A generalized Luria-Delbrück model.

We develop extensions of the Luria-Delbrück model that explicitly consider non-exponential growth of normal cells and a birth-death process with mean exponential or Gompertz growth of mutants. Death of mutant cells can be important in clones arising during cancer progression. The use of a birth-death process for growth of mutant cells, as opposed to a pure birth process as in previous work on the Luria-Delbrück model, leads to a large increase in the extra Poisson variation in the size of the mutant cell populations, which needs to be addressed in statistical analyses. We also discuss connections with previous work on carcinogenesis models.

[1]  E G Luebeck,et al.  Stochastic analysis of intermediate lesions in carcinogenesis experiments. , 1991, Risk analysis : an official publication of the Society for Risk Analysis.

[2]  W. Y. Tan A stochastic Gompertz birth-death process , 1986 .

[3]  E G Luebeck,et al.  Quantitative analysis of enzyme-altered foci in rat hepatocarcinogenesis experiments--I. Single agent regimen. , 1990, Carcinogenesis.

[4]  F. M. Stewart,et al.  Fluctuation analysis: the probability distribution of the number of mutants under different conditions. , 1990, Genetics.

[5]  David G. Hoel,et al.  Mathematical models for estimating mutation rates in cell populations , 1974 .

[6]  R. Fisher,et al.  The Relation Between the Number of Species and the Number of Individuals in a Random Sample of an Animal Population , 1943 .

[7]  Qi Zheng,et al.  Statistical and algorithmic methods for fluctuation analysis with SALVADOR as an implementation. , 2002, Mathematical biosciences.

[8]  S H Moolgavkar,et al.  Mutation and cancer: a model for human carcinogenesis. , 1981, Journal of the National Cancer Institute.

[9]  P. Armitage,et al.  The Statistical Theory of Bacterial Populations Subject to Mutation , 1952 .

[10]  E G Luebeck,et al.  Quantitative analysis of enzyme-altered liver foci in rats initiated with diethylnitrosamine and promoted with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin. , 1996, Toxicology and applied pharmacology.

[11]  S. Sarkar,et al.  On fluctuation analysis: a new, simple and efficient method for computing the expected number of mutants , 2004, Genetica.

[12]  Sahotra Sarkar,et al.  Analysis of the Luria–Delbrück distribution using discrete convolution powers , 1992, Journal of Applied Probability.

[13]  Norman T. J. Bailey The Elements of Stochastic Processes with Applications to the Natural Sciences , 1964 .

[14]  S. Moolgavkar,et al.  Two-event models for carcinogenesis: incidence curves for childhood and adult tumors☆ , 1979 .

[15]  E. Luebeck,et al.  Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on initiation and promotion of GST-P-positive foci in rat liver: A quantitative analysis of experimental data using a stochastic model. , 2000, Toxicology and applied pharmacology.

[16]  Emanuel Parzen,et al.  Stochastic Processes , 1962 .

[17]  L. Natarajan,et al.  Estimation of Spontaneous Mutation Rates , 2003, Biometrics.

[18]  S H Moolgavkar,et al.  A stochastic two-stage model for cancer risk assessment. II. The number and size of premalignant clones. , 1989, Risk analysis : an official publication of the Society for Risk Analysis.

[19]  Q Zheng,et al.  Progress of a half century in the study of the Luria-Delbrück distribution. , 1999, Mathematical biosciences.

[20]  T. Kepler,et al.  Improved inference of mutation rates: II. Generalization of the Luria-Delbrück distribution for realistic cell-cycle time distributions. , 2001, Theoretical population biology.

[21]  Mathisca C M de Gunst,et al.  Exploring heterogeneity in tumour data using Markov chain Monte Carlo. , 2003, Statistics in medicine.

[22]  T. Kepler,et al.  Improved inference of mutation rates: I. An integral representation for the Luria-Delbrück distribution. , 2001, Theoretical Population Biology.

[23]  W P Angerer,et al.  An explicit representation of the Luria–Delbrück distribution , 2001, Journal of mathematical biology.

[24]  M. Delbrück,et al.  Mutations of Bacteria from Virus Sensitivity to Virus Resistance. , 1943, Genetics.