Showing papers by "Margaret R. Karagas published in 2015"
Joshua N. Sampson1, William Wheeler, Meredith Yeager1, Orestis A. Panagiotou1 +445 more•Institutions (113)
TL;DR: Correlation analysis indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the Genetic etiology for the same disease can vary by population and environmental exposures.
Abstract: Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the add ...
158 citations
French Institute of Health and Medical Research1, Harvard University2, Katholieke Universiteit Leuven3, University of Rennes4, University of Wisconsin–Milwaukee5, Dartmouth College6, University of Occupational and Environmental Health Japan7, University of Rochester8, Columbia University9, University of Illinois at Chicago10, University of Cincinnati11, University of Missouri12, Boston University13, University of Queensland14, University of Turku15, University of Texas Health Science Center at Houston16
TL;DR: Vulnerable exposure windows that can occur as early as the preconception period and epigenetics as a major mechanism than can lead to disadvantageous "reprogramming" of the genome, thereby potentially resulting in transgenerational effects are highlighted.
Abstract: The Developmental Origins of Health and Disease (DOHaD) paradigm is one of the most rapidly expanding areas of biomedical research. Environmental stressors that can impact on DOHaD encompass a variety of environmental and occupational hazards as well as deficiency and oversupply of nutrients and energy. They can disrupt early developmental processes and lead to increased susceptibility to disease/dysfunctions later in life. Presentations at the fourth Conference on Prenatal Programming and Toxicity in Boston, in October 2014, provided important insights and led to new recommendations for research and public health action. The conference highlighted vulnerable exposure windows that can occur as early as the preconception period and epigenetics as a major mechanism than can lead to disadvantageous “reprogramming” of the genome, thereby potentially resulting in transgenerational effects. Stem cells can also be targets of environmental stressors, thus paving another way for effects that may last a lifetime. Current testing paradigms do not allow proper characterization of risk factors and their interactions. Thus, relevant exposure levels and combinations for testing must be identified from human exposure situations and outcome assessments. Testing of potential underpinning mechanisms and biomarker development require laboratory animal models and in vitro approaches. Only few large-scale birth cohorts exist, and collaboration between birth cohorts on a global scale should be facilitated. DOHaD-based research has a crucial role in establishing factors leading to detrimental outcomes and developing early preventative/remediation strategies to combat these risks.
135 citations
TL;DR: Accumulating evidence suggests that arsenic may increase risk of skin lesions and skin cancers at levels not previously considered harmful, and that genetic factors may influence risk.
Abstract: Skin lesions and cancer are known manifestations of chronic exposure to arsenic contaminated drinking water. Epidemiologic data primarily comes from regions with exposures 1–2 orders of magnitude above the current World Health Organization (WHO) guidelines of 10 μg/L. Emerging evidence indicates that more common exposures may also be related to both noncancerous and cancerous changes to the skin. In this review, we focus on the body of epidemiologic literature that encompasses exposures within the WHO guidelines, excluding studies that lacked individual exposure estimates and case reports. For skin lesions and skin cancers, 15 and 10 studies were identified that met our criteria, respectively. For skin lesions, a consistent dose-response relationship with water arsenic has been observed, with increased risk evident at low- to moderate-dose exposure. Of the larger studies of specific histologic types of skin cancers, although with differing exposure definitions, there was evidence of dose-related relationships with both basal cell carcinomas and squamous cell carcinomas. The effect of arsenic exposure on skin lesion risk is likely modified by genetic variants that influence arsenic metabolism. Accumulating evidence suggests that arsenic may increase risk of skin lesions and skin cancers at levels not previously considered harmful, and that genetic factors may influence risk.
126 citations
TL;DR: Findings relating breastfeeding to respiratory outcomes, gut diversity to prolonged periods of health, and specific bacterial communities in the gut prior to respiratory complications in CF highlight a connection between the intestinal microbiome and health and point to potential opportunities for antibiotic or probiotic interventions.
115 citations
TL;DR: The hypothesis that mercury may be contributing to epigenetic variability and immune cell proportion changes is supported, and it is suggested that in utero exposure to mercury and arsenic, even at low levels, may interact to impact the epigenome.
