Publications by authors named "Harvey J Murff"

74 Publications

Magnesium Treatment on Methylation Changes of Transmembrane Serine Protease 2 (TMPRSS2).

medRxiv 2021 Mar 12. Epub 2021 Mar 12.

Background: The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike (S) protein priming.

Objectives: To test the hypothesis that Mg treatment leads to DNA methylation changes in .

Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized.

Results: We found that 12-week of personalized Mg treatment significantly increased 5-mC methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to placebo arm (decreased by 0.1%) in those aged < 65 years old. The difference remained statistically significant after adjusting for age, sex and baseline methylation as well as FDR correction (FDR-adjusted =0.014). Additionally, Mg treatment significantly reduced 5-hmC level at cg26337277 (close proximity to TSS200 and 5'UTR, promoter) by 2.3% compared to increases by 7.1% in the placebo arm after adjusting for covariates in those aged < 65 years old ( =0.003). The effect remained significant at FDR of 0.10 (adjusted value=0.088).

Conclusion: Among individuals aged younger than 65 years with the Ca:Mg intake ratios equal to or over 2.6, reducing Ca:Mg ratios to around 2.3 increased 5-mC modifications (i.e. cg16371860) and reduced 5-hmC modifications (i.e. cg26337277) in the gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention for the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the genotype.
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http://dx.doi.org/10.1101/2021.03.11.21253287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987044PMC
March 2021

Magnesium and imidazole propionate.

Clin Nutr ESPEN 2021 Feb 7;41:436-438. Epub 2021 Jan 7.

Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Background & Aims: Circulating levels of imidazole propionate (ImP), a microbial metabolite of histidine, were higher in participants with type 2 diabetes (T2D) compared to those without and also induced insulin resistance. We hypothesize that low intake of magnesium (Mg) and/or low body Mg status in humans may lead to low Mg concentrations in gut microbiota, and, in turn, elevated microbial production of ImP and increased levels of circulating ImP.

Methods: We tested this hypothesis in the Personalized Prevention of Colorectal Cancer Trial (PPCCT) (registered at clinicaltrials.gov as NCT01105169), a double-blind 2 × 2 factorial randomized controlled trial enrolling 240 participants at high risk of Mg deficiency. Among 68 participants (34 each in the treatment and placebo arms), we measured plasma metabolites using the untargeted Metabolon's global Precision Metabolomics™ LC-MS platform.

Results: Mg treatment significantly reduced ImP by 39.9% compared to a 6.0% increase in the placebo arm (P = 0.02). We found the correlation coefficients were -0.12 (P = 0.32) and -0.31 (P < 0.01) between the change in ImP and changes in serum Mg and urinary Mg, respectively. In addition, we found Mg treatment increased circulating levels of propionic acid (InP) by 27.5% (P = 0.07) and reduced levels of glutarate by 17.9% (P = 0.04) compared to the placebo arm.

Conclusions: Further studies are needed to replicate these findings and to investigate whether Mg treatment specifically changes the production of ImP by microbiota. Also, future studies are warranted to confirm the effect of Mg treatment on glutarate and InP.
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http://dx.doi.org/10.1016/j.clnesp.2020.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835418PMC
February 2021

Evaluation of determinants for age disparities in the survival improvement of colon cancer: results from a cohort of more than 486,000 patients in the United States.

Am J Cancer Res 2020 1;10(10):3395-3405. Epub 2020 Oct 1.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center Nashville, Tennessee, USA.

Over the past two decades, elderly colon cancer patients experienced less improvement in survival than their younger counterparts, yet the contributing factors remain unknown. We aimed to evaluate factors that may contribute to the age disparity of survival improvement among patients with colon cancer. Using data from the National Cancer Database, we identified patients diagnosed with colon cancer between 2004 and 2012 with follow-up data up to 2017. The hazard ratios (HR) and 95% confidence intervals (CI) for 5-year OS associated with study variables were estimated using multivariable Cox regression. Among 486,284 patients included in this study, elderly patients (aged ≥75) had a lower adherence to National Comprehensive Cancer Network (NCCN) treatment guidelines (% of non-adherence: 45.3%) than younger patients (aged <50, 19.3%; <0.001). After adjusting for demographics, access to care and clinical characteristics, compared with patients diagnosed between 2004 and 2006, younger and older patients diagnosed between 2010 and 2012 experienced 16% (HR: 0.84, 95% CI: 0.81-0.88) and 6% (HR: 0.94, 95% CI: 0.93-0.95) reductions in mortality (=1.42×10), respectively. After an additional adjustment for guideline adherence status, no significant difference in the improvement of survival was noted (=0.17). The association patterns were similar regardless of tumor stage, race, and high comorbidity scores (all >0.05). Several patient-related factors were identified in association with noncompliance to NCCN guidelines, including comorbidity status. However, over 60% of noncompliance elderly patients had a Charlson comorbidity score of 0. The observed age disparity in survival improvement among colon cancer patients was primarily explained by a slower improvement in adherence to NCCN treatment guidelines in elderly than younger patients. Many older adults were not receiving recommended therapies despite minimal comorbidities. Our findings call for measures to increase adherence to treatment guidelines among elderly patients to improve survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642646PMC
October 2020

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 Dec 23;29(12):2735-2739. Epub 2020 Sep 23.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome.

Methods: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data.

Results: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex.

Conclusions: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk.

Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710600PMC
December 2020

Ca:Mg Ratio, APOE Cytosine Modifications, and Cognitive Function: Results from a Randomized Trial.

J Alzheimers Dis 2020 ;75(1):85-98

Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Deterioration of ionized calcium (Ca2+) handling in neurons could lead to neurodegenerative disease. Magnesium (Mg) antagonizes Ca during many physiologic activities, including energy metabolism and catalyzation of demethylation from 5-methylcytosine(5-mC) to 5-hydroxymethylcytosine(5-hmC).

