1
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- Radiation Carcinogenesis: Applying Basic Science to Epidemiological
Estimates of Low-Dose Risks
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2
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- Bayesian methods and CML
- Linear-Quadratic-Exponential model
- Likelihood and prior data sets
- Baseline LQE estimate of CML risk
- Improved risk estimates based on BCR-to-ABL distances and CML target cell numbers
- Net lifetime CML risk: Can it have a
U-shaped low dose response?
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3
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- Priors+ likelihood estimates Þ
posteriors
- Posterior information equals
prior plus likelihood information
- Posterior means are information-weighted averages of prior and
likelihood means
- Posteriors are normal if
the prior and likelihood
estimates are normal
- Priors act as soft constraints on the parameters
- Priors and structures come from the same data
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4
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- CML is homogeneous, prevalent, radiation-induced, and caused by BCR-ABL
- The a2 intron of ABL is unusually large
- Leukemic endpoints have rapid kinetics
- White blood cells need fewer stages
- Linear CML risk is not
biologically-based
- Linear-quadratic-exponential CML
risk does have a biological basis
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5
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6
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7
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8
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- CML is practically absent in Nagasaki
- High dose HF waiting times are too long
- HM data is consistent with prior expectations
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9
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10
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- C1 and k: SEER data
- kt : Patients
irradiated for BGD
- bk, ak and akn : CAFC and MRA assays
- b/a and an/a: Lymphocyte dicentric yields
- C2 : Depends on a,
kt, N, and P(ba|T)
- N: SEER and translocation age structure data
- P(ba|T): BCR and ABL intron sizes, the genome size
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11
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12
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13
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14
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- Linear model
- Rg = 0.0075 Gy-1 and Qg = 0.0158 Gy-1
- LQE posterior model
- Rg = 0.0022 Gy-1 and Qg = 0.0042 Gy-1
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15
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- A comparison of age responses for CML and total translocations suggests
a CML target cell number of 2x108
- 1012 nucleated marrow cells per adult and one LTC-IC per 105
marrow cells suggests 107
CML target cells
- P(ba|T) = 2TablTbcr/G2 may
not hold
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16
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17
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18
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19
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20
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- Transplant doses of 10, 100, and 1000 CRU => CRU levels 1-20%
or 15-60% normal Blood
(1996) 88: 2852-2858
- Broad variation in human HSC levels
Stem Cells (1995) 13:
512-516
- Low levels of HSCs in BMT patients Blood (1998) 91: 1959-1965
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21
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22
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23
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24
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25
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- Bayesian methods provide a natural framework for biologically based risk estimation
- BCR-to-ABL distance data and
knowledge of CML target
cell numbers can be useful in a biologically based approach to CML
risk estimation
- Low dose hypersensitivity to killing might lead to a U-shaped low dose
response if there is a dead-band in the control of target cell numbers
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26
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- Rainer Sachs
- David Hoel
- NIH and DOE
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