Faculty Bibliography
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338
Estimation and selection of complex covariate effects in pooled nested case-control studies with heterogeneity
A major challenge in cancer epidemiologic studies, especially those of rare cancers, is observing enough cases. To address this, researchers often join forces by bringing multiple studies together to achieve large sample sizes, allowing for increased power in hypothesis testing, and improved efficiency in effect estimation. Combining studies, however, renders the analysis difficult owing to the presence of heterogeneity in the pooled data. In this article, motivated by a collaborative nested case-control (NCC) study of ovarian cancer in three cohorts from United States, Sweden, and Italy, we investigate the use of penalty regularized partial likelihood estimation in the context of pooled NCC studies to achieve two goals. First, we propose an adaptive group lasso (gLASSO) penalized approach to simultaneously identify important variables and estimate their effects. Second, we propose a composite agLASSO penalized approach to identify variables with heterogeneous effects. Both methods are readily implemented with the group coordinate gradient decent algorithm and shown to enjoy the oracle property. We conduct simulation studies to evaluate the performance of our proposed approaches in finite samples under various heterogeneity settings, and apply them to the pooled ovarian cancer study.
PMCID:3841381
PMID: 23632625
ISSN: 1465-4644
CID: 316572
Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 x 10(-14)), 18q21.33 (BCL2, P = 7.76 x 10(-11)), 11p15.5 (C11orf21, P = 2.15 x 10(-10)), 4q25 (LEF1, P = 4.24 x 10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 x 10(-9)), 9p21.3 (CDKN2B-AS1, P = 1.27 x 10(-8)), 18q21.32 (PMAIP1, P = 2.51 x 10(-8)), 15q15.1 (BMF, P = 2.71 x 10(-10)) and 2p22.2 (QPCT, P = 1.68 x 10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 x 10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 x 10(-8)) and 5p15.33 (TERT, P = 1.92 x 10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.
PMCID:3729927
PMID: 23770605
ISSN: 1061-4036
CID: 509052
Comparison of 3-point dixon imaging and fuzzy C-means clustering methods for breast density measurement
PURPOSE: To assess two methods of fat and fibroglandular tissue (FGT) segmentation for measuring breast MRI FGT volume and FGT%, the volume percentage of FGT in the breast, in longitudinal studies. MATERIALS AND METHODS: Nine premenopausal women provided one MRI per week for 4 weeks during a natural menstrual cycle for a total of 36 datasets. We compared a fuzzy c-means (FC) and a 3-point Dixon segmentation method for estimation of changes in FGT volume and FGT% across the menstrual cycle. We also assessed whether differences due to changes in positioning each week could be minimized by coregistration, i.e., the application of the breast boundary selected at one visit to images obtained at other visits. RESULTS: FC and Dixon FGT volume were highly correlated (r = 0.93, P < 0.001), as was FC and Dixon FGT% (r = 0.86, P = 0.01), although Dixon measurements were on average 10-20% higher. Although FGT measured by both methods showed the expected pattern of increase during the menstrual cycle, the magnitude, and for one woman the direction, of change varied according to the method used. Measurements of FGT for coregistered images were in close agreement with those for which the boundaries were determined independently. CONCLUSION: The method of segmentation of fat and FGT tissue may have an impact on the results of longitudinal studies of changes in breast MRI FGT. J. Magn. Reson. Imaging 2012;. (c) 2012 Wiley Periodicals, Inc.
PMID: 23292922
ISSN: 1053-1807
CID: 222812
Evaluation of the Kinetic Properties of Background Parenchymal Enhancement throughout the Phases of the Menstrual Cycle
Purpose:To develop and apply a semiautomatic method of segmenting fibroglandular tissue to quantify magnetic resonance (MR) imaging contrast material-enhancement kinetics of breast background parenchyma (BP) and lesions throughout the phases of the menstrual cycle in women with benign and malignant lesions.Materials and Methods:The institutional review board approved this retrospective HIPAA-compliant study, and informed consent was waived. From December 2008 to August 2011, 58 premenopausal women who had undergone contrast material-enhanced MR imaging and MR imaging-guided biopsy were identified. The longest time from the start of the last known period was 34 days. One lesion per patient (37 benign and 21 malignant) was analyzed. The patient groups were stratified according to the week of the menstrual cycle when MR imaging was performed. A method based on principal component analysis (PCA) was applied for quantitative analysis of signal enhancement in the BP and lesions by using the percentage of slope and percentage of enhancement. Linear regression and the Mann-Whitney U test were used to assess the association between the kinetic parameters and the week of the menstrual cycle.Results:In the women with benign lesions, percentages of slope and enhancement for both BP and lesions during week 2 were significantly (P < .05) lower than those in week 4. Percentage of enhancement in the lesion in week 2 was lower than that in week 3 (P < .05). The MR images of women with malignant lesions showed no significant difference between the weeks for any of the parameters. There was a strong positive correlation between lesion and BP percentage of slope (r = 0.72) and between lesion and BP percentage of enhancement (r = 0.67) in the benign group. There was also a significant (P = .03) difference in lesion percentage of slope between the benign and malignant groups at week 2.Conclusion:The PCA-based method can quantify contrast enhancement kinetics of BP semiautomatically, and kinetics of BP and lesions vary according to the week of the menstrual cycle in benign but not in malignant lesions.(c) RSNA, 2013.