Abstract: Mercury and arsenic are known developmental toxicants Prenatal exposures are associated with adverse childhood health outcomes that could be in part mediated by epigenetic alterations that may also contribute to altered immune profiles In this study, we examined the association between prenatal mercury exposure on both DNA methylation and white blood cell composition of cord blood, and evaluated the interaction with prenatal arsenic exposure A total of 138 mother-infant pairs with postpartum maternal toenail mercury, prenatal urinary arsenic concentrations, and newborn cord blood were assessed using the Illumina Infinium Methylation450 array White blood cell composition was inferred from DNA methylation measurements A doubling in toenail mercury concentration was associated with a 25% decrease (95% CI: 50%, 10%) in the estimated monocyte proportion An increase of 35% (95% CI: 10, 70) in B-cell proportion was observed for females only Among the top 100 CpGs associated with toenail mercury levels (ranked on P-value), there was a significant enrichment of loci located in North shore regions of CpG islands (P = 0049), and the majority of these loci were hypermethylated (85%) Among the top 100 CpGs for the interaction between arsenic and mercury, there was a greater than expected proportion of loci located in CpG islands (P = 0045) and in South shore regions (P = 0009) and all of these loci were hypermethylated This work supports the hypothesis that mercury may be contributing to epigenetic variability and immune cell proportion changes, and suggests that in utero exposure to mercury and arsenic, even at low levels, may interact to impact the epigenome
115 citations
TL;DR: In utero arsenic exposure was associated with a higher risk of infection during the first year of life in the study population, particularly infections requiring medical treatment, and with diarrhea and respiratory symptoms.
Abstract: Background:Arsenic has been linked to disrupted immune function and greater infection susceptibility in highly exposed populations. Well arsenic levels above the U.S. EPA limit occur in our U.S. st...
101 citations
TL;DR: The inverse BPA-TSH relation among girls was stronger, but less precise, among iodine deficient versus sufficient mothers, and BPA exposure may reduce TSH among newborn girls, particularly when exposure occurs later in gestation.
96 citations
University of London1, National Institutes of Health2, Imperial College London3, Pompeu Fabra University4, University of Sydney5, Harvard University6, Food and Drug Administration7, University of Milan8, Washington University in St. Louis9, University of Cagliari10, University of Southampton11, Sapienza University of Rome12, Duke University13, Massey University14, University of California, Berkeley15, University of North Carolina at Chapel Hill16, University of Washington17, University of Exeter18, Louisiana State University19, University of Bremen20, Curtin University21, Université de Montréal22, Université Paris-Saclay23, University of Southern Denmark24, Karolinska Institutet25, Netherlands Cancer Institute26, Utrecht University27, German Cancer Research Center28, University of Paris29, University of California, Davis30, North Carolina State University31, Umeå University32, Seoul National University33, Dartmouth College34, National Institute of Occupational Health35, University of Massachusetts Lowell36, University of Caen Lower Normandy37, University of Cincinnati38, University of Iowa39, University of Copenhagen40, Australian National University41, University of Toronto42, World Health Organization43, University of Turin44, City University of New York45, Institut national de la recherche scientifique46, Columbia University47, George Washington University48, Autonomous University of Barcelona49, University of Guelph50, University of California, Los Angeles51, University of Amsterdam52, Uniformed Services University of the Health Sciences53, Texas A&M University54, University of Southern California55, University of Padua56, University of British Columbia57, Baylor College of Medicine58, Colorado State University59, University of Illinois at Chicago60, Emory University61, University of Texas Health Science Center at Houston62, Finnish Institute of Occupational Health63, Medical University of South Carolina64, American Cancer Society65, City of Hope National Medical Center66
TL;DR: Criticism of the IARC classification process are unconvincing, the procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence.
Abstract: BACKGROUND: Recently the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also ...
77 citations
19 Feb 2015
TL;DR: Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
75 citations
TL;DR: The findings suggest that breastfed infants have lower arsenic exposure than formula-fed infants, and that both formula powder and drinking water can be sources of exposure for U.S. infants.
Abstract: Background: Previous studies indicate that concentrations of arsenic in breast milk are relatively low even in areas with high drinking-water arsenic. However, it is uncertain whether breastfeeding...
71 citations
TL;DR: Results are consistent with evidence from more highly exposed populations suggesting a synergistic relationship between arsenic exposure and smoking on health outcomes and support a role for lower-level arsenic exposure in ischemic heart disease mortality.
TL;DR: The data suggest that placenta arsenic concentrations reflect both maternal and infant exposures, and the association between placental arsenic and household drinking water arsenic is examined.
Abstract: Arsenic crosses the placenta and may have adverse consequences in utero and later in life. At present, little is known about arsenic concentrations in placenta and their relation to maternal and infant exposures particularly at common levels of exposure. We measured placenta arsenic in a US cohort potentially exposed via drinking water from private wells, and evaluated the relationships between placenta and maternal and infant biomarker arsenic concentrations. We measured total arsenic concentrations in placental samples from women enrolled in the New Hampshire Birth Cohort Study (N=766). We compared these data to maternal urinary arsenic (total arsenic and individual species) collected at approximately 24-28 week gestation, along with maternal post-partum toenails and infant toenails using non-parametric multivariate analysis of log10-transformed data. We also examined the association between placental arsenic and household drinking water arsenic. Placenta arsenic concentrations were related to arsenic concentrations in maternal urine (β 0.55, P value <0.0001), maternal (β 0.30, P value 0.0196) and infant toenails (β 0.40, P value 0.0293) and household drinking water (β 0.09, P value <0.0001). Thus, our data suggest that placenta arsenic concentrations reflect both maternal and infant exposures.
