Publications by authors named "Joshua N Sampson"

129 Publications

Nonparametric parameters of 24-hour rest-activity rhythms and long-term cognitive decline and incident cognitive impairment in older men.

J Gerontol A Biol Sci Med Sci 2021 Sep 24. Epub 2021 Sep 24.

Research Institute, California Pacific Medical Center, San Francisco, CA.

Altered 24-hour rest-activity rhythms may be associated with cognitive impairment in older adults, but evidence from prospective studies is limited. Non-parametric methods were used to assess actigraphy-based activity patterns in 2,496 older men. Incident cognitive impairment was assessed four times over 12 years using the Modified Mini Mental State Examination (3MS) and Trails B tests, self-reported medication use, and clinical diagnosis. The highest quartile (vs. the lowest) of intradaily variability and the lowest quartiles (vs. the highest) of interdaily stability and relative amplitude were associated with incident cognitive impairment ((Hazard ratio (95% confidence interval): 1.82 (1.31, 2.53)), 1.36 (0.99, 1.86), and 1.85 (1.33, 2.56), respectively). A larger increase in intradaily variability over 7.5 years was associated with a greater subsequent decline in 3MS scores but not in Trails B performance. In conclusion, less stable and more variable rest-activity rhythms may represent early biomarkers of cognitive impairment in older men.
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http://dx.doi.org/10.1093/gerona/glab275DOI Listing
September 2021

Physical Activity From Adolescence Through Midlife and Associations With Body Mass Index and Endometrial Cancer Risk.

JNCI Cancer Spectr 2021 Aug 16;5(4):pkab065. Epub 2021 Jul 16.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Physical activity is associated with lower risk for endometrial cancer, but the extent to which the association is mediated by body mass index (BMI) in midlife is unclear. This study describes the physical activity-endometrial cancer association and whether BMI mediates this relationship.

Methods: Participants were 67 705 women in the National Institutes of Health-AARP Diet and Health Study (50-71 years) who recalled their physical activity patterns starting at age 15-18 years. We identified 5 long-term physical activity patterns between adolescence and cohort entry (ie, inactive, maintained low, maintained high, increasers, decreasers). We used Cox regression to assess the relationship between these patterns and midlife BMI and endometrial cancer, adjusting for covariates. Mediation analysis was used to estimate the proportion of the physical activity-endometrial cancer association that was mediated by midlife BMI.

Results: During an average 12.4 years of follow-up 1468 endometrial cancers occurred. Compared with long-term inactive women, women who maintained high or increased activity levels had a 19% to 26% lower risk for endometrial cancer (maintained high activity: hazard ratio = 0.81, 95% confidence interval [CI] = 0.67 to 0.98; increasers: hazard ratio = 0.74, 95% CI = 0.61 to 0.91). They also had a 50% to 77% lower risk for obesity in midlife (eg, maintained high activity: odds ratio for a BMI of 30-39.9 kg/m = 0.50, 95% CI = 0.46 to 0.55; and maintained high activity, odds ratio for a BMI of ≥40 kg/m = 0.32, 95% CI = 0.26 to 0.39). BMI was a statistically significant mediator accounting for 55.5% to 62.7% of the physical activity-endometrial cancer associations observed.

Conclusions: Both maintaining physical activity throughout adulthood and adopting activity later in adulthood can play a role in preventing obesity and lowering the risk for endometrial cancer.
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http://dx.doi.org/10.1093/jncics/pkab065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406434PMC
August 2021

Amount, Type, and Timing of Domain-Specific Moderate to Vigorous Physical Activity Among US Adults.

J Phys Act Health 2021 08;18(S1):S114-S122

Background: Surveillance of domain-specific physical activity in the United States is lacking. Thus, the authors describe domain-specific moderate to vigorous physical activity (MVPA) in a nationwide sample of US adults.

Methods: Participants from the AmeriSpeak panel (n = 2649; 20-75 y; 50% female) completed the Activities Completed Over Time in 24-Hours previous-day recall. The authors estimated average MVPA duration (in hours per day) overall and in major life domains by sex, age, race/ethnicity, and education. They also described the most commonly reported MVPAs and timing of MVPA during the day.

Results: Across all life domains, participants reported an average of 2.5 hours per day in MVPA. Most MVPA was accumulated during work (50% of total, 1.2 h/d) and household activities (28%, 0.7 h/d) with less MVPA reported in leisure time (15%, 0.4 h/d). Time reported in MVPA varied by sex, and race/ethnicity (P < .05). Walking at work and for exercise, childcare, and walking for transportation were the most commonly reported domain-specific MVPAs. A greater proportion of MVPA took place in the morning (∼06:00 h) and evening (∼18:00 h).

Conclusions: Work and household activities accounted for 78% of overall MVPA reported, while leisure-time MVPA accounted for only 15% of the total. Encouraging MVPA during leisure time and transportation remain important targets for promoting MVPA in US adults.
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http://dx.doi.org/10.1123/jpah.2021-0174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477755PMC
August 2021

Reproducibility, Temporal Variability, and Concordance of Serum and Fecal Bile Acids and Short Chain Fatty Acids in a Population-Based Study.

Cancer Epidemiol Biomarkers Prev 2021 Oct 10;30(10):1875-1883. Epub 2021 Aug 10.

Division of Cancer Epidemiology and Genetics, Metabolic Epidemiology Branch, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Background: Bile acid (BA) and short chain fatty acid (SCFA) production is affected by diet and microbial metabolism. These metabolites may play important roles in human carcinogenesis.

Methods: We used a fully quantitative targeted LC-MS/MS system to measure serum and fecal BA and SCFA concentrations in 136 Costa Rican adults at study baseline and 6-months. We randomly selected 50 participants and measured their baseline samples in duplicate. Our objective was to evaluate: Technical reproducibility; 6-month temporal variability; and concordance between sample type collected from the same individual at approximately the same time.