Objective: To test the hypothesis that actively reducing the Ca:Mg intake ratio in the diet through Mg supplementation improves cognitive function, and to test whether this effect is partially mediated by modified cytosines in Apolipoprotein E (APOE).

Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized.

Results: Among those aged > 65 years old who consumed a high Ca:Mg ratio diet, we found that reducing the Ca:Mg ratio to around 2.3 by personalized Mg supplementation significantly improved cognitive function by 9.1% (p = 0.03). We also found that reducing the Ca:Mg ratio significantly reduced 5-mC at the cg13496662 and cg06750524 sites only among those aged > 65 years old (p values = 0.02 and 0.03, respectively). Furthermore, the beneficial effect of reducing the Ca:Mg ratio on cognitive function in those aged over 65 years was partially mediated by reductions in 5-mC levels (i.e., cg13496662 and cg06750524) in APOE (p for indirect effect = 0.05).

Conclusion: Our findings suggest that, among those age 65 and over with a high dietary Ca:Mg ratio, optimal Mg status may improve cognitive function partially through modifications in APOE methylation. These findings, if confirmed, have significant implications for the prevention of cognitive aging and Alzheimer's disease.Clinical Trial Registry number and website: #100106 https://clinicaltrials.gov/ct2/show/NCT03265483.
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http://dx.doi.org/10.3233/JAD-191223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737669PMC
May 2021

Meat intake, meat cooking methods, and meat-derived mutagen exposure and risk of sessile serrated lesions.

Am J Clin Nutr 2020 06;111(6):1244-1251

Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.

Background: Red and processed meat, recognized carcinogens, are risk factors for colorectal neoplasia, including polyps, the precursor for colorectal cancer. The mechanism is unclear. One possible explanation is the mutagenic activity of these foods, perhaps due to generation during cooking [e.g., heterocyclic amine (HCA) intake]. Few studies have evaluated meat intake and sessile serrated lesion (SSL) risk, a recently recognized precursor, and no study has evaluated meat cooking methods and meat-derived mutagens with SSL risk.

Objective: We evaluated intakes of meat, meat cooking methods, and inferred meat mutagens with SSL risk and in comparison to risk of other polyps.

Methods: Meat, well-done meat, and inferred meat mutagen intakes were evaluated. Polytomous logistic regression models were used to estimate ORs and 95% CIs among cases (556 hyperplastic polyp, 1753 adenoma, and 208 SSL) and controls (3804) in the large colonoscopy-based, case-control study, the Tennessee Colorectal Polyp Study.

Results: The highest quartile intakes of red meat (OR: 2.38; 95% CI: 1.44, 3.93), processed meat (OR: 2.03; 95% CI: 1.30, 3.17), well-done red meat (OR: 2.19; 95% CI: 1.34, 3.60), and the HCA 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQX; OR: 2.48; 95% CI: 1.49, 4.16) were associated with increased risk of SSLs in comparison to the lowest quartile intake.

Conclusions: High intakes of red and processed meats are strongly and especially associated with SSL risk and part of the association may be due to HCA intake. Future studies should evaluate other mechanism(s) and the potential for primary prevention.
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http://dx.doi.org/10.1093/ajcn/nqaa030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266682PMC
June 2020

Yogurt consumption and colorectal polyps.

Br J Nutr 2020 Feb 20:1-12. Epub 2020 Feb 20.

Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Diet modifies the risk of colorectal cancer (CRC), and inconclusive evidence suggests that yogurt may protect against CRC. We analysed the data collected from two separate colonoscopy-based case-control studies. The Tennessee Colorectal Polyp Study (TCPS) and Johns Hopkins Biofilm Study included 5446 and 1061 participants, respectively, diagnosed with hyperplastic polyp (HP), sessile serrated polyp, adenomatous polyp (AP) or without any polyps. Multinomial logistic regression models were used to derive OR and 95 % CI to evaluate comparisons between cases and polyp-free controls and case-case comparisons between different polyp types. We evaluated the association between frequency of yogurt intake and probiotic use with the diagnosis of colorectal polyps. In the TCPS, daily yogurt intake v. no/rare intake was associated with decreased odds of HP (OR 0·54; 95 % CI 0·31, 0·95) and weekly yogurt intake was associated with decreased odds of AP among women (OR 0·73; 95 % CI 0·55, 0·98). In the Biofilm Study, both weekly yogurt intake and probiotic use were associated with a non-significant reduction in odds of overall AP (OR 0·75; 95 % CI 0·54, 1·04) and (OR 0·72; 95 % CI 0·49, 1·06) in comparison with no use, respectively. In summary, yogurt intake may be associated with decreased odds of HP and AP and probiotic use may be associated with decreased odds of AP. Further prospective studies are needed to verify these associations.
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http://dx.doi.org/10.1017/S0007114520000550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438237PMC
February 2020

Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 04 12;29(4):860-870. Epub 2020 Feb 12.

Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk.

Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined.

Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [OR = 0.96; 95% confidence interval (CI) = 0.93-0.98; = 5.2 × 10] and α-linolenic acid (OR = 0.95; 95% CI = 0.92-0.97; = 5.4 × 10), whereas modest increased risks were observed for arachidonic (OR = 1.06; 95% CI = 1.03-1.08; = 3.3 × 10), eicosapentaenoic (OR = 1.04; 95% CI = 1.01-1.07; = 2.5 × 10), and docosapentaenoic acids (OR = 1.03; 95% CI = 1.01-1.06; = 1.2 × 10). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses.

Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk.

Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125012PMC
April 2020

Association of Race and Socioeconomic Status With Colorectal Cancer Screening, Colorectal Cancer Risk, and Mortality in Southern US Adults.

JAMA Netw Open 2019 12 2;2(12):e1917995. Epub 2019 Dec 2.

Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.

Importance: Colorectal cancer (CRC) screening is rarely studied in populations who may face additional barriers to participate in cancer screening, such as African American individuals and individuals with low socioeconomic status (SES).

Objective: To examine the associations of CRC screening and modalities with CRC incidence and mortality by race and SES.

Design, Setting, And Participants: This cohort study used data from the Southern Community Cohort Study, which enrolled more than 85 000 participants from community health centers or stratified random sampling of the general population in 12 states in the southeastern United States. The present study included data from cohort members who were eligible for CRC screening as recommended by expert organizations based on age and family history. Participants completed questionnaires from 2002 to 2009 and were contacted again from 2008 to 2012. Linkages to state cancer registries and the National Death Index as of December 31, 2016, identified incident CRC and vital status. Data analysis was performed from January 1, 2018, to October 30, 2019.

Main Outcomes And Measures: Incident CRC (n = 632) and mortality (n = 10 003). Cox proportional hazards regression models evaluated associations between screening modalities and CRC risk and mortality. Information on fecal occult blood test use was only obtained on the follow-up questionnaire. Self-identified race was measured as African American/black, white, or other, and SES was defined by household income.

Results: This study included 47 596 participants (median baseline age, 54 years [interquartile range, 10 years]; 32 185 [67.6%] African American; 28 884 [60.7%] female; and 26 075 [54.8%] with household income <$15 000). A total of 24 432 participants (63.9%) had never undergone CRC testing at baseline. The CRC testing assessed at baseline and follow-up interviews was associated with significant CRC risk reduction (hazard ratio [HR], 0.55; 95% CI, 0.44-0.70 for ever colonoscopy at baseline). Results were similar in analyses stratified by race (African American: HR, 0.65; 95% CI, 0.50-0.85; white: HR, 0.44; 95% CI, 0.27-0.70) and household income (<$15 000: HR, 0.63; 95% CI, 0.46-0.86, ≥$15 000: HR, 0.49; 95% CI, 0.35-0.69). Ever sigmoidoscopy at baseline was associated with CRC risk reduction (HR, 0.66; 95% CI, 0.51-0.87), and undergoing fecal occult blood test in the interval between baseline and follow-up interview was associated with CRC risk reduction (HR, 0.75; 95% CI, 0.57-0.98). Inverse associations were also observed between CRC mortality and receipt of colonoscopy (HR for women, 0.39; 95% CI, 0.21-0.73; HR for men, 0.69; 95% CI, 0.40-1.18) and sigmoidoscopy (HR for women, 0.37; 95% CI, 0.16-0.85; HR for men, 0.82; 95% CI, 0.46-1.47); however, the association did not extend to fecal occult blood test (HR for women, 1.02; 95% CI, 0.62-1.70; HR for men, 1.03; 95% CI, 0.55-1.93).

Conclusions And Relevance: In this study, CRC test rates were low among African American individuals and those with low SES. The findings suggest that screening, particularly with colonoscopy, is significantly associated with reduced risk of CRC and mortality. The CRC disparities experienced by individuals with low SES and African American individuals may be lessened by improving access to and uptake of CRC screening.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.17995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991213PMC
December 2019

Effects of fish oil supplementation on eicosanoid production in patients at higher risk for colorectal cancer.

Eur J Cancer Prev 2019 05;28(3):188-195

Department of Medicine.

Fish oil supplementation may represent a potential chemopreventive agent for reducing colorectal cancer risk. The mechanism of action of fish oil is unknown but presumed to be related to eicosanoid modification. The purpose of this study was to evaluate the effects of fish oil supplementation on the levels of urinary and rectal eicosanoids. We conducted a randomized, double-blind, controlled trial of 2.5 g of fish oil per day compared with olive oil supplementation over a 6-month period. Study participants had a history of colorectal adenomas. Randomization was stratified based on the gene variant rs174535 in the fatty acid desaturase 1 enzyme (FADS1), which affects tissue levels of arachidonic acid. A total of 141 participants were randomized. Urinary prostaglandin E2 metabolite (PGE-M) was measured at baseline, 3, and 6 months and rectal prostaglandin E2 (PGE2) at baseline and 6 months. Repeated-measures linear regression was used to determine the effect of the intervention on each outcome measure. Overall, fish oil supplementation was found to reduce urinary PGE-M production compared with olive oil (P=0.03). Fish oil did not reduce rectal PGE2 overall; however, it did significantly reduce PGE2 in the subgroup of participants not using aspirin or NSAIDs (P=0.04). FADS1 genotype did not seem to modify effects of fish oil on PGE2 production. We conclude that fish oil supplementation has a modest but beneficial effect on eicosanoids associated with colorectal carcinogenesis, particularly in those not taking aspirin or NSAIDs.
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http://dx.doi.org/10.1097/CEJ.0000000000000455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440821PMC
May 2019

Arachidonic acid and colorectal adenoma risk: a Mendelian randomization study.

Clin Epidemiol 2019 18;11:17-22. Epub 2018 Dec 18.

GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA,

Background: Previous studies have shown a link between increased dietary intake of arachidonic acid (ARA) and colorectal neoplasms. It has been shown that erythrocyte phospholipid membrane concentrations of ARA are strongly determined by genetic variation. Fatty acid desaturase (FADS) controls the rate limiting step in ARA production, and FADS variant rs174537 has been shown to be responsible for up to 18.6% of the variation seen. To determine if a causal association exists between erythrocyte membrane ARA concentrations and colorectal adenomas, we conducted a Mendelian randomization (MR) analysis using rs174537 as an instrumental variable (IV). MR analysis was chosen because it is less susceptible to bias and confounding.

