at TI. (By the subject selection criteria of this study, beryllium-exposed subjects would not have any positive LPT results.) We examined results using three alternative definitions for selecting LPT results at TI: within 6 months of TI, within 12 months of TI, and most recent LPT. Overall results were concordant, and the tables are based on the 6-month definition. If an individual had multiple LPTs within the defined time, results were averaged across all tests to avoid potential biases that would be introduced if the highest values were selected. The deidentified data provided by the Beryllium BioBank were managed in a relational database (Access, Microsoft, Redland, WA), and statistical analyses were conducted using SAS (SAS Institute PC version 9.3, Cary, NC). Data were analyzed with t tests and the nonparametric Wilcoxon test for continuous variables and chi-square or Fisher exact for class variables.
RESULTS Exposure and personal characteristics of the subjects are described elsewhere.8 Analyses assessing whether the LPT is helpful in distinguishing BeS from CBD are summarized in Table 1. Using an LPT SI1 criterion value of 3.0, workers with CBD are significantly less likely to have a positive LPT than those who are classified as BeS (P = 0.04). The average SI was slightly lower among CBD subjects, although the difference was not statistically significant. Application of the traditional criterion value leads to a sensitivity of 43%, specificity of 44%, and predictive value positive of 39% for identifying CBD among persons who have been previously classified as having sensitization. Approximately 3% of the tests had either a negative or a missing positive control result. This was not explicitly considered in the analysis because of its infrequency and because the positive controls did not all use the same stimulant. Analyses of whether the LPT can help predict which BeS subjects will subsequently develop CBD are shown in Table 2. Progressors had significantly higher stimulation indices at TF (P ≤ 0.0001). This was observed for the highest stimulation index (SI1) as well as the second highest (SI2) and the SI1 + SI2 sum, making it less likely that a single aberrant value accounted for the results. In addition, the highly significant difference was noted using a nonparametric test 858
(Wilcoxon) as well as a t test, also reducing the likelihood that the differences are due to a small number of outliers. Interpretation of LPT results at TF by a traditional criterion (eg, SI: ≥3.0) did not differentiate those who subsequently progressed from those who did not. Nevertheless, use of a higher criterion value (6.0) yielded statistically significant differences: 32% of the “positive” subjects progressed, whereas only 19% of those who were “negative” progressed. Similar results were noted using SI2 and the sum (SI1 + SI2). The ability of the LPT interpretation at a traditional cut point to differentiate progressors from nonprogressors is limited. Although sensitivity is high (87%), specificity is poor (13%), and the predictive value of a positive test is only 26%. As an isolated test, however, the sensitivity a criterion value of 6.0 to predict progression was 68% (43 of the 63) and the specificity was 48%. The TF–TI interval was slightly longer for the progressors (8.8 years vs 5.5 years). There was no relationship between the first LPT stimulation index (SI1) and duration before follow-up (r2 = 0.0007), making it unlikely that differential follow-up according to LPT SI would account for the observed differences. The comparable latencies until TF also suggest that length of time until follow-up does not bias the conclusions.8
DISCUSSION Extensive experience has demonstrated the importance of beryllium LPT in clinical screening and diagnosis as well as for biologic monitoring of exposures.3,6,9–12 Soon after the LPT assay became generally available, expert groups provided criteria for considering a test positive and defining who has beryllium sensitization (BeS). Chronic beryllium disease develops in individuals who are sensitized to beryllium. Therefore, persons with sensitization often undergo additional testing, frequently involving bronchoscopy with biopsy, to determine whether they have CBD. Clinicians and screening program directors must therefore determine which sensitized individuals should undergo such intensive additional testing on the basis of the likelihood of having CBD. Three questions were addressed using the systematically collected data from Beryllium BioBank13 : (1) At a point in time, does the LPT help differentiate persons with CBD from those with sensitization but not disease (BeS)? (2) Does the LPT contribute to predicting which persons with BeS are likely to progress to CBD in the future? (3) Are these alternatives to the traditional interpretation approach? The analyses summarized in Table 1 show that on a crosssectional basis, the LPT does not contribute to identifying which sensitized individuals are likely to actually have CBD. Neither a dichotomous classification nor use of the results on a continuous variable seems helpful in selecting persons for more intensive testing. Indeed, using a fixed criterion value, persons classified as having CBD at the data accrual date (TI) were statistically less likely to have a positive LPT than those classified as BeS. (For this study, CBD could be diagnosed even if LPT was negative at the specific date since the diagnostic criteria of the study included considering prior tests.) The LPT does contribute to predicting which sensitized individuals will progress from BeS to CBD (see Table 2). This was demonstrated by comparing the first available LPTs for persons who subsequently progressed from BeS to CBD to those who did not progress. The average LPT SI of those who progressed was statistically significantly greater than the SI of those who remained in BeS. Using dichotomous classification, those who progressed were significantly more likely to have a positive LPT if the reference criterion value was 6.0. Nevertheless, the early LPT was not predictive when using a more traditional criterion value of 3.0. The sensitivity and specificity of the LPT as a predictor (68% and 48%, respectively) are not adequate to rely solely upon the LPT