Results: Technical reproducibility was excellent, with intraclass correlation coefficients (ICC) ≥0.83 for all BAs except serum tauroursodeoxycholic acid (ICC = 0.72) and fecal glycolithocholic acid (ICC = 0.66) and ICCs ≥0.81 for all SCFAs except serum 2-methylbutyric acid (ICC = 0.56) and serum isobutyric acid (ICC = 0.64). Temporal variability ICCs were generally low, but several BAs (i.e., deoxycholic, glycoursodeoxycholic, lithocholic, taurocholic, and tauroursodeoxycholic acid) and SCFAs (i.e., 2-methylbutyric, butyric, propionic, and valeric acid) had 6-month ICCs ≥0.44. The highest degree of concordance was observed for secondary and tertiary BAs.

Conclusions: Serum and fecal BAs and SCFAs were reproducibly measured. However, 6-month ICCs were generally low, indicating that serial biospecimen collections would increase statistical power in etiologic studies. The low concordance for most serum and fecal metabolites suggests that consideration should be paid to treating these as proxies.

Impact: Our findings will inform the design and interpretation of future human studies on associations of BAs, SCFAs, and potentially other microbial metabolites, with disease risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0361DOI Listing
October 2021

Sedentary Behavior in United States Adults: Fall 2019.

Med Sci Sports Exerc 2021 Jul 23. Epub 2021 Jul 23.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Division of Population Health, Centers for Disease Control and Prevention, Atlanta, GA Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute; Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, Saint Louis, MO Risk Factor Assessment Branch, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD Division of Nutrition, Physical Activity, and Obesity, Centers for Disease Control, Atlanta, GA Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD Department of Geography, University of Hong Kong, Hong Kong, China Department of Kinesiology, California Polytechnic State University, San Luis Obispo, CA Health Behaviors Research Branch, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD.

Purpose: Higher levels of sedentary behavior are associated with early mortality, but the distribution of sedentary time by classes of behavior and demographic groups is poorly described in United States (US) adults. To quantify the amount and sources of sedentary time in US adults we conducted a nationwide survey using a novel validated self-administerd previous-day recall method and compare these values with a commonly used sitting time question.

Methods: Participants from the AmeriSpeak panel aged 20 to 75 years (N = 2,640) completed up to two Activities Completed over Time in 24 Hours (ACT24) previous day recalls. Recalls were conducted on randomly selected days in October and November 2019. Survey sample design were applied to reflect the US population.

Results: Mean age was 45.3 years, 51% were female, 67% non-Hispanic white, and 37% had a body mass index of ≥30 kg/m2. US adults reported a mean 9.5 hrs/d of sedentary time (95% confidence interval [CI] 9.4, 9.7 hrs/d), which was 34% more than reported using a common surveillance measure (p < 0.01). Most daily sedentary time was accumulated in the leisure and work life domains, with leisure accounting for 47% (4.3 hrs/d [95%CI 4.2, 4.5 hrs/d]) of the total sedentary time. Eighty-two percent of leisure time was spent sedentary, mainly watching television/videos or engaged in internet/computer use.

Conclusions: US adults appear to spend more time in sedentary behavior than previously thought and the majority of this time is accumulated at work and in leisure-time. Reducing sedentary screen-time during leisure in favor of physically active could be an important intervention target in the effort to increase physical activity in US adults.
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http://dx.doi.org/10.1249/MSS.0000000000002751DOI Listing
July 2021

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study.

JNCI Cancer Spectr 2021 Apr 23;5(2):pkab007. Epub 2021 Jan 23.

Basic Research Subdirection, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico.

Background: Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study.

Methods: Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons.

Results: Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided  = 3 × 10). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including , , , , and . A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (, , , ), Wilms tumor (, ), non-Hodgkin lymphoma (), and soft tissue sarcomas (, , , , ) compared with other pediatric cancers.

Conclusion: In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.
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http://dx.doi.org/10.1093/jncics/pkab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023430PMC
April 2021

Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident.

Science 2021 05 22;372(6543). Epub 2021 Apr 22.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (I)-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose-dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.
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http://dx.doi.org/10.1126/science.abg2538DOI Listing
May 2021

Efficient mixed model approach for large-scale genome-wide association studies of ordinal categorical phenotypes.

Am J Hum Genet 2021 05 8;108(5):825-839. Epub 2021 Apr 8.

Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Graduate School of Data Science, Seoul National University, Seoul 08826, Republic of Korea. Electronic address:

In genome-wide association studies, ordinal categorical phenotypes are widely used to measure human behaviors, satisfaction, and preferences. However, because of the lack of analysis tools, methods designed for binary or quantitative traits are commonly used inappropriately to analyze categorical phenotypes. To accurately model the dependence of an ordinal categorical phenotype on covariates, we propose an efficient mixed model association test, proportional odds logistic mixed model (POLMM). POLMM is computationally efficient to analyze large datasets with hundreds of thousands of samples, can control type I error rates at a stringent significance level regardless of the phenotypic distribution, and is more powerful than alternative methods. In contrast, the standard linear mixed model approaches cannot control type I error rates for rare variants when the phenotypic distribution is unbalanced, although they performed well when testing common variants. We applied POLMM to 258 ordinal categorical phenotypes on array genotypes and imputed samples from 408,961 individuals in UK Biobank. In total, we identified 5,885 genome-wide significant variants, of which, 424 variants (7.2%) are rare variants with MAF < 0.01.
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http://dx.doi.org/10.1016/j.ajhg.2021.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206161PMC
May 2021

Maternal autoimmune disease is not associated with cancer in the offspring.