Patients And Methods: A case-control study was performed using the Tennessee Colorectal Polyps Study. Patients were matched on age, gender, race, facility site, and year of colonoscopy. Cases were defined as any colorectal adenoma on colonoscopy (n=909) and controls were polyp free (n=855). A two-stage logistic regression was conducted using rs174537 as the IV with the dependent variable being the presence of a colorectal adenoma on colonoscopy.

Results: Cases were older (59 vs 57 years of age, <0.0001), and more likely to use alcohol (47.4% vs 19.8%, =0.001) and to smoke (77.0% vs 66.9%, <0.0001). There was no statistically significant difference in: age, sex, alcohol use, body mass index (BMI), or NSAID use when stratified by the rs174537 alleles. Genotype was strongly associated with erythrocyte membrane ARA concentrations (<0.0001). We found no evidence of an association between our IV (rs174537) and colorectal adenomas (=0.41).

Conclusion: In our MR study increased erythrocyte ARA concentrations were not associated with the risk of colorectal adenomas.
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http://dx.doi.org/10.2147/CLEP.S186883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302799PMC
December 2018

Metformin use and incidence cancer risk: evidence for a selective protective effect against liver cancer.

Cancer Causes Control 2018 Sep 18;29(9):823-832. Epub 2018 Jul 18.

Veterans Health Administration-Tennessee Valley Healthcare System Geriatric Research Education Clinical Center (GRECC), HSR&D Center, Nashville, TN, USA.

Purpose: Several observational studies suggest that metformin reduces incidence cancer risk; however, many of these studies suffer from time-related biases and several cancer outcomes have not been investigated due to small sample sizes.

Methods: We constructed a propensity score-matched retrospective cohort of 84,434 veterans newly prescribed metformin or a sulfonylurea as monotherapy. We used Cox proportional hazard regression to assess the association between metformin use compared to sulfonylurea use and incidence cancer risk for 10 solid tumors. We adjusted for clinical covariates including hemoglobin A1C, antihypertensive and lipid-lowering medications, and body mass index. Incidence cancers were defined by ICD-9-CM codes.

Results: Among 42,217 new metformin users and 42,217 matched-new sulfonylurea users, we identified 2,575 incidence cancers. Metformin was inversely associated with liver cancer (adjusted hazard ratio [aHR] = 0.44, 95% CI 0.31, 0.64) compared to sulfonylurea. We found no association between metformin use and risk of incidence bladder, breast, colorectal, esophageal, gastric, lung, pancreatic, prostate, or renal cancer when compared to sulfonylurea use.

Conclusions: In this large cohort study that accounted for time-related biases, we observed no association between the use of metformin and most cancers; however, we found a strong inverse association between metformin and liver cancer. Randomized trials of metformin for prevention of liver cancer would be useful to verify these observations.
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http://dx.doi.org/10.1007/s10552-018-1058-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108939PMC
September 2018

A prospective study of dietary polyunsaturated fatty acids intake and lung cancer risk.

Int J Cancer 2018 11 7;143(9):2225-2237. Epub 2018 Aug 7.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.

Animal studies have shown that polyunsaturated fatty acids (PUFAs) have antineoplastic and anti-inflammatory properties. Results from epidemiologic studies on specific types of PUFAs for lung cancer risk, however, are inconclusive. We prospectively evaluated the association of specific types of dietary PUFA intakes and lung cancer risk in two population-based cohort studies, the Shanghai Women's Health Study (SWHS) and Shanghai Men's Health Study (SMHS) with a total of 121,970 study participants (i.e., 65,076 women and 56,894 men). Dietary fatty acid intakes were derived from data collected at the baseline using validated food frequency questionnaires (FFQs). Cox proportional hazards model was performed to assess the association between PUFAs and lung cancer risk. Total, saturated and monounsaturated fatty acid intakes were not significantly associated with lung cancer risk. Total PUFAs intake was inversely associated with lung cancer risk [HRs and respective 95% CIs for quintiles 2-5 vs quintile 1: 0.84 (0.71-0.98), 0.97 (0.83-1.13), 0.86 (0.74-1.01) and 0.85 (0.73-1.00), p  = 0.11]. However, DHA intake was positively associated with lung cancer risk [HRs and 95% CIs: 1.01 (0.86-1.19), 1.20 (1.03-1.41), 1.21 (1.03-1.42) and 1.24 (1.05-1.47), p  = 0.001]. The ratio of n-6 PUFAs to n-3 PUFAs (i.e., 7:1) was inversely associated with lung cancer risk, particularly among never-smokers and adenocarcinoma patients. Total PUFAs and the ratio between n-6 PUFAs and n-3 PUFAs were inversely associated with lung cancer risk. This study highlights an important public health impact of PUFA intakes toward intervention/prevention programs of lung cancer.
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http://dx.doi.org/10.1002/ijc.31608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195443PMC
November 2018

Inter-niche and inter-individual variation in gut microbial community assessment using stool, rectal swab, and mucosal samples.

Sci Rep 2018 03 7;8(1):4139. Epub 2018 Mar 7.

Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.

