Deborah M. Winn

Replicating genotype-phenotype associations.

What constitutes replication of a genotype–phenotype association, and how best can it be achieved?

Snuff Dipping and Oral Cancer among Women in the Southern United States

A case-control study in North Carolina involving 255 women with oral and pharyngeal cancer and 502 controls revealed that the exceptionally high mortality from this cancer among white women in the South is primarily related to chronic use of snuff. The relative risk associated with snuff dipping among white nonsmokers was 4.2 (95 per cent confidence limits, 2.6 to 6.7), and among chronic users the risk approached 50-fold for cancers of the gum and buccal mucosa--tissues that come in direct contact with the tobacco powder. In the absence of snuff dipping, oral and pharyngeal cancer resulted mainly from the combined effects of cigarette smoking and alcohol consumption. The carcinogenic hazard of oral snuff is of special concern in view of the recent upswing in consumption of smokeless tobacco in the United States.

Interaction between tobacco and alcohol use and the risk of head and neck cancer: Pooled analysis in the international head and neck cancer Epidemiology consortium

Background: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. Methods: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter (ψ) and population attributable risks (PAR). Results: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk (ψ = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases <45 years, 73% for cases >60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). Conclusions: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases. (Cancer Epidemiol Biomarkers Prev 2009;18(2):541–50)

Coronal caries in the primary and permanent dentition of children and adolescents 1-17 years of age: United States, 1988-1991.

The Third National Health and Nutrition Examination Survey-Phase 1, conducted from 1988 to 1991 in the United States, included an assessment of dental caries in US children and adolescents and provided the opportunity for differences in dental caries status to be viewed by age, sex, race, and race-ethnicity. The measurement of dental caries in children and adolescents from 2 to 17 years of age included the number of decayed, missing, and filled permanent tooth surfaces and teeth, and the number of decayed and filled primary tooth surfaces and teeth. Additionally, a brief visual inspection for the presence or absence of early childhood caries in the maxillary incisors was conducted for children 12 to 23 months of age. The survey yielded weighted estimates for 1988–1991 for over 58 million US children and adolescents 1 to 17 years of age. For infants aged 12 to 23 months, 0.8% were scored positive for early childhood caries. Over 60% (62.1%) of the children aged 2 to 9 years were caries-free in their primary dentition. Over half (54.7%) of the children 5 to 17 years were caries-free in their permanent dentition. The occurrence of caries in the permanent dentition is clustered: A quarter of the children and adolescents ages 5 to 17 with at least one permanent tooth accounted for about 80% of the caries experienced in permanent teeth. Differences in caries experience were found among race and race-ethnicity subpopulations, and caries patterns for the primary and permanent dentition were dissimilar. Further analyses are needed to explore other potential determinants of caries in children.

Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium

BACKGROUND Sexual contact may be the means by which head and neck cancer patients are exposed to human papillomavirus (HPV). METHODS We undertook a pooled analysis of four population-based and four hospital-based case-control studies from the International Head and Neck Cancer Epidemiology (INHANCE) consortium, with participants from Argentina, Australia, Brazil, Canada, Cuba, India, Italy, Spain, Poland, Puerto Rico, Russia and the USA. The study included 5642 head and neck cancer cases and 6069 controls. We calculated odds ratios (ORs) of associations between cancer and specific sexual behaviours, including practice of oral sex, number of lifetime sexual partners and oral sex partners, age at sexual debut, a history of same-sex contact and a history of oral-anal contact. Findings were stratified by sex and disease subsite. RESULTS Cancer of the oropharynx was associated with having a history of six or more lifetime sexual partners [OR = 1.25, 95% confidence interval (CI) 1.01, 1.54] and four or more lifetime oral sex partners (OR = 2.25, 95% CI 1.42, 3.58). Cancer of the tonsil was associated with four or more lifetime oral sex partners (OR = 3.36, 95 % CI 1.32, 8.53), and, among men, with ever having oral sex (OR = 1.59, 95% CI 1.09, 2.33) and with an earlier age at sexual debut (OR = 2.36, 95% CI 1.37, 5.05). Cancer of the base of the tongue was associated with ever having oral sex among women (OR = 4.32, 95% CI 1.06, 17.6), having two sexual partners in comparison with only one (OR = 2.02, 95% CI 1.19, 3.46) and, among men, with a history of same-sex sexual contact (OR = 8.89, 95% CI 2.14, 36.8). CONCLUSIONS Sexual behaviours are associated with cancer risk at the head and neck cancer subsites that have previously been associated with HPV infection.

Coronal and root caries in the dentition of adults in the United States, 1988-1991.

Dental public health policy planning requires accurate and current information about the extent of caries in the United States population. These data are available from the caries examination from Phase 1 of the Third National Health and Nutrition Examination Survey, which found that 94% of adults in the United States show evidence of past or present coronal caries. Among the dentate, the mean number of decayed and filled coronal surfaces per person was 21.5. Dentate females had a lower number of untreated coronal tooth surfaces with caries (1.5), but a higher mean number of treated and untreated surfaces per person (22.7) than males, with scores of 2.1 and 20.2, respectively. Estimates for race-ethnicity groups were standardized by age and gender to control for population differences among them. Dentate non-Hispanic blacks (11.9) and Mexican-Americans (14.1) had half the number of decayed and filled coronal surfaces as non-Hispanic whites (24.3), but more untreated surfaces (non-Hispanic whites, 1.5; non-Hispanic blacks, 3.4; Mexican-Americans, 2.8). Mexican-Americans were most likely to be dentate, had the highest average number of teeth, and had 25% fewer decayed, missing, and filled coronal surfaces (37.6) than non-Hispanic blacks (49.2) and non-Hispanic whites (51.0). Root caries affected 22.5% of the dentate population. Blacks had the most treated and untreated root surfaces with caries (1.6), close to the value for Mexican-Americans (1.4). The score for non-Hispanic whites was 1.1. Untreated root caries is most common in dentate non-Hispanic blacks (1.5), followed by Mexican-Americans (1.2), with non-Hispanic whites (0.6) having the fewest untreated carious root surfaces. Race-ethnicity groups were disparate with respect to dental caries; effort is needed to treat active caries common in some population subgroups.