Acta Paediatr 2021 07 8;110(7):2259-2266. Epub 2021 Mar 8.

Pediatrics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Aim: Autoimmune disease and its medication are associated with increased cancer risk in adults, but it is unknown whether maternal autoimmune disease and/or medication use in pregnancy are associated with increased cancer risk in offspring.

Methods: In this case-control study, we identified all patients under 20 years of age with their first cancer diagnosis in 1996-2014 from the Finnish Cancer Registry (n = 2029) and 1:5 population-based controls (n = 10,103) from the Medical Birth Register. We obtained information on maternal autoimmune disease and its medication from the relevant Finnish registries and used conditional logistic regression to analyse the risk of offspring cancer after maternal autoimmune disease exposure.

Results: The odds ratio (OR) for cancer in offspring following maternal autoimmune exposure was 0.76 (95% confidence interval [CI] 0.47-1.23). Individual ORs for inflammatory bowel and connective tissue diseases were 1.08 (95% CI 0.56-2.01) and 0.50 (95% CI 0.23-1.08), respectively. The OR for maternal autoimmune medication was 0.95 (95% CI 0.80-1.14) overall and similar by drug subtype. There was an increased risk with medication in late pregnancy but the ORs were unstable owing to small numbers.

Conclusion: Our study does not support an increased cancer risk among offspring of women with autoimmune disease or its medication during pregnancy.
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http://dx.doi.org/10.1111/apa.15821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270501PMC
July 2021

A Metabolomics Analysis of Postmenopausal Breast Cancer Risk in the Cancer Prevention Study II.

Metabolites 2021 Feb 10;11(2). Epub 2021 Feb 10.

Department of Population Science, American Cancer Society, Atlanta, GA 30303, USA.

Breast cancer is the most common cancer in women, but its incidence can only be partially explained through established risk factors. Our aim was to use metabolomics to identify novel risk factors for breast cancer and to validate recently reported metabolite-breast cancer findings. We measured levels of 1275 metabolites in prediagnostic serum in a nested case-control study of 782 postmenopausal breast cancer cases and 782 matched controls. Metabolomics analysis was performed by Metabolon Inc using ultra-performance liquid chromatography and a Q-Exactive high resolution/accurate mass spectrometer. Controls were matched by birth date, date of blood draw, and race/ethnicity. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer at the 90th versus 10th percentile (modeled on a continuous basis) of metabolite levels were estimated using conditional logistic regression, with adjustment for age. Twenty-four metabolites were significantly associated with breast cancer risk at a false discovery rate <0.20. For the nine metabolites positively associated with risk, the ORs ranged from 1.75 (95% CI: 1.29-2.36) to 1.45 (95% CI: 1.13-1.85), and for the 15 metabolites inversely associated with risk, ORs ranged from 0.59 (95% CI: 0.43-0.79) to 0.69 (95% CI: 0.55-0.87). These metabolites largely comprised carnitines, glycerolipids, and sex steroid metabolites. Associations for three sex steroid metabolites validated findings from recent studies and the remainder were novel. These findings contribute to growing data on metabolite-breast cancer associations by confirming prior findings and identifying novel leads for future validation efforts.
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http://dx.doi.org/10.3390/metabo11020095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916573PMC
February 2021

Risk Factors for Non-Human Papillomavirus (HPV) Type 16/18 Cervical Infections and Associated Lesions Among HPV DNA-Negative Women Vaccinated Against HPV-16/18 in the Costa Rica Vaccine Trial.

J Infect Dis 2021 Aug;224(3):503-516

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

Background: Factors that lead human papillomavirus (HPV) infections to persist and progress to cancer are not fully understood. We evaluated co-factors for acquisition, persistence, and progression of non-HPV-16/18 infections among HPV-vaccinated women.

Methods: We analyzed 2153 women aged 18-25 years randomized to the HPV-vaccine arm of the Costa Rica HPV Vaccine Trial. Women were HPV DNA negative for all types at baseline and followed for approximately 11 years. Generalized estimating equation methods were used to account for correlated observations. Time-dependent factors evaluated were age, sexual behavior, marital status, hormonally related factors, number of full-term pregnancies (FTPs), smoking behavior, and baseline body mass index.

Results: A total of 1777 incident oncogenic non-HPV-16/18 infections were detected in 12 292 visits (average, 0.14 infections/visit). Age and sexual behavior-related variables were associated with oncogenic non-HPV-16/18 acquisition. Twenty-six percent of incident infections persisted for ≥1 year. None of the factors evaluated were statistically associated with persistence of oncogenic non-HPV-16/18 infections. Risk of progression to Cervical Intraepithelial Neoplasia grade 2 or worst (CIN2+) increased with increasing age (P for trend = .001), injectable contraceptive use (relative risk, 2.61 [95% confidence interval, 1.19-5.73] ever vs never), and increasing FTPs (P for trend = .034).

Conclusions: In a cohort of HPV-16/18-vaccinated women, age and sexual behavior variables are associated with acquisition of oncogenic non-HPV-16/18 infections; no notable factors are associated with persistence of acquired infections; and age, parity, and hormonally related exposures are associated with progression to CIN2+.
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http://dx.doi.org/10.1093/infdis/jiaa768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496490PMC
August 2021

Efficacy of the bivalent HPV vaccine against HPV 16/18-associated precancer: long-term follow-up results from the Costa Rica Vaccine Trial.

Lancet Oncol 2020 12;21(12):1643-1652

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

Background: Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+).

Methods: Women aged 18-25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov, NCT00867464.

