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Article: A Multiple-Testing Procedure for High-Dimensional Mediation Hypotheses

Dai, James Y. / Stanford, Janet L. / LeBlanc, Michael

Journal of the American Statistical Association. 2022 Jan. 2, v. 117, no. 537

2022

Abstract: Mediation analysis is of rising interest in epidemiologic studies and clinical trials. Among existing methods, the joint significance test yields an overly conservative Type I error rate and low power, particularly for high-dimensional mediation ... ...

Abstract	Mediation analysis is of rising interest in epidemiologic studies and clinical trials. Among existing methods, the joint significance test yields an overly conservative Type I error rate and low power, particularly for high-dimensional mediation hypotheses. In this article, we develop a multiple-testing procedure that accurately controls the family-wise error rate (FWER) and the false discovery rate (FDR) when testing high-dimensional mediation hypotheses. The core of our procedure is based on estimating the proportions of component null hypotheses and the underlying mixture null distribution of p-values. Theoretical developments and simulation experiments prove that the proposed procedure effectively controls FWER and FDR. Two mediation analyses on DNA methylation and cancer research are presented: assessing the mediation role of DNA methylation in genetic regulation of gene expression in primary prostate cancer samples; exploring the possibility of DNA methylation mediating the effect of exercise on prostate cancer progression. Results of data examples include well-behaved quantile-quantile plots and improved power to detect novel mediation relationships. An R package HDMT implementing the proposed procedure is freely accessible in CRAN. Supplementary materials for this article are available online.
Keywords	DNA methylation ; exercise ; gene expression regulation ; neoplasm progression ; prostatic neoplasms
Language	English
Dates of publication	2022-0102
Size	p. 198-213.
Publishing place	Taylor & Francis
Document type	Article
ZDB-ID	2064981-2
ISSN	1537-274X
ISSN	1537-274X
DOI	10.1080/01621459.2020.1765785
Database	NAL-Catalogue (AGRICOLA)

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Article: A multiple-testing procedure for high-dimensional mediation hypotheses.

Dai, James Y / Stanford, Janet L / LeBlanc, Michael

Journal of the American Statistical Association

2020 Volume 117, Issue 537, Page(s) 198–213

Abstract: Mediation analysis is of rising interest in epidemiology and clinical trials. Among existing methods, the joint significance (JS) test yields an overly conservative type I error rate and low power, particularly for high-dimensional mediation hypotheses. ... ...

Abstract	Mediation analysis is of rising interest in epidemiology and clinical trials. Among existing methods, the joint significance (JS) test yields an overly conservative type I error rate and low power, particularly for high-dimensional mediation hypotheses. In this article we develop a multiple-testing procedure that accurately controls the family-wise error rate (FWER) and the false discovery rate (FDR) when testing high-dimensional mediation hypotheses. The core of our procedure is based on estimating the proportions of component null hypotheses and the underlying mixture null distribution of p-values. Theoretical developments and simulation experiments prove that the proposed procedure effectively controls FWER and FDR. Two mediation analyses on DNA methylation and cancer research are presented: assessing the mediation role of DNA methylation in genLetic regulation of gene expression in primary prostate cancer samples; exploring the possibility of DNA methylation mediating the effect of exercise on prostate cancer progression. Results of data examples include wellL-behaved quantile-quantile plots and improved power to detect novel mediation relationships. An R package HDMT implementing the proposed procedure is freely accessible in CRAN.
Language	English
Publishing date	2020-06-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2064981-2
ISSN	1537-274X ; 0162-1459 ; 0003-1291
ISSN (online)	1537-274X
ISSN	0162-1459 ; 0003-1291
DOI	10.1080/01621459.2020.1765785
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Article ; Online: Genetic predisposition to prostate cancer: Update and future perspectives.

Demichelis, Francesca / Stanford, Janet L

Urologic oncology

2015 Volume 33, Issue 2, Page(s) 75–84

Abstract: Objective: Prostate cancer is the second most frequent cancer in men worldwide and kills over 250,000 men worldwide every year. Prostate cancer is a heterogeneous disease at the clinical and the molecular level. The Scandinavian Twin Registry Study ... ...

