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Item Intake of Calcium, Magnesium, and Phosphorus and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial(Taylor & Francis, 2021) Hoyt, Margaret; Song, Yiqing; Gao, Sujuan; O'Palka, Jacquelynn; Zhang, Jianjun; Epidemiology, School of Public HealthObjectiveFew epidemiological studies have investigated the associations between calcium, magnesium, and phosphorus intake and pancreatic cancer. We examined these associations in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.MethodsDiet was assessed using the Dietary Questionnaire (DQX) at baseline in the intervention arm and the Dietary History Questionnaire (DHQ) in 1999 or around the third anniversary of randomization in both the intervention and control arms. During a median follow-up of 12.2 years, 279 cases of pancreatic cancer occurred from 58,477 participants who completed DQX; 380 cases arose from 101,622 participants who responded to DHQ over a median follow-up of 8.9 years. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI).ResultsTotal calcium intake was inversely associated with pancreatic cancer [HR (95% CI) for the fourth vs. the first quartiles in the DHQ cohort: 0.67 (0.47, 0.96); p-trend: 0.035]. An inverse association was also observed for total magnesium intake [HR (95% CI) for the fourth vs. the first quartiles in the DQX cohort: 0.61 (0.37, 1.00); p-trend: 0.023]. Reduced risk associated with total calcium intake was confined to subjects with a high fat intake (>73 g/day) in the DHQ cohort (p-interaction: 0.16).ConclusionsThere was not a significant association between dietary phosphorus intake and pancreatic cancer risk in both cohorts. Total intake of calcium and magnesium are associated with a lower pancreatic cancer risk. The effect of total calcium intake was modified by fat intake.Item Probiotic and Oxytocin Combination Therapy in Patients with Autism Spectrum Disorder: A Randomized, Double-Blinded, Placebo-Controlled Pilot Trial(MDPI, 2021-05-05) Kong, Xue-Jun; Liu, Jun; Liu, Kevin; Koh, Madelyn; Sherman, Hannah; Liu, Siyu; Tian, Ruiyi; Sukijthamapan, Piyawat; Wang, Jiuju; Fong, Michelle; Xu, Lei; Clairmont, Cullen; Jeong, Min-Seo; Li, Alice; Lopes, Maria; Hagan, Veronica; Dutton, Tess; Chan, Suk-Tak (Phoebe); Lee, Hang; Kendall, Amy; Kwong, Kenneth; Song, Yiqing; Epidemiology, School of Public HealthAutism spectrum disorder (ASD) is a rapidly growing neurodevelopmental disorder. Both probiotics and oxytocin were reported to have therapeutic potential; however, the combination therapy has not yet been studied. We conducted a randomized, double-blinded, placebo-controlled, 2-stage pilot trial in 35 individuals with ASD aged 3-20 years (median = 10.30 years). Subjects were randomly assigned to receive daily Lactobacillus plantarum PS128 probiotic (6 × 1010 CFUs) or a placebo for 28 weeks; starting on week 16, both groups received oxytocin. The primary outcomes measure socio-behavioral severity using the Social Responsiveness Scale (SRS) and Aberrant Behavior Checklist (ABC). The secondary outcomes include measures of the Clinical Global Impression (CGI) scale, fecal microbiome, blood serum inflammatory markers, and oxytocin. All outcomes were compared between the two groups at baseline, 16 weeks, and 28 weeks into treatment. We observed improvements in ABC and SRS scores and significant improvements in CGI-improvement between those receiving probiotics and oxytocin combination therapy compared to those receiving placebo (p < 0.05). A significant number of favorable gut microbiome network hubs were also identified after combination therapy (p < 0.05). The favorable social cognition response of the combination regimen is highly correlated with the abundance of the Eubacterium hallii group. Our findings suggest synergic effects between probiotics PS128 and oxytocin in ASD patients, although further investigation is warranted.Item Improving Notifiable Disease Case Reporting Through Electronic Information Exchange–Facilitated Decision Support: A Controlled Before-and-After