Publications by authors named "Melinda C Aldrich"

108 Publications

Immunotherapy-Mediated Thyroid Dysfunction: Genetic Risk and Impact on Outcomes with PD-1 Blockade in Non-Small Cell Lung Cancer.

Clin Cancer Res 2021 Sep 8;27(18):5131-5140. Epub 2021 Jul 8.

Department of Medicine, University of California San Francisco, San Francisco, California.

Purpose: Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE).

Experimental Design: In patients with non-small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI.

Results: Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52-0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29-1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08-1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit.

Conclusions: Thyroid irAEs were associated with response to anti-PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-0921DOI Listing
September 2021

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

Prostate Cancer Prostatic Dis 2021 Jun 14. Epub 2021 Jun 14.

School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA.

Background: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.

Materials And Methods: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.

Results: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.

Conclusion: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41391-021-00403-7DOI Listing
June 2021

Genetic landscape of Gullah African Americans.

Am J Phys Anthropol 2021 08 19;175(4):905-919. Epub 2021 May 19.

Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

Objectives: Gullah African Americans are descendants of formerly enslaved Africans living in the Sea Islands along the coast of the southeastern U.S., from North Carolina to Florida. Their relatively high numbers and geographic isolation were conducive to the development and preservation of a unique culture that retains deep African features. Although historical evidence supports a West-Central African ancestry for the Gullah, linguistic and cultural evidence of a connection to Sierra Leone has led to the suggestion of this country/region as their ancestral home. This study sought to elucidate the genetic structure and ancestry of the Gullah.

Materials And Methods: We leveraged whole-genome genotype data from Gullah, African Americans from Jackson, Mississippi, African populations from Sierra Leone, and population reference panels from Africa and Europe to infer population structure, ancestry proportions, and global estimates of admixture.

Results: Relative to non-Gullah African Americans from the Southeast US, the Gullah exhibited higher mean African ancestry, lower European admixture, a similarly small Native American contribution, and increased male-biased European admixture. A slightly tighter bottleneck in the Gullah 13 generations ago suggests a largely shared demographic history with non-Gullah African Americans. Despite a slightly higher relatedness to populations from Sierra Leone, our data demonstrate that the Gullah are genetically related to many West African populations.

Discussion: This study confirms that subtle differences in African American population structure exist at finer regional levels. Such observations can help to inform medical genetics research in African Americans, and guide the interpretation of genetic data used by African Americans seeking to explore ancestral identities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajpa.24333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286328PMC
August 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Fate or coincidence: do COPD and major depression share genetic risk factors?

Hum Mol Genet 2021 May;30(7):619-628

Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

Major depressive disorder (MDD) is a common comorbidity in chronic obstructive pulmonary disease (COPD), affecting up to 57% of patients with COPD. Although the comorbidity of COPD and MDD is well established, the causal relationship between these two diseases is unclear. A large-scale electronic health record clinical biobank and genome-wide association study summary statistics for MDD and lung function traits were used to investigate potential shared underlying genetic susceptibility between COPD and MDD. Linkage disequilibrium score regression was used to estimate genetic correlation between phenotypes. Polygenic risk scores (PRS) for MDD and lung function traits were developed and used to perform a phenome-wide association study (PheWAS). Multi-trait-based conditional and joint analysis identified single-nucleotide polymorphisms (SNPs) influencing both lung function and MDD. We found genetic correlations between MDD and all lung function traits were small and not statistically significant. A PRS-MDD was significantly associated with an increased risk of COPD in a PheWAS [odds ratio (OR) = 1.12, 95% confidence interval (CI): 1.09-1.16] when adjusting for age, sex and genetic ancestry, but this relationship became attenuated when controlling for smoking history (OR = 1.08, 95% CI: 1.04-1.13). No significant associations were found between the lung function PRS and MDD. Multi-trait-based conditional and joint analysis identified three SNPs that may contribute to both traits, two of which were previously associated with mood disorders and COPD. Our findings suggest that the observed relationship between COPD and MDD may not be driven by a strong shared genetic architecture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120137PMC
May 2021

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

PLoS Genet 2021 03 5;17(3):e1009254. Epub 2021 Mar 5.