Abstract	Objective: Prostate cancer is the second most frequent cancer in men worldwide and kills over 250,000 men worldwide every year. Prostate cancer is a heterogeneous disease at the clinical and the molecular level. The Scandinavian Twin Registry Study demonstrated that in contrast to most malignancies where environment was the overriding influence, heritable factors account for more than fifty percent of prostate cancers. Methods and materials: We review the literature on prostate cancer risk variants (rare and common) including SNPs and Copy Number Variants (CNVs) and discuss the potential implications of significant variants for prostate cancer patient care. Results: The search for prostate cancer susceptibility genes has included both family-based studies and case-control studies utilizing a variety of approaches from array-based to sequencing-based studies. A major challenge is to identify genetic variants associated with more aggressive, potentially lethal prostate cancer and to understand their role in the progression of the disease. Conclusion: Future risk models useful in the clinical setting will likely incorporate several risk loci rather than single variants and may be dependent on an individual patient's ethnic background.
MeSH term(s)	Genetic Predisposition to Disease ; Humans ; Male ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology
Language	English
Publishing date	2015-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	1336505-8
ISSN	1873-2496 ; 1078-1439
ISSN (online)	1873-2496
ISSN	1078-1439
DOI	10.1016/j.urolonc.2014.04.021
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Article ; Online: Association of a novel BRCA2 mutation with prostate cancer risk further supports germline genetic testing.

Foley, Georgea R / Marthick, James R / Ostrander, Elaine A / Stanford, Janet L / Dickinson, Joanne L / FitzGerald, Liesel M

European journal of cancer (Oxford, England : 1990)

2022 Volume 180, Page(s) 155–157

MeSH term(s)	Male ; Humans ; Genetic Testing ; BRCA2 Protein/genetics ; Prostatic Neoplasms/genetics ; Mutation ; Germ-Line Mutation ; Genetic Predisposition to Disease
Chemical Substances	BRCA2 Protein ; BRCA2 protein, human
Language	English
Publishing date	2022-12-10
Publishing country	England
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	82061-1
ISSN	1879-0852 ; 0277-5379 ; 0959-8049 ; 0964-1947
ISSN (online)	1879-0852
ISSN	0277-5379 ; 0959-8049 ; 0964-1947
DOI	10.1016/j.ejca.2022.11.034
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Article ; Online: Germline Genetic Variants Associated with Somatic TMPRSS2:ERG Fusion Status in Prostate Cancer: A Genome-Wide Association Study.

Ma, Chaoran / Wang, Xiaoyu / Dai, James Y / Turman, Constance / Kraft, Peter / Stopsack, Konrad H / Loda, Massimo / Pettersson, Andreas / Mucci, Lorelei A / Stanford, Janet L / Penney, Kathryn L

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2023 Volume 32, Issue 10, Page(s) 1436–1443

Abstract: Background: The prostate cancer subtype defined by the presence of TMPRSS2:ERG has been shown to be molecularly and epidemiologically distinct. However, few studies have investigated germline genetic variants associating with TMPRSS2:ERG fusion status.!# ...

Abstract	Background: The prostate cancer subtype defined by the presence of TMPRSS2:ERG has been shown to be molecularly and epidemiologically distinct. However, few studies have investigated germline genetic variants associating with TMPRSS2:ERG fusion status. Methods: We performed a genome-wide association study with 396 TMPRSS2:ERG(+) cases, 390 TMPRSS2:ERG(-) cases, and 2,386 cancer-free controls from the Physicians' Health Study (PHS), the Health Professionals Follow-up Study (HPFS), and a Seattle-based Fred Hutchinson (FH) Cancer Center Prostate Cancer Study. We applied logistic regression models to test the associations between ∼5 million SNPs with TMPRSS2:ERG fusion status accounting for population stratification. Results: We did not identify genome-wide significant variants comparing the TMPRSS2:ERG(+) to the TMPRSS2:ERG(-) prostate cancer cases in the meta-analysis. When comparing TMPRSS2:ERG(+) prostate cancer cases with controls without prostate cancer, 10 genome-wide significant SNPs on chromosome 17q24.3 were observed in the meta-analysis. When comparing TMPRSS2:ERG(-) prostate cancer cases with controls without prostate cancer, two SNPs on chromosome 8q24.21 in the meta-analysis reached genome-wide significance. Conclusions: We observed SNPs at several known prostate cancer risk loci (17q24.3, 1q32.1, and 8q24.21) that were differentially and exclusively associated with the risk of developing prostate tumors either with or without the gene fusion. Impact: Our findings suggest that tumors with the TMPRSS2:ERG fusion exhibit a different germline genetic etiology compared with fusion negative cases.
MeSH term(s)	Male ; Humans ; Genome-Wide Association Study ; Follow-Up Studies ; Oncogene Proteins, Fusion/genetics ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Germ-Line Mutation ; Transcriptional Regulator ERG/genetics ; Serine Endopeptidases/genetics
Chemical Substances	Oncogene Proteins, Fusion ; Transcriptional Regulator ERG ; ERG protein, human ; TMPRSS2 protein, human (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2023-08-08
Publishing country	United States
Document type	Meta-Analysis ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1153420-5
ISSN	1538-7755 ; 1055-9965
ISSN (online)	1538-7755
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-23-0275
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Article ; Online: Self-reported Prostate Cancer Progression Status Is Accurate: A Validation Study.

