Faculty Bibliography
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543
Risk-Stratified Screening for Colorectal Cancer Using Genetic and Environmental Risk Factors: A Cost-Effectiveness Analysis Based on Real-World Data
BACKGROUND & AIMS/OBJECTIVE:Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death. METHODS:Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40-60 years), end age (70-85 years), and screening interval (5-15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45-75, every 10 years). Key assumptions were varied in sensitivity analyses. RESULTS:Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test. CONCLUSIONS:Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.
PMID: 36906080
ISSN: 1542-7714
CID: 5502372
Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort
BACKGROUND:Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance. METHODS:The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group). RESULTS:In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity. CONCLUSIONS:The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort. IMPACT:The proposed model has potential utility in risk-stratified colorectal cancer prevention.
PMCID:9992158
PMID: 36622766
ISSN: 1538-7755
CID: 5431952
PM2.5 and Cardiovascular Health Risks
PM2.5 is a frequently studied particulate matter metric, due to its wide range of identified overall adverse health effects, particularly cardiovascular health risks. However, there are no clear clinical practice guidelines for air pollution in regard to the prevention of cardiovascular health risks, since most of the current medical guidelines for CVD focus on metabolic risk factors such as hyperlipidemia or diabetes. We sought to determine the relationship between PM2.5 and cardiovascular disease, cardiovascular events, and all-cause mortality by performing a systematic review and meta-analysis. We searched Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Scopus, and Web of Science from the database inception to December 2022 for studies that reported an association between PM2.5 and cardiovascular disease, cardiovascular events, and all-cause mortality. We used the DerSimonian & Laird random-effects method to pool hazard ratios or risk ratios separately from the included studies. Of the total 18 prospective studies, 7,300,591 individuals were followed for a median follow-up of 9 years. Compared to low long-term exposure to PM 2.5 levels, an increase in exposure to PM 2.5 levels resulted in an increase in all-cause mortality (HR 1.08 95% CI of 1.05-1.11, P < 0.05). Similarly, when compared to a low long-term exposure to PM 2.5 levels, an increase in exposure to PM 2.5 levels resulted in an increase in cardiovascular disease (HR 1.09, 95% CI of 1.00-1.18, P < 0.05) and an increase in cardiovascular disease mortality (HR 1.12, 95% CI of 1.07-1.18, P < 0.05). Increased exposure to PM 2.5 levels is significantly associated with an increased risk of all-cause mortality, cardiovascular disease, and cardiovascular disease mortality. Although federal primary and secondary standards are in place, those standards are not low enough to prevent CVD health effects. Clinicians should emphasize PM2.5 as a modifiable CV risk factors for their patients to potentially reduce the development of CV complications. A clinical action guideline is needed specifically for air pollution effects on CVD, and how to mitigate them.
PMID: 36828043
ISSN: 1535-6280
CID: 5434092
Author Correction: Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
PMID: 36782065
ISSN: 1546-1718
CID: 5427102
Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
PMID: 36539618
ISSN: 1546-1718
CID: 5394972
Risk factors for head and neck cancer in more and less developed countries: Analysis from the INHANCE consortium
OBJECTIVE:We analyzed the pooled case-control data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium to compare cigarette smoking and alcohol consumption risk factors for head and neck cancer between less developed and more developed countries. SUBJECTS AND METHODS/METHODS:The location of each study was categorized as either a less developed or more developed country. We compared the risk of overall head and neck cancer and cancer of specific anatomic subsites associated with cigarette smoking and alcohol consumption. Additionally, age and sex distribution between categories was compared. RESULTS:The odds ratios for head and neck cancer sites associated with smoking duration differed between less developed and more developed countries. Smoking greater than 20Â years conferred a higher risk for oral cavity and laryngeal cancer in more developed countries, whereas the risk was greater for oropharynx and hypopharynx cancer in less developed countries. Alcohol consumed for more than 20Â years conferred a higher risk for oropharynx, hypopharynx, and larynx cancer in less developed countries. The proportion of cases that were young (<45Â years) or female differed by country type for some HNC subsites. CONCLUSION/CONCLUSIONS:These findings suggest the degree of industrialization and economic development affects the relationship between smoking and alcohol with head and neck cancer.