The purpose of this study is to evaluate similarities and differences in gut bacterial measurements and stability in the microbial communities of three different types of samples that could be used to assess different niches of the gut microbiome: rectal swab, stool, and normal rectal mucosa samples. In swab-stool comparisons, there were substantial taxa differences with some taxa varying largely by sample type (e.g. Thermaceae), inter-individual subject variation (e.g. Desulfovibrionaceae), or by both sample type and participant (e.g. Enterobacteriaceae). Comparing all three sample types with whole-genome metagenome shotgun sequencing, swab samples were much closer to stool samples than mucosa samples although all KEGG functional Level 1 and Level 2 pathways were significantly different across all sample types (e.g. transcription and environmental adaptation). However, the individual signature of participants was also observed and was largely stable between two time points. Thus, we found that while the distribution of some taxa was associated with these different sampling techniques, other taxa largely reflected individual differences in the microbial community that were insensitive to sampling technique. There is substantial variability in the assessment of the gut microbial community according to the type of sample.
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http://dx.doi.org/10.1038/s41598-018-22408-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841359PMC
March 2018

PUFA levels in erythrocyte membrane phospholipids are differentially associated with colorectal adenoma risk.

Br J Nutr 2017 Jun 29;117(11):1615-1622. Epub 2017 Jun 29.

3Geriatric Research Education and Clinical Center (GRECC),Department of Veterans Affairs,Tennessee Valley Healthcare System,1310 24th Avenue S,Nashville, TN 37212,USA.

Dietary intake of PUFA has been associated with colorectal neoplasm risk; however, results from observational studies have been inconsistent. Most prior studies have utilised self-reported dietary measures to assess fatty acid exposure which might be more susceptible to measurement error and biases compared with biomarkers. The purpose of this study was to determine whether erythrocyte phospholipid membrane PUFA percentages are associated with colorectal adenoma risk. We included data from 904 adenoma cases and 835 polyp-free controls who participated in the Tennessee Colorectal Polyp Study, a large colonoscopy-based case-control study. Erythrocyte membrane PUFA percentages were measured using GC. Conditional logistic regression was used to calculate adjusted OR for risk of colorectal adenomas with erythrocyte membrane PUFA. Higher erythrocyte membrane percentages of arachidonic acid was associated with an increased risk of colorectal adenomas (adjusted OR 1·66; 95 % CI 1·05, 2·62, P trend=0·02) comparing the highest tertile to the lowest tertile. The effect size for arachidonic acid was more pronounced when restricting the analysis to advanced adenomas only. Higher erythrocyte membrane EPA percentages were associated with a trend towards a reduced risk of advanced colorectal adenomas (P trend=0·05). Erythrocyte membrane arachidonic acid percentages are associated with an increased risk of colorectal adenomas.
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http://dx.doi.org/10.1017/S0007114517001490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891121PMC
June 2017

Review: In adults with diabetes, aspirin does not prevent CV events compared with placebo.

Authors:
Harvey J Murff

Ann Intern Med 2016 11;165(10):JC53

Vanderbilt University Medical CenterNashville, Tennessee, USA.

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http://dx.doi.org/10.7326/ACPJC-2016-165-10-053DOI Listing
November 2016

Comparative Effectiveness of Second-Line Agents for the Treatment of Diabetes Type 2 in Preventing Kidney Function Decline.

Clin J Am Soc Nephrol 2016 12 8;11(12):2177-2185. Epub 2016 Nov 8.

Health Services Research and Development Center, Veterans Health Administration Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, Nashville, Tennessee.

Background And Objectives: Diabetes is the leading cause of ESRD. Glucose control improves kidney outcomes. Most patients eventually require treatment intensification with second-line medications; however, the differential effects of those therapies on kidney function are unknown.

Design, Setting, Participants & Measurements: We studied a retrospective cohort of veterans on metformin monotherapy from 2001 to 2008 who added either insulin or sulfonylurea and were followed through September of 2011. We used propensity score matching 1:4 for those who intensified with insulin versus sulfonylurea, respectively. The primary composite outcome was persistent decline in eGFR≥35% from baseline (GFR event) or a diagnosis of ESRD. The secondary outcome was a GFR event, ESRD, or death. Outcome risks were compared using marginal structural models to account for time-varying covariates. The primary analysis required persistence with the intensified regimen. An effect modification of baseline eGFR and the intervention on both outcomes was evaluated.

Results: There were 1989 patients on metformin and insulin and 7956 patients on metformin and sulfonylurea. Median patient age was 60 years old (interquartile range, 54-67), median hemoglobin A1c was 8.1% (interquartile range, 7.1%-9.9%), and median creatinine was 1.0 mg/dl (interquartile range, 0.9-1.1). The rate of GFR event or ESRD (primary outcome) was 31 versus 26 per 1000 person-years for those who added insulin versus sulfonylureas, respectively (adjusted hazard ratio, 1.27; 95% confidence interval, 0.99 to 1.63). The rate of GFR event, ESRD, or death was 64 versus 49 per 1000 person-years, respectively (adjusted hazard ratio, 1.33; 95% confidence interval, 1.11 to 1.59). Tests for a therapy by baseline eGFR interaction for both the primary and secondary outcomes were not significant (P=0.39 and P=0.12, respectively).

Conclusions: Among patients who intensified metformin monotherapy, the addition of insulin compared with a sulfonylurea was not associated with a higher rate of kidney outcomes but was associated with a higher rate of the composite outcome that included death. These risks were not modified by baseline eGFR.
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http://dx.doi.org/10.2215/CJN.02630316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142060PMC
December 2016

Polyunsaturated fatty acids and prostate cancer risk: a Mendelian randomisation analysis from the PRACTICAL consortium.

Br J Cancer 2016 08 4;115(5):624-31. Epub 2016 Aug 4.

Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University-Sofia, 2 Zdrave Street, 1431 Sofia, Bulgaria.

Background: Prostate cancer is a common cancer worldwide with no established modifiable lifestyle factors to guide prevention. The associations between polyunsaturated fatty acids (PUFAs) and prostate cancer risk have been inconsistent. Using Mendelian randomisation, we evaluated associations between PUFAs and prostate cancer risk.

