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1.  Metabolomics in Epidemiology: Sources of Variability in Metabolite Measurements and Implications 
Metabolite levels within an individual vary over time. This within-individual variability, coupled with technical variability, reduces the power for epidemiological studies to detect associations with disease. Here, the authors assess the variability of a large subset of metabolites and evaluate the implications for epidemiologic studies.
Using LC-MS and GC-MS platforms, 385 metabolites were measured in 60 women at baseline and year-1 of the Shanghai Physical Activity Study, and observed patterns were confirmed in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening study.
Although the authors found high technical reliability (median intra-class correlation = 0.8), reliability over time within an individual was low. Taken together, variability in the assay and variability within the individual accounted for the majority of variability for 64% of metabolites. Given this, a metabolite would need, on average, a Relative Risk of 3 (comparing upper and lower quartiles of “usual” levels) or 2 (comparing quartiles of observed levels) to be detected in 38%, 74% and 97% of studies including 500, 1000, and 5000 individuals. Age, gender, and fasting status, factors which are often of less interest in epidemiological studies were associated with 30%, 67%, and 34% of metabolites, respectively, but the associations were weak, and explained only a small proportion of the total metabolite variability.
Metabolomics will require large, but feasible, sample sizes to detect the moderate effect sizes typical for epidemiological studies.
We offer guidelines for determining the sample sizes needed to conduct metabolomic studies in epidemiology.
PMCID: PMC3617076  PMID: 23396963
metabolomics; power; variance components; measurement error
2.  Androgen Receptor CAG Repeat Length and Association with Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial 
The Journal of urology  2010;184(6):2297-2302.
We investigated the association between the length of the polymorphic trinucleotide CAG microsatellite repeats in exon 1 of the androgen receptor (AR) gene and the risk of prostate cancer.
This is a nested case-control study of 1159 cases and 1353 controls drawn from the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial testing whether finasteride, a 5α-reductase inhibitor, could reduce the 7-year period prevalence of prostate cancer. During the course of the PCPT, men underwent annual DRE and PSA measures and a prostate biopsy was recommended for all men with an abnormal DRE or a finasteride-adjusted PSA of > 4.0 ng/mL. Cases were drawn from men with biopsy-determined prostate cancer identified either by a for-cause or end-of-study biopsy and controls were selected from men who completed the end-of-study biopsy procedure.
CAG repeat mean lengths were not different between cases and controls. The frequency distribution for cases and controls for the AR CAG repeat length is similar. There were no significant associations of CAG repeat length with prostate cancer risk, either when stratified by treatment arm (finasteride or placebo) or when combined together. There was also no significant association between CAG repeat length and the risk of low- or high-grade prostate cancer.
There were no associations of the AR CAG repeat length and prostate cancer risk. Knowledge of AR CAG repeat length provides no clinical useful information for predicting prostate cancer risk.
PMCID: PMC3930175  PMID: 20952028
androgen receptor; CAG repeat length; prostate cancer
The role of the insulin-like growth factor (IGF) axis and whether IGFs interact with androgen-suppressing agents in relation to prostate carcinogenesis is unclear. This nested case-control study (n=1652 cases/1543 controls) examined whether serum IGF1, IGF2, IGFBP2, IGFBP3 and the IGF1:IGFBP3 ratio were associated with prostate cancer in the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Baseline serum was assayed for IGF-axis analytes using ELISA. Logistic regression estimated odds ratios and 95% confidence intervals for risk of total, low-grade (Gleason 2–6) and high-grade (Gleason 7–10) cancers. Results were stratified by intervention assignment. In both the placebo and finasteride arms, serum IGF1, IGF2, IGFBP3 and the IGF1:IGFBP3 ratio were not associated with prostate cancer. However men in the highest vs. lowest quartile of serum IGFBP2 had a 48% (P-trend =0.02) and 55% (P-trend=0.01) increased risk for total and low-grade cancers respectively. These IGFBP2 associations were attenuated and no longer statistically significant in the finasteride arm. Our results suggest that in general, serum IGF-axis analytes were not associated with prostate cancer risk in the PCPT where presence or absence of all cancers was biopsy-determined. The exception was the finding that high serum IGFBP2 is a risk factor for low-grade disease, which was attenuated for men on finasteride. Further research is needed to understand better the risk incurred by high IGFBP2 and whether androgen-suppressing agents such as finasteride influence aspects of IGFBP2 physiology relevant to prostate carcinogenesis.
PMCID: PMC3565024  PMID: 23315596
prostate cancer; insulin-like growth factors; randomized trials; 5-α reductase inhibitors
4.  Individual Variations in Serum Melatonin Levels through Time: Implications for Epidemiologic Studies 
PLoS ONE  2013;8(12):e83208.
