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1.  Case-control study of the PERIOD3 clock gene length polymorphism and colorectal adenoma formation 
Oncology Reports  2014;33(2):935-941.
Clock genes are expressed in a self-perpetuating, circadian pattern in virtually every tissue including the human gastrointestinal tract. They coordinate cellular processes critical for tumor development, including cell proliferation, DNA damage response and apoptosis. Circadian rhythm disturbances have been associated with an increased risk for colon cancer and other cancers. This mechanism has not been elucidated, yet may involve dysregulation of the ‘period’ (PER) clock genes, which have tumor suppressor properties. A variable number tandem repeat (VNTR) in the PERIOD3 (PER3) gene has been associated with sleep disorders, differences in diurnal hormone secretion, and increased premenopausal breast cancer risk. Susceptibility related to PER3 has not been examined in conjunction with adenomatous polyps. This exploratory case-control study was the first to test the hypothesis that the 5-repeat PER3 VNTR sequence is associated with increased odds of adenoma formation. Information on demographics, medical history, occupation and lifestyle was collected prior to colonoscopy. Cases (n=49) were individuals with at least one histopathologically confirmed adenoma. Controls (n=97) included patients with normal findings or hyperplastic polyps not requiring enhanced surveillance. Unconditional multiple logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), after adjusting for potential confounding. Adenomas were detected in 34% of participants. Cases were more likely to possess the 5-repeat PER3 genotype relative to controls (4/5 OR, 2.1; 95% CI, 0.9–4.8; 5/5 OR, 5.1; 95% CI, 1.4–18.1; 4/5+5/5 OR, 2.5; 95% CI, 1.7–5.4). Examination of the Oncomine microarray database indicated lower PERIOD gene expression in adenomas relative to adjacent normal tissue. Results suggest a need for follow-up in a larger sample.
PMCID: PMC4306271  PMID: 25501848
adenoma; clock gene; circadian rhythm; colorectal cancer; variable number tandem repeat
2.  Case-Control Study of Breast Cancer in India: Role of PERIOD3 Clock Gene Length Polymorphism and Chronotype 
Cancer investigation  2014;32(7):321-329.
This study examined a PERIOD3 (PER3) gene variable number tandem repeat polymorphism and chronotype as potential BrCA risk factors among Indian women.
This case-control study included sporadic, histologically confirmed BrCA cases (n=255) and controls (n=249) from India with data collection from 2010–2012.
Women with the 4/5 or 5/5 PER3 genotype had a non-statistically significant 33% increased odds of BrCA. BrCA cases were more likely to have a morning (OR=2.43, 95% CI=1.23–4.81) or evening (OR=2.55, 95% CI=1.19–5.47) chronotype.
Findings are consistent with the possibility that extremes in chronotype may elicit circadian desynchronization, resulting in adverse health outcomes.
PMCID: PMC4100474  PMID: 24903750
3.  Reducing Colorectal Cancer Incidence and Disparities: Performance and Outcomes of a Screening Colonoscopy Program in South Carolina 
Advances in public health  2014;2014:787282.
This study evaluated the efficiency, effectiveness, and racial disparities reduction potential of Screening Colonoscopies for People Everywhere in South Carolina (SCOPE SC), a state-funded program for indigent persons aged 50–64 years (45–64 years for African American (AA)) with a medical home in community health centers. Patients were referred to existing referral network providers, and the centers were compensated for patient navigation. Data on procedures and patient demographics were analyzed. Of 782 individuals recruited (71.2% AA), 85% (665) completed the procedure (71.1% AA). The adenoma detection rate was 27.8% (males 34.6% and females 25.1%), advanced neoplasm rate 7.7% (including 3 cancers), cecum intubation rate 98.9%, inadequate bowel preparation rate 7.9%, and adverse event rate 0.9%. All indicators met the national quality benchmarks. The adenoma rate of 26.0% among AAs aged 45–49 years was similar to that of older Whites and AAs. We found that patient navigation and a medical home setting resulted in a successful and high-quality screening program. The observed high adenoma rate among younger AAs calls for more research with larger cohorts to evaluate the appropriateness of the current screening guidelines for AAs, given that they suffer 47% higher colorectal cancer mortality than Whites.
PMCID: PMC4332847  PMID: 25705719
4.  Examination of wrist and hip actigraphy using a novel sleep estimation procedure ☆ 
Sleep science  2014;7(2):74-81.