The reemergence of smokeless tobacco

Smokeless tobacco (snuff and chewing tobacco) is reemerging as a popular form of tobacco, particularly among male adolescents. In different regions of the United States, from 8 to 36 percent of male high-school students are regular users. The use of smokeless tobacco has been shown to cause oral-pharyngeal cancer. The strongest link is with cancers of the cheek and gum. White mucosal lesions (leukoplakia) are found in 18 to 64 percent of users, often at the site where the tobacco was held. Other associations have been suggested for cancers of the esophagus, larynx, and pancreas. Nitrosamines, found in high concentrations in smokeless tobacco, most likely have a role in its carcinogenicity. Other health problems include periodontal disease, acute elevations of blood pressure, and dependence. In early 1986, after action at the state level, Congress enacted a federal law requiring health-warning labels on packages of smokeless tobacco and a ban on electronic advertising. Other regulatory measures under consideration include raising state and federal excise taxes, tightening controls on advertising, and prohibiting sales to minors. In view of the recent growth of this problem, policy makers are taking the opportunity to intervene with preventive measures to protect a new generation of tobacco users.

TOBACCO AND ALCOHOL USE AND ORAL CANCER IN PUERTO RICO

Objectives: To determine risk for oral cancer in Puerto Rico associated with use of alcohol and tobacco.Methods: In Puerto Rico, alcohol and tobacco use were compared among nonsalivary gland cancers of the mouth and pharynx (n=342), cancers of major and minor salivary glands (n=25) and 521 population-based controls.Results: Alcohol (usual use, Ptrend<0.0001 for men and Ptrend=0.02 for women) and tobacco (usual use, Ptrend<0.0001, for both men and women) were strong independent risk factors for oral cancer in Puerto Rico, with a multiplicative effect from combined exposures. Risks did not vary systematically by use of filter vs. nonfilter cigarettes. Risks with use of other forms of smoked tobacco were about sevenfold among both men and women. Risks decreased only gradually after cessation of tobacco and alcohol use. Tobacco use, but not alcohol, was linked to cancers of the salivary glands. The burden of oral cancer due to alcohol and tobacco use in Puerto Rico (76% for men, 52% for women) agreed closely with earlier estimates for the mainland US population, while about 72% of salivary gland cancer (men and women, combined) was due to tobacco use.Conclusions: Excess risks for oral cancer in Puerto Rico are largely explained by patterns of alcohol and tobacco use. Smoking filter vs. nonfilter cigarettes does not alter risk, while cessation of alcohol and tobacco use appears to reduce risk only gradually.

Cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk

BACKGROUND Quitting tobacco or alcohol use has been reported to reduce the head and neck cancer risk in previous studies. However, it is unclear how many years must pass following cessation of these habits before the risk is reduced, and whether the risk ultimately declines to the level of never smokers or never drinkers. METHODS We pooled individual-level data from case-control studies in the International Head and Neck Cancer Epidemiology Consortium. Data were available from 13 studies on drinking cessation (9167 cases and 12 593 controls), and from 17 studies on smoking cessation (12 040 cases and 16 884 controls). We estimated the effect of quitting smoking and drinking on the risk of head and neck cancer and its subsites, by calculating odds ratios (ORs) using logistic regression models. RESULTS Quitting tobacco smoking for 1-4 years resulted in a head and neck cancer risk reduction [OR 0.70, confidence interval (CI) 0.61-0.81 compared with current smoking], with the risk reduction due to smoking cessation after > or =20 years (OR 0.23, CI 0.18-0.31), reaching the level of never smokers. For alcohol use, a beneficial effect on the risk of head and neck cancer was only observed after > or =20 years of quitting (OR 0.60, CI 0.40-0.89 compared with current drinking), reaching the level of never drinkers. CONCLUSIONS Our results support that cessation of tobacco smoking and cessation of alcohol drinking protect against the development of head and neck cancer.

Genome-Wide Association Studies, Field Synopses, and the Development of the Knowledge Base on Genetic Variation and Human Diseases

Genome-wide association studies (GWAS) have led to a rapid increase in available data on common genetic variants and phenotypes and numerous discoveries of new loci associated with susceptibility to common complex diseases. Integrating the evidence from GWAS and candidate gene studies depends on concerted efforts in data production, online publication, database development, and continuously updated data synthesis. Here the authors summarize current experience and challenges on these fronts, which were discussed at a 2008 multidisciplinary workshop sponsored by the Human Genome Epidemiology Network. Comprehensive field synopses that integrate many reported gene-disease associations have been systematically developed for several fields, including Alzheimers disease, schizophrenia, bladder cancer, coronary heart disease, preterm birth, and DNA repair genes in various cancers. The authors summarize insights from these field synopses and discuss remaining unresolved issues—especially in the light of evidence from GWAS, for which they summarize empirical P-value and effect-size data on 223 discovered associations for binary outcomes (142 with P < 10−7). They also present a vision of collaboration that builds reliable cumulative evidence for genetic associations with common complex diseases and a transparent, distributed, authoritative knowledge base on genetic variation and human health. As a next step in the evolution of Human Genome Epidemiology reviews, the authors invite investigators to submit field synopses for possible publication in the American Journal of Epidemiology.