Trial(Sage, 2020) Dixon, Brian E.; Zhang, Zuoyi; Arno, Janet N.; Revere, Debra; Gibson, P. Joseph; Grannis, Shaun J.; Epidemiology, School of Public HealthObjective: Outbreak detection and disease control may be improved by simplified, semi-automated reporting of notifiable diseases to public health authorities. The objective of this study was to determine the effect of an electronic, prepopulated notifiable disease report form on case reporting rates by ambulatory care clinics to public health authorities. Methods: We conducted a 2-year (2012-2014) controlled before-and-after trial of a health information exchange (HIE) intervention in Indiana designed to prepopulate notifiable disease reporting forms to providers. We analyzed data collected from electronic prepopulated reports and "usual care" (paper, fax) reports submitted to a local health department for 7 conditions by using a difference-in-differences model. Primary outcomes were changes in reporting rates, completeness, and timeliness between intervention and control clinics. Results: Provider reporting rates for chlamydia and gonorrhea in intervention clinics increased significantly from 56.9% and 55.6%, respectively, during the baseline period (2012) to 66.4% and 58.3%, respectively, during the intervention period (2013-2014); they decreased from 28.8% and 27.5%, respectively, to 21.7% and 20.6%, respectively, in control clinics (P < .001). Completeness improved from baseline to intervention for 4 of 15 fields in reports from intervention clinics (P < .001), although mean completeness improved for 11 fields in both intervention and control clinics. Timeliness improved for both intervention and control clinics; however, reports from control clinics were timelier (mean, 7.9 days) than reports from intervention clinics (mean, 9.7 days). Conclusions: Electronic, prepopulated case reporting forms integrated into providers' workflow, enabled by an HIE network, can be effective in increasing notifiable disease reporting rates and completeness of information. However, it was difficult to assess the effect of using the forms for diseases with low prevalence (eg, salmonellosis, histoplasmosis).Item Association of genetic variants of TMEM135 and PEX5 in the peroxisome pathway with cutaneous melanoma-specific survival(AME Publishing, 2021-03) Wang, Haijiao; Liu, Hongliang; Dai, Wei; Luo, Sheng; Amos, Christopher I.; Lee, Jeffrey E.; Li, Xin; Yue, Ying; Nan, Hongmei; Wei, Qingyi; Epidemiology, School of Public HealthBackground: Peroxisomes are ubiquitous and dynamic organelles that are involved in the metabolism of reactive oxygen species (ROS) and lipids. However, whether genetic variants in the peroxisome pathway genes are associated with survival in patients with melanoma has not been established. Therefore, our aim was to identify additional genetic variants in the peroxisome pathway that may provide new prognostic biomarkers for cutaneous melanoma (CM). Methods: We assessed the associations between 8,397 common single-nucleotide polymorphisms (SNPs) in 88 peroxisome pathway genes and CM disease-specific survival (CMSS) in a two-stage analysis. For the discovery, we extracted the data from a published genome-wide association study from The University of Texas MD Anderson Cancer Center (MDACC). We then replicated the results in another dataset from the Nurse Health Study (NHS)/Health Professionals Follow-up Study (HPFS). Results: Overall, 95 (11.1%) patients in the MDACC dataset and 48 (11.7%) patients in the NHS/HPFS dataset died of CM. We found 27 significant SNPs in the peroxisome pathway genes to be associated with CMSS in both datasets after multiple comparison correction using the Bayesian false-discovery probability method. In stepwise Cox proportional hazards regression analysis, with adjustment for other covariates and previously published SNPs in the MDACC dataset, we identified 2 independent SNPs (TMEM135 rs567403 C>G and PEX5 rs7969508 A>G) that predicted CMSS (P=0.003 and 0.031, respectively, in an additive genetic model). The expression quantitative