Daugherty, Sarah E / Wright, Jonathan L / Black, Amanda / Stanford, Janet L / Hoover, Robert / Berndt, Sonja I

Epidemiology (Cambridge, Mass.)

2020 Volume 31, Issue 3, Page(s) 441–447

Abstract: Background: Studies of prostate cancer progression are important for discovering risk factors that may increase the risk of prostate cancer-specific death; however, little is known about the validity of self-reported prostate cancer progression.: ... ...

Abstract	Background: Studies of prostate cancer progression are important for discovering risk factors that may increase the risk of prostate cancer-specific death; however, little is known about the validity of self-reported prostate cancer progression. Methods: We conducted a validation study of self-reported prostate cancer progression in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and in a prostate cancer cohort enrolled in a Fred Hutchinson Cancer Research Center (FHCRC)-based study. We calculated measures of validity for self-reported progression, including sensitivity, specificity, positive predictive value, and negative predictive value using medical records as the gold standard. Results: Our results suggest that ascertaining prostate cancer progression-related events (i.e., prostate-specific antigen elevation, recurrence, metastasis, and use of secondary treatment) through self-report may be a viable option for identifying men whose disease has progressed after diagnosis or initial therapy, particularly when multiple questions related to progression are included in the assessment (aggregate cluster of questions: sensitivity = 0.76 [PLCO]; 0.93 [FHCRC], specificity = 0.80 [PLCO]; 0.97 [FHCRC]). With an aggregate positive predictive value of 0.50 (PLCO), however, our PLCO results suggest that additional medical record verification of self-reported progression events may be necessary to rule out false positives. Most individuals reporting no evidence of progression-related events, however, were true negatives (aggregate negative predictive value = 0.92 [PLCO]; 0.98 [FHCRC]). Thus, there may be limited utility to investing resources in chart review to confirm self-reported nonevents. Conclusion: Ascertaining prostate cancer progression through self-report provides an efficient and valid approach to enhancing existing cancer cohorts with updated data on progression status. See video abstract at, http://links.lww.com/EDE/B658.
MeSH term(s)	Disease Progression ; Humans ; Male ; Prostatic Neoplasms/pathology ; Reproducibility of Results ; Self Report
Language	English
Publishing date	2020-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Validation Study
ZDB-ID	1053263-8
ISSN	1531-5487 ; 1044-3983
ISSN (online)	1531-5487
ISSN	1044-3983
DOI	10.1097/EDE.0000000000001170
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Article ; Online: Combining multiple biomarkers linearly to maximize the partial area under the ROC curve.

Yan, Qingxiang / Bantis, Leonidas E / Stanford, Janet L / Feng, Ziding

Statistics in medicine

2017 Volume 37, Issue 4, Page(s) 627–642

Abstract: It is now common in clinical practice to make clinical decisions based on combinations of multiple biomarkers. In this paper, we propose new approaches for combining multiple biomarkers linearly to maximize the partial area under the receiver operating ... ...