PMCID:3721056
PMID: 23657893
ISSN: 0033-8419
CID: 394542
Effect of soy protein isolate supplementation on biochemical recurrence of prostate cancer after radical prostatectomy: a randomized trial
IMPORTANCE: Soy consumption has been suggested to reduce risk or recurrence of prostate cancer, but this has not been tested in a randomized trial with prostate cancer as the end point. OBJECTIVE: To determine whether daily consumption of a soy protein isolate supplement for 2 years reduces the rate of biochemical recurrence of prostate cancer after radical prostatectomy or delays such recurrence. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind trial conducted from July 1997 to May 2010 at 7 US centers comparing daily consumption of a soy protein supplement vs placebo in 177 men at high risk of recurrence after radical prostatectomy for prostate cancer. Supplement intervention was started within 4 months after surgery and continued for up to 2 years, with prostate-specific antigen (PSA) measurements made at 2-month intervals in the first year and every 3 months thereafter. INTERVENTION: Participants were randomized to receive a daily serving of a beverage powder containing 20 g of protein in the form of either soy protein isolate (n=87) or, as placebo, calcium caseinate (n=90). MAIN OUTCOMES AND MEASURES: Biochemical recurrence rate of prostate cancer (defined as development of a PSA level of >/=0.07 ng/mL) over the first 2 years following randomization and time to recurrence. RESULTS: The trial was stopped early for lack of treatment effects at a planned interim analysis with 81 evaluable participants in the intervention group and 78 in the placebo group. Overall, 28.3% of participants developed biochemical recurrence within 2 years of entering the trial (close to the a priori predicted recurrence rate of 30%). Among these, 22 (27.2%) occurred in the intervention group and 23 (29.5%) in the placebo group. The resulting hazard ratio for active treatment was 0.96 (95% CI, 0.53-1.72; log-rank P = .89). Adherence was greater than 90% and there were no apparent adverse events related to supplementation. CONCLUSION AND RELEVANCE: Daily consumption of a beverage powder supplement containing soy protein isolate for 2 years following radical prostatectomy did not reduce biochemical recurrence of prostate cancer in men at high risk of PSA failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00765479.
PMCID:3921119
PMID: 23839751
ISSN: 0098-7484
CID: 472042
Circulating prolactin levels and risk of epithelial ovarian cancer
PURPOSE: Indirect evidence from experimental and epidemiological studies suggests that prolactin may be involved in ovarian cancer development. However, the relationship between circulating prolactin levels and risk of ovarian cancer is unknown. METHODS: We conducted a nested case-control study of 230 cases and 432 individually matched controls within three prospective cohorts to evaluate whether pre-diagnostic circulating prolactin is associated with subsequent risk of ovarian cancer. We also assessed whether lifestyle and reproductive factors are associated with circulating prolactin among controls. RESULTS: Prolactin levels were significantly lower among post- versus pre-menopausal women, parous versus nulliparous women, and past versus never users of oral contraceptives in our cross-sectional analysis of controls. In our nested case-control study, we observed a non-significant positive association between circulating prolactin and ovarian cancer risk (OR(Q4vsQ1) 1.56, 95 % CI 0.94, 2.63, p trend 0.15). Our findings were similar in multivariate-adjusted models and in the subgroup of women who donated blood >/=5 years prior to diagnosis. We observed a significant positive association between prolactin and risk for the subgroup of women with BMI >/=25 kg/m(2) (OR(Q4vsQ1) 3.10, 95 % CI 1.39, 6.90), but not for women with BMI <25 kg/m(2) (OR(Q4vsQ1) 0.81, 95 % CI 0.40, 1.64). CONCLUSIONS: Our findings suggest that prolactin may be associated with increased risk of ovarian cancer, particularly in overweight/obese women. Factors associated with reduced risk of ovarian cancer, such as parity and use of oral contraceptives, were associated with lower prolactin levels, which suggests that modulation of prolactin may be a mechanism underlying their association with risk.