Melatonin, a marker for the circadian rhythm with serum levels peaking between 2AM and 5AM, is hypothesized to possess anti-cancer properties, making it a mechanistic candidate for the probable carcinogenic effect of circadian rhythm disruption. In order to weigh epidemiologic evidence on the association of melatonin with cancer, we must first understand the laboratory and biological sources of variability in melatonin levels measured in samples. Participants for this methodological study were men enrolled in the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO). We measured serum melatonin levels over a five year period in 97 individuals to test if melatonin levels are steady over time. The Pearson correlation coefficient between two measures separated by 1 year was 0.87, while the correlation between two measures separated by 5 years was to 0.70. In an additional cross-sectional study of 292 individuals, we used Analysis of Variance to identify differences in melatonin levels between different lifestyle and environmental characteristics. Serum melatonin levels were slightly higher in samples collected from 130 individuals during the winter, (6.36±0.59 pg/ml) than in samples collected from 119 individuals during the summer (4.83±0.62 pg/ml). Serum melatonin levels were lowest in current smokers (3.02±1.25 pg/ml, p = 0.007) compared to never (6.66±0.66 pg/ml) and former (5.59±0.50 pg/ml) smokers whereas BMI did not significantly affect serum melatonin levels in this study. In conclusion, the high 5 year correlation of melatonin levels implies that single measurements may be used to detect population level associations between melatonin and risk of cancer. Furthermore, our results reiterate the need to record season of sample collection, and individual characteristics in order to maximize study power and prevent confounding.
PMCID: PMC3871612  PMID: 24376664
5.  Finasteride modifies the relation between serum C-peptide and prostate cancer risk: results from the Prostate Cancer Prevention Trial 
Cancer prevention research (Philadelphia, Pa.)  2010;3(3):10.1158/1940-6207.CAPR-09-0188.
Hyperinsulinemia and obesity-related metabolic disturbances are common and have been associated with increased cancer risk and poor prognosis.
Data are from a case-control study within the Prostate Cancer Prevention Trial (PCPT), a randomized, placebo-controlled trial testing finasteride vs. placebo for primary prevention of prostate cancer. Cases (n=1803) and controls (n= 1797) were matched on age, PCPT treatment arm, and family history of prostate cancer; controls included all eligible non-whites. Outcomes were biopsy-determined. Baseline bloods were assayed for serum C-peptide (marker of insulin secretion) and leptin (an adipokine) using ELISA. Logistic regression calculated odds ratios for total prostate cancer and polytomous logistic regression calculated odds ratios for low-grade (Gleason < 7) and high-grade (Gleason ≥ 7) disease. Results were stratified by treatment arm for C-peptide.
For men on placebo, higher vs. lower serum C-peptide was associated with a near two-fold increased risk of high-grade prostate cancer (Gleason ≥ 7) (multivariate-adjusted OR= 1.88, 95%CI 1.19-2.97, p trend = 0.004). When C-peptide was modeled as a continuous variable, every unit increase in [log(C-peptide)], resulted in a 39% increased risk of high-grade disease (p=0.01). In contrast, there was no significant relationship between C-peptide and high-grade prostate cancer among men receiving finasteride. Leptin was not independently associated with high-grade prostate cancer.
These results support findings from other observational studies that high serum C-peptide and insulin-resistance, but not leptin, are associated with increased risk of high-grade prostate cancer. Our novel finding is that the C-peptide-associated risk was attenuated by use of finasteride.
PMCID: PMC3846551  PMID: 20179296
prostate neoplasms; finasteride; obesity; insulin; insulin resistance; C-peptide; leptin
6.  Non-steroidal anti-inflammatory drug use and the risk of benign prostatic hyperplasia-related outcomes and nocturia in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 
BJU international  2012;110(7):1050-1059.
To investigate the relationship between non-steroidal anti-inflammatory drug (NSAID) use and the incidence of benign prostatic hyperplasia (BPH)-related outcomes and nocturia, a lower urinary tract symptom (LUTS) of BPH, in light of accumulating evidence suggesting a role for inflammation in BPH/LUTS development.
Patients and methods
At baseline, participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial completed questions on recent, regular aspirin and ibuprofen use, BPH surgery, diagnosis of an enlarged prostate/BPH, and nocturia. Participants in the intervention arm also underwent a digital rectal examination (DRE), from which prostate dimensions were estimated, as well as a prostate-specific antigen (PSA) test. Only participants in the intervention arm without BPH/LUTS at baseline were included in the analysis (n = 4771).
During follow-up, participants underwent annual DREs and PSA tests, provided annual information on finasteride use, and completed a supplemental questionnaire in 2006–2008 that included additional questions on diagnosis of an enlarged prostate/BPH and nocturia.
Information collected was used to investigate regular aspirin or ibuprofen use in relation to the incidence of six BPH/LUTS definitions: diagnosis of an enlarged prostate/BPH, nocturia (waking two or more times per night to urinate), finasteride use, any self-reported BPH/LUTS, prostate enlargement (estimated prostate volume ≥ 30 mL on any follow-up DRE) and elevation in PSA level (> 1.4 ng/mL on any follow-up PSA test).
Generally, null results were observed for any recent, regular aspirin or ibuprofen use (risk ratio = 0.92–1.21, P = 0.043–0.91) and frequency of use (risk ratio for one category increase in NSAID use = 0.98–1.11, P-trends = 0.10–0.99) with incident BPH/LUTS.
The findings obtained in the present study do not support a protective role for recent NSAID use in BPH/LUTS development.
PMCID: PMC3382045  PMID: 22429766
aspirin; benign prostatic hyperplasia; ibuprofen; lower urinary tract symptoms; non-steroidal anti-inflammatory drugs
Cancer causes & control : CCC  2012;23(9):1511-1518.