PMID: 35322907
ISSN: 1601-0825
CID: 5200562
Microbial Risk Score for Capturing Microbial Characteristics, Integrating Multi-omics Data, and Predicting Disease Risk
BACKGROUND/UNASSIGNED:With the rapid accumulation of microbiome-wide association studies, a great amount of microbiome data are available to study the microbiome's role in human disease and advance the microbiome's potential use for disease prediction. However, the unique features of microbiome data hinder its utility for disease prediction. METHODS/UNASSIGNED:Motivated from the polygenic risk score framework, we propose a microbial risk score (MRS) framework to aggregate the complicated microbial profile into a summarized risk score that can be used to measure and predict disease susceptibility. Specifically, the MRS algorithm involves two steps: 1) identifying a sub-community consisting of the signature microbial taxa associated with disease, and 2) integrating the identified microbial taxa into a continuous score. The first step is carried out using the existing sophisticated microbial association tests and pruning and thresholding method in the discovery samples. The second step constructs a community-based MRS by calculating alpha diversity on the identified sub-community in the validation samples. Moreover, we propose a multi-omics data integration method by jointly modeling the proposed MRS and other risk scores constructed from other omics data in disease prediction. RESULTS/UNASSIGNED:Through three comprehensive real data analyses using the NYU Langone Health COVID-19 cohort, the gut microbiome health index (GMHI) multi-study cohort, and a large type 1 diabetes cohort separately, we exhibit and evaluate the utility of the proposed MRS framework for disease prediction and multi-omics data integration. In addition, the disease-specific MRSs for colorectal adenoma, colorectal cancer, Crohn's disease, and rheumatoid arthritis based on the relative abundances of 5, 6, 12, and 6 microbial taxa respectively are created and validated using the GMHI multi-study cohort. Especially, Crohn's disease MRS achieves AUCs of 0.88 ([0.85-0.91]) and 0.86 ([0.78-0.95]) in the discovery and validation cohorts, respectively. CONCLUSIONS/UNASSIGNED:The proposed MRS framework sheds light on the utility of the microbiome data for disease prediction and multi-omics integration, and provides great potential in understanding the microbiome's role in disease diagnosis and prognosis.
PMID: 35702150
ISSN: 2692-8205
CID: 5686512
Elevated dietary carbohydrate and glycemic intake associate with an altered oral microbial ecosystem in two large U.S. cohorts
The human oral microbiome is associated with chronic diseases including cancer. However, our understanding of its relationship with diet is limited. We assessed the associations between carbohydrate and glycemic index (GI) with oral microbiome composition in 834 non-diabetic subjects from the NCI-PLCO and ACS-CPSII cohorts. The oral microbiome was characterized using 16Sv3-4 rRNA-sequencing from oral mouthwash samples. Daily carbohydrate and GI were assessed from food frequency questionnaires. We used linear regression, permutational MANOVA, and negative binomial Generalized Linear Models (GLM) to test associations of diet with α- and β-diversity and taxon abundance (adjusting for age, sex, cohort, BMI, smoking, caloric intake, and alcohol). A q-value (FDR-adjusted P-value) of <0.05 was considered significant. Oral bacterial α-diversity trended higher in participants in the highest quintiles of carbohydrate intake, with marginally increased richness and Shannon diversity (p-trend=0.06 and 0.07). Greater carbohydrate intake was associated with greater abundance of class Fusobacteriia (q=0.02) and genus Leptotrichia (q=0.01) and with lesser abundance of an Actinomyces OTU (q=4.7E-04). Higher GI was significantly related to greater abundance of genus Gemella (q=0.001). This large, nationwide study provides evidence that diets high in carbohydrates and GI may influence the oral microbiome.
PMCID:9770587
PMID: 36567732
ISSN: 2767-9764
CID: 5592052
Benzene exposure and risk of benzene poisoning in Chinese workers
OBJECTIVES/OBJECTIVE:Benzene is a known haematoxin and leukemogen that can cause benzene poisoning (BP), that is, a persistent reduction in white cell counts that is strongly associated with increased risk of lymphohaematopoietic malignancies. Data are needed on the exposure-response, particularly at low doses and susceptible populations for clinical and regulatory purposes. METHODS:In a case-cohort study among 110 631 Chinese workers first employed 1949-1987 and followed up during 1972-1999, we evaluated BP risk according to benzene exposure level and investigated risk modification by subject (sex, attained age) and exposure-related factors (latency, exposure windows, age at first benzene exposure, coexposure to toluene) using excess relative risk and excess absolute risk models. RESULTS:There were 538 BP cases and 909 benzene-exposed referents. The exposure metric with best model fit was cumulative benzene exposure during a 5-year risk window, followed by a 9-month lag period before BP diagnosis. Estimated excess absolute risk of BP at age 60 increased from 0.5% for subjects in the lowest benzene exposure category (>0 to 10 ppm-years) to 5.0% for those in the highest category (>100 ppm-years) compared with unexposed subjects. Increased risks were apparent at low cumulative exposure levels and for workers who were first exposed at <30 years of age. CONCLUSIONS:Our data show a clear association between benzene exposure and BP, beginning at low cumulative benzene exposure levels with no threshold, and with higher risks for workers exposed at younger ages. These findings are important because BP has been linked to a strongly increased development of lymphohaematopoietic malignancies.
PMID: 35273074
ISSN: 1470-7926
CID: 5394042
Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk
Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E-4), and Aspartylglucosaminidase (AGA: p = 4.5E-4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.
PMID: 36344807
ISSN: 2045-2322
CID: 5357132
