Margaret R Spitz

Baylor College of Medicine, Houston, Texas, United States

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Publications (524)3184.02 Total impact

  • Epidemiology (Cambridge, Mass.) 11/2014; 25(6):934-935. · 5.51 Impact Factor
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    ABSTRACT: There is expanding consensus on the need to modernize the training of cancer epidemiologists to accommodate rapidly emerging technological advancements and the digital age, which are transforming the practice of cancer epidemiology. There is also a growing imperative to extend cancer epidemiology research that is etiological to that which is applied and has the potential to affect individual and public health. Medical schools and schools of public health are recognizing the need to develop such integrated programs; however, we lack the data to estimate how many current training programs are effectively equipping epidemiology students with the knowledge and tools to design, conduct, and analyze these increasingly complex studies. There is also a need to develop new mentoring approaches to account for the transdisciplinary team-science environment that now prevails. With increased dialogue among schools of public health, medical schools, and cancer centers, revised competencies and training programs at predoctoral, doctoral, and postdoctoral levels must be developed. Continuous collection of data on the impact and outcomes of such programs is also recommended.
    American journal of epidemiology. 09/2014;
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    ABSTRACT: Background:There is an urgent need to improve lung cancer outcome by identifying and validating markers of risk. We previously reported that the cytokinesis-blocked micronucleus assay (CBMN) is a strong predictor of lung cancer risk. Here we validate our findings in an independent external lung cancer population and test discriminatory power improvement of the Spitz risk prediction model upon extension with this biomarker. Methods:1,506 participants were stratified into a test set of 995 (527 cases /468 controls) from MD Anderson Cancer Center and a validation set of 511 (239 cases / 272 controls) from Massachusetts General Hospital. An epidemiologic questionnaire was administered and genetic instability was assessed using the CBMN assay. Results:Excellent concordance was observed between the two populations in levels and distribution of CBMN endpoints [binucleated-micronuclei (BN-MN), binucleated-nucleoplasmic bridges (BN-NPB)] with significantly higher mean BN-MN and BN-NPB values among cases (P<0.0001). Extension of the Spitz model led to an overall improvement in the AUC (95% CI) from 0.61 (55.5 - 65.7) with epidemiological variables to 0.92 (89.4 - 94.2) with the addition of BN-MN endpoint. The most dramatic improvement was observed with the never smokers extended model followed by the former and current smokers. Conclusions:The CBMN assay is a sensitive and specific predictor of lung cancer risk and extension of the Spitz risk prediction model led to an AUC that may prove useful in population screening programs to identify the "true" high risk individuals. Impact: Identifying high-risk subgroups that would benefit from screening surveillance has immense public health significance.
    08/2014;
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    ABSTRACT: Background: Smoking experimentation in Mexican American youth is problematic. In light of the research showing that preventing smoking experimentation is a valid strategy for smoking prevention, there is a need to identify Mexican American youth at high risk for experimentation. Methods: A prospective population-based cohort of 1179 adolescents of Mexican descent was followed for 5 years starting in 2005-06. Participants completed a baseline interview at a home visit followed by three telephone interviews at intervals of approximately 6 months and additional interviews at two home visits in 2008-09 and 2010-11. The primary end point of interest in this study was smoking experimentation. Information regarding social, cultural, and behavioral factors (e.g., acculturation, susceptibility to experimentation, home characteristics, household influences) was collected at baseline using validated questionnaires. Results: Age, sex, cognitive susceptibility, household smoking behavior, peer influence, neighborhood influence, acculturation, work characteristics, positive outcome expectations, family cohesion, degree of tension, ability to concentrate, and school discipline were found to be associated with smoking experimentation. In a validation dataset, the proposed risk prediction model had an AUC of 0.719 (95% confidence interval, 0.637 to 0.801) for predicting absolute risk for smoking experimentation within 1 year. Conclusions: The proposed risk prediction model is able to quantify the risk of smoking experimentation in Mexican American adolescents. Impact: Accurately identifying Mexican American adolescents who are at higher risk for smoking experimentation who can be intervened will substantially reduce the incidence of smoking and thereby subsequent health risks.
