Welcome to my research web page. Details on new findings from my research group, grants and interesting tidbits from the broader epidemiology and biostatistics worlds will be highlighted on this home page from time to time. A more detailed description of my current areas of interest, funded projects and publications can be found on the various pages listed in the header. I enjoy photography as a hobby and have included a link to my gallery for those interested in such things. Thanks for visiting!
BMC Gastroenterol. 2019 Jun 27;19(1):109. doi: 10.1186/s12876-019-1022-0.
Vaughan TL, Onstad L, Dai JY.
A key barrier to controlling esophageal adenocarcinoma (EAC) is identifying those most likely to benefit from screening and surveillance. We aimed to develop an online educational tool, termed IC-RISC™, for providers and patients to estimate more precisely their absolute risk of developing EAC, interpret this estimate in the context of risk of dying from other causes, and aid in decision-making.
U.S. incidence and mortality data and published relative risk estimates from observational studies and clinical trials were used to calculate absolute risk of EAC over 10?years adjusting for competing risks. These input parameters varied depending on presence of the key precursor, Barrett’s esophagus. The open source application works across common devices to gather risk factor data and graphically illustrate estimated risk on a single page. Changes to input data are immediately reflected in the colored graphs. We used the calculator to compare the risk distribution between EAC cases and controls from six population-based studies to gain insight into the discrimination metrics of current practice guidelines for screening, observing that current guidelines sacrifice a significant amount of specificity to identify 78-86% of eventual cases in the US population.
Figure 1. Risk calculator tab. In example a) A 60-year-old white male with moderate physical activity, non-use of NSAIDs or statins, no family history of BE or EAC, weekly – daily reflux symptoms, a body mass index (BMI) of 28 (“overweight”), who never smoked cigarettes, and has not been screened (BE status unknown) is estimated to have a 10-year risk of developing EAC of 5.7 per 1000, or 1 in 175 people of similar characteristics. This is higher than the 10-year risk of dying from colon cancer and stroke for a 60-year-old white male, but lower than that from injury or heart disease. In example b) this same individual has undergone an upper endoscopy and found to have a visible Barrett’s segment length of 5?cm, but no evidence of dysplasia. His 10-year risk is now estimated to be 34.0 per 1000 (1 in 29 people) which is approximately equal to his risk of dying from heart disease.
Fig. 2. Metrics describing estimated 10-year risk in EAC cases and controls based on data from six population-based studies in the BEACON consortium. The bottom panel shows the distribution of 10-year risk estimates by case status. The solid vertical lines represent examples of an individual for whom current ACG guidelines suggest that screening endoscopy be considered. The first (10-year risk?=?0.66/1000) is for a 40-year-old male with weekly-daily reflux and two additional risk factors (white and BMI?>?25). The second (10-year risk?=?0.97/1000) is for a 50-year-old male with weekly-daily reflux and with two different additional risk factors (age?>?50 and positive cigarette smoking history). The top, second and third panels show how specificity, sensitivity and positive predictive value (ppv), respectively, vary according to possible thresholds for further action.
This educational tool provides a simple and rapid means to graphically communicate risk of EAC in the context of other health risks, facilitates “what-if” scenarios regarding potential preventative actions, and can inform discussions regarding screening, surveillance and treatment options. Its generic architecture lends itself to being easily extended to other cancers with distinct pathways and/or intermediate stages, such as hepatocellular cancer. IC-RISC™ extends current qualitative clinical practice guidelines into a quantitative assessment, which brings the possibility of preventative actions being offered to persons not currently targeted for screening and, conversely, reducing unnecessary procedures in those at low risk. Prospective validation and application to existing well-characterized cohort studies are needed.
Absolute risk; Barrett’s esophagus; Esophageal adenocarcinoma; Esophageal cancer; R language; Risk calculator; Risk prediction; Shiny application; Web application
Clin Gastroenterol Hepatol. 2019 Feb 1. pii: S1542-3565(19)30088-6. doi: 10.1016/j.cgh.2019.01.041. [Epub ahead of print]
No Association Between Vitamin D Status and Risk of Barrett’s Esophagus or Esophageal Adenocarcinoma-a Mendelian Randomization Study.