C 2014 American College of Occupational and Environmental Medicine
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
JOEM r Volume 56, Number 8, August 2014
Beryllium BioBank: 2. Lymphocyte Proliferation Testing
TABLE 1. Lymphocyte Proliferation Test at TI in Beryllium-Exposed and CBD Cases* SI1 Status
n
BeS CBD P Values
192 157
SI1 + SI2
SI2
Mean (SD)
Range
Mean (SD)
Range
Mean (SD)
Range
8.3 (17.2) 7.6 (17.5)
0.5–177.1 0.6–139.1
5.2 (8.6) 4.7 (10.9)
0–70.9 0–78.5
13.5 (25.4) 12.2 (28.0)
0.9–248 1.2–212.8
0.73 BeS n (Row%) 52 (47) 67 (61)
Proportion Positive Negative (
Beryllium BioBank: 2. Lymphocyte Proliferation Testing Philip Harber, MD, MPH, Jing Su, MS, and Gabriela Alongi, BS
Objective: To incrementally improve the use of beryllium lymphocyte proliferation test (LPT) results. Methods: Beryllium BioBank data were analyzed for 532 subjects in three groups: beryllium-exposed, sensitized, or chronic beryllium disease. Predictor variables were LPT stimulation index (SI) at the date of the earliest available data and at the study entry date. Results: Cross-sectionally, LPT SI magnitude does not distinguish among the three groups. The likelihood of progression from sensitization to disease is associated with the absolute value of SI, but LPT SI interpreted by traditional cut point criteria was not predictive. Conclusions: Updating the criteria for interpreting beryllium LPT data should be considered. Prediction of progression to chronic beryllium disease may be improved by changing the cut point for interpretation or by using the SI as a continuous variable.
E
xposure to beryllium produces chronic beryllium disease (CBD), a serious disease that may lead to respiratory morbidity and even death. The disease develops sequentially—individuals who are beryllium-exposed may develop allergic sensitization and be considered beryllium-sensitized (BeS). Some of the latter may progress to develop the pulmonary disease known as CBD, a disorder characterized by granulomatous and lymphocytic inflammatory response of the lung.1 Published evidence indicates that treatment of early CBD with immunosuppressant medications (eg, prednisone) may reduce the likelihood of developing serious or fatal disease.1–5 Development of immunologic sensitization to beryllium is considered to be a necessary precursor to developing CBD. The beryllium lymphocyte proliferation test (LPT) measures the immunologic responsiveness of a person’s lymphocytes to beryllium. Lymphocyte proliferation test serves several purposes: (1) It is frequently incorporated in screening programs of exposed workers to identify patients with beryllium sensitization who may then be referred for more in-depth diagnostic testing including bronchoscopy and biopsy to determine whether they have CBD. (2) Clinicians may use LPT results to help determine whether a specific patient’s pulmonary abnormalities are related to beryllium exposure. (3) LPT results may influence the decision about whether a worker may be placed in a job with potential beryllium exposure. (4) In the United States, many current and former Department of Energy (DOE) employees or contractor employees are eligible to receive compensation and medical surveillance testing benefits on the basis of LPT results under the auspices of the Department of Labor Energy Employees Occupational Illness Compensation Act. (5) LPT may serve as a form of biologic monitoring for hazard surveillance. Development of positive test results among new workers who have had no previous exposure suggests that exposure controls may be inadequate.6
From the Community, Environment, and Policy Division, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson. The Beryllium BioBank was developed with funding from the US Department of Energy. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.joem.org). The authors declare no conflicts of interest. Address correspondence to: Philip Harber, MD, MPH, University of Arizona, 1656 E. Mabel St, Room 112, Tucson, AZ 85724 ([email protected]). C 2014 by American College of Occupational and Environmental Copyright Medicine DOI: 10.1097/JOM.0000000000000199