    07/2014;
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    ABSTRACT: Genome-wide association studies (GWAS) have mapped risk alleles for at least ten distinct cancers to a small region of 63,000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (ASSET) across six distinct cancers in 34,248 cases and 45,036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single nucleotide polymorphisms (SNPs): five in the TERT gene (region 1: rs7726159, P=2.10x10-39; region 3: rs2853677, P=3.30x10-36 and PConditional=2.36x10-8; region 4: rs2736098, P=3.87x10-12 and PConditional=5.19x10-6, region 5: rs13172201, P=0.041 and PConditional=2.04x10-6; and region 6: rs10069690, P=7.49x10-15 and PConditional=5.35x10-7) and one in the neighboring CLPTM1L gene (region 2: rs451360; P=1.90x10-18 and PConditional=7.06x10-16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. 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. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
    Human Molecular Genetics 07/2014; · 7.69 Impact Factor
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    ABSTRACT: Wingless-type protein (Wnt)/β-catenin pathway alterations in non-small cell lung cancer (NSCLC) are associated with poor prognosis and resistance. In 598 stage III-IV NSCLC patients receiving platinum-based chemotherapy at the MD Anderson Cancer Center (MDACC), we correlated survival with 441 host single-nucleotide polymorphisms (SNPs) in 50 Wnt pathway genes. We then assessed the most significant SNPs in 240 Mayo Clinic patients receiving platinum-based chemotherapy for advanced NSCLC, 127 MDACC patients receiving platinum-based adjuvant chemotherapy and 340 early stage MDACC patients undergoing surgery alone (cohorts 2-4). In multivariate analysis, survival correlates with SNPs for AXIN2 (rs11868547 and rs4541111, of which rs11868547 was assessed in cohorts 2-4), Wnt-5B (rs12819505), CXXC4 (rs4413407) and WIF-1 (rs10878232). Median survival was 19.7, 15.6 and 10.7 months for patients with 1, 2 and 3-5 unfavorable genotypes, respectively (P=3.8 × 10(-9)). Survival tree analysis classified patients into two groups (median survival time 11.3 vs 17.3 months, P=4.7 × 10(-8)). None of the SNPs achieved significance in cohorts 2-4; however, there was a trend in the same direction as cohort 1 for 3 of the SNPs. Using online databases, we found rs10878232 displayed expression quantitative trait loci correlation with the expression of LEMD3, a neighboring gene previously associated with NSCLC survival. In conclusion, results from cohort 1 provide further evidence for an important role for Wnt in NSCLC. Investigation of Wnt inhibitors in advanced NSCLC would be reasonable. Lack of an SNP association with outcome in cohorts 2-4 could be due to low statistical power, impact of patient heterogeneity or false-positive observations in cohort 1.The Pharmacogenomics Journal advance online publication, 1 July 2014; doi:10.1038/tpj.2014.21.
    The pharmacogenomics journal. 07/2014;
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    ABSTRACT: Inflammation is a facilitating process for multiple cancer types. It is believed to affect cancer development and progression through several etiologic pathways including increased levels of DNA adduct formation, increased angiogenesis and altered anti-apoptotic signaling. This review highlights the application of inflammatory biomarkers in epidemiologic studies and discusses the various cellular mediators of inflammation characterizing the innate immune system response to infection and chronic insult from environmental factors. Included is a review of six classes of inflammation-related biomarkers: cytokines/chemokines, immune-related effectors, acute phase proteins, reactive oxygen and nitrogen species, prostaglandins and cyclooxygenase-related factors, and mediators such as transcription factors and growth factors. For each of these biomarkers we provide a brief overview of the etiologic role in the inflammation response and how they have been related to cancer etiology and progression within the literature. We provide a discussion of the common techniques available for quantification of each marker including strengths, weaknesses and potential pitfalls. Subsequently, we highlight a few under-studied measures to characterize the inflammatory response and their potential utility in epidemiologic studies of cancer. Finally, we suggest integrative methods for future studies to apply multi-faceted approaches to examine the relationship between inflammatory markers and their roles in cancer development.