Dong J, Gharahkhani P, Chow WH, et al.
BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett’s esophagus (BE).
METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett’s and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC.
RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio (OR) per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P=.41). The OR for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P=.18).
CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC.
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
Communications Biology 2018 Oct 24;1:174.
doi: 10.1038/s42003-018-0182-8. eCollection 2018
Whole-genome sequencing of esophageal adenocarcinoma in Chinese patients reveals distinct mutational signatures and genomic alterations
James Y. Dai, Xiaoyu Wang, Matthew F. Buas, et al
While the incidence of esophageal adenocarcinoma (EAC) has risen drastically in Western countries over the last 40 years, a similar trend has not been observed for EAC in China. Here, we analyzed mutational spectrum, copy number alterations, and structural variants from whole-genome sequencing of 10 Chinese EAC tumor samples and their matched normal samples, and compared them to previously reported EAC tumor specimens from Western countries. The mutational burden in Chinese EAC was significantly lower than that found in EAC from Western countries. The hallmark A>C mutational signature observed at high frequency in EAC from Western countries, which has been linked to acid reflux, is completely absent in Chinese samples. Furthermore, none of the Chinese samples showed evidence of chromothripsis and genome doubling that are often found in EAC from Western countries. In summary, Chinese EAC tumor samples had distinct genomic profiles and signatures, suggesting that EAC in Chinese individuals may arise from a different etiological pathway.
Clin. Gastroenterol. Hepatol. (2018). doi:10.1016/j.cgh.2018.05.002
Lorenz Curves and Gini Coefficient Analyses Indicate Inefficiencies in Esophageal Adenocarcinoma Screening.
Hur C, Zhan T, Thrift AP, Vaughan TL & Feuer, EJ
Rates of esophageal adenocarcinoma (EAC) have increased rapidly in the US and much of western Europe, and five year survival continues to be poor. Prevention and early detection efforts for EAC have focused on identifying persons with EAC precursor state, Barrett’s Esophagus (BE), but the survival benefit has been disappointingly low. Precise risk stratification could improve early identification of individuals who will develop EAC, allowing for such high-risk individuals to be targeted for new and evolving preventive and minimally invasive screening technologies. This underlying issue of efficiency is conceptually similar to the Gini coefficient, a widely accepted method to depict the income distribution of a group to assess wealth inequality. A Lorenz curve plots percentage of wealth against the percentage of the population; perfect wealth distribution would result in a slope of 1 and a Gini coefficient of 0 whereas severe wealth inequity results in higher Gini values closer to 1. Some examples of Gini coefficients are shown in Supplementary Figure 1. In this article, we use relative risks of stratified groups to construct Lorenz curves and quantitively analyze the distribution of EAC burden in the US population, for which a higher Gini coefficient indicates more efficient risk stratification.
Eur J Epidemiol. 2017 Nov;32(11):1007-1017
Li N, Petrick JL, Steck SE, Bradshaw PT, McClain KM, Niehoff NM, Engel LS, Shaheen NJ, Corley DA, Vaughan TL, Gammon MD
Barrett’s esophagus (BE) is the key precursor lesion of esophageal adenocarcinoma, a lethal cancer that has increased rapidly in westernized countries over the past four decades. Dietary sugar intake has also been increasing over time, and may be associated with these tumors by promoting hyperinsulinemia. The study goal was to examine multiple measures of sugar/starches intake in association with BE. This pooled analysis included 472 BE cases and 492 controls from two similarly conducted case-control studies in the United States. Dietary intake data, collected by study-specific food frequency questionnaires, were harmonized across studies by linking with the University of Minnesota Nutrient Database, and pooled based on study-specific quartiles. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race, total energy intake, study indicator, body mass index, frequency of gastro-esophageal reflux, and fruit/vegetable intake. In both studies, intake of sucrose (cases vs. controls, g/day: 36.07 vs. 33.51; 36.80 vs. 35.06, respectively) and added sugar (46.15 vs. 41.01; 44.18 vs. 40.68, respectively) were higher in cases than controls. BE risk was increased 79% and 71%, respectively, for associations comparing the fourth to the first quartile of intake of sucrose (ORQ4vs.Q1 = 1.79, 95% CI = 1.07-3.02, P trend = 0.01) and added sugar (ORQ4vs.Q1 = 1.71, 95% CI = 1.05-2.80, P trend = 0.15). Intake of sweetened desserts/beverages was associated with 71% increase in BE risk (ORQ4vs.Q1 = 1.71, 95% CI = 1.07-2.73, P trend = 0.04). Limiting dietary intake of foods and beverages that are high in added sugar, especially refined table sugar, may reduce the risk of developing BE
Int J Epidem. 2017 Dec 1;46(6):1836-1846
A pooled analysis of dietary sugar/carbohydrate intake and esophageal and gastric cardia adenocarcinoma incidence and survival in the United States (US).