University of Salzburg, Department of Biosciences and Cancer Cluster Salzburg, Salzburg, Austria.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1009254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968735PMC
March 2021

Determinants of stage at diagnosis of HPV-related cancer including area deprivation and clinical factors.

J Public Health (Oxf) 2021 Jan 29. Epub 2021 Jan 29.

Department of Medicine, Division of Geriatrics, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Collecting social determinants of health in electronic health records is time-consuming. Meanwhile, an Area Deprivation Index (ADI) aggregates sociodemographic information from census data. The objective of this study was to ascertain whether ADI is associated with stage of human papillomavirus (HPV)-related cancer at diagnosis.

Methods: We tested for the association between the stage of HPV-related cancer presentation and ADI as well as the association between stage and the value of each census-based measure using ordered logistic regression, adjusting for age, race and sex.

Results: Among 3247 cases of HPV-related cancers presenting to an urban academic medical center, the average age at diagnosis was 57. The average stage at diagnosis was Surveillance, Epidemiology and End Results Stage 3. In the study population, 43% of patients were female and 87% were white. In this study population, there was no association between stage of HPV-related cancer presentation and either aggregate or individual census variables.

Conclusions: These results may reflect insufficient sample size, a lack of socio-demographic diversity in our population, or suggest that simplifying social determinants of health into a single geocoded index is not a reliable surrogate for assessing a patient's risk for HPV-related cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/pubmed/fdaa246DOI Listing
January 2021

Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model.

Cancer Res 2021 03 20;81(6):1607-1615. Epub 2021 Jan 20.

Institute for Clinical and Translational Research, Baylor Medical College, Houston, Texas.

Lung cancer is the leading cause of cancer-related death globally. An improved risk stratification strategy can increase efficiency of low-dose CT (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. On the basis of 13,119 patients with lung cancer and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK Biobank data ( = 335,931). Absolute risk was estimated on the basis of age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial ( = 50,772 participants). The lung cancer ORs for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 [95% confidence interval (CI) = 1.92-3.00; = 1.80 × 10] in the validation set ( = 5.26 × 10). The OR per SD of PRS increase was 1.26 (95% CI = 1.20-1.32; = 9.69 × 10) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status, and family history. Collectively, these results suggest that individual's genetic background may inform the optimal lung cancer LDCT screening strategy. SIGNIFICANCE: Three large-scale datasets reveal that, after accounting for risk factors, an individual's genetics can affect their lung cancer risk trajectory, thus may inform the optimal timing for LDCT screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-1237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969419PMC
March 2021

Establishing a Cohort and a Biorepository to Identify Biomarkers for Early Detection of Lung Cancer: The Nashville Lung Cancer Screening Trial Cohort.

Ann Am Thorac Soc 2021 07;18(7):1227-1234

Department of Radiology and Radiological Sciences.

A prospective longitudinal cohort of individuals at high risk of developing lung cancer was established to build a biorepository of carefully annotated biological specimens and low-dose computed tomography (LDCT) chest images for derivation and validation of candidate biomarkers for early detection of lung cancer. The goal of this study is to characterize individuals with high risk for lung cancer, accumulating valuable biospecimens and LDCT chest scans longitudinally over 5 years. Participants 55-80 years of age with a 5-year estimated risk of developing lung cancer >1.5% were recruited and enrolled from clinics at the Vanderbilt University Medical Center, Veteran Affairs Medical Center, and Meharry Medical Center. Individual demographic characteristics were assessed via questionnaire at baseline. Participants underwent an LDCT scan, spirometry, sputum cytology, and research bronchoscopy at the time of enrollment. Participants will be followed yearly for 5 years. Positive LDCT scans are followed-up according to standard of care. The clinical, imaging, and biospecimen data are collected prospectively and stored in a biorepository. Participants are offered smoking cessation counseling at each study visit. A total of 480 participants were enrolled at study baseline and consented to sharing their data and biospecimens for research. Participants are followed with yearly clinic visits to collect imaging data and biospecimens. To date, a total of 19 cancers (13 adenocarcinomas, four squamous cell carcinomas, one large cell neuroendocrine, and one small-cell lung cancer) have been identified. We established a unique prospective cohort of individuals at high risk for lung cancer, enrolled at three institutions, for whom full clinical data, well-annotated LDCT scans, and biospecimens are being collected longitudinally. This repository will allow for the derivation and independent validation of clinical, imaging, and molecular biomarkers of risk for diagnosis of lung cancer.Clinical trial registered with ClinicalTrials.gov (NCT01475500).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1513/AnnalsATS.202004-344OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328369PMC
July 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

A Call to Action: Dismantling Racial Injustices in Preclinical Research and Clinical Care of Black Patients Living with Small Cell Lung Cancer.