TL;DR: It is demonstrated that a functional tumor suppressive role for miR‐34a in cultured urothelial cells, including reduced matrigel invasion and growth in soft agar, highlights the need for further clinical studies of miR-34a as a guide for recurrence screening and as a possible candidate therapeutic target in the bladder.
Abstract: Bladder cancer is the fourth most common cancer among men in the United States and more than half of patients experience recurrences within 5 years after initial diagnosis. Additional clinically informative and actionable biomarkers of the recurrent bladder cancer phenotypes are needed to improve screening and molecular therapeutic approaches for recurrence prevention. MicroRNA-34a (miR-34a) is a short noncoding regulatory RNA with tumor suppressive attributes. We leveraged our unique, large, population-based prognostic study of bladder cancer in New Hampshire, United States to evaluate miR-34a expression levels in individual tumor cells to assess prognostic value. We collected detailed exposure and medical history data, as well as tumor tissue specimens from bladder patients and followed them long-term for recurrence, progression and survival. Fluorescence-based in situ hybridization assays were performed on urothelial carcinoma tissue specimens (n = 229). A larger proportion of the nonmuscle invasive tumors had high levels of miR-34a within the carcinoma cells compared to those tumors that were muscle invasive. Patients with high miR-34a levels in their baseline nonmuscle invasive tumors experienced lower risks of recurrence (adjusted hazard ratio 0.57, 95% confidence interval 0.34-0.93). Consistent with these observations, we demonstrated a functional tumor suppressive role for miR-34a in cultured urothelial cells, including reduced matrigel invasion and growth in soft agar. Our results highlight the need for further clinical studies of miR-34a as a guide for recurrence screening and as a possible candidate therapeutic target in the bladder.
TL;DR: It is found that useful data can be extracted directly from electronic medical records for epidemiologic research and exposure to low-level arsenic may be associated with reduced head circumference in a sex dependent manner that warrants further investigation.
Abstract: Early life exposure to arsenic is associated with decreased birth weight in highly exposed populations but little is known about effects of low-level arsenic exposure on growth in utero. Using a sample of 272 pregnancies from New Hampshire we obtained biometric measurements directly from fetal ultrasound reports commonly found in electronic medical records. We used information extraction methods to develop and validate an automated approach for mining biometric measurements from the text of clinical reports. As a preliminary analysis, we examined associations between in utero low-level arsenic exposure (as measured by maternal urinary arsenic concentration) and fetal growth measures (converted to Z-scores based on reference populations for estimated fetal weight, head, and other body measures) at approximately 18 weeks of gestation. In a preliminary cross-sectional analysis of 223 out of 272 pregnancies, maternal urinary arsenic concentration (excluding arsenobetaine) was associated with a reduction in head circumference Z-score (Spearman correlation coefficient, rs = -0.08, p-value = 0.21) and a stronger association was observed among female fetuses at approximately 18 weeks of gestation (rs = - 0.21, p-value < 0.05). Although, associations were attenuated in adjusted analyses — among female fetuses a 1 μg/L increase in maternal urinary arsenic concentration was associated with a decrease of 0.047 (95% CI: -0.115, 0.021) in head circumference and 0.072 (95% CI: -0.151, 0.007) decrease in biparietal head diameter Z-score. Our study demonstrates that useful data can be extracted directly from electronic medical records for epidemiologic research. We also found evidence that exposure to low-level arsenic may be associated with reduced head circumference in a sex dependent manner that warrants further investigation.
TL;DR: Clinicians should become familiar with childhood arsenic exposure, potential health effects, and strategies to reduce exposure because of the concern about children's consumption of arsenic in rice.
TL;DR: There were significant differences in survival between those with SCC, BCC and controls, with significantly greater risk of mortality after SCC compared to controls, and the excess deaths persisted after adjustment for numerous personal risk factors including time‐varying non‐skin cancer occurrence, age, sex and smoking.