Improving and validating sleep scoring algorithms for actigraphs enhances their usefulness in clinical and research applications. The MTI® device (ActiGraph, Pensacola, FL) had not been previously validated for sleep. The aims were to (1) compare the accuracy of sleep metrics obtained via wrist- and hip-mounted MTI® actigraphs with polysomnographic (PSG) recordings in a sample that included both normal sleepers and individuals with presumed sleep disorders; and (2) develop a novel sleep scoring algorithm using spline regression to improve the correspondence between the actigraphs and PSG.
Original actigraphy data were amplified and their pattern was estimated using a penalized spline. The magnitude of amplification and the spline were estimated by minimizing the difference in sleep efficiency between wrist- (hip-) actigraphs and PSG recordings. Sleep measures using both the original and spline-modified actigraphy data were compared to PSG using the following: mean sleep summary measures; Spearman rank-order correlations of summary measures; percent of minute-by-minute agreement; sensitivity and specificity; and Bland–Altman plots.
The original wrist actigraphy data showed modest correspondence with PSG, and much less correspondence was found between hip actigraphy and PSG. The spline-modified wrist actigraphy produced better approximations of interclass correlations, sensitivity, and mean sleep summary measures relative to PSG than the original wrist actigraphy data. The spline-modified hip actigraphy provided improved correspondence, but sleep measures were still not representative of PSG.
The results indicate that with some refinement, the spline regression method has the potential to improve sleep estimates obtained using wrist actigraphy.
PMCID: PMC4286157  PMID: 25580202
Actigraphy; Polysomnography; Penalized spline
5.  Blunted Heart Rate Recovery Is Improved Following Exercise Training in Overweight Adults with Obstructive Sleep Apnea 
International journal of cardiology  2012;167(4):1610-1615.
Obstructive sleep apnea (OSA) predisposes individuals to cardiovascular morbidity, and cardiopulmonary exercise test (CPET) markers prognostic for cardiovascular disease have been found to be abnormal in adults with OSA. Due to the persistence of OSA and its cardiovascular consequences, whether the cardiovascular adaptations normally conferred by exercise are blunted in adults not utilizing established OSA treatment is unknown. The aims of this study were to document whether OSA participants have abnormal CPET responses and determine whether exercise modifies these CPET markers in individuals with OSA.
The CPET responses of 43 sedentary, overweight adults (body mass index [BMI]>25) with untreated OSA (apnea-hypopnea index [AHI]≥15) were compared against matched non-OSA controls (n=9). OSA participants were then randomized to a 12-week exercise training (n=27) or stretching control treatment (n=16), followed by a post-intervention CPET. Measures of resting, exercise, and post-exercise recovery heart rate (HRR), blood pressure, and ventilation, as well as peak oxygen consumption (VO2peak), were obtained.
OSA participants had blunted HRR compared to non-OSA controls at 1 (P=.03), 3 (P=.02), and 5 min post-exercise (P=.03). For OSA participants, exercise training improved VO2peak (P=.04) and HRR at 1 (P=.03), 3 (P<.01), and 5 min post-exercise (P<.001) compared to control. AHI change was associated with change in HRR at 5-min post-exercise (r=−.30, P<.05), but no other CPET markers.
These results suggest that individuals with OSA have autonomic dysfunction, and that exercise training, by increasing HRR and VO2peak, may attenuate autonomic imbalance and improve functional capacity independent of OSA severity reduction.
PMCID: PMC3417075  PMID: 22572632
obstructive sleep apnea; exercise testing; exercise training; heart rate recovery; peak oxygen consumption
6.  Mercury in fish and adverse reproductive outcomes: results from South Carolina 
Mercury is a metal with widespread distribution in aquatic ecosystems and significant neurodevelopmental toxicity in humans. Fish biomonitoring for total mercury has been conducted in South Carolina (SC) since 1976, and consumption advisories have been posted for many SC waterways. However, there is limited information on the potential reproductive impacts of mercury due to recreational or subsistence fish consumption.
To address this issue, geocoded residential locations for live births from the Vital Statistics Registry (1995–2005, N = 362,625) were linked with spatially interpolated total mercury concentrations in fish to estimate potential mercury exposure from consumption of locally caught fish. Generalized estimating equations were used to test the hypothesis that risk of low birth weight (LBW, <2,500 grams) or preterm birth (PTB, <37 weeks clinical gestation) was greater among women living in areas with elevated total mercury in fish, after adjustment for confounding. Separate analyses estimated term LBW and PTB risks using residential proximity to rivers with fish consumption advisories to characterize exposure.