Abstract	It is now common in clinical practice to make clinical decisions based on combinations of multiple biomarkers. In this paper, we propose new approaches for combining multiple biomarkers linearly to maximize the partial area under the receiver operating characteristic curve (pAUC). The parametric and nonparametric methods that have been developed for this purpose have limitations. When the biomarker values for populations with and without a given disease follow a multivariate normal distribution, it is easy to implement our proposed parametric approach, which adopts an alternative analytic expression of the pAUC. When normality assumptions are violated, a kernel-based approach is presented, which handles multiple biomarkers simultaneously. We evaluated the proposed as well as existing methods through simulations and discovered that when the covariance matrices for the disease and nondisease samples are disproportional, traditional methods (such as the logistic regression) are more likely to fail to maximize the pAUC while the proposed methods are more robust. The proposed approaches are illustrated through application to a prostate cancer data set, and a rank-based leave-one-out cross-validation procedure is proposed to obtain a realistic estimate of the pAUC when there is no independent validation set available.
MeSH term(s)	Algorithms ; Area Under Curve ; Biomarkers/analysis ; Biostatistics ; Computer Simulation ; DNA Methylation/genetics ; Disease Progression ; Humans ; Linear Models ; Logistic Models ; Male ; Medical Overuse/prevention & control ; Normal Distribution ; Prostatic Neoplasms/diagnosis ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/therapy ; ROC Curve ; Statistics, Nonparametric
Chemical Substances	Biomarkers
Language	English
Publishing date	2017-10-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	843037-8
ISSN	1097-0258 ; 0277-6715
ISSN (online)	1097-0258
ISSN	0277-6715
DOI	10.1002/sim.7535
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Article ; Online: Methylation Subtypes of Primary Prostate Cancer Predict Poor Prognosis.

Wang, Xiaoyu / Jordahl, Kristina M / Zhu, Chenghao / Livingstone, Julie / Rhie, Suhn K / Wright, Jonathan L / Grady, William M / Boutros, Paul C / Stanford, Janet L / Dai, James Y

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2022 Volume 31, Issue 7, Page(s) 1473–1482

Abstract: Background: Patients with prostate cancer experience heterogeneous outcomes after radical prostatectomy. Genomic studies including The Cancer Genome Atlas (TCGA) have reported molecular signatures of prostate cancer, but few studies have assessed the ... ...

Abstract	Background: Patients with prostate cancer experience heterogeneous outcomes after radical prostatectomy. Genomic studies including The Cancer Genome Atlas (TCGA) have reported molecular signatures of prostate cancer, but few studies have assessed the prognostic effects of DNA methylation profiles. Methods: We conducted the largest methylome subtyping analysis for primary prostate tumors to date, using methylome data from three patient populations: TCGA, a prostate cancer cohort study conducted at the Fred Hutchinson Cancer Research Center (FH; Seattle, WA), and the Canadian International Cancer Genome Consortium (ICGC) cohort. Four subtypes were detected in the TCGA dataset, then independently assigned to FH and ICGC cohort data. The identified methylation subtypes were assessed for association with cancer prognosis in the above three patient populations. Results: Using a set of hypermethylated CpG sites, four methylation subtypes were identified in TCGA. Compared with subtype 1, subtype 4 had an HR of 2.09 (P = 0.029) for biochemical recurrence (BCR) in TCGA patients. HRs of 2.76 (P = 0.002) for recurrence and 9.73 (P = 0.002) for metastatic-lethal (metastasis or prostate cancer-specific death) outcomes were observed in the FH cohort. A similar pattern of association was noted in the Canadian ICGC cohort, though HRs were not statistically significant. Conclusions: A hypermethylated subtype was associated with an increased hazard of recurrence and mortality in three studies with prostate tumor methylome data. Further molecular work is needed to understand the effect of methylation subtypes on cancer prognosis. Impact: This study identified a DNA methylation subtype that was associated with worse prostate cancer prognosis after radical prostatectomy.
MeSH term(s)	Biomarkers, Tumor/genetics ; Canada ; Cohort Studies ; DNA Methylation ; Humans ; Male ; Prognosis ; Prostatectomy ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms/surgery
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2022-04-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1153420-5
ISSN	1538-7755 ; 1055-9965
ISSN (online)	1538-7755
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-22-0007
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Article ; Online: Coffee Intake, Caffeine Metabolism Genotype, and Survival Among Men with Prostate Cancer.