Abstract: A retrospective cohort analysis of survival after keratinocyte cancer (KC) was conducted using data from a large, population-based case-control study of KC in New Hampshire. The original study collected detailed information during personal interviews between 1993 and 2002 from individuals with squamous (SCC) and basal (BCC) cell carcinoma, and controls identified through the Department of Transportation, frequency-matched on age and sex. Participants without a history of non-skin cancer at enrolment were followed as a retrospective cohort to assess survival after either SCC or BCC, or a reference date for controls. Through 2009, cancers were identified from the New Hampshire State Cancer Registry and self-report; death information was obtained from state death certificate files and the National Death Index. There were significant differences in survival between those with SCC, BCC and controls (p = 0.040), with significantly greater risk of mortality after SCC compared to controls (adjusted hazard ratio [HR] 1.25; 95% confidence interval 1.01-1.54). Mortality after BCC was not significantly altered (HR 0.96; 95% CI 0.77-1.19). The excess mortality after SCC persisted after adjustment for numerous personal risk factors including time-varying non-skin cancer occurrence, age, sex and smoking. Survival from the date of the intervening cancer, however, did not vary (HR for SCC 0.98; 95% CI 0.70-1.38). Mortality also remained elevated when individuals with subsequent melanoma were excluded (HR for SCC 1.30; 95% CI 1.05-1.61). Increased mortality after SCC cannot be explained by the occurrence of intervening cancers, but may reflect a more general predisposition to life threatening illness that merits further investigation.
TL;DR: In a U.S. cohort of pregnant women, arsenic exposure was associated with greater increases in blood pressure over the course of pregnancy, which may have important implications because even modest increases inBlood pressure impact cardiovascular disease risk.
Abstract: BackgroundInorganic arsenic exposure has been related to the risk of increased blood pressure based largely on cross-sectional studies conducted in highly exposed populations. Pregnancy is a period...
TL;DR: Generally, preterm birth has a stronger spatial association with groundwater arsenic than term LBW, suggesting an inconsistency in the impact of arsenic on the two reproductive outcomes, as well as evident spatial associations between the two adverse human reproductive outcomes and groundwater arsenic in New Hampshire, USA.
Abstract: There is increasing evidence of the role of arsenic in the etiology of adverse human reproductive outcomes. Because drinking water can be a major source of arsenic to pregnant women, the effect of arsenic exposure through drinking water on human birth may be revealed by a geospatial association between arsenic concentration in groundwater and birth problems, particularly in a region where private wells substantially account for water supply, like New Hampshire, USA. We calculated town-level rates of preterm birth and term low birth weight (term LBW) for New Hampshire, by using data for 1997–2009 stratified by maternal age. We smoothed the rates by using a locally weighted averaging method to increase the statistical stability. The town-level groundwater arsenic probability values are from three GIS data layers generated by the US Geological Survey: probability of local groundwater arsenic concentration >1 µg/L, probability >5 µg/L, and probability >10 µg/L. We calculated Pearson’s correlation coefficients (r) between the reproductive outcomes (preterm birth and term LBW) and the arsenic probability values, at both state and county levels. For preterm birth, younger mothers (maternal age 10 µg/L; for older mothers, r = 0.19 when the smoothing threshold = 3,500; a majority of county level r values are positive based on the arsenic data of probability >10 µg/L. For term LBW, younger mothers (maternal age 1 µg/L; for older mothers, r = 0.14 when the rates are smoothed with a threshold = 1,000 births and also adjusted by town median household income in 1999, and the arsenic values are the town minimum based on probability >10 µg/L. At the county level for younger mothers, positive r values prevail, but for older mothers, it is a mix. For both birth problems, the several most populous counties—with 60–80 % of the state’s population and clustering at the southwest corner of the state—are largely consistent in having a positive r across different smoothing thresholds. We found evident spatial associations between the two adverse human reproductive outcomes and groundwater arsenic in New Hampshire, USA. However, the degree of associations and their sensitivity to different representations of arsenic level are variable. Generally, preterm birth has a stronger spatial association with groundwater arsenic than term LBW, suggesting an inconsistency in the impact of arsenic on the two reproductive outcomes. For both outcomes, younger maternal age has stronger spatial associations with groundwater arsenic.
TL;DR: It is suggested that allergies and atopy may influence risk of early onset BCC and SCC, and that effects may be gender specific.
Abstract: Background: Little is known about whether history of allergies and atopy is related to the occurrence of keratinocyte cancers. Thus, we evaluated the association between history of allergies and atopy and the incidence of squamous cell carcinoma (SCC) and early onset basal cell carcinoma (BCC).
Methods: As part of a population-based case–control study, interviews were conducted with 1,050 residents of New Hampshire (375 early onset BCC cases and 251 controls, 254 SCC cases and 432 controls). ORs of SCC and early onset BCC and history of allergy and atopic dermatitis were computed using logistic regression, while controlling for potential confounding factors.