Methods: We used individual-level data from a consortium of 22 721 cases and 23 034 controls of European ancestry. Externally-weighted PUFA-specific polygenic risk scores (wPRSs), with explanatory variation ranging from 0.65 to 33.07%, were constructed and used to evaluate associations with prostate cancer risk per one standard deviation (s.d.) increase in genetically-predicted plasma PUFA levels using multivariable-adjusted unconditional logistic regression.

Results: No overall association was observed between the genetically-predicted PUFAs evaluated in this study and prostate cancer risk. However, risk reductions were observed for short-chain PUFAs, linoleic (ORLA=0.95, 95%CI=0.92, 0.98) and α-linolenic acids (ORALA=0.96, 95%CI=0.93, 0.98), among men <62 years; whereas increased risk was found among men ⩾62 years for LA (ORLA=1.04, 95%CI=1.01, 1.07). For long-chain PUFAs (i.e., arachidonic, eicosapentaenoic, and docosapentaenoic acids), increased risks were observed among men <62 years (ORAA=1.05, 95%CI=1.02, 1.08; OREPA=1.04, 95%CI=1.01, 1.06; ORDPA=1.05, 95%CI=1.02, 1.08).

Conclusion: Results from this study suggest that circulating ω-3 and ω-6 PUFAs may have a different role in the aetiology of early- and late-onset prostate cancer.
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http://dx.doi.org/10.1038/bjc.2016.228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997551PMC
August 2016

Endogenous Production of Long-Chain Polyunsaturated Fatty Acids and Metabolic Disease Risk.

Curr Cardiovasc Risk Rep 2014 Dec;8(12)

Division of Epidemiology, Vanderbilt University School of Medicine.

Long chain polyunsaturated fatty acids (PUFAs) are important structural components of cellular membranes and are converted into eicosanoids which serve various biological roles. The most common dietary n-6 and n-3 PUFAs are linoleic acid and α-linoleic acid, respectively. These 18-carbon chain fatty acids undergo a series of desaturation and elongation steps to become the 20-carbon fatty acids arachidonic acid and eicosapentaenoic acid, respectively. Evidence from genome wide association studies has consistently demonstrated that plasma and tissue levels of the n-6 long-chain PUFA arachidonic acid and to a lesser extent the n-3 long-chain PUFA eicosapentaenoic acid, are strongly influenced by variation in , and genes. Studies of functional variants in these genes, as well as studies in which desaturase activity has been indirectly estimated by fatty acid product-to -precursor ratios, have suggested that endogenous capacity to synthesize long-chain PUFAs may be associated with metabolic diseases such as diabetes mellitus. Interventional studies are starting to tease out the complicated relationship between dietary intakes of specific fatty acids, variation in desaturase and elongase genes and tissue levels of long chain PUFAs. Thus future studies of dietary PUFA interventions designed to reduce inflammatory and metabolic diseases will need to carefully consider how an individual's genetically-determined endogenous long-chain PUFA synthesis capacity might modify therapeutic response.
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http://dx.doi.org/10.1007/s12170-014-0418-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574498PMC
December 2014

The role of matching when adjusting for baseline differences in the outcome variable of comparative effectiveness studies.

J Comp Eff Res 2015 Aug;4(4):341-9

VA Tennessee Valley Geriatric Research Education Clinical Center (GRECC), Nashville, TN, 37212 USA.

Aim: Evaluate performance of analytical strategies commonly used to adjust for baseline differences in continuous outcome variables for comparative effectiveness studies.

Patients & Methods: Data simulations resembling a comparison of HbA1c values after initiation of antidiabetic treatments adjusting for baseline HbA1c. We evaluated change scores, analyses of covariance including linear, nonlinear with/without robust variance estimations, before and after optimal matching. We also evaluated the impact of measurement error.

Results: With increasing HbA1c baseline differences between groups, bias in effect estimates and suboptimal CI coverage probabilities increased in all approaches. These issues were further compounded by measurement error. Matching on baseline HbA1c, substantially mitigated these issues.

Conclusion: In comparative studies with continuous outcomes, matching on baseline values of the outcome variable improves analytical performance.
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http://dx.doi.org/10.2217/cer.15.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699664PMC
August 2015

Thiazolidinedione and Metformin Use and the Risk of Benign Prostate Hyperplasia in Veterans with Diabetes Mellitus.

J Mens Health 2014 Dec;11(4):157-162

Veterans Health Administration-Tennessee Valley Healthcare System Geriatric Research Education Clinical Center (GRECC), HSR&D Center, Nashville, TN ; Department of Medicine, Vanderbilt University, Nashville, TN ; Department of Preventive Medicine, Vanderbilt University, Nashville, TN.

Background: Chronic inflammation is important in the development of benign prostatic hyperplasia (BPH) and certain oral antidiabetic medications have anti-inflammatory properties. The purpose of this study was to determine if use of thiazolidinediones or metformin was associated with a reduced risk of requiring medical or surgical treatment for BPH compared to sulfonylureas among diabetic men.

Methods: We constructed a retrospective cohort of 192,457 male veterans newly prescribed either rosiglitazone, pioglitazone, metformin, or a sulfonylurea. We used Cox proportional hazard regression to assess the association between thiazolidinedione or metformin use and the risk of requiring medical or surgical treatment for BPH compared to sulfonylurea use. New BPH treatment was defined by either a new prescription for a α-1 blocker or 5α-reductase inhibitors or a surgical procedure indicated for severe BPH.

Results: In 259,995 person-years of follow up we identified 14,690 new treatments for BPH. After adjusting for covariates including age, HbA1c, and body mass index, we found no association between rosiglitazone (adjusted hazard ratio [aHR] 1.02, 95% CI 0.86, 1.20), pioglitazone (aHR 0.79, 95% CI 0.45, 1.38), or metformin use (aHR 0.99, 95% CI 0.94, 1.03) and risk of new medical or surgical treatment for BPH compared to sulfonylureas. Analyses ignoring prescriptions for non-selective α-1 blockers (terazosin, doxazosin, prazosin) from our BPH case definition (n = 11,079), yielded similar results.