Term LBW was more likely among women residing in areas in the upper quartile of predicted total mercury in fish (odds ratio [OR] = 1.04; 95% confidence interval [CI]: 1.00-1.09) or within 8 kilometers of a river with a ‘do not eat’ fish advisory (1.05; 1.00-1.11) compared to the lowest quartile, or rivers without fish consumption restrictions, respectively. When stratified by race, risks for term LBW or PTB were 10-18% more likely among African-American (AA) mothers living in areas with the highest total fish mercury concentrations.
To our knowledge, this is the first study to examine the relationship between fish total mercury concentrations and adverse reproductive outcomes in a large population-based sample that included AA women. The ecologic nature of exposure assessment in this study precludes causal inference. However, the results suggest a need for more detailed investigations to characterize patterns of local fish consumption and potential dose–response relationships between mercury exposure and adverse reproductive outcomes, particularly among AA mothers.
PMCID: PMC4154616  PMID: 25127892
Low birth weight; Environmental public health tracking; Geographic information system; Preterm birth
7.  Angiotensin Receptor Blockers and Risk of Prostate Cancer among United States Veterans 
Journal of clinical pharmacology  2013;53(7):773-778.
To address concerns regarding increased risk of prostate cancer (PrCA) among Angiotensin Receptor Blocker users, we used national retrospective data from the Department of Veterans Affairs (VA) through the Veterans Affairs Informatics and Computing Infrastructure (VINCI).
We identified a total of 543,824 unique Veterans who were classified into either ARB treated or not-treated in 1:15 ratio. The two groups were balanced using inverse probability of treatment weights. A double-robust cox-proportional hazards model was used to estimate the hazard ratio for PrCA incidence. To evaluate for a potential Gleason score stage migration we conducted weighted Cochrane-Armitage test.
Post weighting, the rates of PrCA in treated and not-treated groups were 506 (1.5%) and 8,269 (1.6%), respectively; representing a hazard ratio of (0.91, p-value 0.049). There was no significant difference in Gleason scores between the two groups.
We found a small, but statistically significant, reduction in the incidence of clinically detected PrCA among patients assigned to receive ARB with no countervailing effect on degree of differentiation (as indicated by Gleason score). Findings from this study support FDA’s recent conclusion that ARB use does not increase risk of incident PrCA.
PMCID: PMC3768141  PMID: 23686462
Angiotensin Receptor Blockers; Prostate Cancer; Department of Veterans Affairs; Inverse Probability of Treatment Weight; Propensity Score; Survival analysis; Cancer Registry; Drug Safety
8.  Circadian Disruption, Per3, and Human Cytokine Secretion 
Integrative cancer therapies  2009;8(4):329-336.
Circadian disruption has been linked with inflammation, an established cancer risk factor. Per3 clock gene polymorphisms have also been associated with circadian disruption and with increased cancer risk. Patients completed a questionnaire and provided a blood sample prior to undergoing a colonoscopy (n = 70). Adjusted mean serum cytokine concentrations (IL-6, TNF-alpha, gamma-INF, IL-I ra, IL-I-beta, VEGF) were compared among patients with high and low scores for fatigue (Multidimensional Fatigue Inventory), depressive symptoms (Beck Depression Inventory II), or sleep disruption (Pittsburgh Sleep Quality Index), or among patients with different Per3 clock gene variants. Poor sleep was associated with elevated VEGF, and fatigue-related reduced activity was associated with elevated TNF-alpha concentrations. Participants with the 4/5 or 5/5 Per3 variable tandem repeat sequence had elevated IL-6 concentrations compared to those with the 4/4 genotype. Biological processes linking circadian disruption with cancer remain to be elucidated. Increased inflammatory cytokine secretion may playa role.
PMCID: PMC2959170  PMID: 19926609
circadian rhythm; clock gene; cytokine; inflammation
9.  Colonoscopy Screening Rates Among Patients of Colonoscopy-trained African-American Primary Care Physicians 
Cancer  2011;117(22):5151-5160.
When performed competently, colonoscopy screening can reduce colorectal cancer rates, especially in high-risk groups such as African Americans (AAs). Training primary care physicians (PCPs) to perform colonoscopy may improve screening rates among underserved high-risk populations.
We compared colonoscopy screening rates and computed adjusted odds ratios for colonoscopy-eligible patients of trained AA PCPs (study group) vs. untrained PCPs (comparison group), before and since initiating colonoscopy training. All colonoscopies were performed at a licensed ambulatory surgery center with specialist standby support. Retrospective chart review was conducted on 200 consecutive, established outpatients aged ≥50 years at each of 12 PCP offices (7 trained AA PCPs and 5 untrained PCPs, practicing in the same geographic region), total 1,244 study group and 923 comparison group patients.