Results: An overall inverse association was observed between a history of allergy and early onset BCC [OR, 0.61; 95% confidence interval (CI), 0.38–0.97] but not SCC (OR, 1.18; 95% CI, 0.78–1.79). Among women, we found reduced ORs of both early onset BCC and of SCC in relation to allergy history (early onset BCC OR, 0.53; 95% CI, 0.31–0.92 and SCC OR, 0.59; 95% CI, 0.29–1.19). Among men, we observed no clear association with early onset BCC (OR, 0.87; 95% CI, 0.39–1.99) and an increased risk of SCC (OR, 1.58; 95% CI, 0.93–2.69).
Conclusion: Our findings suggest that allergies and atopy may influence risk of early onset BCC and SCC, and that effects may be gender specific.
Impact: A deeper understanding of the immune mechanisms underlying allergies and atopy may provide new routes of preventing keratinocyte cancers. Cancer Epidemiol Biomarkers Prev; 24(4); 1–6. ©2015 AACR.
TL;DR: To identify genetic variants that modify bladder cancer prognosis focusing on genes involved in major biological carcinogenesis processes, as nearly half of patients with bladder cancer experience recurrences reliable predictors of this recurrent phenotype are needed to guide surveillance and treatment.
Abstract: Objective
To identify genetic variants that modify bladder cancer prognosis focusing on genes involved in major biological carcinogenesis processes (apoptosis, proliferation, DNA repair, hormone regulation, immune surveillance, and cellular metabolism), as nearly half of patients with bladder cancer experience recurrences reliable predictors of this recurrent phenotype are needed to guide surveillance and treatment.
Patients and methods
We analysed variant genotypes hypothesised to modify these processes in 563 patients with urothelial-cell carcinoma enrolled in a population-based study of incident bladder cancer conducted in New Hampshire, USA. After diagnosis, patients were followed over time to ascertain recurrence and survival status, making this one of the first population-based studies with detailed prognosis data. Cox proportional hazards regression was used to assess the relationship between single nucleotide polymorphisms (SNPs) and prognosis endpoints.
Results
Patients with aldehyde dehydrogenase 2 (ALDH2) variants had a shorter time to first recurrence (adjusted non-invasive hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.29–2.78). There was longer survival among patients with non-invasive tumours associated with DNA repair X-ray repair cross-complementing protein 4 (XRCC4) heterozygous genotype compared with wild-type (adjusted HR 0.53, 95% CI 0.38–0.74). Time to recurrence was shorter for patients who had a variant allele in vascular cellular adhesion molecule 1 (VCAM1) and were treated with immunotherapy (P interaction < 0.001).
Conclusions
Our analysis suggests candidate prognostic SNPs that could guide personalised bladder cancer surveillance and treatment.
University of Leeds1, University of Sydney2, King's College London3, The Hertz Corporation4, Leiden University5, University of New Mexico6, University of California, San Francisco7, University of Auckland8, Dartmouth College9, QIMR Berghofer Medical Research Institute10, BC Cancer Research Centre11, University of Hawaii12, University of Glasgow13, Lund University14, University of Pennsylvania15, Queen Mary University of London16, Institute of Cancer Research17, The Breast Cancer Research Foundation18, University of Lübeck19
TL;DR: A cutaneous melanoma risk algorithm based upon seven factors, hair color, skin type, family history, freckling, nevus count, number of large nevi, and history of sunburn, is developed to form the basis of a self-assessment Web tool for the general public.
Abstract: Background: We report the development of a cutaneous melanoma risk algorithm based upon seven factors; hair color, skin type, family history, freckling, nevus count, number of large nevi, and history of sunburn, intended to form the basis of a self-assessment Web tool for the general public.
Methods: Predicted odds of melanoma were estimated by analyzing a pooled dataset from 16 case–control studies using logistic random coefficients models. Risk categories were defined based on the distribution of the predicted odds in the controls from these studies. Imputation was used to estimate missing data in the pooled datasets. The 30th, 60th, and 90th centiles were used to distribute individuals into four risk groups for their age, sex, and geographic location. Cross-validation was used to test the robustness of the thresholds for each group by leaving out each study one by one. Performance of the model was assessed in an independent UK case–control study dataset.
Results: Cross-validation confirmed the robustness of the threshold estimates. Cases and controls were well discriminated in the independent dataset [area under the curve, 0.75; 95% confidence interval (CI), 0.73–0.78]. Twenty-nine percent of cases were in the highest risk group compared with 7% of controls, and 43% of controls were in the lowest risk group compared with 13% of cases.
Conclusion: We have identified a composite score representing an estimate of relative risk and successfully validated this score in an independent dataset.
