Including additional controls from public databases improves the power of a genome-wide association study.

Though genome-wide association studies (GWAS) have identified numerous susceptibility loci for common diseases, their use is limited due to the expense of genotyping large cohorts of individuals. One potential solution is to use 'additional controls', or genotype data from control individuals deposited in public repositories. While this approach has been used by several groups, the genetically heterogeneous nature of the population of the United States makes this approach potentially problematic. We empirically investigated the utility of this approach in a US-based GWAS. In a small GWAS of pancreatic cancer in New York, we observed clear population structure differences relative to controls from the database of Genotypes and Phenotypes (dbGaP). When we conduct the GWAS using these additional controls, we find large inflation of the test statistic that is properly corrected by using eigenvectors from principal components analysis as covariates. To deal with errors introduced due to different sources, we propose simultaneously genotyping a small number of controls along with cases and then comparing this group to the additional controls. We show that removing SNPs that show differences between these control groups reduces false-positive findings. Thus, through an empirical approach, this report provides practical guidance for using additional controls from publicly available datasets.

Feasibility and yield of screening in relatives from familial pancreatic cancer families.

OBJECTIVES: Pancreatic adenocarcinoma is a lethal disease. Over 80% of patients are found to have metastatic disease at the time of diagnosis. Strategies to improve disease-specific outcome include identification and early detection of precursor lesions or early cancers in high-risk groups. In this study, we investigate whether screening at-risk relatives of familial pancreatic cancer (FPC) patients is safe and has significant yield. METHODS: We enrolled 309 asymptomatic at-risk relatives into our Familial Pancreatic Tumor Registry (FPTR) and offered them screening with magnetic resonance cholangiopancreaticogram (MRCP) followed by endoscopic ultrasound (EUS) with fine needle aspiration if indicated. Relatives with findings were referred for surgical evaluation. RESULTS: As of 1 August 2009, 109 relatives had completed at least one cycle of screening. Abnormal radiographic findings were present on initial screening in 18/109 patients (16.5%), 15 of whom underwent EUS. A significant abnormality was confirmed in 9 of 15 patients, 6 of whom ultimately had surgery for an overall diagnostic yield of 8.3% (9/109). Yield was greatest in relatives >65 years old (35%, 6/17) when compared with relatives 55-65 years (3%, 1/31) and relatives <55 years (3%, 2/61). CONCLUSIONS: Screening at-risk relatives from FPC families has a significant diagnostic yield, particularly in relatives >65 years of age, confirming prior studies. MRCP as initial screening modality is safe and effective.

Adherence to the dietary guidelines for Americans and endometrial cancer risk.

The Healthy Eating Index (HEI) was developed by the US Department of Agriculture with the goal of quantifying adherence to the Dietary Guidelines for Americans. The purpose of this study was to evaluate the impact of the HEI-2005 score and each of its components on endometrial cancer risk in a population-based case-control study in New Jersey. A total of 424 cases and 398 controls completed a Food Frequency Questionnaire, which was used to derive the HEI-2005 score. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression while adjusting for potential covariates, which included all major endometrial cancer risk factors. The adjusted OR for women in the highest quartile when compared to the lowest quartile was 0.83 (95% CI: 0.52-1.34). For the meat and beans component comprising meat, eggs, poultry, fish, and beans, the OR was 0.70 (95% CI: 0.45-1.11; p for trend: 0.07), with little evidence of an association with any of the individual foods. There was no indication of an association for any of the other components of the HEI or of effect modification by body mass index. This study suggested limited value for the HEI-2005 in predicting endometrial cancer risk.

Allergies, obesity, other risk factors and survival from pancreatic cancer.

Survival from pancreatic adenocarcinoma remains extremely poor, approximately 5% at 5 years. Risk factors include smoking, high body mass index (BMI), family history of pancreatic cancer, and long-standing diabetes; in contrast, allergies are associated with reduced risk. Little is known about associations between these factors and survival. We analyzed overall survival in relation to risk factors for 475 incident cases who took part in a hospital based case-control study. Analyses were conducted separately for those who did (160) and did not (315) undergo tumor resection. Kaplan-Meier methods were used to describe survival according to smoking, BMI, family history, diabetes, and presence of allergies. Cox proportional hazards models were used to adjust for covariates. There was no association with survival based on smoking, family history, or history of diabetes in either group. Among patients with resection, those with allergies showed nonstatistically significant longer survival, a median of 33.1 months (95% CI: 19.0-52.5) vs. 21.8 months (95% CI: 18.0-33.1), p = 0.25. The adjusted hazard ratio (HR) was 0.72 (95% CI: 0.43-1.23), p = 0.23. Among patients without resection, those with self-reported allergies survived significantly longer than those without allergies: 13.3 months (95% CI: 10.6-16.9) compared to 10.4 months (95% CI: 8.8-11.0), p = 0.04, with an adjusted HR of 0.68 (95% CI: 0.49-0.95), p = 0.02. Obesity was nonsignificantly associated with poorer survival, particularly in the resected group (HR = 1.62, 95% CI: 0.76-3.44). The mechanisms underlying the association between history of allergies and improved survival are unknown. These novel results need to be confirmed in other studies.

