Analysis of gene-smoking interaction in lung cancer.
The Louisiana Lung Cancer Dataset, consisting of 337 extended pedigrees, is analyzed to determine whether a major Mendelian gene interacts with cumulative tobacco smoking (pack-years). The proportional hazards model is utilized, as it is a natural framework for estimating relative risks while adjusting for variability in age of disease onset. Segregation analyses show evidence that a Mendelian gene is segregating in these families, with the most parsimonious model, including sex, pack-years, pack-years squared, and a dominant major gene. The estimated frequency of the high-risk allele is 2% and carriers are estimated to have relative risk of 17.3 for developing lung cancer, compared to noncarriers. The addition of a gene x pack-years interaction does not significantly improve the fit of the model, indicating that on a multiplicative scale, these two factors independently influence lung cancer risk. Smoking history is missing for 23% of the study subjects and degree of "missingness" depends on disease status, age, and birth-year. To account for the nonrandomness of the missing data, a Markov chain Monte Carlo method for covariate imputation is proposed and implemented. Results from this analysis also support a nonsignificant gene-smoking interaction and an allele frequency of 2%, but a lower genetic relative risk (9.0) compared to the "complete case" analysis.
Gauderman
W J
WJ
Department of Preventive Medicine, University of Southern California, Los Angeles 90033, USA. jimg@ref.usc.edu
Morrison
J L
JL
Carpenter
C L
CL
Thomas
D C
DC
D017668:Age of Onset; D016208:Databases, Factual; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D006801:Humans; D008145:Louisiana; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics; D008297:Male; D008540:Meiosis / Q000235:genetics*; D010375:Pedigree; D011336:Probability; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012907:Smoking / Q000009:adverse effects*