Impact: This score may be a useful tool to inform members of the public about their melanoma risk. Cancer Epidemiol Biomarkers Prev; 24(5); 1–8. ©2015 AACR.
TL;DR: Investigating the association between in utero arsenic exposure and infant cord blood leptin concentrations within 156 mother-infant pairs from the New Hampshire Birth Cohort Study indicates that urinary arsenic species concentrations were predictive of infant Cord blood leptin levels following adjustment for creatinine.
01 Jan 2015
TL;DR: The heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites are estimated, providing important insights into the genetic architecture of cancers and suggest new avenues for investigation.
Abstract: Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl 2, on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation. Studies of related individuals have consistently demonstrated that there is notable familial aggregation of cancer. The three largest studies, based on the Swedish Family-Cancer Database (1–3), the Utah Population and Cancer Registry Database (4,5), and the Icelandic Cancer Registry (6), have shown familial aggregation for cancer at nearly every anatomical site. For common cancers such as prostate, breast, and lung, the familial relative risk (FRR), defined as the increase in risk associated with each affected first-degree relative of an individual, is generally estimated to be below or around 2.0. In contrast, for some rare cancers occurring early in life, such as those of testes and bone, estimates of FRR can exceed 5. Although shared environmental factors contribute to this aggregation, studies of twins (7,8) and extended family members (6,9,10) have clearly identified a substantial genetic contribution, commonly known as heritability. Genome-wide association studies (GWAS) have provided an opportunity to study the contribution of common single-nucleotide polymorphisms (SNPs) to the heritability of complex traits, including cancers. In addition to identifying specific susceptibility SNPs, novel mixed-effect modeling methods (11–13) can utilize GWAS data to quantify the additive heritability attributable to all common susceptibility SNPs captured by genotyping arrays, regardless of whether those SNPs individually have reached the stringent level of genome-wide statistical significance. Understanding the total contribution of common SNPs will be instrumental for evaluating the potential clinical applications of genetics in risk stratification and for guiding future genetic studies of cancer(14,15). Evidence also suggests that there is overlap between cancers with respect to their genetic architectures. Previous family studies have observed familial co-aggregation of cancers among certain sites (5,6), including pairs of cancers at neighboring sites, such as the colon and rectum, as well as for more distant and seemingly unrelated sites such as the cervix and esophagus (6). GWAS have also directly identified shared regions such as 8q24.1 and 5p15.33 (TERT-CLPTM1L) containing SNPs affecting cancer at multiple sites, while earlier studies have identified major genes such as TP53 (16) and BRCA (17) containing highly penetrant rare variants affecting multiple cancers. Sites with overlapping genetic architectures may be studied together to understand shared biology and to increase power to detect susceptibility loci. In this study, we performed an analysis of heritability and shared heritability for cancer at 13 different sites using data from case/control GWAS of more than 80 000 individuals carried out or reported to the US National Cancer Institute. We expand upon recent GWAS estimates of heritability (13) by nearly doubling the number of cases evaluated, exploring six new cancer (sub)types, and considering populations of nonEuropean ancestry. We use detailed information on multiple D ow naded rom http/academ ic.p.com /jnci/article-ab07/12/djv279/2457731 by U niersity of Vrona user on 19 Feruary 2020 7 of 11 | JNCI J Natl Cancer Inst, 2015, Vol. 107, No. 12 a r t ic le a r t ic le smoking characteristics to assess the proportion of heritability in smoking-related cancers that can be attributed to the genetic determinants of cigarette smoking. Furthermore, we use genetic correlation analysis to assess shared heritability across cancer sites and for lung cancer across two distinct ethnic populations to assess the evidence of gene-environment interactions for this complex malignancy. These analyses provide insights into the contribution of common SNPs to cancer heritability, coheritability and their relationships to a major environmental risk-factor, smoking.
TL;DR: The results suggest that genetic variability may contribute to As-associated increases in BP over time.
TL;DR: GLI3 is identified as a key signaling node that is affected by arsenic, mediating a subset of its effects on developmental signaling and fetal health.
TL;DR: The informatics framework suggests a new methodology for embedding functional analysis in network modeling of statistical epistasis in genetic association studies by identifying several GO categories that have significant dyadicity or heterophilicity associated with bladder cancer susceptibility.