Gregg, Justin R / Kim, Jeri / Logothetis, Christopher / Hanash, Sam / Zhang, Xiaotao / Manyam, Ganiraju / Muir, Kenneth / Giles, Graham G / Stanford, Janet L / Berndt, Sonja I / Kogevinas, Manolis / Brenner, Hermann / Eeles, Rosalind A / Wei, Peng / Daniel, Carrie R

European urology oncology

2022 Volume 6, Issue 3, Page(s) 282–288

Abstract: Background: Coffee intake may lower prostate cancer risk and progression, but postdiagnosis outcomes by caffeine metabolism genotype are not well characterized.: Objective: To evaluate associations between coffee intake, caffeine metabolism genotype, ...

Abstract	Background: Coffee intake may lower prostate cancer risk and progression, but postdiagnosis outcomes by caffeine metabolism genotype are not well characterized. Objective: To evaluate associations between coffee intake, caffeine metabolism genotype, and survival in a large, multicenter study of men with prostate cancer. Design, setting, and participants: Data from The PRACTICAL Consortium database for 5727 men with prostate cancer from seven US, Australian, and European studies were included. The cases included had data available for the CYP1A2 -163C>A rs762551 single-nucleotide variant associated with caffeine metabolism, coffee intake, and >6 mo of follow-up. Outcome measurements and statistical analysis: Multivariable-adjusted Cox proportional hazards models across pooled patient-level data were used to compare the effect of coffee intake (categorized as low [reference], high, or none/very low) in relation to overall survival (OS) and prostate cancer-specific survival (PCSS), with stratified analyses conducted by clinical disease risk and genotype. Results and limitations: High coffee intake appeared to be associated with longer PCSS (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.68-1.08; p = 0.18) and OS (HR 0.90, 95% CI 0.77-1.07; p = 0.24), although results were not statistically significant. In the group with clinically localized disease, high coffee intake was associated with longer PCSS (HR 0.66, 95% CI 0.44-0.98; p = 0.040), with comparable results for the group with advanced disease (HR 0.92, 95% CI 0.69-1.23; p = 0.6). High coffee intake was associated with longer PCSS among men with the CYP1A2 AA (HR 0.67, 95% CI 0.49-0.93; p = 0.017) but not the AC/CC genotype (p = 0.8); an interaction was detected (p = 0.042). No associations with OS were observed in subgroup analyses (p > 0.05). Limitations include the nominal statistical significance and residual confounding. Conclusions: Coffee intake was associated with longer PCSS among men with a CYP1A2 -163AA (1F/1F) genotype, a finding that will require further replication. Patient summary: It is likely that coffee intake is associated with longer prostate cancer-specific survival in certain groups, but more research is needed to fully understand which men may benefit and why.
MeSH term(s)	Male ; Humans ; Caffeine/metabolism ; Coffee ; Cytochrome P-450 CYP1A2/genetics ; Cytochrome P-450 CYP1A2/metabolism ; Risk Factors ; Australia ; Genotype ; Prostatic Neoplasms/genetics
Chemical Substances	Caffeine (3G6A5W338E) ; Coffee ; Cytochrome P-450 CYP1A2 (EC 1.14.14.1)
Language	English
Publishing date	2022-08-20
Publishing country	Netherlands
Document type	Multicenter Study ; Journal Article
ISSN	2588-9311
ISSN (online)	2588-9311
DOI	10.1016/j.euo.2022.07.008
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Article ; Online: Reply to circumcision unlikely to be associated with prostate cancer risk.

Wright, Jonathan L / Lin, Daniel W / Stanford, Janet L

Cancer

2013 Volume 119, Issue 1, Page(s) 246

MeSH term(s)	Circumcision, Male/statistics & numerical data ; Humans ; Male ; Prostatic Neoplasms/epidemiology ; Sexually Transmitted Diseases/epidemiology
Language	English
Publishing date	2013-01-01
Publishing country	United States
Document type	Comment ; Letter
ZDB-ID	1429-1
ISSN	1097-0142 ; 0008-543X ; 1934-662X
ISSN (online)	1097-0142
ISSN	0008-543X ; 1934-662X
DOI	10.1002/cncr.27714
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