Conclusions: In this large cohort, we observed no association between the use of thiazolidinediones or metformin and new medical or surgical treatment for BPH compared to sulfonylureas.
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http://dx.doi.org/10.1089/jomh.2014.0051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364420PMC
December 2014

Plasma lipid levels and colorectal adenoma risk.

Cancer Causes Control 2015 Apr 12;26(4):635-43. Epub 2015 Mar 12.

Florida State University College of Medicine, Tallahassee, FL, USA.

Purpose: Abnormalities in lipid levels have been associated with colorectal neoplasm risk; however, few studies have adjusted for use of cholesterol-lowering medications. The objective of this study was to determine the association of plasma lipid levels with adenoma risk while accounting for statin medication use.

Methods: We included 254 subjects with advanced adenoma, 246 with single small adenoma, 179 with multiple small adenoma cases, and 403 control participants in the Tennessee Colorectal Polyp Study who also had plasma lipid measurements performed. Data on the use of statin medications were available for 83.4% of these participants. The association between plasma lipids and adenoma risk was evaluated using logistic regression models.

Results: Participants in the highest quartile of HDL cholesterol (range 52-106 mg/dl) had an adjusted odds ratio of 0.49 (95% CI 0.23, 1.07), 0.35 (95% CI 0.13, 0.91), and 0.22 (95% CI 0.09, 0.54) for single small, multiple small, and advanced adenomas compared to the lowest quartile (range 12-34 mg/dl), respectively. Participants with the highest quartile of triglyceride levels (range 178-721 mg/dl) had an adjusted odds ratio of 2.40 (95% CI 1.26, 4.55), 1.67 (95% CI 0.66, 4.23), and 2.79 (95% CI 1.25, 6.23) for single small, multiple small, and advanced adenoma, respectively, compared to the lowest quartile (range 40-84 mg/dl). When restricted to individuals with known statin medication use, adjusting for statin use did not appreciably affect these results.

Conclusion: We found a direct association between triglyceride plasma levels and an inverse association between plasma HDL cholesterol levels and adenoma risk. Both effects were not appreciably changed when accounting for the regular use of statin medication.
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http://dx.doi.org/10.1007/s10552-015-0555-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375726PMC
April 2015

Association between intensification of metformin treatment with insulin vs sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes.

JAMA 2014 Jun;311(22):2288-96

Veterans Health Administration-Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, HSR&D Center, Nashville, Tennessee2Department of Medicine, Vanderbilt University, Nashville, Tennessee4Department of Health Policy, Vanderbilt.

Importance: Preferred second-line medication for diabetes treatment after metformin failure remains uncertain.

Objective: To compare time to acute myocardial infarction (AMI), stroke, or death in a cohort of metformin initiators who added insulin or a sulfonylurea.

Design, Setting, And Participants: Retrospective cohort constructed with national Veterans Health Administration, Medicare, and National Death Index databases. The study population comprised veterans initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. Propensity score matching on characteristics was performed, matching each participant who added insulin to 5 who added a sulfonylurea. Patients were followed through September 2011 for primary analyses or September 2009 for cause-of-death analyses.

Main Outcomes And Measures: Risk of a composite outcome of AMI, stroke hospitalization, or all-cause death was compared between therapies with marginal structural Cox proportional hazard models adjusting for baseline and time-varying demographics, medications, cholesterol level, hemoglobin A1c level, creatinine level, blood pressure, body mass index, and comorbidities.

Results: Among 178,341 metformin monotherapy patients, 2948 added insulin and 39,990 added a sulfonylurea. Propensity score matching yielded 2436 metformin + insulin and 12,180 metformin + sulfonylurea patients. At intensification, patients had received metformin for a median of 14 months (IQR, 5-30), and hemoglobin A1c level was 8.1% (IQR, 7.2%-9.9%). Median follow-up after intensification was 14 months (IQR, 6-29 months). There were 172 vs 634 events for the primary outcome among patients who added insulin vs sulfonylureas, respectively (42.7 vs 32.8 events per 1000 person-years; adjusted hazard ratio [aHR], 1.30; 95% CI, 1.07-1.58; P = .009). Acute myocardial infarction and stroke rates were statistically similar, 41 vs 229 events (10.2 and 11.9 events per 1000 person-years; aHR, 0.88; 95% CI, 0.59-1.30; P = .52), whereas all-cause death rates were 137 vs 444 events, respectively (33.7 and 22.7 events per 1000 person-years; aHR, 1.44; 95% CI, 1.15-1.79; P = .001). There were 54 vs 258 secondary outcomes: AMI, stroke hospitalizations, or cardiovascular deaths (22.8 vs 22.5 events per 1000 person-years; aHR, 0.98; 95% CI, 0.71-1.34; P = .87).

Conclusions And Relevance: Among patients with diabetes who were receiving metformin, the addition of insulin vs a sulfonylurea was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all-cause mortality. These findings require further investigation to understand risks associated with insulin use in these patients.
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http://dx.doi.org/10.1001/jama.2014.4312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149288PMC
June 2014

Genome-wide association study identifies possible genetic risk factors for colorectal adenomas.

Cancer Epidemiol Biomarkers Prev 2013 Jul 15;22(7):1219-26. Epub 2013 May 15.

Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, TN 37203, USA.

Background: Colorectal cancer is the second leading cause of cancer-related death, and most colorectal cancer usually arises from colorectal adenomas. Removal of polyps reduces mortality from colorectal cancer. Colorectal adenomas are known to aggregate in families; however, the genetic determinants for risk of polyps are largely unknown.