To investigate serologic evidence of infection by cytomegalovirus (CMV), a herpesvirus with known oncogenic potential that has been detected in malignant prostate tissue, in relation to prostate cancer (PCa) risk in a large case-control study nested in the Prostate Cancer Prevention Trial (PCPT).
Cases were men with a confirmed diagnosis of PCa after visit 2 (n=614) and controls were men not diagnosed with PCa during the trial who also had a negative end-of-study biopsy (n=616). Controls were frequency-matched to cases by age, treatment arm, and family history of PCa. Sera from visit 2 were tested for CMV IgG antibodies.
No association was observed between CMV serostatus and PCa risk (adjusted CMV seroprevalence=67.9% for cases and 65.2% for controls, odds ratio=1.13, 95% confidence interval: 0.89–1.45).
Considering our null findings in the context of the full CMV literature, CMV infection, as measured by serostatus, does not appear to increase PCa risk.
PMCID: PMC3433040  PMID: 22810146
Cytomegalovirus; infection; prostate cancer; epidemiology
8.  Evolution and Taxonomic Classification of Alphapapillomavirus 7 Complete Genomes: HPV18, HPV39, HPV45, HPV59, HPV68 and HPV70 
PLoS ONE  2013;8(8):e72565.
The species Alphapapillomavirus 7 (alpha-7) contains human papillomavirus genotypes that account for 15% of invasive cervical cancers and are disproportionately associated with adenocarcinoma of the cervix. Complete genome analyses enable identification and nomenclature of variant lineages and sublineages.
The URR/E6 region was sequenced to screen for novel variants of HPV18, 39, 45, 59, 68, 70, 85 and 97 from 1147 cervical samples obtained from multiple geographic regions that had previously been shown to contain an alpha-7 HPV isolate. To study viral heterogeneity, the complete 8 kb genome of 128 isolates, including 109 sequenced for this analysis, were annotated and analyzed. Viral evolution was characterized by constructing phylogenic trees using maximum-likelihood and Bayesian algorithms. Global and pairwise alignments were used to calculate total and ORF/region nucleotide differences; lineages and sublineages were assigned using an alphanumeric system. The prototype genome was assigned to the A lineage or A1 sublineage.
The genomic diversity of alpha-7 HPV types ranged from 1.1% to 6.7% nucleotide sequence differences; the extent of genome-genome pairwise intratype heterogeneity was 1.1% for HPV39, 1.3% for HPV59, 1.5% for HPV45, 1.6% for HPV70, 2.1% for HPV18, and 6.7% for HPV68. ME180 (previously a subtype of HPV68) was designated as the representative genome for HPV68 sublineage C1. Each ORF/region differed in sequence diversity, from most variable to least variable: noncoding region 1 (NCR1) / noncoding region 2 (NCR2) > upstream regulatory region (URR) > E6 / E7 > E2 / L2 > E1 / L1.
These data provide estimates of the maximum viral genomic heterogeneity of alpha-7 HPV type variants. The proposed taxonomic system facilitates the comparison of variants across epidemiological and molecular studies. Sequence diversity, geographic distribution and phylogenetic topology of this clinically important group of HPVs suggest an independent evolutionary history for each type.
PMCID: PMC3745470  PMID: 23977318
9.  High prevalence of polyclonal hypergamma-globulinemia in adult males in Ghana, Africa 
American journal of hematology  2011;86(7):554-558.
Chronic antigenic stimulation is associated with hypergamma-globulinemia. Higher rates of hypergamma-globulinemia in tropical populations are maintained even with migration to temperate regions. We conducted a population-based screening study to assess the prevalence and risk factors for hypergamma-globulinemia in Ghana, Africa. 917 Ghanaian males (50–74 years) underwent in-person interviews and health examinations. Serum from all persons was analyzed by electrophoresis performed on agarose gel; serum with a discrete/localized band was subjected to immunofixation. 54 persons with monoclonal proteins were excluded and 17 samples were insufficient for analysis. Using logistic regression and Chi-square statistics we analyzed patterns of hypergamma-globulinemia. Among 846 study subjects, the median γ-globulin level was 1.86 g/dL. On the basis of a U.S. reference, 616 (73%) had hypergamma-globulinemia (>1.6 g/dL) and 178 (21%) had γ-globulin levels >2.17 gm/dl. On multivariate analyses, lower education status (P = 0.0013) and never smoking (P = 0.038) were associated with increased γ-globulin levels. Self-reported history of syphilis was associated with hypergamma-globulinemia. We conclude that three quarters of this population-based adult Ghanaian male sample had hypergamma-globulinemia with γ-globulin levels >1.6 g/dL. Future studies are needed to uncover genetic and environmental underpinnings of our finding, and to define the relationship between hypergamma-globulinemia, monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma.
PMCID: PMC3736856  PMID: 21674575
10.  Detectability and reproducibility of plasma levels of chemokines and soluble receptors☆ 
Results in Immunology  2013;3:79-84.
Background: Multiplex assays are available to measure an array of circulating chemokines, soluble cytokine receptors and growth factors. However, there is limited information regarding whether these analytes are suitable for large-scale epidemiological studies to assess their relationships with chronic diseases, including cancer.