Findings: 7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0-4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7-11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1-11·7), 4·6 years (4·3-5·3) for the original control group, and 6·2 years (5·5-6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2-100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0-99·6). Similar protection was observed against HPV 16/18-associated CIN3-specifically at year 11, vaccine efficacy was 100% (95% CI 78·8-100·0) and cumulative vaccine efficacy was 94·9% (73·7-99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine.

Interpretation: The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable.

Funding: US National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(20)30524-6DOI Listing
December 2020

Impact of residential mobility on estimated environmental exposures in a prospective cohort of older women.

Environ Epidemiol 2020 Oct 24;4(5):e110. Epub 2020 Aug 24.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Longitudinal studies of environmental hazards often rely on exposure estimated at the participant's enrollment residence. This could lead to exposure misclassification if participants move over time.

Methods: We evaluated residential mobility in the Iowa Women's Health Study (age 55-69 years) over 19 years of follow-up (1986-2004). We assessed several environmental exposures of varying spatial scales at enrollment and follow-up addresses. Exposures included average nitrate concentrations in public water supplies, percent of agricultural land (row crops and pasture/hay) within 750 m, and the presence of concentrated animal feeding operations within 5 km. In comparison to gold standard duration-based exposures averaged across all residences, we evaluated the sensitivity and specificity of exposure metrics and attenuation bias for a hypothetical nested case-control study of cancer, which assumed participants did not move from their enrollment residence.

Results: Among 41,650 participants, 32% moved at least once during follow-up. Mobility was predicted by working outside the home, being a former/current smoker, having a higher education level, using a public drinking water supply, and town size of previous residence. Compared with duration-based exposures, the sensitivity and specificity of exposures at enrollment ranged from 94% to 99% and 97% to 99%, respectively. A hypothetical true odds ratio of 2.0 was attenuated 8% for nitrate, 9%-10% for agricultural land, and 6% for concentrated animal feeding operation exposures.

Conclusions: Overall, we found low rates of mobility and mobility-related exposure misclassification in the Iowa Women's Health Study. Misclassification and attenuation of hypothetical risk estimates differed by spatial variability and exposure prevalence.
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http://dx.doi.org/10.1097/EE9.0000000000000110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595244PMC
October 2020

Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast.

NPJ Breast Cancer 2020 7;6:41. Epub 2020 Sep 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD USA.

Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts ( = 0.004), but not with acini counts ( = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.
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http://dx.doi.org/10.1038/s41523-020-00184-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477555PMC
September 2020

Preanalytical Sample Handling Conditions and Their Effects on the Human Serum Metabolome in Epidemiologic Studies.

Am J Epidemiol 2021 02;190(3):459-467

Many epidemiologic studies use metabolomics for discovery-based research. The degree to which sample handling may influence findings, however, is poorly understood. In 2016, serum samples from 13 volunteers from the US Department of Agriculture's Beltsville Human Nutrition Research Center were subjected to different clotting (30 minutes/120 minutes) and refrigeration (0 minutes/24 hours) conditions, as well as different numbers (0/1/4) and temperatures (ice/refrigerator/room temperature) of thaws. The median absolute percent difference (APD) between metabolite levels and correlations between levels across conditions were estimated for 628 metabolites. The potential for handling artifacts to induce false-positive associations was estimated using variable hypothetical scenarios in which 1%-100% of case samples had different handling than control samples. All handling conditions influenced metabolite levels. Across metabolites, the median APD when extending clotting time was 9.08%. When increasing the number of thaws from 0 to 4, the median APD was 10.05% for ice and 5.54% for room temperature. Metabolite levels were correlated highly across conditions (all r's ≥ 0.84), indicating that relative ranks were preserved. However, if handling varied even modestly by case status, our hypotheticals showed that results can be biased and can result in false-positive findings. Sample handling affects levels of metabolites, and special care should be taken to minimize effects. Shorter room-temperature thaws should be preferred over longer ice thaws, and handling should be meticulously matched by case status.
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http://dx.doi.org/10.1093/aje/kwaa202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086237PMC
February 2021

Serum Concentrations of Per- and Polyfluoroalkyl Substances and Risk of Renal Cell Carcinoma.

J Natl Cancer Inst 2021 May;113(5):580-587

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Background: Per- and polyfluoroalkyl substances (PFAS) are highly persistent chemicals that have been detected in the serum of over 98% of the US population. Studies among highly exposed individuals suggest an association with perfluorooctanoic acid (PFOA) exposure and kidney cancer. It remains unclear whether PFOA or other PFAS are renal carcinogens or if they influence risk of renal cell carcinoma (RCC) at concentrations observed in the general population.

Methods: We measured prediagnostic serum concentrations of PFOA and 7 additional PFAS in 324 RCC cases and 324 individually matched controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) relating serum PFAS concentrations and RCC risk. Individual PFAS were modeled continuously (log2-transformed) and categorically, with adjustment for kidney function and additional potential confounders. All statistical tests were 2-sided.

Results: We observed a positive association with RCC risk for PFOA (doubling in serum concentration, ORcontinuous = 1.71, 95% CI = 1.23 to 2.37, P = .002) and a greater than twofold increased risk among those in the highest quartile vs the lowest (OR = 2.63, 95% CI = 1.33 to 5.20, Ptrend = .007). The association with PFOA was similar after adjustment for other PFAS (ORcontinuous = 1.68, 95% CI = 1.07 to 2.63, P = .02) and remained apparent in analyses restricted to individuals without evidence of diminished kidney function and in cases diagnosed 8 or more years after phlebotomy.

Conclusions: Our findings add substantially to the weight of evidence that PFOA is a renal carcinogen and may have important public health implications for the many individuals exposed to this ubiquitous and highly persistent chemical.
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http://dx.doi.org/10.1093/jnci/djaa143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096365PMC
May 2021

Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study.

