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Biologically-Based Risk Estimation for Radiation-Induced Chronic Myeloid Leukemia

Biologically-Based Risk Estimation for Radiation-Induced Chronic Myeloid Leukemia. Radiation Carcinogenesis: Applying Basic Science to Epidemiological Estimates of Low-Dose Risks. Overview. Bayesian methods and CML Linear-Quadratic-Exponential model Likelihood and prior data sets

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Biologically-Based Risk Estimation for Radiation-Induced Chronic Myeloid Leukemia

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  1. Biologically-Based Risk Estimation for Radiation-Induced Chronic Myeloid Leukemia Radiation Carcinogenesis: Applying Basic Science to Epidemiological Estimates of Low-Dose Risks

  2. Overview • 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?

  3. Bayesian Methods • Priors+ likelihood estimates  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

  4. Chronic Myeloid Leukemia • 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

  5. Linear Risk Model Using the BCR-ABL to CML waiting time density and the linear model we maximized the log-likelihood

  6. Linear-Quadratic-Exponential Model The LQE model is where Di and Dni are the gamma and neutron doses in gray N is the number of CML target cells per adult P(ba|T)is the probability of BCR-ABL given a translocation This is a one-stage model of carcinogenesis.

  7. Likelihood Data • CML is practically absent in Nagasaki • High dose HF waiting times are too long • HM data is consistent with prior expectations

  8. aage at diagnosis bO = observed cases (E = expected background cases based on U.S. incidence rates) ctsx = average of the times since exposure for the cases

  9. Prior Data: Sources • C1 and k: SEER data • kt : Patients irradiated for BGD • k, k and kn : CAFC and MRA assays • / and n/: Lymphocyte dicentric yields • C2 : Depends on , kt, N, and P(ba|T) • N: SEER and translocation age structure data • P(ba|T): BCR and ABL intron sizes, the genome size

  10. Parameter Estimates

  11. CML Risk Estimates • Linear model • R = 0.0075 Gy-1 and Q = 0.0158 Gy-1 • LQE posterior model • R = 0.0022 Gy-1 and Q = 0.0042 Gy-1 The lifetime excess CML risk in the limit of low -ray doses yields

  12. CML Target Cell Numbers • 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/2 may not hold

  13. BCR-to-ABL 2D distances in lymphocytes Kozubek et al. (1999) Chromosoma 108: 426-435

  14. Theory of Dual Radiation Action • P(ba|D)= probability of a BCR-ABL translocation per G0/G1 cell given a dose D • tD(r)dr = expected energy at r given an ionization event at the origin • = intra-track component + inter-track component • Sba(r) = the BCR-to-ABL distance probability density • g(r) = probability that two DSBs misrejoin if they are created r units apart • Y = 0.0058 DSBs per Mb per Gy;  = mass density • TBCR = 5.8 kbp; TABL = 300 kbp

  15. Estimation of g(r) din [.01, .025], dx in [.04, .05], d in [.05, .06] G=35 DSB/Gy per cell 6.25 kev/um3 = 1 Gy R = 3.7 um r0 = 0.24 m, p0 = 0.06

  17. Dead-Band Control of HSC levels • 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

  18. Figure 3: Hypersensitivity ratios in the literature (left panel) and the log-survival dose response for T98G human glioma cells (right panel). Figures from Joiner, M.C., Marples, B., Lambin, P., Short, S.C. and Turesson, I., Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol Biol Phys (2001) 49: 379-389.

  19. Net Lifetime CML Risk The net lifetime excess risk of CML is Letting Dn = 0 while D 0 We solved R0 = 0 for ks as a function of exposure age x.

  20. Conclusions • 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

  21. Acknowledgments • Rainer Sachs • David Hoel • NIH and DOE

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