trait loci analysis further revealed that the TMEM135 rs567403 GG and PEX5 rs7969508 GG genotypes were associated with increased and decreased levels of mRNA expression of their genes, respectively. Conclusions: Once our findings are replicated by other investigators, these genetic variants may serve as novel biomarkers for the prediction of survival in patients with CM.Item Viime: Visualization and Integration of Metabolomics Experiments(Open Journals, 2020) Choudhury, Roni; Beezley, Jon; Davis, Brandon; Tomeck, Jared; Gratzl, Samuel; Golzarri-Arroyo, Lilian; Wan, Jun; Raftery, Daniel; Baumes, Jeff; O’Connell, Thomas M.; Epidemiology, School of Public HealthMetabolomics involves the comprehensive measurement of metabolites from a biological system. The resulting metabolite profiles are influenced by genetics, lifestyle, biological stresses, disease, diet and the environment and therefore provides a more holistic biological readout of the pathological condition of the organism (Beger et al., 2016; Wishart, 2016). The challenge for metabolomics is that no single analytical platform can provide a truly comprehensive coverage of the metabolome. The most commonly used platforms are based on mass-spectrometry (MS) and nuclear magnetic resonance (NMR). Investigators are increasingly using both methods to increase the metabolite coverage. The challenge for this type of multi-platform approach is that the data structure may be very different in these two platforms. For example, NMR data may be reported as a list of spectral features, e.g., bins or peaks with arbitrary intensity units or more directly with named metabolites reported in concentration units ranging from micromolar to millimolar. Some MS approaches can also provide data in the form of identified metabolite concentrations, but given the superior sensitivity of MS, the concentrations can be several orders of magnitude lower than for NMR. Other MS approaches yield data in the form of arbitrary response units where the dynamic range can be more than 6 orders of magnitude. Importantly, the variability and reproducibility of the data may differ across platforms. Given the diversity of data structures (i.e., magnitude and dynamic range) integrating the data from multiple platforms can be challenging. This often leads investigators to analyze the datasets separately, which prevents the observation of potentially interesting relationships and correlations between metabolites detected on different platforms. Viime (VIsualization and Integration of Metabolomics Experiments) is an open-source, web-based application designed to integrate metabolomics data from multiple platforms.Item Long-term effects of a toddler-focused caries prevention programme among Northwestern US tribal children: The TOTS-to-Tweens study(Wiley, 2021-06) Smith, Nicole Holdaway; Lutz, Tam; Maupomé, Gerardo; Lapidus, Jodi; Jimenez, Candice; Janis, Maxine; Schwarz, Eli; Becker, Thomas; Epidemiology, School of Public HealthOBJECTIVES: We sought to determine whether American Indian tribe-based interventions that successfully prevented toddler dental caries in a 2005 cohort study (the Toddler Overweight and Tooth Decay Prevention Study, or TOTS) influenced the prevalence of dental caries in children ages 11 to 13 in the same communities ten years later (the TOTS-to-Tweens study). METHODS: We recruited original TOTS participants and conducted school- and community-based dental screenings at tribal communities that received family plus community-wide interventions (F + CW), community interventions only (CW) or were control communities. We also enrolled children who did not participate in TOTS, but were exposed to CW interventions or to the control environment. Trained clinicians examined children's teeth and recorded whether each tooth was decayed, missing or filled (DMFT). We calculated DMFT scores for each child and evaluated differences in DMFT incidence rate ratios (IRR) and components of DMFT by intervention group. RESULTS: We observed lower age- and sex-adjusted DMFT scores among F + CW