Li N, Petrick JL, Steck SE, Bradshaw PT, McClain KM, Niehoff NM, Engel LS, Shaheen NJ, Risch HA, Vaughan TL, Wu A, Gammon MD
Background: During the past 40 years, esophageal/gastric cardia adenocarcinoma (EA/GCA) incidence increased in Westernized countries, but survival remained low. A parallel increase in sugar intake, which may facilitate carcinogenesis by promoting hyperglycaemia, led us to examine sugar/carbohydrate intake in association with EA/GCA incidence and survival.
Methods: We pooled 500 EA cases, 529 GCA cases and 2027 controls from two US population-based case-control studies with cases followed for vital status. Dietary intake, assessed by study-specific food frequency questionnaires, was harmonized and pooled to estimate 12 measures of sugar/carbohydrate intake. Multivariable-adjusted odds ratios (ORs) and hazard ratios [95% confidence intervals (CIs)] were calculated using multinomial logistic regression and Cox proportional hazards regression, respectively.
Results: A incidence was increased by 51-58% in association with sucrose (ORQ5vs.Q1 = 1.51, 95% CI = 1.01-2.27), sweetened desserts/beverages (ORQ5vs.Q1 = 1.55, 95% CI = 1.06-2.27) and the dietary glycaemic index (ORQ5vs.Q1 = 1.58, 95% CI = 1.13-2.21). Body mass index (BMI) and gastro-esophageal reflux disease (GERD) modified these associations (Pmultiplicative-interaction ? 0.05). For associations with sucrose and sweetened desserts/beverages, respectively, the OR was elevated for BMI < 25 (ORQ4-5vs.Q1-3 = 1.79, 95% CI = 1.26-2.56 and ORQ4-5vs.Q1-3 = 1.45, 95% CI = 1.03-2.06), but not BMI ? 25 (ORQ4-5vs.Q1-3 = 1.05, 95% CI = 0.76-1.44 and ORQ4-5vs.Q1-3 = 0.85, 95% CI = 0.62-1.16). The EA-glycaemic index association was elevated for BMI ? 25 (ORQ4-5vs.Q1-3 = 1.38, 95% CI = 1.03-1.85), but not BMI < 25 (ORQ4-5vs.Q1-3 = 0.88, 95% CI = 0.62-1.24). The sucrose-EA association OR for GERD < weekly was 1.58 (95% CI = 1.16-2.14), but for GERD ? weekly was 1.01 (95% CI = 0.70-1.47). Sugar/carbohydrate measures were not associated with GCA incidence or EA/GCA survival.
Conclusions: If confirmed, limiting intake of sucrose (e.g. table sugar), sweetened desserts/beverages, and foods that contribute to a high glycaemic index, may be plausible EA risk reduction strategies.
Gastroenterology. 2017 Sep;153(3):657-673
Contino G, Vaughan TL, Whiteman D, Fitzgerald RC
We have recently gained unprecedented insight into genetic factors that determine risk for Barrett’s esophagus (BE) and progression to esophageal adenocarcinoma (EA). Next-generation sequencing technologies have allowed us to identify somatic mutations that initiate BE and track genetic changes during development of tumors and invasive cancer. These technologies led to identification of mechanisms of tumorigenesis that challenge the current multistep model of progression to EA. Newer, cost-effective technologies create opportunities to rapidly translate the analysis of DNA into tools that can identify patients with BE at high risk for cancer, detect dysplastic lesions more reliably, and uncover mechanisms of carcinogenesis.