Methods: We examined detectability, assay repeatability, and 3-year within-subject reproducibility of plasma levels of 25 chemokines and 11 soluble receptors of cytokines and growth factors selected from the Human Millipore Panels. Plasma samples were obtained from 36 men (average age 62 years) and 17 women (average age 32 years) who participated in two epidemiological studies. Inter-assay and within-subject reproducibility were assessed by intraclass correlation coefficients (ICC).
Results: All analytes, except lymphotactin (47% detectability), were detectable in >90% of plasma samples. Inter-assay reproducibility for all analytes in 36 men tested three times on separate days were good to excellent (ICCs: 0.71–1.00). Within-subject reproducibility in 17 women sampled three times in three years were excellent (ICC ≥ 0.75) for five chemokines (eotaxin, fractalkine, 6Ckine, eotaxin 3, and SDF-1α+β) and three soluble receptors (sIL-1R2, sIL-4R and sVEGFR2); ICCs were fair to good (0.4 ≤ ICC < 0.75) for 15 chemokines and eight soluble receptors. However, five chemokines (GRO, IP-10, MIP-1β, BCA-1, and MIP-3α) had ICC < 0.4, suggesting biological variability.
Conclusion: Multiplex assays for plasma levels of selected chemokines and soluble receptors showed good to excellent assay detectability and repeatability. Most analytes also had good 3-year within-subject reproducibility, indicating that a single measurement of these analytes may be used to assess biomarker-disease associations.
PMCID: PMC3908322  PMID: 24600562
Chemokines; Soluble receptors; Within-subject variability; Biomarker; Limit of detection
11.  Physical activity, diabetes, and thyroid cancer risk: a pooled analysis of five prospective studies 
Cancer causes & control : CCC  2012;10.1007/s10552-012-9896-y.
Although many studies have linked obesity with increased risk of thyroid cancer, few have investigated the role of obesity-related lifestyle characteristics and medical conditions in the etiology of this disease. We examined the associations of self-reported physical activity and diabetes history with thyroid cancer risk in a large pooled analysis of prospective cohort studies.
Data from five prospective studies in the U.S. (n=362,342 men, 312,149 women) were coded using standardized exposure, covariate, and outcome definitions. Hazard ratios (HR) and 95% confidence intervals (CI) for thyroid cancer were estimated using age as the time metric and adjusting for sex, education, race, marital status, cigarette smoking, body mass index, alcohol intake, and cohort. Effect modification by other risk factors (e.g. age, sex, body mass index) and differences by cancer subtype (e.g. papillary, follicular) were also examined.
Over follow-up (median=10.5 years), 308 men and 510 women were diagnosed with a first primary thyroid cancer. Overall, subjects reporting the greatest amount of physical activity had an increased risk of the disease (HR=1.18, 95% CI:1.00-1.39); however, this association was restricted to participants who were overweight/obese (≥25 kg/m2; HR=1.34, 95% CI:1.09-1.64) as opposed to normal-weight (<25 kg/m2; HR=0.92, 95% CI:0.69-1.22; P-interaction=0.03). We found no overall association between self-reported history of diabetes and thyroid cancer risk (HR=1.08, 95% CI:0.83-1.40).
Neither physical inactivity nor diabetes history was associated with increased risk of thyroid cancer. While it may have been a chance finding, the possible increased risk associated with greater physical activity warrants further investigation.
PMCID: PMC3586378  PMID: 22294499
physical activity; energy expenditure; type 2 diabetes; insulin resistance; thyroid neoplasms; prospective study
12.  Interactions Between Genome-wide Significant Genetic Variants and Circulating Concentrations of Insulin-like Growth Factor 1, Sex Hormones, and Binding Proteins in Relation to Prostate Cancer Risk in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium 
American Journal of Epidemiology  2012;175(9):926-935.
Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. There is limited information on the mechanistic basis of these associations, particularly about whether they interact with circulating concentrations of growth factors and sex hormones, which may be important in prostate cancer etiology. Using conditional logistic regression, the authors compared per-allele odds ratios for prostate cancer for 39 GWAS-identified SNPs across thirds (tertile groups) of circulating concentrations of insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), testosterone, androstenedione, androstanediol glucuronide, estradiol, and sex hormone-binding globulin (SHBG) for 3,043 cases and 3,478 controls in the Breast and Prostate Cancer Cohort Consortium. After allowing for multiple testing, none of the SNPs examined were significantly associated with growth factor or hormone concentrations, and the SNP-prostate cancer associations did not differ by these concentrations, although 4 interactions were marginally significant (MSMB-rs10993994 with androstenedione (uncorrected P = 0.008); CTBP2-rs4962416 with IGFBP-3 (uncorrected P = 0.003); 11q13.2-rs12418451 with IGF-1 (uncorrected P = 0.006); and 11q13.2-rs10896449 with SHBG (uncorrected P = 0.005)). The authors found no strong evidence that associations between GWAS-identified SNPs and prostate cancer are modified by circulating concentrations of IGF-1, sex hormones, or their major binding proteins.
PMCID: PMC3390010  PMID: 22459122
gene-environment interaction; gonadal steroid hormones; insulin-like growth factor binding protein 3; insulin-like growth factor I; molecular epidemiology; prostatic neoplasms
13.  Prostate Cancer Incidence Rates in Africa 
Prostate Cancer  2011;2011:947870.