Several characteristics of the LPT are desirable for these purposes. The test is minimally invasive, requiring only a sample of blood. Because the test measures immunologic reactivity, it is inherently biologically logical that it should play a role in the detection of CBD. Several laboratories in the United States perform this routinely using standardized methodology, and automated testing makes the cost reasonable. The test is performed by placing the patient’s cells into a series of tubes. Different concentrations of beryllium are added to several of the tubes (“stimulated”). Another tube has nothing added (“unstimulated”). An antigen such as tetanus toxoid or phytohemagglutinin to which most persons respond is added to another tube (“positive control”). The extent of cell proliferation is measured in each of the tubes by measuring the uptake of radiolabeled thymidine, which is incorporated in newly synthesized DNA. The stimulation index (SI) is the ratio of radioactive counts in the stimulated tube to counts in the unstimulated tube. This is generally measured at two different times (eg, at 5 and 7 days) for each of the tubes. Therefore, several individual SIs from the same blood specimen are calculated on the basis of the concentration of beryllium added and the day measured. During the formative years of testing, experts defined criteria to facilitate the classification of results as positive or negative. The experts chose criteria to limit the number of false-positive tests. To be considered positive, the highest SI from the blood sample must be greater than a criterion value chosen to limit false-positive results to less than 5%. Several recommendations for applying LPT results to clinical decision making have been widely used. To classify an individual is having beryllium sensitization (BeS), he/she should have at least two positive LPT results or one positive and one borderline from different dates. Several factors contribute to variability of LPTs. Studies have demonstrated differences among laboratories testing the same specimen.7 As with most biologic tests, results for a specific person may vary over time. The testing depends upon living cells shipped to one of the reference laboratories, and therefore transportation issues may affect the degree of cell viability. In addition, on some occasions the “positive control,” which is expected to show cell proliferation simulation, does not respond or the total number of radioactive counts in all cells is too low to calculate a stable value. Therefore, results may be considered borderline or indeterminate as well as positive or negative. The LPT evidence of immunologic sensitization is frequently the basis for concluding that pulmonary abnormalities may be related to beryllium. This article considers four issues: (1) Does the LPT help distinguish BeS from CBD? (2) Can the LPT predict who will develop CBD in the future and therefore guide the frequency of future examinations? (3) What is the potential utility of a single LPT result? (4) What interpretation criteria might be alternatives to the current approach?
METHODS This article reports the analyses of LPT data derived from the Beryllium BioBank, a program sponsored by the US DOE to develop a tissue and clinical data resource for future research. Recruitment processes and a description of eligibility criteria are described elsewhere.8 Persons classified as probable CBD and definite CBD were combined into a single class (CBD) for this analysis.
JOEM r Volume 56, Number 8, August 2014 Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
857
JOEM r Volume 56, Number 8, August 2014
Harber et al
Additional clarification of classification terminology is included in an online supplement (http://links.lww.com/JOM/A158). At the time of enrollment, each subject had a detailed standardized interview and agreed to inclusion of his/her deidentified clinical data and biologic specimens in the central repository. This date is considered the time of interview (TI). Nearly all subjects had clinical data available from visits before the TI. The date of the first available data for each subject is the first time (TF) date. Persons with BeS at TF were classified as either a progressor or a nonprogressor on the basis of their classification at TI (ie, progressors had changed from BeS to CBD between TF and TI). Please see more detailed description elsewhere. Subjects could be classified as having sensitization (BeS) at the time of the first LPT record included in the database because they may have had testing performed before results were incorporated in the available records. For blood beryllium LPT results, each record includes the highest and second-highest stimulation indices (SI1, SI2). Statistical analyses were conducted using the SI as a continuous (absolute) variable and dichotomous classification as positive/negative using a cut point of 3.0, representing the most frequently used interpretation method. Analyses were conducted separately using the highest SI (SI1), the second highest (SI2), and the sum of SI1 and SI2. The record for each test also included indication of whether cells in a tube with a positive control agent (eg, phytohemagglutinin, concanavalin A lectin, or tetanus toxoid) reacted. Analyses were performed for the LPT data for BeS and CBD groups at TI. (By the subject selection criteria of this study, beryllium-exposed subjects would not have any positive LPT results.) We examined results using three alternative definitions for selecting LPT results at TI: within 6 months of TI, within 12 months of TI, and most recent LPT. Overall results were concordant, and the tables are based on the 6-month definition. If an individual had multiple LPTs within the defined time, results were averaged across all tests to avoid potential biases that would be introduced if the highest values were selected. The deidentified data provided by the Beryllium BioBank were managed in a relational database (Access, Microsoft, Redland, WA), and statistical analyses were conducted using SAS (SAS Institute PC version 9.3, Cary, NC). Data were analyzed with t tests and the nonparametric Wilcoxon test for continuous variables and chi-square or Fisher exact for class variables.