Abstract: The interaction effect among multiple genetic factors, i.e. epistasis, plays an important role in explaining susceptibility on common human diseases and phenotypic traits. The uncertainty over the number of genetic attributes involved in interactions poses great challenges in genetic association studies and calls for advanced bioinformatics methodologies. Network science has gained popularity in modeling genetic interactions thanks to its structural characterization of large numbers of entities and their complex relationships. However, little has been done on functionally interpreting statistically inferred epistatic interactions using networks. In this study, we propose to characterize gene functional properties in the context of interaction network structure. We used Gene Ontology (GO) to functionally annotate genes as vertices in a statistical epistasis network, and quantitatively characterize the correlation between the distribution of gene functional properties and the network structure by measuring dyadicity and heterophilicity of each functional category in the network. These two parameters quantify whether genetic interactions tend to occur more frequently for genes from the same functional category, i.e. dyadic effect, or more frequently for genes from across different functional categories, i.e. heterophilic effect. By applying this framework to a population-based bladder cancer dataset, we were able to identify several GO categories that have significant dyadicity or heterophilicity associated with bladder cancer susceptibility. Thus, our informatics framework suggests a new methodology for embedding functional analysis in network modeling of statistical epistasis in genetic association studies.
TL;DR: The results, combined with an in-depth evaluation of other studies, suggested that confounding from smoking intensity or duration could explain this association, and highlighted the need to carefully evaluate the confounding association of smoking in the selenium-bladder cancer association.
Abstract: Selenium has been linked to a reduced risk of bladder cancer in some studies. Smoking, a well-established risk factor for bladder cancer, has been associated with lower selenium levels in the body. We investigated the selenium-bladder cancer association in subjects from Maine, New Hampshire, and Vermont in the New England Bladder Cancer Case-Control Study. At interview (2001-2005), participants provided information on a variety of factors, including a comprehensive smoking history, and submitted toenail samples, from which we measured selenium levels. We estimated odds ratios and 95% confidence intervals among 1,058 cases and 1,271 controls using logistic regression. After controlling for smoking, we saw no evidence of an association between selenium levels and bladder cancer (for fourth quartile vs. first quartile, odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.77, 1.25). When results were restricted to regular smokers, there appeared to be an inverse association (OR = 0.76, 95% CI: 0.58, 0.99); however, when pack-years of smoking were considered, this association was attenuated (OR = 0.91, 95% CI: 0.68, 1.20), indicating potential confounding by smoking. Despite some reports of an inverse association between selenium and bladder cancer overall, our results, combined with an in-depth evaluation of other studies, suggested that confounding from smoking intensity or duration could explain this association. Our study highlights the need to carefully evaluate the confounding association of smoking in the selenium-bladder cancer association.
TL;DR: The results showed a weak positive association between ever consuming alcohol and melanoma occurrence, and do not provide strong support for the hypothesis that alcohol consumption plays a role in the development of melanoma in women.
Abstract: While alcohol consumption is known to increase the risk of several types of cancer, evidence regarding the association between alcohol and melanoma is inconclusive. This pooled analysis was conducted to examine total alcohol consumption (grams per day), and type of alcohol consumed (beer, wine, beer and wine combined, and liquor) in relation to melanoma among women using original data from eight completed case-control studies (1886 cases and 2113 controls), with adjustment for the potential confounding effects of sun exposure-related factors. We found a positive association with ever consuming alcohol [adjusted pooled odds ratio (pOR) 1.3, 95 % confidence interval (CI) 1.1-1.5]. Specifically the pORs were 1.4 (95 % CI 1.1-1.8) for wine, 1.1 (95 % CI 0.9-1.5) for beer and 1.2 (95 % CI 1.0-1.4) for liquor. However, the pOR for the highest fourth of consumption compared with never consumption was 1.0 (95 % CI 0.7-1.3) without evidence of a trend with increasing amount of total alcohol, or separately with amount of beer, wine or liquor consumed. Stratifying by anatomic site of lesion, number of nevi, age group, or histologic subtype did not alter these results. Although the results showed a weak positive association between ever consuming alcohol and melanoma occurrence, our findings do not provide strong support for the hypothesis that alcohol consumption plays a role in the development of melanoma in women.
TL;DR: Using cluster models as a data reduction step to identify jobs with similar response patterns prior to obtaining expert ratings has the potential to aid rule-based assessment by systematically reducing the number of exposure decisions needed.