children (a mean of 2.1 DMFT; 95% confidence interval [CI]: 1.4-2.7) and among CW children (2.2; 95% CI: 1.9-2.6), than control children (3.0; 95% CI: 2.3-3.7). The F + CW group had 32% lower DMFT scores than control children (IRR = 0.68; 95% CI: 0.46-1.01), and CW children had 26% lower DMFT scores than control (IRR = 0.74; 95% CI: 0.55-1.00). The proportion of children with filled teeth was higher in control than intervention communities (37.9% in F + CW, 47.1% in CW, and 67.1% in control, P = .002). CONCLUSIONS: Our findings suggest modest yet significant long-term effects of interventions that prevented toddler dental caries on the DMFT scores of tweens evaluated ten years later. Further study of effective interventions and their sustainability is clearly warranted among tribal children, who remain at high risk for dental caries.Item Neurodegenerative Patterns of Cognitive Clusters of Early-Onset Alzheimer's Disease Subjects: Evidence for Disease Heterogeneity(Karger, 2019) Phillips, Meredith L.; Stage, Eddie C., Jr.; Lane, Kathleen A.; Gao, Sujuan; Risacher, Shannon L.; Goukasian, Naira; Saykin, Andrew J.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; Epidemiology, School of Public HealthBackground/aims: Alzheimer's disease (AD) with onset before 65 (early-onset AD [EOAD]) occurs in approximately 6% of cases and can affect nonmemory domains. Here, we analyze patterns of impairment in amnestic EOAD individuals using data-driven statistical analyses. Methods: Cognitive data of 146 EOAD subjects were Z-normalized to 395 cognitively normal (CN) individuals. Domain-averaged Z-scores were adjusted for age, sex, and education followed by Wald cluster analysis of residuals. Magnetic resonance imaging and positron emission tomography comparisons of EOAD clusters to age-matched CN were done using Statistic Parametric Mapping 8. Cluster-level-family-wise error (p < 0.05) correction was applied. Mixed-effect models were used to compute longitudinal change across clusters. Results: Scree plot using the pseudo-T-squared suggested a 4-cluster solution. Cluster 1 (memory-predominant impairment) showed atrophy/hypometabolism in medial/lateral temporal, lateral parietal, and posterior cingulate regions. Cluster 2 (memory/visuospatial-predominant) showed atrophy/hypometabolism of medial temporal, temporoparietal, and frontal cortices. Cluster 3 (memory, language, and executive function) and Cluster 4 (globally impaired) manifested atrophy and hypometabolism throughout the brain. Longitudinally between-cluster differences in the visuospatial and language/executive domains were significant, suggesting phenotypic variation. Conclusion: We observed significant heterogeneity in cognitive presentation among amnestic EOAD subjects and patterns of atrophy/hypometabolism in each cluster in agreement with the observed cognitive phenotype.Item Citrus Consumption and Risk of Cutaneous Malignant Melanoma in the Women’s Health Initiative(Routledge, 2020) Melough, Melissa M.; Wu, Shaowei; Li, Wen-Qing; Eaton, Charles; Nan, Hongmei; Snetselaar, Linda; Wallace, Robert; Qureshi, Abrar A.; Chun, Ock K.; Cho, Eunyoung; Epidemiology, School of Public HealthCitrus products are rich sources of furocoumarins, a class of photoactive compounds. Certain furocoumarins combined with ultraviolet radiation can induce skin cancer. We examined the relationship between citrus consumption and cutaneous melanoma risk among 56,205 Caucasian postmenopausal women in the Women’s Health Initiative. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma by citrus intake level. During a mean follow-up of 15.7 years, 956 incident melanoma cases were documented. In multivariable adjusted models, the HR (95% CI) for melanoma was 1.12 (0.91, 1.37) among the highest citrus consumers (1.5+ servings/day of fruit or juice) versus the lowest (<2 servings/week), 0.95 (0.76, 1.20) among the highest citrus fruit consumers (5+ servings/week) versus non-consumers, and was 1.13 (0.96, 1.32) for the highest citrus juice consumers (1+ servings/day) versus the lowest (<1 serving/week). In stratified analyses, an increased melanoma risk associated with citrus juice intake was observed among women who spent the most time outdoors in summer as adults; the HR for the highest versus lowest intake was 1.22 (1.02, 1.46) (p-trend = 0.03). Further research is needed to explore the association of melanoma with citrus juices among women with high sun exposure.Item The Effects of a Mediterranean Diet Intervention on Targeted Plasma Metabolic Biomarkers among US Firefighters: A Pilot Cluster-Randomized Trial(MDPI, 2020-11-24) Sotos-Prieto, Mercedes; Ruiz-Canela, Miguel; Song, Yiqing; Christophi, Costas; Mofatt, Steven; Rodriguez-Artalejo, Fernando; Kales, Stefanos N.; Epidemiology, School of Public HealthMetabolomics is improving the understanding of the mechanisms of the health effects of diet. Previous research has identified several metabolites associated with the Mediterranean Diet (MedDiet), but knowledge about longitudinal changes in metabolic biomarkers after a MedDiet intervention is scarce. A subsample of 48 firefighters from a cluster-randomized trial at Indianapolis fire stations was randomly selected for the metabolomics study at 12 months of follow up (time point 1), where Group 1 (n = 24) continued for another 6 months in a self-sustained MedDiet intervention, and Group 2 (n = 24), the control group at that time, started with an active MedDiet intervention for 6 months (time point 2). A total of 225 metabolites were assessed at the two time points by using a targeted NMR platform. The MedDiet score improved slightly but changes were non-significant (intervention: 24.2 vs. 26.0 points and control group: 26.1 vs. 26.5 points). The MedDiet intervention led to favorable changes in biomarkers related to lipid metabolism, including lower LDL-C, ApoB/ApoA1 ratio, remnant cholesterol, M-VLDL-CE; and higher HDL-C, and better lipoprotein composition. This MedDiet intervention induces only modest changes in adherence to the MedDiet and consequently in metabolic biomarkers. Further research should confirm these results based on larger study samples in workplace interventions with powerful study designs.Item Novel Genetic Variants of ALG6 and GALNTL4 of the Glycosylation Pathway Predict Cutaneous Melanoma-Specific Survival(MDPI, 2020-01-24) Zhou, Bingrong; Zhao, Yu Chen; Liu, Hongliang; Luo, Sheng; Amos, Christopher I.; Lee, Jeffrey E.; Li, Xin; Nan, Hongmei; Wei, Qingyi; Epidemiology, School of Public HealthBecause aberrant glycosylation is known to play a role in the progression of melanoma, we hypothesize that genetic variants of glycosylation pathway genes are associated with the survival of cutaneous melanoma (CM) patients. To test this hypothesis, we used a Cox proportional hazards regression model in a single-locus analysis to evaluate associations between 34,096 genetic variants of 227 glycosylation pathway genes and CM disease-specific survival (CMSS) using genotyping data from two previously published genome-wide association studies. The discovery dataset included 858 CM patients with 95 deaths from The University of Texas MD Anderson Cancer Center, and the replication dataset included 409 CM patients with 48 deaths from Harvard University nurse/physician cohorts. In the multivariable Cox regression analysis, we found that two novel single-nucleotide polymorphisms (SNPs) (ALG6 rs10889417 G>A and GALNTL4 rs12270446 G>C) predicted CMSS, with an adjusted hazards ratios of 0.60 (95% confidence interval = 0.44–0.83 and p = 0.002) and 0.66 (0.52–0.84 and 0.004), respectively. Subsequent expression quantitative trait loci (eQTL) analysis revealed that ALG6 rs10889417 was associated with mRNA expression levels in the cultured skin fibroblasts and whole blood cells and that GALNTL4 rs12270446 was associated with mRNA expression levels in the skin tissues (all p < 0.05). Our findings suggest that, once validated by other large patient cohorts, these two novel SNPs in the glycosylation pathway genes may be useful prognostic biomarkers for CMSS, likely through modulating their gene expression.