Appendix B
Air Force Beryllium Program Clinical Decision Logic

This appendix presents the recommended algorithm for using the beryllium lymphocyte proliferation test (BeLPT) in an Air Force beryllium medical-surveillance program, and the rationale for using it (see Figure B-1).

BeLPT Result Definitions

Normal:

All BeLPT test values (stimulation index [SI] or least absolute value [LAV]) within reference range

Abnormal:

Two BeLPT test values (SI or LAV) increased over reference range in a single test

Borderline:

One increased value (SI or LAV) over reference range with at least one control in normal range

Uninterpretable:

Phytohemagglutinin <50 and tetanus toxid <3 with no increase in Sis over reference range

Confirmed abnormal:

Two abnormal BeLPT values or one abnormal and one borderline, either in split sample or in two different samples separated in time

Decision Logic for BeLPT Testing

First Test:

Single BeLPT

Second Test:

Use a split sample with two laboratories



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Appendix B Air Force Beryllium Program Clinical Decision Logic This appendix presents the recommended algorithm for using the beryl- lium lymphocyte proliferation test (BeLPT) in an Air Force beryllium medical- surveillance program, and the rationale for using it (see Figure B-1). BeLPT Result Definitions Normal: All BeLPT test values (stimulation index [SI] or least absolute value [LAV]) within reference range Abnormal: Two BeLPT test values (SI or LAV) increased over reference range in a single test Borderline: One increased value (SI or LAV) over reference range with at least one control in normal range Uninterpretable: Phytohemagglutinin <50 and tetanus toxid <3 with no increase in Sis over reference range Confirmed abnormal: Two abnormal BeLPT values or one abnormal and one borderline, either in split sample or in two different samples separated in time Decision Logic for BeLPT Testing First Test: Single BeLPT Second Test: Use a split sample with two laboratories 165

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166 Managing Health Effects of Beryllium Exposure ROUND 1 (1 BeLPT) AB? BL? NO NO YES YES ROUND 2 ROUND 2 (2 BeLPTs) (2 BeLPTs) ≥1 AB ? or NOT ≥1 AB ? NO CONFIRMED2 ≥1 BL ? YES YES CONFIRMED1 NO FIGURE B-1 BeLPT algorithm. 1 Met confirmation criteria of 2AB or 1AB and 1 BL. 2 Did not meet confirmation criteria. Abbreviations: AB, abnormal; BL, borderline. Source: Middleton et al. 2006. Reprinted with permission; copyright 2006, American Journal of Industrial Medicine. (1) BeLPT Test 1: Normal: NO FURTHER ACTIONS; retest periodically per protocol Abnormal: RETEST split sample in two laboratories Borderline: RETEST split sample in two laboratories Uninterpretable: RETEST split sample in two laboratories

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167 Appendix B (2) BeLPT Test 1, plus Tests 2 and 3 (any combination of the three): Two of three tests abnormal: Clinical evaluation One abnormal plus one borderline: Clinical evaluation One abnormal, other tests normal or Repeat in 1 year uninterpretable: No abnormal tests (combinations of Report as normal, retest per protocol normal, borderline): Uninterpretable, uninterpretable, Consult with medical director uninterpretable: (3) Retest periodically per protocol; send sample to single laboratory: Any confirmed abnormal: Clinical evaluation Any single abnormal plus a single Clinical evaluation borderline: One abnormal or borderline among Periodically retest per protocol all 4 tests: Rationale for Algorithm Middleton et al. (2006, 2008) reviewed available information on the per- formance of the BeLPT and calculated the sensitivity and specificity of two test- ing algorithms (2006). In the “basic” algorithm (outlined in Figure B-1), blood is initially sent to one laboratory, and nonnormal tests are re-evaluated with a split sample sent to two laboratories. The sensitivity of this algorithm is 65.7% (that is, the program would capture 65.7% of true-positive results). The “enhanced” algorithm uses a split sample sent to two laboratories for the initial test; this ap- proach increases the sensitivity to 86%. As discussed in Chapter 3, the prevalence of beryllium sensitization (BeS) in the population being screened affects the predictive value of the test. As the background prevalence of any condition decreases, the likelihood that a positive result is a “true” positive decreases, and the likelihood of a false positive in- creases. Middleton et al. (2008) used the data from Stange et al. (2004) to esti- mate the positive predictive value (PPV) of a single or confirmed abnormal BeLPT result for sensitization. They calculated that a confirmed abnormal BeLPT result would have a PPV of 0.968 in a population with a 1% prevalence of BeS, and a single abnormal test result would have a PPV of 0.383 in the same population. Middleton et al. estimate a PPV of 0.872 for a single abnormal BeLPT result when the prevalence of BeS is 10%, but in settings with a lower prevalence of BeS a single unconfirmed abnormal has less value because of a low PPV for sensitization.

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168 Managing Health Effects of Beryllium Exposure The committee does not know the prevalence of BeS in the populations of concern for the Air Force. Initial rounds of screening will determine whether the decision to use the basic algorithm is appropriate. If the prevalence of BeS in the population is higher than 5%, the committee recommends that the Air Force use the enhanced algorithm because of its increased sensitivity. The committee recommends that the Air Force explore the feasibility of establishing a harmonization protocol between two laboratories (see Chapter 3). If the harmonization program is successful and the split tests converge to a high level of agreement with each other, the Air Force should consider the use of a single sample for the second confirmatory test rather than a split sample. Most medical-surveillance programs for beryllium use all available tests to determine whether a person has a confirmed abnormal test result. For example, if a person has a single abnormal test result among three samples in the initial round of screening and then has a single abnormal sample when tested in any later year, the person would be considered to have a confirmed abnormal. This approach is more sensitive than one that would require confirmation of a single abnormal result in the same round of testing. The committee does not have enough information on the performance of the BeLPT to recommend how to interpret BeLPT results over the timeframe of several years. The committee therefore recommends that the Air Force use the approach that is generally ac- cepted and use all available tests to determine whether a person has a confirmed abnormal test result. If the Air Force is able to achieve harmonization between two laboratories, the variation in a single person’s test results is likely to decrease.