Abstract: Objectives: Rule-based expert exposure assessment based on questionnaire response patterns in population-based studies improves the transparency of the decisions The number of unique response patterns, however, can be nearly equal to the number of jobs An expert may reduce the number of patterns that need assessment using expert opinion, but each expert may identify different patterns of responses that identify an exposure scenario Here, hierarchical clustering methods are proposed as a systematic data reduction step to reproducibly identify similar questionnaire response patterns prior to obtaining expert estimates As a proof-of-concept, we used hierarchical clustering methods to identify groups of jobs (clusters) with similar responses to diesel exhaust-related questions and then evaluated whether the jobs within a cluster had similar (previously assessed) estimates of occupational diesel exhaust exposure Methods: Using the New England Bladder Cancer Study as a case study, we applied hierarchical cluster models to the diesel-related variables extracted from the occupational history and job- and industry-specific questionnaires (modules) Cluster models were separately developed for two subsets: (i) 5395 jobs with ≥1 variable extracted from the occupational history indicating a potential diesel exposure scenario, but without a module with diesel-related questions; and (ii) 5929 jobs with both occupational history and module responses to diesel-relevant questions For each subset, we varied the numbers of clusters extracted from the cluster tree developed for each model from 100 to 1000 groups of jobs Using previously made estimates of the probability (ordinal), intensity (μg m-3 respirable elemental carbon), and frequency (hours per week) of occupational exposure to diesel exhaust, we examined the similarity of the exposure estimates for jobs within the same cluster in two ways First, the clusters' homogeneity (defined as >75% with the same estimate) was examined compared to a dichotomized probability estimate (<5 versus ≥5%; <50 versus ≥50%) Second, for the ordinal probability metric and continuous intensity and frequency metrics, we calculated the intraclass correlation coefficients (ICCs) between each job's estimate and the mean estimate for all jobs within the cluster Results: Within-cluster homogeneity increased when more clusters were used For example, ≥80% of the clusters were homogeneous when 500 clusters were used Similarly, ICCs were generally above 07 when ≥200 clusters were used, indicating minimal within-cluster variability The most within-cluster variability was observed for the frequency metric (ICCs from 04 to 08) We estimated that using an expert to assign exposure at the cluster-level assignment and then to review each job in non-homogeneous clusters would require ~2000 decisions per expert, in contrast to evaluating 4255 unique questionnaire patterns or 14983 individual jobs Conclusions: This proof-of-concept shows that using cluster models as a data reduction step to identify jobs with similar response patterns prior to obtaining expert ratings has the potential to aid rule-based assessment by systematically reducing the number of exposure decisions needed While promising, additional research is needed to quantify the actual reduction in exposure decisions and the resulting homogeneity of exposure estimates within clusters for an exposure assessment effort that obtains cluster-level expert assessments as part of the assessment process © 2014 Published by Oxford University Press on behalf of the British Occupational Hygiene Society 2014
TL;DR: In this paper, the authors used ordinal classification trees (CTs) to predict occupational diesel exhaust exposure in a case-control study and found that the best ordinal tree predicted fewer cases of large disagreement with the expert assessments.
Abstract: Objectives To evaluate occupational exposures in case-control studies, exposure assessors typically review each job individually to assign exposure estimates. This process lacks transparency and does not provide a mechanism for recreating the decision rules in other studies. In our previous work, nominal (unordered categorical) classification trees (CTs) generally successfully predicted expert-assessed ordinal exposure estimates (i.e. none, low, medium, high) derived from occupational questionnaire responses, but room for improvement remained. Our objective was to determine if using recently developed ordinal CTs would improve the performance of nominal trees in predicting ordinal occupational diesel exhaust exposure estimates in a case-control study. Methods We used one nominal and four ordinal CT methods to predict expert-assessed probability, intensity, and frequency estimates of occupational diesel exhaust exposure (each categorized as none, low, medium, or high) derived from questionnaire responses for the 14983 jobs in the New England Bladder Cancer Study. To replicate the common use of a single tree, we applied each method to a single sample of 70% of the jobs, using 15% to test and 15% to validate each method. To characterize variability in performance, we conducted a resampling analysis that repeated the sample draws 100 times. We evaluated agreement between the tree predictions and expert estimates using Somers' d, which measures differences in terms of ordinal association between predicted and observed scores and can be interpreted similarly to a correlation coefficient. Results From the resampling analysis, compared with the nominal tree, an ordinal CT method that used a quadratic misclassification function and controlled tree size based on total misclassification cost had a slightly better predictive performance that was statistically significant for the frequency metric (Somers' d: nominal tree = 0.61; ordinal tree = 0.63) and similar performance for the probability (nominal = 0.65; ordinal = 0.66) and intensity (nominal = 0.65; ordinal = 0.65) metrics. The best ordinal CT predicted fewer cases of large disagreement with the expert assessments (i.e. no exposure predicted for a job with high exposure and vice versa) compared with the nominal tree across all of the exposure metrics. For example, the percent of jobs with expert-assigned high intensity of exposure that the model predicted as no exposure was 29% for the nominal tree and 22% for the best ordinal tree. Conclusions The overall agreements were similar across CT models; however, the use of ordinal models reduced the magnitude of the discrepancy when disagreements occurred. As the best performing model can vary by situation, researchers should consider evaluating multiple CT methods to maximize the predictive performance within their data.