Post-training colonoscopy rates in both groups were higher than pre-training rates: 48.3% vs. 9.3% in the study group, 29.6% vs. 9.8% in the comparison group (both p<0.001). AA patients in the study group showed over 5-fold increase (8.9% pre-training vs. 52.8% post training), with no change among Whites (18.2% vs. 25.0%). Corresponding pre- and post-training rates among comparison patients were 10.4% and 38.7% respectively among AAs (p<0.001), and 13.3% vs. 13.2% respectively among Whites. After adjusting for demographics, duration since becoming the PCP’s patient, and health insurance, the study group had a 66% higher likelihood of colonoscopy in the post-training period (OR=1.66; CI, 1.30, 2.13), and AAs had a five-fold increased likelihood of colonoscopy relative to Whites.
Colonoscopy-trained PCPs may help reduce colorectal cancer disparities.
PMCID: PMC3145827  PMID: 21523762
Screening colonoscopy; Colorectal cancer screening; African American screening rate; Colonoscopy-trained primary care physicians
10.  Groundwater uranium and cancer incidence in South Carolina 
Cancer causes & control : CCC  2010;22(1):41-50.
This ecologic study tested the hypothesis that census tracts with elevated groundwater uranium and more frequent groundwater use have increased cancer incidence.
Data sources included: incident total, leukemia, prostate, breast, colorectal, lung, kidney, and bladder cancers (1996–2005, SC Central Cancer Registry); demographic and groundwater use (1990 US Census); and groundwater uranium concentrations (n = 4,600, from existing federal and state databases). Kriging was used to predict average uranium concentrations within tracts. The relationship between uranium and standardized cancer incidence ratios was modeled among tracts with substantial groundwater use via linear or semiparametric regression, with and without stratification by the proportion of African Americans in each area.
A total of 134,685 cancer cases were evaluated. Tracts with ≥50% groundwater use and uranium concentrations in the upper quartile had increased risks for colorectal, breast, kidney, prostate, and total cancer compared to referent tracts. Some of these relationships were more likely to be observed among tracts populated primarily by African Americans.
SC regions with elevated groundwater uranium and more groundwater use may have an increased incidence of certain cancers, although additional research is needed since the design precluded adjustment for race or other predictive factors at the individual level.
PMCID: PMC3383652  PMID: 21080052
Cancer; GIS; Uranium; Groundwater; Disparities
11.  Uranium Exposures in a Community near a Uranium Processing Facility: Relationship with Hypertension and Hematologic Markers 
Environmental research  2010;110(8):786-797.
Environmental uranium exposure originating as a byproduct of uranium processing can impact human health. The Fernald Feed Materials Production Center functioned as a uranium processing facility from 1951 to 1989, and potential health effects among residents living near this plant were investigated via the Fernald Medical Monitoring Program (FMMP).
Data from 8,216 adult FMMP participants were used to test the hypothesis that elevated uranium exposure was associated with indicators of hypertension or changes in hematologic parameters at entry into the program. A cumulative uranium exposure estimate, developed by FMMP investigators, was used to classify exposure. Systolic and diastolic blood pressure and physician diagnoses were used to assess hypertension; and red blood cells, platelets, and white blood cell differential counts were used to characterize hematology. The relationship between uranium exposure and hypertension or hematologic parameters was evaluated using generalized linear models and quantile regression for continuous outcomes, and logistic regression or ordinal logistic regression for categorical outcomes, after adjustment for potential confounding factors.
Of 8,216 adult FMMP participants 4,187 (51%) had low cumulative uranium exposure, 1,273 (15%) had moderate exposure, and 2,756 (34%) were in the high (>0.50 Sievert) cumulative lifetime uranium exposure category. Participants with elevated uranium exposure had decreased white blood cell and lymphocyte counts and increased eosinophil counts. Female participants with higher uranium exposures had elevated systolic blood pressure compared to women with lower exposures. However, no exposure-related changes were observed in diastolic blood pressure or hypertension diagnoses among female or male participants.
Results from this investigation suggest that residents in the vicinity of the Fernald plant with elevated exposure to uranium primarily via inhalation exhibited decreases in white blood cell counts, and small, though statistically significant, gender-specific alterations in systolic blood pressure at entry into the FMMP.
PMCID: PMC2978648  PMID: 20889151
Hematology; hypertension; uranium
12.  Soil zinc content, groundwater usage, and prostate cancer incidence in South Carolina 
Cancer causes & control : CCC  2008;20(3):345-353.
Prostate cancer (PrCA) incidence in South Carolina (SC) exceeds the national average, particularly among African Americans (AAs). Though data are limited, low environmental zinc exposures and down-regulation of prostatic zinc transporter proteins among AAs may explain, in part, the racial PrCA disparity.