JCO Precis Oncol 2020 21;4. Epub 2020 Aug 21.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Purpose: Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown.

Patients And Methods: We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based values using a Bonferroni-corrected significance threshold of < 8.06 × 10.

Results: Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; = 4.79 × 10), most notably but nonsignificantly for (patient cases, 4.0%; matched controls, 0.6%; = 9.64 × 10). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with variants (patient cases, 1.8%; controls, 0.4%; = 3.31 × 10), another gene implicated in DNA double-strand break repair.

Conclusion: In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.
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http://dx.doi.org/10.1200/PO.20.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469586PMC
August 2020

Efficacy of AS04-Adjuvanted Vaccine Against Human Papillomavirus (HPV) Types 16 and 18 in Clearing Incident HPV Infections: Pooled Analysis of Data From the Costa Rica Vaccine Trial and the PATRICIA Study.

J Infect Dis 2021 May;223(9):1576-1581

Divison of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Clinical trial data and real-world evidence suggest that the AS04-adjuvanted vaccine targeting human papillomavirus types 16 and 18 (AS04-HPV-16/18) vaccine provides nearly 90% protection against cervical intraepithelial neoplasia grade 3 or higher irrespective of type, among women vaccinated before sexual debut. This high efficacy is not fully explained by cross-protection. Although AS04-HPV-16/18 vaccination does not affect clearance of prevalent infections, it may accelerate clearance of newly acquired infections. We pooled data from 2 large-scale randomized controlled trials to evaluate efficacy of the AS04-HPV-16/18 vaccine against clearance of nontargeted incident infections. Results of our analysis do not suggest an effect in expediting clearance of incident infections.
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http://dx.doi.org/10.1093/infdis/jiaa561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248553PMC
May 2021

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.

PLoS One 2020 3;15(9):e0237792. Epub 2020 Sep 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America.

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.

Methods: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).

Results: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8).

Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.

Impact: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237792PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470401PMC
October 2020

Evaluation of serological assays to monitor antibody responses to single-dose HPV vaccines.

Vaccine 2020 08 24;38(38):5997-6006. Epub 2020 Jul 24.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Introduction: Whether existing serological assays are sufficiently robust to measure the lower antibody levels expected following single-dose HPV vaccination is unknown.

Methods: We evaluated seven assays measuring HPV-16/18 immunological responses overall and by number of doses in 530 serum samples from participants receiving varying doses of Cervarix or Gardasil up to 36-months post-vaccination. Serum was evaluated by simplex (HPV-16 ELISA, HPV-18 ELISA), multiplex (LIA-4, VLP-MIA, M9ELISA, GST-L1), and high-throughput pseudovirion-based neutralization assays (HT-PBNA), and results were compared to the gold standard HPV-16/18 secreted alkaline phosphatase neutralization assay (SEAP-NA). Reproducibility was assessed by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Percent agreement, Pearson correlation, and weighted-kappa were used to assess validity. Determinants of seronegativity were evaluated by chi-squared test.

Results: HPV-16: Seropositivity range was 97.1-99.5% for single dose and 98.8-99.8% overall. CV range was 4.0-18.0% for single dose and 2.9-19.5% overall. ICC range was 0.77-0.99 for single dose and 0.74-0.99 overall. Correlation with SEAP-NA range was 0.43-0.85 for single dose and 0.51-0.90 overall. Weighted-kappa range was 0.34-0.82 for single dose and 0.45-0.84 overall. HPV-18: Seropositivity range was 63.9-94.7% for single dose and 86.2-97.9% overall. CV range was 8.1-18.2% for single dose and 4.6-18.6% overall. ICC range was 0.75-0.99 for single dose and 0.83-0.99 overall. Correlation with SEAP-NA range was 0.31-0.99 for single dose and 0.27-0.96 overall. Weighted-kappa range was 0.35-0.83 for single dose and 0.45-0.84 overall. HPV-16 seronegativity was <5% for all assays. HPV-18 seronegativity range was 5.5-17.3%. For LIA-4 and GST-L1 where the proportion of seronegativity was >10%, the strongest correlates of seronegativity were receiving a single vaccine dose and receiving Gardasil.

Conclusions: These results support the utility of existing serological assays to monitor antibody responses following single-dose HPV vaccination.
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http://dx.doi.org/10.1016/j.vaccine.2020.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429278PMC
August 2020

Association Between Common Vaginal Infections and Cervical Non-Human Papillomavirus (HPV) 16/18 Infection in HPV-Vaccinated Women.

J Infect Dis 2021 02;223(3):445-451

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: How vaginal infections such as bacterial vaginosis, Candida spp, and Trichomonas vaginalis affect persistence of human papillomavirus (HPV) infection is not well established. Our study aimed to evaluate the association between common vaginal infections and cervical non-HPV16/18 infection, as risk factors associated with persistence of nonvaccine HPV types will become increasingly relevant in the setting of HPV vaccination.

Methods: We performed an analysis in 2039 AS04-HPV16/18-vaccinated women enrolled in a phase II/III trial in China, who were HPV DNA negative at month 0 and 6 and had at least 1 subsequent follow-up visit. Vaginal infections were detected in liquid-based cytology according to the diagnostic criteria of the Bethesda System. Associations between vaginal infections and incident and 6-month persistent non-HPV16/18 infections in the cervix were evaluated using generalized estimating equations, adjusting for the age at initial vaccination, as well as HPV types in the persistence analysis.

Results: Study visits with any vaginal infection had a statistically significant increased risk of incident non-HPV16/18 infection compared to those without vaginal infections (odds ratio [OR], 1.44 [95% confidence interval {CI}, 1.09-1.92]). However, vaginal infections were not associated with 6-month persistent non-HPV16/18 infection (OR, 1.02 [95% CI, .62-1.69]).