RESULTS Exposure and personal characteristics of the subjects are described elsewhere.8 Analyses assessing whether the LPT is helpful in distinguishing BeS from CBD are summarized in Table 1. Using an LPT SI1 criterion value of 3.0, workers with CBD are significantly less likely to have a positive LPT than those who are classified as BeS (P = 0.04). The average SI was slightly lower among CBD subjects, although the difference was not statistically significant. Application of the traditional criterion value leads to a sensitivity of 43%, specificity of 44%, and predictive value positive of 39% for identifying CBD among persons who have been previously classified as having sensitization. Approximately 3% of the tests had either a negative or a missing positive control result. This was not explicitly considered in the analysis because of its infrequency and because the positive controls did not all use the same stimulant. Analyses of whether the LPT can help predict which BeS subjects will subsequently develop CBD are shown in Table 2. Progressors had significantly higher stimulation indices at TF (P ≤ 0.0001). This was observed for the highest stimulation index (SI1) as well as the second highest (SI2) and the SI1 + SI2 sum, making it less likely that a single aberrant value accounted for the results. In addition, the highly significant difference was noted using a nonparametric test 858
(Wilcoxon) as well as a t test, also reducing the likelihood that the differences are due to a small number of outliers. Interpretation of LPT results at TF by a traditional criterion (eg, SI: ≥3.0) did not differentiate those who subsequently progressed from those who did not. Nevertheless, use of a higher criterion value (6.0) yielded statistically significant differences: 32% of the “positive” subjects progressed, whereas only 19% of those who were “negative” progressed. Similar results were noted using SI2 and the sum (SI1 + SI2). The ability of the LPT interpretation at a traditional cut point to differentiate progressors from nonprogressors is limited. Although sensitivity is high (87%), specificity is poor (13%), and the predictive value of a positive test is only 26%. As an isolated test, however, the sensitivity a criterion value of 6.0 to predict progression was 68% (43 of the 63) and the specificity was 48%. The TF–TI interval was slightly longer for the progressors (8.8 years vs 5.5 years). There was no relationship between the first LPT stimulation index (SI1) and duration before follow-up (r2 = 0.0007), making it unlikely that differential follow-up according to LPT SI would account for the observed differences. The comparable latencies until TF also suggest that length of time until follow-up does not bias the conclusions.8
DISCUSSION Extensive experience has demonstrated the importance of beryllium LPT in clinical screening and diagnosis as well as for biologic monitoring of exposures.3,6,9–12 Soon after the LPT assay became generally available, expert groups provided criteria for considering a test positive and defining who has beryllium sensitization (BeS). Chronic beryllium disease develops in individuals who are sensitized to beryllium. Therefore, persons with sensitization often undergo additional testing, frequently involving bronchoscopy with biopsy, to determine whether they have CBD. Clinicians and screening program directors must therefore determine which sensitized individuals should undergo such intensive additional testing on the basis of the likelihood of having CBD. Three questions were addressed using the systematically collected data from Beryllium BioBank13 : (1) At a point in time, does the LPT help differentiate persons with CBD from those with sensitization but not disease (BeS)? (2) Does the LPT contribute to predicting which persons with BeS are likely to progress to CBD in the future? (3) Are these alternatives to the traditional interpretation approach? The analyses summarized in Table 1 show that on a crosssectional basis, the LPT does not contribute to identifying which sensitized individuals are likely to actually have CBD. Neither a dichotomous classification nor use of the results on a continuous variable seems helpful in selecting persons for more intensive testing. Indeed, using a fixed criterion value, persons classified as having CBD at the data accrual date (TI) were statistically less likely to have a positive LPT than those classified as BeS. (For this study, CBD could be diagnosed even if LPT was negative at the specific date since the diagnostic criteria of the study included considering prior tests.) The LPT does contribute to predicting which sensitized individuals will progress from BeS to CBD (see Table 2). This was demonstrated by comparing the first available LPTs for persons who subsequently progressed from BeS to CBD to those who did not progress. The average LPT SI of those who progressed was statistically significantly greater than the SI of those who remained in BeS. Using dichotomous classification, those who progressed were significantly more likely to have a positive LPT if the reference criterion value was 6.0. Nevertheless, the early LPT was not predictive when using a more traditional criterion value of 3.0. The sensitivity and specificity of the LPT as a predictor (68% and 48%, respectively) are not adequate to rely solely upon the LPT
C 2014 American College of Occupational and Environmental Medicine
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
JOEM r Volume 56, Number 8, August 2014
Beryllium BioBank: 2. Lymphocyte Proliferation Testing
TABLE 1. Lymphocyte Proliferation Test at TI in Beryllium-Exposed and CBD Cases* SI1 Status
n
BeS CBD P Values
192 157
SI1 + SI2
SI2
Mean (SD)
Range
Mean (SD)
Range
Mean (SD)
Range
8.3 (17.2) 7.6 (17.5)
0.5–177.1 0.6–139.1
5.2 (8.6) 4.7 (10.9)
0–70.9 0–78.5
13.5 (25.4) 12.2 (28.0)
0.9–248 1.2–212.8
0.73 BeS n (Row%) 52 (47) 67 (61)
Proportion Positive Negative (