Phytoestrogen consumption and endometrial cancer risk: a population-based case-control study in New Jersey.

Phytoestrogens have been shown to exert anti-estrogenic and estrogenic effects in some tissues, including the breast. However, only a few studies have evaluated their role in endometrial cancer risk. We evaluated this association in a population-based case-control study in New Jersey. A total of 424 cases and 398 controls completed an interview, including a food frequency questionnaire with supplemental questions for phytoestrogen foods. Risk estimates were derived using an unconditional logistic regression, adjusting for major risk factors for endometrial cancer. There was some suggestion of a decreased risk with quercetin intake (OR: 0.65; 95% CI: 0.41-1.01 for the highest compared to the lowest quartile; p for trend: 0.02). We found a limited evidence of an association with any of the lignans evaluated, total lignans, coumestrol, individual isoflavones, total isoflavones, or total phytoestrogens. However, there was some suggestion of an inverse association with total isoflavone intake limited to lean women (BMI <25; OR for the highest tertile: 0.50; 95% CI: 0.25-0.98) and those with a waist-to-hip ratio

Risk of endometrial cancer in relation to medical conditions and medication use.

We studied the relation of medical conditions related to obesity and medications used for these conditions with endometrial cancer. We also investigated the association of other medical conditions and medications with risk. This U.S. population-based case-control study included 469 endometrial cancer cases and 467 controls. Information on putative risk factors for endometrial cancer was collected through personal interviews. We asked women about their medical history and medications used for six months or longer and the number of years each medication was taken. Risk was strongly associated with increasing obesity (P for trend < 0.001). Among the conditions related to obesity, and after adjustment for age, body mass index, and other risk factors and conditions, uterine fibroids were independently related to an increased cancer risk [adjusted odds ratio (OR), 1.8; 95% confidence interval (95% CI), 1.2-2.5]. Although hypertension was not significantly related to endometrial cancer after adjustment for age and body mass index, the use of thiazide diuretics was independently associated with increased risk (OR, 1.8; 95% CI, 1.1-3.0). Anemia was associated with decreased risk (OR, 0.6; 95% CI, 0.5-0.9). Use of nonsteroidal anti-inflammatory drugs was related to a decreased risk (OR, 0.7; 95% CI, 0.5-0.97). To our knowledge, the observation about thiazide diuretics is novel and requires confirmation in other studies and populations.

Variants in hormone biosynthesis genes and risk of endometrial cancer.

We investigated the risk associated with variants in three genes involved in estrogen biosynthesis, CYP11A1, CYP17A1, and CYP19A1, in the population-based case-control study of Estrogen, Diet, Genetics, and Endometrial Cancer. This study was conducted in New Jersey in 2001-2006 with 417 cases and 402 controls. For CYP11A1, there was no association between the number of [TTTTA]( n ) repeats (D15S520) and risk. For CYP17A1, risk was somewhat lower among women with the C/C genotype at T-34C (rs743572) (adjusted OR = 0.65, 95% CI 0.41-1.02). For CYP19A1, risk was lower among women homozygous for the 3-bp deletion (rs11575899) in exon 4 (adjusted OR = 0.44, 95% CI 0.26-0.76), while the number of [TTTA]( n ) repeats was not significantly related to risk: the adjusted OR for n = 7/7 repeats versus n > 7/>7 repeats was 0.81 (95% CI 0.54-1.23). In stratified analyses, results for CYP19A1 were stronger among women with higher (> or =27.4) body mass index: for the homozygous deletion, OR = 0.30 (95% CI 0.15-0.62); for the n = 7/7 genotype, OR = 0.49 (95% CI 0.26-0.93). The interaction between the n = 7/7 genotype and BMI was statistically significant (p = 0.01). The insertion/deletion variant in CYP19A1 appears to be related to risk of endometrial cancer; risk associated with variants in this gene may vary according to BMI.

Allergies, variants in IL-4 and IL-4R alpha genes, and risk of pancreatic cancer.

BACKGROUND: Several studies in epidemiology indicate that risk of pancreatic cancer is reduced in individuals with allergies. Although genes have been identified that are critical in allergic response, polymorphisms in these genes have not been studied in relation to risk of pancreatic cancer. We hypothesized that variants in these genes are related to risk. METHODS: We investigated the association of allergies and pancreatic cancer in a hospital-based case-control study with 405 cases and 212 controls. In a subgroup of 149 cases and 135 controls, we studied the association of variants in IL-4 (C-589T, G3017T) and IL-4R alpha (Gln576Arg) with allergies and with risk of pancreatic cancer. RESULTS: We found reduced risk of pancreatic cancer associated with allergies, with adjusted odds ratios of 0.58 (95% CI 0.40-0.84) for any allergies, 0.45 (95% CI 0.29-0.70) for hay fever, and 0.43 (95% CI 0.23-0.80) for animals. The minor allele at each locus studied was associated with reduced risk of allergies in controls, leading us to hypothesize that they would be associated with increased risk of pancreatic cancer. Overall, there was no association between the genotypes studied and risk of pancreatic cancer. In analyses within strata defined by presence or absence of allergies, there were differences in risk associated with genotype for IL-4 G3017T: there was slightly increased risk among those with allergies and reduced risk among those without allergies. CONCLUSIONS: The consistent association of allergies with risk of pancreatic cancer and these results suggest that associations between variants in genes related to allergic response and pancreatic cancer warrant further study.