Conclusions: Our study suggests that common vaginal infections are not associated with persistence of non-HPV16/18 infection among HPV16/18-vaccinated women.
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http://dx.doi.org/10.1093/infdis/jiaa384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982446PMC
February 2021

Group testing in mediation analysis.

Stat Med 2020 Aug 4;39(18):2423-2436. Epub 2020 May 4.

Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

We consider the scenario where there is an exposure, multiple biologically defined sets of biomarkers, and an outcome. We propose a new two-step procedure that tests if any of the sets of biomarkers mediate the exposure/outcome relationship, while maintaining a prespecified familywise error rate. The first step of the proposed procedure is a screening step that removes all groups that are unlikely to be strongly associated with both the exposure and the outcome. The second step adapts recent advances in postselection inference to test if there are true mediators in each of the remaining candidate sets. We use simulation to show that this simple two-step procedure has higher statistical power to detect true mediating sets when compared with existing procedures. We then use our two-step procedure to identify a set of Lysine-related metabolites that potentially mediate the known relationship between increased body mass index and the increased risk of estrogen-receptor positive breast cancer in postmenopausal women.
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http://dx.doi.org/10.1002/sim.8546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262108PMC
August 2020

Serum Metabolomic Response to Low- and High-Dose Vitamin E Supplementation in Two Randomized Controlled Trials.

Cancer Epidemiol Biomarkers Prev 2020 07 20;29(7):1329-1334. Epub 2020 Apr 20.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Background: Vitamin E is an essential micronutrient and critical human antioxidant previously tested for cancer preventative effects with conflicting clinical trial results that have yet to be explained biologically.

Methods: We examined baseline and on-trial serum samples for 154 men randomly assigned to receive 400 IU vitamin E (as alpha-tocopheryl acetate; ATA) or placebo daily in the Vitamin E Atherosclerosis Prevention Study (VEAPS), and for 100 men administered 50 IU ATA or placebo daily in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC). Over 970 metabolites were identified using ultrahigh-performance LC/MS-MS. Linear regression models estimated the change in serum metabolites of men supplemented with vitamin E versus those receiving placebo in VEAPS as compared with ATBC.

Results: Serum alpha-carboxyethyl hydrochroman (CEHC) sulfate, alpha-tocopherol, and beta/gamma-tocopherol were significantly altered by ATA supplementation in both trials (all values ≤5.1 × 10, the Bonferroni multiple comparisons corrected statistical threshold). Serum C lactone sulfate was significantly decreased in response to the high-dose vitamin E in VEAPS (β = -0.70, = 8.1 × 10), but not altered by the low dose in ATBC (β = -0.17, = 0.4). In addition, changes in androgenic steroid metabolites were strongly correlated with the vitamin E supplement-associated change in C lactone sulfate only in the VEAPS trial.

Conclusions: We found evidence of a dose-dependent vitamin E supplementation effect on a novel C lactone sulfate compound that was correlated with several androgenic steroids.

Impact: Our data add information on a differential hormonal response based on vitamin E dose that could have direct relevance to opposing prostate cancer incidence results from previous large controlled trials.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340214PMC
July 2020

Confidence intervals for the difference between two relative risks.

Stat Methods Med Res 2020 Oct 16;29(10):3048-3058. Epub 2020 Apr 16.

Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

We provide methods to estimate the confidence interval for the difference between two relative risks. Letting , , and be the probabilities of an event in three groups (i.e. control, treatment 1, treatment 2), our methods estimate a confidence interval for  = / - /. We highlight that our methods can handle small sample sizes, covariates, and study populations from multiple strata. We specifically developed these methods for vaccine trials to estimate the difference between two vaccine efficacies, where VE = 1 - /, VE = 1 - / and  = VE - VE. We showcase our methods by using interim data from one of these trials to suggest that one dose of the human papillomavirus vaccine may be as efficacious as two doses of the vaccine.
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http://dx.doi.org/10.1177/0962280220915737DOI Listing
October 2020

Durability of Cross-Protection by Different Schedules of the Bivalent HPV Vaccine: The CVT Trial.

J Natl Cancer Inst 2020 10;112(10):1030-1037

Agencia Costarricense de Investigaciones Biomédicas, formerly Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, San José, Costa Rica.

Background: The Costa Rica HPV Vaccine Trial has documented cross-protection of the bivalent HPV vaccine against HPV31/33/45 up to 7 years after vaccination, even with one dose of the vaccine. However, the durability of such protection remains unknown. Here, we evaluate the efficacy of different schedules of the vaccine against HPV31/33/45 out to 11 years postvaccination, expanding to other nontargeted HPV types.

Methods: We compared the rates of HPV infection in vaccinated women with the rates in a comparable cohort of unvaccinated women. We estimated the average vaccine efficacy (VEavg) against incident infections and tested for a change in VE over time.

Results: Among 3-dose women, we observed statistically significant cross-protection against HPV31/33/45 (VEavg = 64.4%, 95% confidence interval [CI] = 57.7% to 70.0%). Additionally, we observed borderline, statistically significant cross-protection against HPV35 (VEavg = 23.2%, 95% CI = 0.3% to 40.8%) and HPV58 (VEavg = 21.2%, 95% CI = 4.2% to 35.3%). There was no decrease in VE over time (two-sided Ptrend > .05 for HPV31, -33, -35, -45, and -58). As a benchmark, VEavg against HPV16/18 was 82.0% (95% CI = 77.3% to 85.7%). Among 1-dose women, we observed comparable efficacy against HPV31/33/45 (VEavg = 54.4%, 95% CI = 21.0% to 73.7%). Acquisition of nonprotected HPV types was similar between vaccinated and unvaccinated women, indicating that the difference in HPV infection rates was not attributable to differential genital HPV exposure.