African American men have among the highest prostate cancer incidence rates in the world yet rates among their African counterparts are unclear. In this paper, we compared reported rates among black men of Sub-Saharan African descent using data from the International Agency for Research on Cancer (IARC) and the National Cancer Institute Surveillance, Epidemiology, and End Results Program for 1973–2007. Although population-based data in Africa are quite limited, the available data from IARC showed that rates among blacks were highest in the East (10.7–38.1 per 100,000 man-years, age-adjusted world standard) and lowest in the West (4.7–19.8). These rates were considerably lower than those of 80.0–195.3 observed among African Americans. Rates in Africa increased over time (1987–2002) and have been comparable to those for distant stage in African Americans. These patterns are likely due to differences between African and African American men in medical care access, screening, registry quality, genetic diversity, and Westernization. Incidence rates in Africa will likely continue to rise with improving economies and increasing Westernization, warranting the need for more high-quality population-based registration to monitor cancer incidence in Africa.
PMCID: PMC3200287  PMID: 22111004
14.  Predictive performance of prostate cancer risk in Chinese men using 33 reported prostate cancer risk-associated SNPs 
The Prostate  2011;72(5):577-583.
Genome-wide association studies (GWAS) have identified more than 30 single nucleotide polymorphisms (SNPs) that were reproducibly associated with prostate cancer (PCa) risk in populations of European descent. In aggregate, these variants have shown potential to predict risk for PCa in European men. However, their utility for PCa risk prediction in Chinese men is unknown.
We selected 33 PCa risk-related SNPs that were originally identified in populations of European descent. Genetic scores were estimated for subjects in a Chinese case-control study (1,108 cases and 1,525 controls) based on these SNPs. To assess the performance of the genetic score on its ability to predict risk for PCa, we calculated Area under the curve (AUC) of the receiver operating characteristic (ROC) in combination with 10-fold cross-validation.
The genetic score was significantly higher for cases than controls (P = 5.91×10-20), and was significantly associated with risk of PCa in a dose-dependent manner (P for trend: 4.78×10-18). The AUC of the genetic score was 0.604 for risk prediction of PCa in Chinese men. When ORs derived from this Chinese study population were used to calculate genetic score, the AUCs were 0.631 for all 33 SNPs and 0.617 when using only the 11 significant SNPs.
Our results indicate that genetic variants related to PCa risk may be useful for risk prediction in Chinese men. Prospective studies are warranted to further evaluate these findings.
PMCID: PMC3232337  PMID: 21796652
Genetic score; Cumulative risk; Prostate cancer; AUC; Risk prediction; Susceptibility; Chinese
15.  Measuring Serum Melatonin in Epidemiologic Studies 
Epidemiologic data on serum melatonin, a marker of circadian rhythms, and cancer are sparse due largely to the lack of reliable assays with high sensitivity to detect relatively low melatonin levels in serum collected during daylight, as commonly available in most epidemiologic studies.
To help expand epidemiologic research on melatonin, we assessed the reproducibility and refined a currently available melatonin radioimmunoassay, and evaluated its application to epidemiologic investigations by characterizing melatonin levels in serum, urine, and/or plasma in 135 men from several ethnic groups.
Reproducibility was high for the standard 1.0 ml serum- (mean coefficient of variation (CV)=6.9%, intraclass correlation coefficient (ICC)=97.4%, n=2 serum pools in triplicate) and urine-based (mean CV=3.5%, ICC=99.9%) assays. Reproducibility for the 0.5 ml refined-serum assay was equally good (mean CV=6.6%%;ICC=99.0%). There was a positive correlation between morning serum melatonin and 6-sulfatoxymelatonin in 24-hour urine(r=0.46, P=0.008; n=49 subjects). Melatonin levels in serum-plasma pairs had a high correlation (r=0.97, P<1 × 10−4; n=20) Morning serum melatonin levels were five times higher than those from the afternoon (before 9 AM mean = 11.0 pg/mL versus after 11 AM mean=2.0 pg/mL). Chinese men had lower melatonin levels (mean=3.4 pg/mL), while Caucasian, African American, and Ghanaian men had similar levels (mean=6.7–8.6 pg/mL).
These results suggest that melatonin can be detected reliably in serum samples collected in epidemiologic studies in various racial groups.
With improved assays, it may be possible to investigate the role of melatonin and the emerging circadian rhythm hypothesis in cancer etiology in epidemiologic studies.
PMCID: PMC2856692  PMID: 20332275
melatonin; radioimmunoassay; assay variation; reproducibility
16.  A systematic confirmation study of reported prostate cancer risk-associated SNPs in Chinese men 
Cancer science  2011;102(10):1916-1920.