PMCID:3602319
PMID: 23378139
ISSN: 0957-5243
CID: 222782
Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4
PURPOSE: The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed. METHODS: Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (<0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition. RESULTS: When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95 %CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95 %CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95 %CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers. CONCLUSIONS: This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.
PMCID:4127987
PMID: 23334854
ISSN: 0957-5243
CID: 222802
Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case-control study
INTRODUCTION: Experimental evidence suggests a protective role for circulating 25-hydroxyvitamin D (25(OH)D) in breast cancer development, but the results of epidemiological studies have been inconsistent. METHODS: We conducted a case-control study nested within two prospective cohorts, the New York University Women's Health Study and the Northern Sweden Mammary Screening Cohort. Blood samples were collected at enrollment, and women were followed up for breast cancer ascertainment. In total, 1,585 incident breast cancer cases were individually-matched to 2,940 controls. Of these subjects, 678 cases and 1,208 controls contributed two repeat blood samples, at least one year apart. Circulating levels of 25(OH)D were measured, and multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS: No association was observed between circulating levels of 25(OH)D and overall breast cancer risk (multivariate-adjusted model OR = 0.94, 95% CI = 0.76-1.16 for the highest vs. lowest quintile, ptrend = 0.30). The temporal reliability of 25(OH)D measured in repeat blood samples was high (intraclass correlation coefficients for season-adjusted 25(OH)D > 0.70). An inverse association between 25(OH)D levels and breast cancer risk was observed among women who were
PMCID:3672761
PMID: 23442740
ISSN: 1465-5411
CID: 316582
Fruit and vegetable intake and risk of breast cancer by hormone receptor status
Background Estrogen receptor-negative (ER(-)) breast cancer has few known or modifiable risk factors. Because ER(-) tumors account for only 15% to 20% of breast cancers, large pooled analyses are necessary to evaluate precisely the suspected inverse association between fruit and vegetable intake and risk of ER(-) breast cancer. Methods Among 993 466 women followed for 11 to 20 years in 20 cohort studies, we documented 19 869 estrogen receptor positive (ER(+)) and 4821 ER(-) breast cancers. We calculated study-specific multivariable relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression analyses and then combined them using a random-effects model. All statistical tests were two-sided. Results Total fruit and vegetable intake was statistically significantly inversely associated with risk of ER(-) breast cancer but not with risk of breast cancer overall or of ER(+) tumors. The inverse association for ER(-) tumors was observed primarily for vegetable consumption. The pooled relative risks comparing the highest vs lowest quintile of total vegetable consumption were 0.82 (95% CI = 0.74 to 0.90) for ER(-) breast cancer and 1.04 (95% CI = 0.97 to 1.11) for ER(+) breast cancer (P (common-effects) by ER status < .001). Total fruit consumption was non-statistically significantly associated with risk of ER(-) breast cancer (pooled multivariable RR comparing the highest vs lowest quintile = 0.94, 95% CI = 0.85 to 1.04). Conclusions We observed no association between total fruit and vegetable intake and risk of overall breast cancer. However, vegetable consumption was inversely associated with risk of ER(-) breast cancer in our large pooled analyses.
PMCID:3593764
PMID: 23349252
ISSN: 0027-8874
CID: 222792
Serum taurine and risk of coronary heart disease: a prospective, nested case-control study
PURPOSE: Taurine (2-aminoethanesulfonic acid), a molecule obtained from diet, is involved in bile acid conjugation, blood pressure regulation, anti-oxidation and anti-inflammation. We performed the first prospective study of taurine and CHD risk. METHODS: We conducted a case-control study nested in the New York University Women's Health Study to evaluate the association between circulating taurine levels and risk of coronary heart disease (CHD). Taurine was measured in two yearly pre-diagnostic serum samples of 223 CHD cases and 223 matched controls and averaged for a more reliable measurement of long-term taurine levels. RESULTS: Mean serum taurine was positively related to age and dietary intake of poultry, niacin, vitamin B1, fiber and iron, and negatively related to dietary intake of saturated fat (all p values 250 mg/dL) (adjusted OR = 0.39 (0.19-0.83) for the third versus first tertile; p for trend = 0.02) but not among those with low total serum cholesterol (p for interaction = 0.01). The data suggest a possible inverse association of serum taurine with diabetes and hypertension risk. CONCLUSIONS: The findings suggest that high levels of taurine may be protective against CHD among individuals with high serum cholesterol levels.
PMCID:3920833
PMID: 22322924
ISSN: 1436-6207
CID: 162479