Conclusions: Substantial cross-protection afforded by the bivalent vaccine against HPV31/33/45, and to a lesser extent, HPV35 and HPV58, was sustained and remained stable after 11 years postvaccination, reinforcing the notion that the bivalent vaccine is an effective option for protection against HPV-associated cancers.
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http://dx.doi.org/10.1093/jnci/djaa010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566371PMC
October 2020

Evaluation of Durability of a Single Dose of the Bivalent HPV Vaccine: The CVT Trial.

J Natl Cancer Inst 2020 10;112(10):1038-1046

HPV Immunology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Background: The authors investigated the durability of vaccine efficacy (VE) against human papillomavirus (HPV)16 or 18 infections and antibody response among nonrandomly assigned women who received a single dose of the bivalent HPV vaccine compared with women who received multiple doses and unvaccinated women.

Methods: HPV infections were compared between HPV16 or 18-vaccinated women aged 18 to 25 years who received one (N = 112), two (N = 62), or three (N = 1365) doses, and age- and geography-matched unvaccinated women (N = 1783) in the long-term follow-up of the Costa Rica HPV Vaccine Trial. Cervical HPV infections were measured at two study visits, approximately 9 and 11 years after initial HPV vaccination, using National Cancer Institute next-generation sequencing TypeSeq1 assay. VE and 95% confidence intervals (CIs) were estimated. HPV16 or 18 antibody levels were measured in all one- and two-dose women, and a subset of three-dose women, using a virus-like particle-based enzyme-linked immunosorbent assay (n = 448).

Results: Median follow-up for the HPV-vaccinated group was 11.3 years (interquartile range = 10.9-11.7 years) and did not vary by dose group. VE against prevalent HPV16 or 18 infection was 80.2% (95% CI = 70.7% to 87.0%) among three-dose, 83.8% (95% CI = 19.5% to 99.2%) among two-dose, and 82.1% (95% CI = 40.2% to 97.0%) among single-dose women. HPV16 or 18 antibody levels did not qualitatively decline between years four and 11 regardless of the number of doses given, although one-dose titers continue to be statistically significantly lower compared with two- and three-dose titers.

Conclusion: More than a decade after HPV vaccination, single-dose VE against HPV16 or 18 infection remained high and HPV16 or 18 antibodies remained stable. A single dose of bivalent HPV vaccine may induce sufficiently durable protection that obviates the need for more doses.
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http://dx.doi.org/10.1093/jnci/djaa011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566548PMC
October 2020

Genetic variation in POT1 and risk of thyroid subsequent malignant neoplasm: A report from the Childhood Cancer Survivor Study.

PLoS One 2020 10;15(2):e0228887. Epub 2020 Feb 10.

Department of Pediatrics, Baylor College of Medicine and Dan L. Duncan Cancer Center, Houston, TX, United States of America.

Background: Telomere length is associated with risk for thyroid subsequent malignant neoplasm in survivors of childhood cancer. Here, we investigated associations between thyroid subsequent malignant neoplasm and inherited variation in telomere maintenance genes.

Methods: We used RegulomeDB to annotate the functional impact of variants mapping to 14 telomere maintenance genes among 5,066 five-or-more year survivors who participate in the Childhood Cancer Survivor Study (CCSS) and who are longitudinally followed for incidence of subsequent cancers. Hazard ratios for thyroid subsequent malignant neoplasm were calculated for 60 putatively functional variants with minor allele frequency ≥1% in or near telomere maintenance genes. Functional impact was further assessed by measuring telomere length in leukocyte subsets.

Results: The minor allele at Protection of Telomeres-1 (POT1) rs58722976 was associated with increased risk for thyroid subsequent malignant neoplasm (adjusted HR = 6.1, 95% CI: 2.4, 15.5, P = 0.0001; Fisher's exact P = 0.001). This imputed SNP was present in three out of 110 survivors who developed thyroid cancer vs. 14 out of 4,956 survivors who did not develop thyroid cancer. In a subset of 83 survivors with leukocyte telomere length data available, this variant was associated with longer telomeres in B lymphocytes (P = 0.004).

Conclusions: Using a functional variant approach, we identified and confirmed an association between a low frequency intronic regulatory POT1 variant and thyroid subsequent malignant neoplasm in survivors of childhood cancer. These results suggest that intronic variation in POT1 may affect key protein binding interactions that impact telomere maintenance and genomic integrity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228887PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010302PMC
May 2020

Identification of 102 Correlations between Serum Metabolites and Habitual Diet in a Metabolomics Study of the Prostate, Lung, Colorectal, and Ovarian Cancer Trial.

J Nutr 2020 04;150(4):694-703

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Metabolomics has proven useful for detecting objective biomarkers of diet that may help to improve dietary measurement. Studies to date, however, have focused on a relatively narrow set of lipid classes.

Objective: The aim of this study was to uncover candidate dietary biomarkers by identifying serum metabolites correlated with self-reported diet, particularly metabolites in underinvestigated lipid classes, e.g. triglycerides and plasmalogens.

Methods: We assessed dietary questionnaire data and serum metabolite correlations from 491 male and female participants aged 55-75 y in an exploratory cross-sectional study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Self-reported intake was categorized into 50 foods, food groups, beverages, and supplements. We examined 522 identified metabolites using 2 metabolomics platforms (Broad Institute and Massachusetts General Hospital). Correlations were identified using partial Pearson's correlations adjusted for age, sex, BMI, smoking status, study site, and total energy intake [Bonferroni-corrected level of 0.05/(50 × 522) = 1.9 × 10-6]. We assessed prediction of dietary intake by multiple-metabolite linear models with the use of 10-fold crossvalidation least absolute shrinkage and selection operator (LASSO) regression.