More than 30 prostate cancer (PCa) risk-associated loci have been identified in populations of European descent by genome-wide association studies (GWAS). We hypothesized that a subset of these loci may be associated with PCa risk in Chinese men. To test this hypothesis, 33 single nucleotide polymorphisms (SNPs), one each from the 33 independent PCa risk-associated loci reported in populations of European descent, were investigated for their associations with PCa risk in a case-control study of Chinese men (1,108 cases and 1,525 controls). We found that 11 of the 33 SNPs were significantly associated with PCa risk in Chinese men (P < 0.05). The reported risk alleles were associated with increased risk for PCa, with allelic odds ratios ranging from 1.12 to 1.44. The most significant locus was located on 8q24 Region 2 (rs16901979, P = 5.14×10−9) with a genome-wide significance (P < 10−8), and three loci reached the Bonferroni correction significance level (P < 1.52×10−3), including 8q24 Region 1 (rs1447295, P = 7.04×10−6), 8q24 Region 5 (rs10086908, P = 9.24×10−4), and 8p21 (rs1512268, P = 9.39×10−4). Our results suggest that a subset of the PCa risk-associated SNPs discovered by GWAS among men of European descent is also associated with PCa risk in Chinese men. This finding provides evidence of ethnic differences and similarity in genetic susceptibility to PCa. GWAS in Chinese men are needed to identify Chinese-specific PCa risk-associated SNPs.
PMCID: PMC3581323  PMID: 21756274
17.  Replication and cumulative effects of GWAS-identified genetic variations for prostate cancer in Asians: a case–control study in the ChinaPCa consortium 
Carcinogenesis  2011;33(2):356-360.
A recent genome-wide association study has identified five new genetic variants for prostate cancer susceptibility in a Japanese population, but it is unknown whether these newly identified variants are associated with prostate cancer risk in other populations, including Chinese men. We genotyped these five variants in a case–control study of 1524 patients diagnosed with prostate cancer and 2169 control subjects from the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa). We found that three of the five genetic variants were associated with prostate cancer risk (P = 4.33 × 10−8 for rs12653946 at 5p15, 4.43 × 10−5 for rs339331 at 6q22 and 8.42 × 10−4 for rs9600079 at 13q22, respectively). A cumulative effect was observed in a dose-dependent manner with increasing numbers of risk variant alleles (Ptrend = 2.58 × 10−13), and men with 5–6 risk alleles had a 2-fold higher risk of prostate cancer than men with 0–2 risk alleles (odds ratio = 2.26, 95% confidence interval = 1.78–2.87). Furthermore, rs339331 T allele was significantly associated with RFX6 and GPRC6A higher messenger RNA expression, compared with the C allele. However, none of the variants was associated with clinical stage, Gleason score or family history. These results provide further evidence that the risk loci identified in Japanese men also contribute to prostate cancer susceptibility in Chinese men.
PMCID: PMC3271266  PMID: 22114074
18.  Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up 
The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was undertaken to determine whether there is a reduction in prostate cancer mortality from screening using serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE). Mortality after 7–10 years of follow-up has been reported previously. We report extended follow-up to 13 years after the trial.
A total of 76 685 men, aged 55–74 years, were enrolled at 10 screening centers between November 1993 and July 2001 and randomly assigned to the intervention (organized screening of annual PSA testing for 6 years and annual DRE for 4 years; 38 340 men) and control (usual care, which sometimes included opportunistic screening; 38 345 men) arms. Screening was completed in October 2006. All incident prostate cancers and deaths from prostate cancer through 13 years of follow-up or through December 31, 2009, were ascertained. Relative risks (RRs) were estimated as the ratio of observed rates in the intervention and control arms, and 95% confidence intervals (CIs) were calculated assuming a Poisson distribution for the number of events. Poisson regression modeling was used to examine the interactions with respect to prostate cancer mortality between trial arm and age, comorbidity status, and pretrial PSA testing. All statistical tests were two-sided.
Approximately 92% of the study participants were followed to 10 years and 57% to 13 years. At 13 years, 4250 participants had been diagnosed with prostate cancer in the intervention arm compared with 3815 in the control arm. Cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10 000 person-years, respectively, resulting in a relative increase of 12% in the intervention arm (RR = 1.12, 95% CI = 1.07 to 1.17). After 13 years of follow-up, the cumulative mortality rates from prostate cancer in the intervention and control arms were 3.7 and 3.4 deaths per 10 000 person-years, respectively, resulting in a non-statistically significant difference between the two arms (RR = 1.09, 95% CI = 0.87 to 1.36). No statistically significant interactions with respect to prostate cancer mortality were observed between trial arm and age (Pinteraction = .81), pretrial PSA testing (Pinteraction = .52), and comorbidity (Pinteraction = .68).
After 13 years of follow-up, there was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing.
PMCID: PMC3260132  PMID: 22228146
19.  The association between inflammation-related genes and serum androgen levels in men: The Prostate, Lung, Colorectal, and Ovarian Study 
The Prostate  2011;72(1):65-71.
Androgens and inflammation have been implicated in the etiology of several cancers, including prostate cancer. Serum androgens have been shown to correlate with markers of inflammation and expression of inflammation-related genes.
In this report, we evaluated associations between 9,932 single nucleotide polymorphisms (SNPs) marking common genetic variants in 774 inflammation-related genes and four serum androgen levels (total testosterone [T], bioavailable T [BioT]; 5α-androstane-3α, 17β-diol glucuronide [3αdiol G], and 4-Androstene-3,17-dione [androstenedione]), in 560 healthy men (median age 64 years) drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Baseline serum androgens were measured by radioimmunoassay. Genotypes were determined as part of the Cancer Genetic Markers of Susceptibility Study genome-wide scan. SNP-hormone associations were evaluated using linear regression of hormones adjusted for age. Gene-based p-values were generated using an adaptive rank truncated product method.
