Analysis of gene-smoking interaction in lung cancer

Genet Epidemiol. 1997;14(2):199-214. doi: 10.1002/(SICI)1098-2272(1997)14:2<199::AID-GEPI8>3.0.CO;2-2.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age of Onset
  • Databases, Factual*
  • Female
  • Genes, Dominant
  • Genes, Recessive
  • Humans
  • Louisiana
  • Lung Neoplasms / etiology*
  • Lung Neoplasms / genetics
  • Male
  • Meiosis / genetics*
  • Pedigree
  • Probability
  • Proportional Hazards Models
  • Retrospective Studies
  • Risk Assessment
  • Smoking / adverse effects*