Cancer Discov 2021 Feb 14;11(2):240-244. Epub 2020 Dec 14.

Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee.

Small cell lung cancer (SCLC) is an aggressive disease with dismal survival rates and limited therapeutic options. SCLC development is strongly associated with exposure to tobacco carcinogens. However, additional genetic and environmental risk factors that contribute to SCLC pathogenesis are beginning to emerge. Here, we specifically assess disparities pertaining to SCLC in Black populations. In contrast to non-small cell lung cancer, preliminary data suggest that Black individuals may actually be at a lower risk of developing SCLC relative to white individuals. This difference remains unexplained but urgently needs to be verified in larger data sets, because it could provide important new insights and approaches to understanding this recalcitrant tumor. Importantly, little biological information exists on SCLC in Black individuals, and few patient-derived preclinical SCLC models from diverse ancestries are available in the laboratory. Unfortunately, we note strikingly low numbers of Black participants in clinical trials testing new treatments for SCLC. Evidence further indicates that care for patients with SCLC may vary between communities with a large fraction of Black patients and those without. Together, these observations underscore the need to better investigate genetic, environmental, and socioeconomic factors associated with SCLC development, preclinical research, clinical care, and outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-20-1592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858238PMC
February 2021

Predicting DNA methylation from genetic data lacking racial diversity using shared classified random effects.

Genomics 2021 Jan 5;113(1 Pt 2):1018-1028. Epub 2020 Nov 5.

Vanderbilt University Medical Center, Nashville, TN, United States of America.

Public genomic repositories are notoriously lacking in racially and ethnically diverse samples. This limits the reaches of exploration and has in fact been one of the driving factors for the initiation of the All of Us project. Our particular focus here is to provide a model-based framework for accurately predicting DNA methylation from genetic data using racially sparse public repository data. Epigenetic alterations are of great interest in cancer research but public repository data is limited in the information it provides. However, genetic data is more plentiful. Our phenotype of interest is cervical cancer in The Cancer Genome Atlas (TCGA) repository. Being able to generate such predictions would nicely complement other work that has generated gene-level predictions of gene expression for normal samples. We develop a new prediction approach which uses shared random effects from a nested error mixed effects regression model. The sharing of random effects allows borrowing of strength across racial groups greatly improving predictive accuracy. Additionally, we show how to further borrow strength by combining data from different cancers in TCGA even though the focus of our predictions is DNA methylation in cervical cancer. We compare our methodology against other popular approaches including the elastic net shrinkage estimator and random forest prediction. Results are very encouraging with the shared classified random effects approach uniformly producing more accurate predictions - overall and for each racial group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygeno.2020.10.036DOI Listing
January 2021

Addressing Disparities in Lung Cancer Screening Eligibility and Healthcare Access. An Official American Thoracic Society Statement.

Am J Respir Crit Care Med 2020 10;202(7):e95-e112

There are well-documented disparities in lung cancer outcomes across populations. Lung cancer screening (LCS) has the potential to reduce lung cancer mortality, but for this benefit to be realized by all high-risk groups, there must be careful attention to ensuring equitable access to this lifesaving preventive health measure. To outline current knowledge on disparities in eligibility criteria for, access to, and implementation of LCS, and to develop an official American Thoracic Society statement to propose strategies to optimize current screening guidelines and resource allocation for equitable LCS implementation and dissemination. A multidisciplinary panel with expertise in LCS, implementation science, primary care, pulmonology, health behavior, smoking cessation, epidemiology, and disparities research was convened. Participants reviewed available literature on historical disparities in cancer screening and emerging evidence of disparities in LCS. Existing LCS guidelines do not consider racial, ethnic, socioeconomic, and sex-based differences in smoking behaviors or lung cancer risk. Multiple barriers, including access to screening and cost, further contribute to the inequities in implementation and dissemination of LCS. This statement identifies the impact of LCS eligibility criteria on vulnerable populations who are at increased risk of lung cancer but do not meet eligibility criteria for screening, as well as multiple barriers that contribute to disparities in LCS implementation. Strategies to improve the selection and dissemination of LCS in vulnerable groups are described.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202008-3053STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528802PMC
October 2020

Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer.