Suggestive associations were observed for two inflammation-related genes and circulating androgen levels (false discovery rate [FDR] q-value<0.1) in both SNP and gene-based tests. Specifically, T was associated with common variants in MMP2 and CD14, with the most significant SNPs being rs893226G>T in MMP2 and rs3822356T>C in CD14 (FDR q-value=0.09 for both SNPs). Other genes implicated in either SNP or gene-based tests were IK with T and BioT, PRG2 with T, and TNFSF9 with androstenedione.
These results suggest possible cross-talk between androgen levels and inflammation pathways, but larger studies are needed to confirm these findings and to further clarify the interrelationship between inflammation and androgens and their effects on cancer risk.
PMCID: PMC3156884  PMID: 21520164
Inflammation; Androgens; Genes; Testosterone; Polymorphism; Single Nucleotide
20.  Joint Associations Between Genetic Variants and Reproductive Factors in Glioma Risk Among Women 
American Journal of Epidemiology  2011;174(8):901-908.
In a pooled analysis of 4 US epidemiologic studies (1993–2001), the authors evaluated the role of 5 female reproductive factors in 357 women with glioma and 822 controls. The authors further evaluated the independent association between 5 implicated gene variants and glioma risk among the study population, as well as the joint associations of female reproductive factors (ages at menarche and menopause, menopausal status, use of oral contraceptives, and menopausal hormone therapy) and these gene variants on glioma risk. Risk estimates were calculated as odds ratios and 95% confidence intervals that were adjusted for age, race, and study. Three of the gene variants (rs4295627, a variant of CCDC26; rs4977756, a variant of CDKN2A and CDKN2B; and rs6010620, a variant of RTEL1) were statistically significantly associated with glioma risk in the present population. Compared with women who had an early age at menarche (<12 years of age), those who reported menarche at 12–13 years of age or at 14 years of age or older had a 1.7-fold higher risk and a 1.9-fold higher risk of glioma, respectively (P for trend = 0.009). Postmenopausal women and women who reported ever having used oral contraceptives had a decreased risk of glioma. The authors did not observe joint associations between these reproductive characteristics and the implicated glioma gene variants. These results require replication, but if confirmed, they would suggest that the gene variants that have previously been implicated in the development of glioma are unlikely to act through the same hormonal mechanisms in women.
PMCID: PMC3218628  PMID: 21920947
genes; glioma; menstrual cycle; polymorphism, single nucleotide; reproduction; women
21.  Inflammatory gene variants and the risk of biliary tract cancers and stones: a population-based study in China 
BMC Cancer  2012;12:468.
Genetic variants in inflammation-related genes have been associated with biliary stones and biliary tract cancers in previous studies.
To follow-up on these findings, we examined 35 single nucleotide polymorphism (SNPs) in 5 genes related to inflammation (IL8, NFKBIL, RNASEL, TNF, and VEGFA) in 456 participants with incident biliary tract cancer cases (262 gallbladder, 141 extrahepatic bile duct, 53 ampulla of Vater), 982 participants with biliary stones, and 860 healthy controls in a population–based case–control study in Shanghai, China.
Suggestive associations were observed for SNPs in VEGFA with biliary stones, IL8 with gallbladder and ampulla of Vater cancers, and RNASEL with ampulla of Vater cancer (false discovery rate≤0.2).
These findings provide additional support for the role of inflammation in biliary stones and biliary tract cancer risk and need further validation.
PMCID: PMC3524039  PMID: 23057767
Biliary tract cancer; Biliary stones; Inflammation; Genetic susceptibility
22.  Persistence of Type-Specific Human Papillomavirus Infection and Increased Long-term Risk of Cervical Cancer 
Human papillomavirus (HPV) persistence is the pivotal event in cervical carcinogenesis. We followed a large-scale community-based cohort for 16 years to investigate the role of genotype-specific HPV persistence in predicting cervical cancer including invasive and in situ carcinoma.
At the baseline examination in 1991–1992, 11 923 participants (aged 30–65 years) consented to HPV testing and cytology; 6923 participants were reexamined in 1993–1995. For HPV testing, we used a polymerase chain reaction–based assay that detected 39 HPV types. Women who developed cervical cancer were identified from cancer and death registries. Cumulative risks for developing cervical cancer among infected and persistently infected women were calculated by the Kaplan–Meier method.
Of 10 123 women who were initially cytologically normal, 68 developed cervical cancer. The 16-year cumulative risks of subsequent cervical cancer for women with HPV16, HPV58 (without HPV16), or other carcinogenic HPV types (without HPV16 or HPV58) were 13.5%, 10.3%, and 4.0%, respectively, compared with 0.26% for HPV-negative women. Women with type-specific persistence of any carcinogenic HPV had greatly increased risk compared with women who were HPV-negative at both visits (hazard ratio = 75.4, 95% confidence interval = 31.8 to 178.9). The cumulative cervical cancer risks following persistent carcinogenic HPV infections increased with age: The risks were 5.5%, 14.4%, and 18.1% for women aged 30–44 years, 45–54 years, and 55 years and older, respectively. However, newly acquired infections were associated with a low risk of cervical cancer regardless of age.