Age-adjusted PrCA rates were calculated by census tract. Demographic data were obtained from the 1990 census. Hazardous waste site locations and soil zinc concentrations were obtained from existing federal and state databases. A geographic information system and Poisson regression were used to test the hypothesis that census tracts with reduced soil zinc concentrations, elevated groundwater use, or more agricultural or hazardous waste sites had elevated PrCA risks.
Census tracts with high groundwater use and low zinc concentrations had higher PrCA rate ratios (RR: 1.270; 95% confidence interval: 1.079, 1.505). This effect was not more apparent in areas populated primarily by AAs.
Increased PrCA rates were associated with reduced soil zinc concentrations and elevated groundwater use, although this observation is not likely to contribute to SC’s racial PrCA disparity. Statewide mapping and statistical modeling of relationships between environmental factors, demographics, and cancer incidence can be used to screen hypotheses focusing on novel PrCA risk factors.
PMCID: PMC2959174  PMID: 18949566
South Carolina; Cancer statistics; Race; Geographic information systems; Disparities
13.  Mapping Cancer Mortality-to-Incidence Ratios to Illustrate Racial and Sex Disparities in a High-risk Population 
Cancer  2009;115(11):2539-2552.
Comparisons of incidence and mortality rates are the metrics used most commonly to define cancer-related racial disparities. In the US, and particularly in South Carolina, these largely disfavor African Americans (AAs). Computed from readily available data sources, the mortality-to-incidence rate ratio (MIR) provides a population-based indicator of survival.
South Carolina Central Cancer Registry incidence data and Vital Registry death data were used to construct MIRs. ArcGIS 9.2 mapping software was used to map cancer MIRs by sex and race for 8 Health Regions within South Carolina for all cancers combined and for breast, cervical, colorectal, lung, oral, and prostate cancers.
Racial differences in cancer MIRs were observed for both sexes for all cancers combined and for most individual sites. The largest racial differences were observed for female breast, prostate, and oral cancers, and AAs had MIRs nearly twice those of European Americans (EAs).
Comparing and mapping race- and sex-specific cancer MIRs provides a powerful way to observe the scope of the cancer problem. By using these methods, in the current study, AAs had much higher cancer MIRs compared with EAs for most cancer sites in nearly all regions of South Carolina. Future work must be directed at explaining and addressing the underlying differences in cancer outcomes by region and race. MIR mapping allows for pinpointing areas where future research has the greatest likelihood of identifying the causes of large, persistent, cancer-related disparities. Other regions with access to high-quality data may find it useful to compare MIRs and conduct MIR mapping.
PMCID: PMC2688832  PMID: 19296515
epidemiologic methods-data collection; neoplasms by site; health status disparities; healthcare disparities; geographic information systems; incidence; mortality; continental population groups; South Carolina
14.  Radio Frequency Nonionizing Radiation in a Community Exposed to Radio and Television Broadcasting 
Environmental Health Perspectives  2005;114(2):248-253.
Exposure to radio frequency (RF) nonionizing radiation from telecommunications is pervasive in modern society. Elevated disease risks have been observed in some populations exposed to radio and television transmissions, although findings are inconsistent. This study quantified RF exposures among 280 residents living near the broadcasting transmitters for Denver, Colorado. RF power densities outside and inside each residence were obtained, and a global positioning system (GPS) identified geographic coordinates and elevations. A viewshed model within a geographic information system (GIS) characterized the average distance and percentage of transmitters visible from each residence. Data were collected at the beginning and end of a 2.5-day period, and some measurements were repeated 8–29 months later. RF levels logged at 1-min intervals for 2.5 days varied considerably among some homes and were quite similar among others. The greatest differences appeared among homes within 1 km of the transmitters. Overall, there were no differences in mean residential RF levels compared over 2.5 days. However, after a 1- to 2-year follow-up, only 25% of exterior and 38% of interior RF measurements were unchanged. Increasing proximity, elevation, and line-of-sight visibility were each associated with elevated RF exposures. At average distances from > 1–3 km, exterior RF measurements were 13–30 times greater among homes that had > 50% of the transmitters visible compared with homes with ≤ 50% visibility at those distances. This study demonstrated that both spatial and temporal factors contribute to residential RF exposure and that GPS/GIS technologies can improve RF exposure assessment and reduce exposure misclassification.
PMCID: PMC1367839  PMID: 16451862
broadcasting; electromagnetic fields; exposure assessment; GIS; nonionizing radiation; radio; television

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