Genet Epidemiol 2021 02 14;45(1):99-114. Epub 2020 Sep 14.

Faculty of Medical Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1β pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855632PMC
February 2021

Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization.

Int J Cancer 2021 03 23;148(5):1077-1086. Epub 2020 Sep 23.

The National Institute of Occupational Health (STAMI), Oslo, Norway.

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (OR = 1.28, 95% CI = 1.06-1.55, P = .011), and an inverse effect on lung adenocarcinoma (OR = 0.86, 95% CI = 0.77-0.96, P = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (OR = 1.19, 95% CI = 1.01-1.40, P = .036), but this effect disappeared after adjustment of smoking (OR = 1.02, 95% CI = 0.90-1.16, P = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.33292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845289PMC
March 2021

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma.

Front Med 2021 Apr 5;15(2):275-291. Epub 2020 Sep 5.

National Institute of Occupational Health (STAMI), Oslo, Pb 5330, Norway.

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11684-020-0779-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374896PMC
April 2021

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.

Eur Urol 2020 09 12;78(3):316-320. Epub 2020 May 12.

Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2020.04.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805560PMC
September 2020

Protein-altering germline mutations implicate novel genes related to lung cancer development.

Nat Commun 2020 05 11;11(1):2220. Epub 2020 May 11.

Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10) and replication (adjusted OR = 2.93, P = 2.22 × 10) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-15905-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214407PMC
May 2020

Association Analysis of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls.

Cancer Epidemiol Biomarkers Prev 2020 07 10;29(7):1423-1429. Epub 2020 Apr 10.

National Institute of Occupational Health (STAMI), Oslo, Norway.

Background: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated.

Methods: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project.

Results: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery ( < 0.001) and validation ( < 0.05) stages. Among these loci, rs78062588 in (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, = 1.65 × 10). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele ( in 1q21.3) was associated with elevated somatic copy number of (OR = 1.16, = 0.02). In lung adenocarcinomas, rs1611182 ( in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, = 1.76 × 10).

Conclusions: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility.

Impact: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-19-1085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120681PMC
July 2020

Disparities in Lung Cancer Screening: A Review.

Ann Am Thorac Soc 2020 04;17(4):399-405

Department of Thoracic Surgery.

Lung cancer is the leading cause of cancer mortality in the United States. Certain groups are at increased risk of developing lung cancer and experience greater morbidity and mortality than the general population. Lung cancer screening provides an opportunity to detect lung cancer at an early stage when surgical intervention can be curative; however, current screening guidelines may overlook vulnerable populations with disproportionate lung cancer burden. This review aims to characterize disparities in lung cancer screening eligibility, as well as access to lung cancer screening, focusing on underrepresented racial/ethnic minorities and high-risk populations, such as individuals with human immunodeficiency virus. We also explore potential system- and patient-level barriers that may influence smoking patterns and healthcare access. Improving access to high-quality health care with a focus on smoking cessation is essential to reduce the burden of lung cancer experienced by vulnerable populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1513/AnnalsATS.201907-556CMEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175982PMC
April 2020

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility.

Nat Commun 2020 01 7;11(1):27. Epub 2020 Jan 7.

BC Cancer Agency, Vancouver, BC, Canada.

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV: r = 0.098, p = 2.3 × 10) and the ratio of FEV to forced vital capacity (FEV/FVC: r = 0.137, p = 2.0 × 10). Mendelian randomization analyses demonstrate that reduced FEV increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-13855-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946810PMC
January 2020

Defining Equity in Eligibility for Cancer Screening-Reply.