Results: Eighteen foods, beverages, and supplements were correlated with ≥1 serum metabolite at the Bonferroni-corrected significance threshold, for a total of 102 correlations. Of these, only 5 have been reported previously, to our knowledge. Our strongest correlations were between citrus and proline betaine (r = 0.55), supplements and pantothenic acid (r = 0.46), and fish and C40:9 phosphatidylcholine (PC) (r = 0.35). The multivariate analysis similarly found reasonably large correlations between metabolite profiles and citrus (r = 0.59), supplements (r = 0.57), and fish (r = 0.44).

Conclusions: Our study of PLCO participants identified many novel food-metabolite associations and replicated 5 previous associations. These candidate biomarkers of diet may help to complement measures of self-reported diet in nutritional epidemiology studies, though further validation work is still needed.
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http://dx.doi.org/10.1093/jn/nxz300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138659PMC
April 2020

Comparison of Radiation Dose Reconstruction Methods to Investigate Late Adverse Effects of Radiotherapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

Radiat Res 2020 02 3;193(2):95-106. Epub 2019 Dec 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Quantification of radiation dose to normal tissue during radiotherapy is critical for assessing risk for radiotherapy-related late effects, including subsequent neoplasms (SNs). Case-control studies of SNs typically reconstruct absorbed radiation dose to the specific SN location using individual treatment parameters. A simplified method estimates the maximum prescribed target dose to the body region in which the SN arises. We compared doses and risk estimates from these methods using data from case-control studies of subsequent brain tumors (64 cases, 244 controls) and breast cancer (94 cases, 358 controls) nested within the Childhood Cancer Survivor Study (≥5-year survivors of childhood cancer diagnosed 1970-1986). The weighted kappa statistic [95% confidence interval (CI)] evaluating agreement between categorical (>0-9.9/10-19.9/20-29.9/≥30 Gy) body-region and tumor location-specific doses was 0.95 (0.91-0.98) for brain and 0.76 (0.69-0.82) for breast. The body-region and location-specific doses were assigned to the same dose category for a smaller proportion of patients treated with fields delivering a heterogeneous dose across the tissue of interest (e.g., partial brain field = 57.1%; mantle field = 61.3%) than patients treated with fields delivering a more homogeneous dose (e.g., whole brain field = 100%). Excess odds ratios per Gy (95% CI) from conditional logistic regression were 1.25 (0.33-6.33) and 1.20 (0.31-6.14) for brain tumors and 0.21 (0.05-0.77) and 0.10 (0.02-0.44) for breast cancer, using location-specific and body-region doses, respectively. We observed that body-region doses can approximate location-specific doses when the tissue of interest is clearly in the radiation field or outside the treated body region. Agreement is lower when there is greater ambiguity of SN location relative to the treatment field.
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http://dx.doi.org/10.1667/RR15308.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063664PMC
February 2020

Efficacy of the AS04-Adjuvanted HPV16/18 Vaccine: Pooled Analysis of the Costa Rica Vaccine and PATRICIA Randomized Controlled Trials.

J Natl Cancer Inst 2020 08;112(8):818-828

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

Background: The AS04-adjuvanted HPV16/18 (AS04-HPV16/18) vaccine provides excellent protection against targeted human papillomavirus (HPV) types and a variable degree of cross-protection against others, including types 6/11/31/33/45. High efficacy against any cervical intraepithelial neoplasia grade 3 or greater (CIN3+; >90%) suggests that lower levels of protection may exist for a wide range of oncogenic HPV types, which is difficult to quantify in individual trials. Pooling individual-level data from two randomized controlled trials, we aimed to evaluate AS04-HPV16/18 vaccine efficacy against incident HPV infections and cervical abnormalities .

Methods: Data were available from the Costa Rica Vaccine Trial (NCT00128661) and Papilloma Trial Against Cancer in Young Adults trial (NCT00122681), two large-scale, double-blind randomized controlled trials of the AS04-HPV16/18 vaccine. Primary analyses focused on disease-free women with no detectable cervicovaginal HPV at baseline.

Results: A total of 12 550 women were included in our primary analyses (HPV arm = 6271, control arm = 6279). Incidence of 6-month persistent oncogenic and nononcogenic infections, excluding known and accepted protected types 6/11/16/18/31/33/45 (focusing on 34/35/39/40/42/43/44/51/52/53/54/56/58/59/66/68/73/70/74), was statistically significantly lower in the HPV arm than in the control arm (efficacy = 9.9%, 95% confidence interval [CI] = 1.7% to 17.4%). Statistically significant efficacy (P < .05) was observed for individual oncogenic types 16/18/31/33/45/52 and nononcogenic types 6/11/53/74. Efficacy against cervical abnormalities (all types) increased with severity, ranging from 27.7% (95% CI = 21.7% to 33.3%) to 58.7% (95% CI = 34.1% to 74.7%) for cytologic outcomes (low-grade squamous intraepithelial neoplasia lesion or greater, and high-grade squamous intraepithelial neoplasia lesion or greater, respectively) and 66.0% (95% CI = 54.4% to 74.9%) to 87.8% (95% CI = 71.1% to 95.7%) for histologic outcomes (CIN2+ and CIN3+, respectively). Comparing Costa Rica Vaccine Trial and Papilloma Trial Against Cancer in Young Adults results, there was no evidence of heterogeneity, except for type 51 (efficacy = -28.6% and 20.7%, respectively; two-sided P = .03).

Conclusions: The AS04-HPV16/18 vaccine provides some additional cross-protection beyond established protected types, which partially explains the high efficacy against CIN3+.
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http://dx.doi.org/10.1093/jnci/djz222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825474PMC
August 2020
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