    06/2014;
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    ABSTRACT: We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10−20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10−13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10−10) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.
    Nature Genetics 06/2014; · 35.21 Impact Factor
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    ABSTRACT: Background:accurate prognostic prediction is challenging for advanced-stage non-small cell lung cancer (NSCLC) patients.Methods:we systematically investigated genetic variants within inflammation pathway as potential prognostic markers for advanced-stage NSCLC patients treated with first-line chemotherapy. A discovery phase in 502 patients and an internal validation in 335 patients were completed at MD Anderson Cancer Center. External validation was performed in 371 patients at Harvard University.Results:a missense SNP (HLA-DOB:rs2071554) predicted to influence protein function was significantly associated with poor survival in the discovery (HR:1.46, 95% CI:1.02-2.09), internal validation (HR:1.51, 95% CI:1.02-2.25), and external validation (HR:1.52, 95% CI:1.01-2.29) populations. KLRK1:rs2900420 was associated with a reduced risk in the discovery (HR:0.76, 95% CI:0.60-0.96), internal validation (HR:0.77, 95% CI:0.61-0.99), and external validation (HR:0.80, 95% CI:0.63-1.02) populations. A strong cumulative effect was observed for these SNPs on overall survival.Conclusions:Genetic variations in inflammation-related genes could have potential to complement prediction of prognosis.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 22 April 2014; doi:10.1038/clpt.2014.89.
    Clinical Pharmacology &#38 Therapeutics 04/2014; · 6.85 Impact Factor
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    ABSTRACT: We scanned through the genomes of 29,141 African Americans, searching for loci where the average proportion of African ancestry deviates significantly from the genome-wide average. We failed to find any genome-wide significant deviations, and conclude that any selection in African Americans since admixture is sufficiently weak that it falls below the threshold of our power to detect it using a large sample size. These results stand in contrast to the findings of a recent study of selection in African Americans. That study, which had 15 times fewer samples, reported six loci with significant deviations. We show that the discrepancy is likely due to insufficient correction for multiple hypothesis testing in the previous study. The same study reported 14 loci that showed greater population differentiation between African Americans and Nigerian Yoruba than would be expected in the absence of natural selection. Four such loci were previously shown to be genome-wide significant and likely to be affected by selection, but we show that most of the 10 additional loci are likely to be false positives. Additionally, the most parsimonious explanation for the loci that have significant evidence of unusual differentiation in frequency between Nigerians and Africans Americans is selection in Africa prior to their forced migration to the Americas.
    12/2013;
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    ABSTRACT: Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
    Genetic Epidemiology 11/2013; · 4.02 Impact Factor
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    ABSTRACT: Symptom clusters, the multiple, co-occurring symptoms experienced by cancer patients, are debilitating and affects quality of life. We assessed if a panel of immune-response genes may underlie the co-occurrence of severe pain, depressed mood, and fatigue and help identify patients with severe versus non-severe symptom clusters. Symptoms were assessed at presentation, prior to cancer treatment in 599 newly diagnosed lung cancer patients. We applied cluster analyses to determine the patients with severe versus non-severe symptom clusters of pain, depressed mood, and fatigue. Two homogenous clusters were identified. One hundred sixteen patients (19 %) comprised the severe symptom cluster, reporting high intensity of pain, depressed mood, and fatigue and 183 (30 %) patients reported low intensity of these symptoms. Using Bayesian model averaging methodology, we found that of the 55 single nucleotide polymorphisms assessed, an additive effect of mutant alleles in endothelial nitric oxide synthase (-1474 T/A) (posterior probability of inclusion (PPI) = 0.78, odds ratio (OR) = 0.54, 95 % credible interval (CI) = (0.31, 0.93)); IL1B T-31C (PPI = 0.72, OR = 0.55, 95 % CI = (0.31, 0.97)); TNFR2 Met(196)Arg (PPI = 0.70, OR = 1.85, 95 % CI = (1.03, 3.36)); PTGS2 exon 10+837T > C (PPI = 0.69, OR = 0.54, 95 % CI = (0.28, 0.99)); and IL10RB Lys(47)Glu (PPI = 0.68; OR = 1.74; 95 % CI = (1.04, 2.92)) were predictive for symptom clusters. Genetic polymorphisms may facilitate identification of high-risk patients and development of individualized symptom therapies.