Factors associated with tuberculosis treatment interruption in New York City.

SETTING: Large urban tuberculosis control program. OBJECTIVES: To determine the frequency and characteristics of treatment interruptions, and the factors associated with the different types of treatment interruptions. DESIGN: This was a case-control study using culture-positive tuberculosis (TB) patients verified in 1998-1999. Case patients included those in whom any of the following mutually exclusive categories of treatment interruption: default with return to therapy, directly observed therapy nonadherence, default without return to therapy, or multiple types of interruptions. Controls were selected randomly from the cohort. RESULTS: Overall, 6.0 percent of patients had treatment interruptions. All types of treatment interruption were associated with prolonged treatment course and decreased treatment completion rates. The median number of months to treatment interruption was 4.0 (range, 0.5-28.9 months). Two factors were significantly associated with every type of interruption: homelessness and lack of awareness of the severity of TB disease. In multivariate analysis, only lack of awareness of the severity of disease remained independently associated with all interruption types. CONCLUSION: Efforts to improve patients' understanding of TB disease and related treatment issues may be an important TB control program strategy and should be emphasized at the initiation of therapy and at intervals throughout the treatment course to minimize treatment interruption.

Fluid intake and the risk of tumor recurrence in patients with superficial bladder cancer.

PURPOSE: High fluid intake has been associated with a decreased risk of bladder cancer development in men. We evaluated whether higher fluid intake can impact tumor recurrence rates in patients with superficial bladder cancer. MATERIALS AND METHODS: We conducted a prospective single institution analysis of fluid intake in 267 consecutive patients with superficial bladder cancer undergoing routine bladder cancer surveillance between January 1998 and December 2001. Fluid intake questionnaires, urine cytology and physical examination were routinely performed at each surveillance cystoscopy. Cytological and histological recurrences were recorded. All patients had a minimum followup of 2 years. RESULTS: No relationship between fluid intake and tumor recurrence was demonstrated. Average daily fluid intake was 2,654 ml daily, which was well within the highest protective level (more than 2,531 ml) previously reported. However, multivariate analysis failed to show a protective effect against recurrence at any level of fluid intake. Increasing age correlated with decreased fluid intake (Pearson's correlation coefficient -0.19, p = 0.0015), but did not increase the risk of recurrence (p = 0.59). Single fluid intake data correlated with the average of additional fluid intakes (median 5 per patient) in the same patient (Pearson's correlation coefficient, 0.45, p < 0.0001). Of the study population 123 patients (46%) experienced 1 or more tumor recurrences (range 0 to 11) within a median followup of 2.6 years. CONCLUSIONS: Our prospective study of fluid intake in patients with superficial bladder cancer at risk for recurrence did not find any association between daily fluid intake levels and tumor recurrence.

Prevalence and antimicrobial patterns of Acinetobacter baumannii on hands and nares of hospital personnel and patients: the iceberg phenomenon again.

OBJECTIVE: To determine the prevalence and antimicrobial susceptibility patterns of Acinetobacter baumannii on the hands and nares of health care workers and patients from intensive care and rehabilitation units at two hospitals in northern Manhattan, New York. DESIGN: Prevalence survey of Acinetobacter on the hands and anterior nares of staff (n = 184) and patients (n = 98) in rehabilitation and intensive care units of two hospitals. RESULTS: Twenty subjects (7.1%) had positive test results for A baumannii (6 staff [3.3%] and 14 patients [14.3%]). Five patients had positive test results at both sites, four in the nares only, and 11 on hands only. Among patients, four significant predictors of A baumannii were days on unit (P = .003), location (hospital A or B) (P = .01), surgery (P = .04), and receiving an antifungal agent (P = .02; OR, 5.6; 95% CI, 1.25-24.52). Among staff, predictors were skin damage (P = .02) and employment in hospital B (P = .03). Nine of the 20 subjects (45%) had positive test results for multiresistant strains, one from a staff member and eight from patients. CONCLUSION: Patients whose conditions are not clinically symptomatic for A baumannii, as well as staff, are often colonized. Staff with damaged skin are more likely to be colonized. Control of this organism will only be possible when the principle of the iceberg phenomenon--all patients (and staff) treated with standard, Universal Precautions--is strictly followed. Further, the endemic prevalence of multiresistant strains may be higher than previously appreciated.