JAMA Oncol 2020 Jan;6(1):156-157

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2019.4604DOI Listing
January 2020

Transcriptome-wide association study reveals candidate causal genes for lung cancer.

Int J Cancer 2020 04 9;146(7):1862-1878. Epub 2019 Dec 9.

Epidemiology Division, Princess Margaret Cancer Center, Toronto, ON, Canada.

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (p = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (p = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (p = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008463PMC
April 2020

Genome-wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk.

Int J Cancer 2020 05 31;146(10):2855-2864. Epub 2019 Oct 31.

Department of Genetic Epidemiology, University Medical Center Goettingen, Goettingen, Germany.

Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 × 10 ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 × 10 ; 12p13.31: rs71450133, Deletion, OR = 1.09, p = 8.83 × 10 ; and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 × 10 ). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101262PMC
May 2020

Evaluation of USPSTF Lung Cancer Screening Guidelines Among African American Adult Smokers.

JAMA Oncol 2019 Sep;5(9):1318-1324

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: The United States Preventive Services Task Force (USPSTF) recommends low-dose computed tomography screening for lung cancer. However, USPSTF screening guidelines were derived from a study population including only 4% African American smokers, and racial differences in smoking patterns were not considered.

Objective: To evaluate the diagnostic accuracy of USPSTF lung cancer screening eligibility criteria in a predominantly African American and low-income cohort.

Design, Setting, And Participants: The Southern Community Cohort Study prospectively enrolled adults visiting community health centers across 12 southern US states from March 25, 2002, through September 24, 2009, and followed up for cancer incidence through December 31, 2014. Participants included African American and white current and former smokers aged 40 through 79 years. Statistical analysis was performed from May 11, 2016, to December 6, 2018.

Exposures: Self-reported race, age, and smoking history. Cumulative exposure smoking histories encompassed most recent follow-up questionnaires.

Main Outcomes And Measures: Incident lung cancer cases assessed for eligibility for lung cancer screening using USPSTF criteria.

Results: Among 48 364 ever smokers, 32 463 (67%) were African American and 15 901 (33%) were white, with 1269 incident lung cancers identified. Among all 48 364 Southern Community Cohort Study participants, 5654 of 32 463 African American smokers (17%) were eligible for USPSTF screening compared with 4992 of 15 901 white smokers (31%) (P < .001). Among persons diagnosed with lung cancer, a significantly lower percentage of African American smokers (255 of 791; 32%) was eligible for screening compared with white smokers (270 of 478; 56%) (P < .001). The lower percentage of eligible lung cancer cases in African American smokers was primarily associated with fewer smoking pack-years among African American vs white smokers (median pack-years: 25.8 [interquartile range, 16.9-42.0] vs 48.0 [interquartile range, 30.2-70.5]; P < .001). Racial disparity was observed in the sensitivity and specificity of USPSTF guidelines between African American and white smokers for all ages. Lowering the smoking pack-year eligibility criteria to a minimum 20-pack-year history was associated with an increased percentage of screening eligibility of African American smokers and with equitable performance of sensitivity and specificity compared with white smokers across all ages (for a 55-year-old current African American smoker, sensitivity increased from 32.2% to 49.0% vs 56.5% for a 55-year-old white current smoker; specificity decreased from 83.0% to 71.6% vs 69.4%; P < .001).

Conclusions And Relevance: Current USPSTF lung cancer screening guidelines may be too conservative for African American smokers. The findings suggest that race-specific adjustment of pack-year criteria in lung cancer screening guidelines would result in more equitable screening for African American smokers at high risk for lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2019.1402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604090PMC
September 2019

A Social Determinant of Health May Modify Genetic Associations for Blood Pressure: Evidence From a SNP by Education Interaction in an African American Population.

Front Genet 2019 10;10:428. Epub 2019 May 10.

Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, United States.