    Supportive Care in Cancer 07/2013; · 2.09 Impact Factor
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic with high prevalence in Western countries. Genome-wide association studies had reported that a variation in the patatin-like phospholipase domain containing 3 (PNPLA3) gene is associated with high susceptibility to NAFLD. However, the relationship between this variation and hepatocellular carcinoma (HCC) has not been well established. We investigated the impact of PNPLA3 genetic variation (rs738409: C>G) on HCC risk and prognosis in the United States by conducting a case-control study that included 257 newly diagnosed and pathologically confirmed Caucasian patients with HCC (cases) and 494 healthy controls. Multivariate logistics and Cox regression models were used to control for the confounding effects of HCC risk and prognostic factors. We observed higher risk of HCC for subjects with a homozygous GG genotype than for those with CC or CG genotypes, the adjusted odds ratio (OR) was 3.21 (95% confidence interval [CI], 1.68-6.41). We observed risk modification among individuals with diabetes mellitus (OR = 19.11; 95% CI, 5.13-71.20). The PNPLA3 GG genotype was significantly associated with underlying cirrhosis in HCC patients (OR = 2.48; 95% CI, 1.05-5.87). Moreover, GG allele represents an independent risk factor for death. The adjusted hazard ratio of the GG genotype was 2.11 (95% CI, 1.26-3.52) compared with CC and CG genotypes. PNPLA3 genetic variation (rs738409: C>G) may determine individual susceptibility to HCC development and poor prognosis. Further experimental investigations are necessary for thorough assessment of the hepatocarcinogenic role of PNPLA3. © 2013 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 06/2013; · 4.27 Impact Factor
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    ABSTRACT: Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the environment and genetics in lung cancer etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression. We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus-low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a false discovery rate (FDR) ≤0.15. We studied whether the identified genes played a role in heme-iron related processes by means of manually curated literature search and gene ontology-based pathway analysis. We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR = 0.12). Sixty-three (∼28%) of the 232 identified genes (12 expected by chance, P-value < 0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, and WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, and UCP3) and oxidative stress (e.g., TPO, SGK2, and MTHFR) that may be indirectly related to heme-toxicity. The study's results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer. © 2013 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 05/2013; · 4.27 Impact Factor
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    ABSTRACT: PURPOSE: Among Mexican-origin teenagers, anxiety is associated with cigarette experimentation, while among girls and young women from other ethnic groups the desire to be thin is associated with smoking. However, little is known about the associations of body image concerns with smoking in Mexican-origin youth, particularly when accounting for anxiety. METHODS: In 2005-2006, 1,328 Mexican-origin adolescents aged 11 to 13 years enrolled in a cohort study to examine nongenetic and genetic factors associated with cigarette experimentation. In 2008-2009, 1,154 participants completed a follow-up when they reported their smoking status, anxiety, and body image. Height and weight were measured. In 2010-2011, 1,001 participants completed another follow-up when they reported their smoking status. Multivariate multinomial regression models were computed to examine associations between smoking behavior assessed in 2010-2011 and body image score, anxiety, and body mass index assessed in 2008-2009, controlling for gender, country of birth, age, and parental education. RESULTS: Of the 892 participants with complete data, 48% were boys, 74% were U.S.-born and in 2008-2009, were 14.29 years (SD = 1) old. Having smoked less than a whole cigarette was associated with being male (OR = 1.53), older age (OR = 1.42), a body mass index <85th percentile (OR = 1.93), and poor body image (OR = 1.12). Having smoked more than one cigarette was associated with being male (OR = 3.54), older age (OR = 1.86), anxiety (OR = 1.04), and poor body image (OR = 1.11). CONCLUSIONS: Poor body image and anxiety were independently associated with cigarette experimentation among Mexican-origin youth. Implications for the design of culturally appropriate smoking prevention messages are discussed.