HPV negativity was associated with a very low long-term risk of cervical cancer. Persistent detection of HPV among cytologically normal women greatly increased risk. Thus, it is useful to perform repeated HPV testing following an initial positive test.
PMCID: PMC3176778  PMID: 21900119
23.  Evaluation of multiplexed cytokine and inflammation marker measurements: A methodologic study 
Chronic inflammation is etiologically-related to several cancers. We evaluated the performance (ability to detect concentrations above the assay’s lower limit of detection, coefficients-of-variation [CVs], and intraclass correlation coefficients [ICCs]) of 116 inflammation, immune, and metabolic markers across two luminex bead-based commercial kits and three specimen types.
From 100 cancer-free participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Trial, serum, heparin plasma, and EDTA plasma samples were utilized. We measured levels of 67 and 97 markers using Bio-Rad and Millipore kits, respectively. Reproducibility was assessed using 40 blinded duplicates (20 within-batches and 20 across-batches) for each specimen type.
A majority of markers were detectable in >25% of individuals on all specimen types/kits. Of the 67 Bio-Rad markers, 51, 52, and 47 markers in serum, heparin plasma, and EDTA plasma, respectively, had across-batch CVs <20%. Likewise, of 97 Millipore markers, 75, 69, and 78 markers in serum, heparin plasma, and EDTA plasma, respectively, had across-batch CVs <20%. When results were combined across specimen types, 45 Bio-Rad and 71 Millipore markers had acceptable performance (>25% detectability on all 3 specimen types and across-batch CVs <20% on at least 2 of 3 specimen types). Median concentrations and ICCs differed to a small extent across specimen types and to a large extent between Bio-Rad and Millipore.
Inflammation and immune markers can be measured reliably in serum and plasma samples using multiplexed luminex-based methods.
Multiplexed assays can be utilized for epidemiologic investigations into the role of inflammation in cancer etiology.
PMCID: PMC3400264  PMID: 21715603
24.  Urinary estrogen metabolites and prostate cancer risk: a pilot study 
The Prostate  2010;71(5):507-516.
The high incidence of and few identified risk factors for prostate cancer underscore the need to further evaluate markers of prostate carcinogenesis. The aim of this pilot study was to evaluate urinary estrogen metabolites as a biomarker of prostate cancer risk.
Using a liquid chromatography-tandem mass spectrometry method, urinary concentrations of 15 estrogen metabolites were determined in 77 prostate cancer cases, 77 healthy controls, and 37 subjects who had no evidence of prostate cancer after a prostate biopsy.
We observed an inverse association between the urinary 16-ketoestradiol (16-KE2) and 17-epiestriol (17-epiE3)- metabolites with high estrogenic activity- and prostate cancer risk. Men in the lowest quartile of 16-KE2, had a 4.6-fold risk of prostate cancer (OR= 4.62, 95% CI =1.34–15.99), compared with those in the highest quartile.
We observed modest differences in estrogen metabolite concentrations between prostate cancer patients and subjects without cancer. Larger studies with both androgen and estrogen measurements are needed to confirm these results to clarify further whether estrogen metabolites are independent biomarkers for prostate cancer risk and whether androgen/estrogen imbalance influences prostate cancer risk.
PMCID: PMC3037420  PMID: 20886539
prostate cancer; estrogen metabolites; benign prostatic hyperplasia; case-control study
25.  Obesity and thyroid cancer risk among U.S. men and women: a pooled analysis of 5 prospective studies 
Thyroid cancer incidence has risen dramatically in the U.S. since the early 1980s. Although the prevalence of obesity has doubled during this time period, the relationship between obesity and thyroid cancer is uncertain.
We examined the association between body mass index (BMI) and thyroid cancer risk in a pooled analysis of five prospective U.S. studies, including 413,979 women and 434,953 men. Proportional hazards models with attained age as the time metric were adjusted for education, race, marital status, smoking, alcohol intake, and (where appropriate) cohort and sex.
Over follow-up (mean=10.3 years), 768 women and 388 men were diagnosed with thyroid cancer. The risk of thyroid cancer was greater with increasing BMI (per 5 kg/m2: hazard ratio [HR] in women, 1.16 [95% confidence interval (CI), 1.08–1.24]; HR in men, 1.21 [95% CI, 0.97–1.49]). There was no significant heterogeneity between studies (both P>0.05). For women and men combined, the HRs for overweight (25.0–29.9 kg/m2) and obesity (≥30 kg/m2) compared to normal-weight (18.5–24.9 kg/m2) were 1.20 (95% CI, 1.04–1.38) and 1.53 (95% CI, 1.31–1.79), respectively. We found no significant effect modification by other factors, and the results did not differ significantly by histologic type. A significant positive association for BMI in young adulthood (ages 18–20) with thyroid cancer risk was also observed (per 5-kg/m2 increase: HR, 1.18 [95% CI, 1.03–1.35]).
BMI was positively associated with thyroid cancer risk in both men and women.
Our study provides strong evidence that obesity is an independent risk factor for thyroid cancer.
PMCID: PMC3079276  PMID: 21266520
obesity; body mass index; thyroid neoplasms; prospective studies; epidemiology

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