Methods: In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to conduct a GWAS of adenoma cases and controls. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian adenoma cases and 3,285 Caucasian controls. We carried out logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis.

Results: No single nucleotide polymorphism (SNP) achieved a genome-wide significant P value; however, the most significantly associated SNPs were either previously associated with colorectal cancer in GWAS, such as rs10505477 in the gene POU5F1 [odds ratio (OR) = 0.87; 95% confidence interval (CI) 0.81-0.94; P = 4.4 × 10(-4)), or have been biologically linked to benign growths in other tissues, such as rs1919314 in the gene histone deacetylase 9 (OR = 1.32; 95% CI, 1.18-1.47; P = 1.1 × 10(-6)).

Conclusions: This study suggests that several SNPs may be related to adenoma risk and provides clues for future studies.

Impact: These results suggest that some known genetic risk factors of colorectal cancer are necessary but not sufficient for carcinogenesis.
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http://dx.doi.org/10.1158/1055-9965.EPI-12-1437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716448PMC
July 2013

Exploring the frontier of electronic health record surveillance: the case of postoperative complications.

Med Care 2013 Jun;51(6):509-16

Tennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, TN, USA.

Background: The aim of this study was to build electronic algorithms using a combination of structured data and natural language processing (NLP) of text notes for potential safety surveillance of 9 postoperative complications.

Methods: Postoperative complications from 6 medical centers in the Southeastern United States were obtained from the Veterans Affairs Surgical Quality Improvement Program (VASQIP) registry. Development and test datasets were constructed using stratification by facility and date of procedure for patients with and without complications. Algorithms were developed from VASQIP outcome definitions using NLP-coded concepts, regular expressions, and structured data. The VASQIP nurse reviewer served as the reference standard for evaluating sensitivity and specificity. The algorithms were designed in the development and evaluated in the test dataset.

Results: Sensitivity and specificity in the test set were 85% and 92% for acute renal failure, 80% and 93% for sepsis, 56% and 94% for deep vein thrombosis, 80% and 97% for pulmonary embolism, 88% and 89% for acute myocardial infarction, 88% and 92% for cardiac arrest, 80% and 90% for pneumonia, 95% and 80% for urinary tract infection, and 77% and 63% for wound infection, respectively. A third of the complications occurred outside of the hospital setting.

Conclusions: Computer algorithms on data extracted from the electronic health record produced respectable sensitivity and specificity across a large sample of patients seen in 6 different medical centers. This study demonstrates the utility of combining NLP with structured data for mining the information contained within the electronic health record.
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http://dx.doi.org/10.1097/MLR.0b013e31828d1210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658153PMC
June 2013

Kidney function decline in metformin versus sulfonylurea initiators: assessment of time-dependent contribution of weight, blood pressure, and glycemic control.

Pharmacoepidemiol Drug Saf 2013 Jun;22(6):623-31

Background And Objective: We recently reported that kidney function declined faster among initiators of sulfonylureas compared to metformin; however, sulfonylurea use compared to metformin use was also associated with increases in body mass index (BMI) and systolic blood pressure (SBP). We sought to determine if differences between sulfonylureas and metformin on kidney function decline were mediated by differential effects on BMI, SBP, or glucose control.

Methods: We identified 13,238 veterans who initiated sulfonylurea or metformin treatment (2000–2007) with a baseline estimated glomerular filtration rate (eGFR) >60 mL/minute, and followed them until a study event occurred, non-persistence on treatment, loss of follow-up, or end of the study. The composite outcome was a sustained decline from baseline eGFR of ≥25%, end-stage renal disease, or death. We estimated the association of cumulative measurements of potential mediators including BMI, SBP, and glycated hemoglobin on the study outcome. We determined if controlling for these time-varying covariates accounted for the differences in outcome between sulfonylurea and metformin initiators.

Results: Compared to sulfonylurea use, metformin use was associated with a lower risk for renal function decline or death [adjusted hazard ratio (aHR) 0.82, 95% confidence interval 0.70, 0.97]. This protective association remained significant [aHR 0.83 (0.70–0.98)] when accounting for the cumulative time-varying measurements of the three mediators of interest.

Conclusion: Metformin initiation was associated with a lower risk of kidney function decline or death compared to sulfonylureas, which which appeared to be independent of changes in BMI, SBP, and glycated hemoglobin over time.
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http://dx.doi.org/10.1002/pds.3432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887572PMC
June 2013

Who said it? Establishing professional attribution among authors of Veterans' Electronic Health Records.

AMIA Annu Symp Proc 2012 3;2012:753-62. Epub 2012 Nov 3.

Health Services Research and Development, Tennessee Valley Healthcare System, Department of Veterans Affairs, 1310 24 Avenue South, Nashville, TN 37212, USA.

Background: A practical data point for assessing information quality and value in the Electronic Health Record (EHR) is the professional category of the EHR author. We evaluated and compared free form electronic signatures against LOINC note titles in categorizing the profession of EHR authors.

Methods: A random 1000 clinical document sample was selected and divided into 500 document sets for training and testing. The gold standard for provider classification was generated by dual clinician manual review, disagreements resolved by a third reviewer. Text matching algorithms composed of document titles and author electronic signatures for provider classification were developed on the training set.

Results: Overall, detection of professional classification by note titles alone resulted in 76.1% sensitivity and 69.4% specificity. The aggregate of note titles with electronic signatures resulted in 95.7% sensitivity and 98.5% specificity.

Conclusions: Note titles alone provided fair professional classification. Inclusion of author electronic signatures significantly boosted classification performance.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540586PMC
July 2013