    Journal of Adolescent Health 05/2013; · 2.97 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10-11) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10-10). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10-8). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10-7), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
    Nature Genetics 04/2013; · 35.21 Impact Factor
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    ABSTRACT: Though several studies have found a positive relationship between exposure to tobacco advertising and/or promotional marketing and smoking status among youth, few have examined these relationships specifically for youth of Mexican origin. The current analysis examines the relationship between perceived exposure to pro-tobacco messages and progression through the smoking continuum from trying to repeated use in a cohort of Mexican origin youth ages 14-19. Data were collected via personal in-home interviews at two time points-in 2008-2009 and 2010-2011 (N = 942). Smoking status, exposure to pro-tobacco messages from five major media sources, demographic variables and established risk factors for adolescent smoking were measured at both waves. Data were analyzed using Pearson's Chi square tests, ANOVA, and multinomial logistic regression. Adolescent perception of the number of pro-tobacco messages seen in 2008-2009 was unrelated to smoking less than one cigarette assessed in 2010-2011. However, having seen a higher number of pro-tobacco messages was significantly associated with being more likely to have smoked more than one cigarette (OR = 1.21; 95 % CI 1.03-1.42) controlling for demographic factors and known psychosocial risk factors of smoking behavior. Results suggest that the more pro-tobacco messages Mexican origin youth are able to recall, the further their progression through the smoking trajectory a year later. These youth are clearly susceptible to pro-tobacco messaging, and our results underscore the need to restrict all forms of messaging that promote tobacco use.
    Journal of Immigrant and Minority Health 04/2013; · 1.16 Impact Factor
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    ABSTRACT: In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving towards more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating "big data" science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits.
    Cancer Epidemiology Biomarkers &amp Prevention 03/2013; · 4.56 Impact Factor
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    ABSTRACT: INTRODUCTION:: Black/white disparities in lung cancer incidence and mortality mandate an evaluation of underlying biological differences. We have previously shown higher risks of lung cancer associated with prior emphysema in African American compared with white patients with lung cancer. METHODS:: We therefore evaluated a panel of 1440 inflammatory gene variants in a two-phase analysis (discovery and replication), added top genome-wide association studies (GWAS) lung cancer hits from white populations, and 28 single-nucleotide polymorphisms (SNPs) from a published gene panel. The discovery set (477 self-designated African Americans cases, 366 controls matched on age, ethnicity, and gender) were from Houston, Texas. The external replication set (330 cases and 342 controls) was from the EXHALE study at Wayne State University. RESULTS:: In discovery, 154 inflammation SNPs were significant (p < 0.05) on univariate analysis, as was one of the gene panel SNPs (rs308738 in REV1, p = 0.0013), and three GWAS hits, rs16969968 p = 0.0014 and rs10519203 p = 0.0003 in the 15q locus and rs2736100, in the HTERT locus, p = 0.0002. One inflammation SNP, rs950286, was successfully replicated with a concordant odds ratio of 1.46 (1.14-1.87) in discovery, 1.37 (1.05-1.77) in replication, and a combined odds ratio of 1.40 (1.17-1.68). This SNP is intergenic between IRF4 and EXOC2 genes. We also constructed and validated epidemiologic and extended risk prediction models. The area under the curve (AUC) for the epidemiologic discovery model was 0.77 and 0.80 for the extended model. For the combined datasets, the AUC values were 0.75 and 0.76, respectively. CONCLUSIONS:: As has been reported for other cancer sites and populations, incorporating top genetic hits into risk prediction models, provides little improvement in model performance and no clinical relevance.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2013; · 4.55 Impact Factor
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    ABSTRACT: Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data. A total of 7,650 sequence variants from 720 genes relevant to inflammation pathways were identified using keyword and pathway searches from Gene Cards and Gene Ontology databases. In Stage 1, six GWAS datasets from the International Lung Cancer Consortium were pooled (4,441 cases and 5,094 controls of European ancestry), and a hierarchical modeling (HM) approach was used to incorporate prior information for each of the variants into the analysis. The prior matrix was constructed using (1) role of genes in the inflammation and immune pathways; (2) physical properties of the variants including the location of the variants, their conservation scores and amino acid coding; (3) LD with other functional variants and (4) measures of heterogeneity across the studies. HM affected the priority ranking of variants particularly among those having low prior weights, imprecise estimates and/or heterogeneity across studies. In Stage 2, we used an independent NCI lung cancer GWAS study (5,699 cases and 5,818 controls) for in silico replication. We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8q21.1 with p value = 7.4 × 10(-6)), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk. HM allows for prior knowledge such as from bioinformatic sources to be incorporated into the analysis systematically, and it represents a complementary analytical approach to the conventional GWAS analysis.
