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Modeling and Estimation of Benchmark Dose ( BMD ) for Binary Response Data

Modeling and Estimation of Benchmark Dose ( BMD ) for Binary Response Data. Wei Xiong. Outline. Benchmark dose ( BMD ) and datasets Statistical models logistic probit multi –s tage gamma multi –h it Model fitting and analyses Conclusions. In environment risk assessment,

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Modeling and Estimation of Benchmark Dose ( BMD ) for Binary Response Data

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  1. Modeling and Estimation of Benchmark Dose (BMD)for Binary Response Data • Wei Xiong

  2. Outline • Benchmark dose (BMD) and datasets • Statistical models • logistic • probit • multi–stage • gamma multi–hit • Model fitting and analyses • Conclusions

  3. In environment risk assessment, NOAEL (no-observed-adverse-effect level) is used to derive a safe dose, where, ADI: acceptable daily intake SF: safety factor

  4. Problem: (Filipsson et al., 2003)

  5. Benchmark dose (BMD) • BMD: Point estimate of the dose which induces a given response (e.g. 10%) above unexposed controls • BMDL: 1–sided 95% confidence lower limit for BMD

  6. Benchmark dose (BMD) • Fit a model to all data • Estimate the BMD • from a given BMR (10%) • Derive “safe dose” • from BMD Advantage: BMD uses all the data information by fitting a model (Filipsson et al., 2003)

  7. Non–cancer dataRyan and Van (1981) 30 mice in each dose group drug: botulinum toxin in 10–15 gram response: death (Y or N) within 24 hrs

  8. Plot of non-cancer Data

  9. Cancer dataBryan and Shimkin (1943) 17 to 21 mice in each dose group drug: carcinogenic methylcholanthrene in 10–6 gram response: tumor (Y or N)

  10. Plot of cancer data

  11. How to estimate BMD ? • What models to be used • ? Need to use different models for the cancer and non-cancer data • How to fit the model curve

  12. Statistical models • Logistic • Probit • Multi–stage • Gamma multi–hit Model form: where, 1> >=0 is the background response as dose0 F is the cumulative dist’n function

  13. Probit model Assuming: log(d) is approx. normally distributed

  14. Logistic model Assuming: log(d) has a logistic distribution

  15. Multi–stage model(Crump, 1981) • Assuming: • Ordered stages of mutation, initiation or transformation • for a cell to become a tumor • Probability of tumor occurrence at jth stage is proportional to dose by jd j

  16. Gamma multi–hit model(Rai and Van, 1981) Assuming:a tumor incidence is induced by at least   1 hits of units of dose and  follows a Poisson distribution The gamma model is derived from the Poisson dist’n of 

  17. Model fitting • Models are fit by maximum likelihood method • Model fitting tested by Pearson’s 2 statistic • If p-value  10%, the model fits the data well and the mle of BMD is obtained from the fitted model where, is estimated from the fitted model

  18. BMDL by LRT(Crump and Howe, 1985) where,  and  are model parameters  P is the log(BMD) at response = p

  19. The BMDL is the value P, which is lower than the mle , so that,

  20. BMDL by Fieller’s Theorem (Morgan, 1992) Fieller’s Theom constructs CI for the ratio of R.V. For logistic model, the BMDL is derived as, where,

  21. BMDL computation • BMDS (benchmark dose software, US EPA) provides the 4 models for BMDL using LRT • S–Plus calculates BMDL using LRT and Fieller’s Theorem

  22. BMDS logistic modeling for non–cancer data(Pearson’s 2, p = 0.325 > 0.1)

  23. BMDS multi–stage modeling for non–cancer data(Pearson’s 2, p = 0.0000)

  24. BMDS two–stage modeling for cancer data (Pearson’s 2, p = 0.556)

  25. BMDL=1.536 by LRT(Probit model for cancer data)

  26. MLE of BMD (non–cancer data) ( p–value by Pearson’s 2 ) (0.325) (0.386)

  27. Summary of BMDL(non–cancer data)

  28. MLE of BMD (cancer data) # 0.585 # 0.666 # 0.556 # 0.602 # p–value by Pearson’s 2

  29. Summary of BMDL(cancer data)

  30. Conclusions • Non–cancer data, BMD = 30.042 (logistic) and 30.039 (probit) in 10–15 gram; cancer data, BMD = 7.168 (logistic), 7.203 (probit), 4.867 (multi–stage) and 6.334 (multi–hit). • Logistic and probit model fit both data sets well, multi–stage and multi–hit fit only the cancer data well. • BMDL obtained by Fieller’s Theorem seems to be smaller than that by LRT, why ?

  31. Questions ?

  32. A note on qchisq( ) of 1–sided 95% • > (qnorm(1 - 0.05))^2 • [1] 2.705543 • > qchisq(1 - 2 * 0.05, 1) • [1] 2.705543

  33. 95% CI for proportion in slides 21 & 22 • When n is large, nP 5 and n(1-P) 5, the sample proportion p is used to infer underlying proportion P. • p is approximately normal with mean P and s.e.=sqrt(P(1-P)/n) • Solving the following equation,

  34. Fitted and re–parameterized model Fitted logistic model Re-parameterized logistic model where,

  35. Abbott’s Formula where, P –observed response c – response at dose zero BMR – benchmark response with default value 10%

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