African Americans experience the highest burden of hypertension in the United States compared with other groups. Genetic contributions to this complex condition are now emerging in this as well as other populations through large-scale genome-wide association studies (GWAS) and meta-analyses. Despite these recent discovery efforts, relatively few large-scale studies of blood pressure have considered the joint influence of genetics and social determinants of health despite extensive evidence supporting their impact on hypertension. To identify these expected interactions, we accessed a subset of the Vanderbilt University Medical Center (VUMC) biorepository linked to de-identified electronic health records (EHRs) of adult African Americans genotyped using the Illumina Metabochip ( = 2,577). To examine potential interactions between education, a recognized social determinant of health, and genetic variants contributing to blood pressure, we used linear regression models to investigate two-way interactions for systolic and diastolic blood pressure (DBP). We identified a two-way interaction between rs6687976 and education affecting DBP ( = 0.052). Individuals homozygous for the minor allele and having less than a high school education had higher DBP compared with (1) individuals homozygous for the minor allele and high school education or greater and (2) individuals not homozygous for the minor allele and less than a high school education. To our knowledge, this is the first EHR -based study to suggest a gene-environment interaction for blood pressure in African Americans, supporting the hypothesis that genetic contributions to hypertension may be modulated by social factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2019.00428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523518PMC
May 2019

Analysis of biogeographic ancestry reveals complex genetic histories for indigenous communities of St. Vincent and Trinidad.

Am J Phys Anthropol 2019 07 24;169(3):482-497. Epub 2019 May 24.

Department of Anthropology, University of Pennsylvania, Philadelphia, Pennsylvania.

Objectives: From a genetic perspective, relatively little is known about how mass emigrations of African, European, and Asian peoples beginning in the 16th century affected Indigenous Caribbean populations. Therefore, we explored the impact of serial colonization on the genetic variation of the first Caribbean islanders.

Materials And Methods: Sixty-four members of St. Vincent's Garifuna Community and 36 members of Trinidad's Santa Rosa First People's Community (FPC) of Arima were characterized for mitochondrial DNA and Y-chromosome diversity via direct sequencing and targeted SNP and STR genotyping. A subset of 32 Garifuna and 18 FPC participants were genotyped using the GenoChip 2.0 microarray. The resulting data were used to examine genetic diversity, admixture, and sex biased gene flow in the study communities.

Results: The Garifuna were most genetically comparable to African descendant populations, whereas the FPC were more similar to admixed American groups. Both communities also exhibited moderate frequencies of Indigenous American matrilines and patrilines. Autosomal SNP analysis indicated modest Indigenous American ancestry in these populations, while both showed varying degrees of African, European, South Asian, and East Asian ancestry, with patterns of sex-biased gene flow differing between the island communities.

Discussion: These patterns of genetic variation are consistent with historical records of migration, forced, or voluntary, and suggest that different migration events shaped the genetic make-up of each island community. This genomic study is the highest resolution analysis yet conducted with these communities, and provides a fuller understanding of the complex bio-histories of Indigenous Caribbean peoples in the Lesser Antilles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajpa.23859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095721PMC
July 2019

Gender equity in epidemiology: a policy brief.

Ann Epidemiol 2019 07 2;35:1-3. Epub 2019 Apr 2.

Sydney School of Public Health, The University of Sydney, Sydney, Australia.

The under-representation of women in leadership in scientific fields presents a serious problem. Gender diversity is integral to innovation and productivity, and inequality leads to loss of gender talent in science including epidemiology. This policy brief summarizes some of the key dimensions and determinants contributing to gender-equity gaps in epidemiology and other scientific fields, relevant to developed countries where there is more published evidence. Women in scientific fields hold fewer positions on editorial boards, lack equal representation in speaking engagements at conferences, and are less likely to publish or receive top tier grant funding. Reasons for these inequities range from unconscious bias, biased promotion systems, and traditional norms in the division of family life and labor in our society leading to the attrition of women in academia. Addressing the problem of gender inequity, as a component of gender inequality, will provide an ethical basis to advance innovation. Data on gender equity in the field of epidemiology are sparse. We call on academic institutions, professional societies and associations, and editorial boards relevant to epidemiology (as well as other academic disciplines more broadly) to take meaningful action to build an evidence base as to the extent of gender inequities in epidemiologic research, teaching, policy, and practice. We outline some of the necessary steps required to achieve gender equity, such as career development and mentoring programs, institutional support, and programs to address bias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.annepidem.2019.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779121PMC
July 2019
-->