    Human Genetics 02/2013; · 4.63 Impact Factor

Publication Stats

17k Citations
3,184.02 Total Impact Points

Institutions

  • 2012–2014
    • Baylor College of Medicine
      • Dan L. Duncan Cancer Center
      Houston, Texas, United States
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
    • Washington University in St. Louis
      • Department of Psychiatry
      Saint Louis, MO, United States
  • 1988–2014
    • University of Texas MD Anderson Cancer Center
      • Department of Epidemiology
      Houston, Texas, United States
  • 2013
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
    • University of Texas at Austin
      Austin, Texas, United States
  • 2012–2013
    • Karmanos Cancer Institute
      • Division of Hematology and Oncology
      Detroit, Michigan, United States
  • 2010–2013
    • International Agency for Research on Cancer
      Lyons, Rhône-Alpes, France
    • Mayo Foundation for Medical Education and Research
      • Department of Health Sciences Research
      Scottsdale, AZ, United States
  • 2006–2013
    • National Cancer Institute (USA)
      • Division of Cancer Epidemiology and Genetics
      Maryland, United States
    • University of Houston
      Houston, Texas, United States
  • 2011
    • United States Army
      Washington, West Virginia, United States
  • 2009–2011
    • National Institutes of Health
      • • Division of Cancer Epidemiology and Genetics
      • • Branch of Radiation Epidemiology
      Bethesda, MD, United States
    • Institute of Cancer Research
      • Division of Genetics and Epidemiology
      Londinium, England, United Kingdom
  • 2008
    • Roswell Park Cancer Institute
      • Department of Thoracic Surgery
      Buffalo, New York, United States
    • Vanderbilt University
      • Department of Medicine
      Nashville, MI, United States
  • 2007
    • Georgia Health Sciences University
      Augusta, Georgia, United States
    • University of Pittsburgh
      • Pittsburgh Cancer Institute
      Pittsburgh, PA, United States
  • 2004
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2000–2001
    • Nanjing Medical University
      • Department of Epidemiology and Biostatistics
      Nanjing, Jiangsu Sheng, China
  • 1999–2000
    • University of California, Los Angeles
      • Department of Epidemiology
      Los Angeles, CA, United States
    • Louisiana State University in Shreveport
      Shreveport, Louisiana, United States
    • New York Eye and Ear Infirmary
      New York City, New York, United States
  • 1998
    • University of Texas Health Science Center at Houston
      Houston, Texas, United States
    • University of California, San Francisco
      • Department of Epidemiology and Biostatistics
      San Francisco, CA, United States
  • 1995
    • Houston Zoo
      Houston, Texas, United States
  • 1990
    • Henry Ford Hospital
      Detroit, Michigan, United States
  • 1985
    • Icahn School of Medicine at Mount Sinai
      Manhattan, New York, United States