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1.  Telomere Content and Risk of Second Malignant Neoplasm in Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Shorter constitutional telomere length has been associated with increased cancer incidence. Furthermore, telomere shortening is observed in response to intensive chemotherapy and/or ionizing radiation exposure. We aimed to determine if less telomere content was associated with treatment-related second malignant neoplasms (SMNs) in childhood cancer survivors.
Using a nested case-control design, 147 cancer survivors with breast cancer, thyroid cancer, or sarcoma developing after treatment for childhood cancer (cases) were matched (1:1) with childhood cancer survivors without a SMN (controls). Cases and controls were matched by primary cancer diagnosis, years since diagnosis, age at time of sample collection, years of follow up from childhood cancer diagnosis, exposure to specific chemotherapy agents, and to specific radiation fields. We performed conditional logistic regression using telomere content (TC) as a continuous variable to estimate odds ratios (ORs) with corresponding 95% confidence intervals (CI) for development of SMN. ORs were also estimated for specific SMN types, i.e., breast cancer, thyroid cancer, and sarcoma.
There was an inverse relationship between TC and SMN, with an adjusted OR of 0.3 per unit change in telomere length to single copy gene ratio (95% CI, 0.09–1.02, p=0.05). Patients with thyroid cancer SMN were less likely to have more telomere content (OR 0.04, 95% CI, 0.00–0.55, p=0.01), but statistically significant associations could not be demonstrated for breast cancer or sarcoma.
A relation between less telomere content and treatment-related thyroid cancer was observed, suggesting that shorter telomeres may contribute to certain SMNs in childhood cancer survivors.
PMCID: PMC3944671  PMID: 24277454
telomere; second malignant neoplasm; risk; childhood cancer
2.  Treatment variation in patients diagnosed with early stage breast cancer in Alberta from 2002 to 2010: a population-based study 
Breast-conserving surgery (BCS) followed by radiotherapy is generally the preferred treatment for women diagnosed with early stage breast cancer. This study aimed to investigate the proportion of patients who receive BCS versus mastectomy and post-BCS radiotherapy, and explore factors associated with receipt of these treatments in Alberta, Canada.
A retrospective population-based study was conducted that including all patients surgically treated with stage I-III breast cancer diagnosed in Alberta from 2002–2010. Clinical characteristics, treatment information and patient age at diagnosis were collected from the Alberta Cancer Registry. Log binomial multiple regression was used to calculate stage-specific relative risk estimates of receiving BCS and post-BCS radiotherapy.
Of the 14 646 patients included in the study, 44% received BCS, and of those, 88% received post-BCS radiotherapy. The adjusted relative risk of BCS was highest in Calgary and lowest in Central Alberta for all disease stages. Relative to surgeries performed in Calgary, those performed in Central Alberta were significantly less likely to be BCS for stage I (RR = 0.65; 95% 0.57, 0.72), II (RR = 0.58; 95% 0.49, 0.68), and III (RR = 0.62; 95% CI: 0.37, 0.95) disease, respectively, adjusting for patient age at diagnosis, clinical and treatment characteristics. No significant variation of post-BCS radiotherapy was found.
Factors such as region of surgical treatment should not be related to the receipt of standard care within a publicly-funded health care system. Further investigation is needed to understand the significant geographic variation present within the province in order to identify appropriate interventions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-015-0680-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4308832  PMID: 25609420
Breast cancer; Population-based; Radiotherapy; Surgery
3.  Improving Google Flu Trends Estimates for the United States through Transformation 
PLoS ONE  2014;9(12):e109209.
Google Flu Trends (GFT) uses Internet search queries in an effort to provide early warning of increases in influenza-like illness (ILI). In the United States, GFT estimates the percentage of physician visits related to ILI (%ILINet) reported by the Centers for Disease Control and Prevention (CDC). However, during the 2012–13 influenza season, GFT overestimated %ILINet by an appreciable amount and estimated the peak in incidence three weeks late. Using data from 2010–14, we investigated the relationship between GFT estimates (%GFT) and %ILINet. Based on the relationship between the relative change in %GFT and the relative change in %ILINet, we transformed %GFT estimates to better correspond with %ILINet values. In 2010–13, our transformed %GFT estimates were within ±10% of %ILINet values for 17 of the 29 weeks that %ILINet was above the seasonal baseline value determined by the CDC; in contrast, the original %GFT estimates were within ±10% of %ILINet values for only two of these 29 weeks. Relative to the %ILINet peak in 2012–13, the peak in our transformed %GFT estimates was 2% lower and one week later, whereas the peak in the original %GFT estimates was 74% higher and three weeks later. The same transformation improved %GFT estimates using the recalibrated 2013 GFT model in early 2013–14. Our transformed %GFT estimates can be calculated approximately one week before %ILINet values are reported by the CDC and the transformation equation was stable over the time period investigated (2010–13). We anticipate our results will facilitate future use of GFT.
PMCID: PMC4281210  PMID: 25551391
4.  Modifiable Risk Factors and Major Cardiac Events Among Adult Survivors of Childhood Cancer 
Journal of Clinical Oncology  2013;31(29):3673-3680.
To evaluate the relative contribution of modifiable cardiovascular risk factors on the development of major cardiac events in aging adult survivors of childhood cancer.
Patients and Methods
Among 10,724 5-year survivors (median age, 33.7 years) and 3,159 siblings in the Childhood Cancer Survivor Study, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity was determined, along with the incidence and severity of major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmia. On longitudinal follow-up, rate ratios (RRs) of subsequent cardiac events associated with cardiovascular risk factors and cardiotoxic therapy were assessed in multivariable Poisson regression models.
Among survivors, the cumulative incidence of coronary artery disease, heart failure, valvular disease, and arrhythmia by 45 years of age was 5.3%, 4.8%, 1.5%, and 1.3%, respectively. Two or more cardiovascular risk factors were reported by 10.3% of survivors and 7.9% of siblings. The risk for each cardiac event increased with increasing number of cardiovascular risk factors (all Ptrend < .001). Hypertension significantly increased risk for coronary artery disease (RR, 6.1), heart failure (RR, 19.4), valvular disease (RR, 13.6), and arrhythmia (RR, 6.0; all P values < .01). The combined effect of chest-directed radiotherapy plus hypertension resulted in potentiation of risk for each of the major cardiac events beyond that anticipated on the basis of an additive expectation. Hypertension was independently associated with risk of cardiac death (RR, 5.6; 95% CI, 3.2 to 9.7).
Modifiable cardiovascular risk factors, particularly hypertension, potentiate therapy-associated risk for major cardiac events in this population and should be the focus of future interventional studies.
PMCID: PMC3804290  PMID: 24002505
5.  Detection Bias and Overestimation of Bladder Cancer Risk in Type 2 Diabetes 
Diabetes Care  2013;36(10):3070-3075.
To investigate whether the risk of bladder cancer in individuals with newly diagnosed type 2 diabetes is influenced by the frequency of physician visits before diagnosis as a measure of detection bias.
With the use of linked administrative databases from 1996 to 2006, we established a cohort of 185,100 adults from British Columbia, Canada, with incident type 2 diabetes matched one to one with nondiabetic individuals on age, sex, and index date. Incidence rates and adjusted hazard ratios (aHRs) for bladder cancer were calculated during annual time windows following the index date. Analyses were stratified by number of physician visits in the 2 years before diabetes diagnosis and adjusted for age, sex, year of cohort entry, and socioeconomic status.
The study population was 54% men and had an average age of 60.7 ± 13.5 years; 1,171 new bladder cancers were diagnosed over a median follow-up of 4 years. In the first year after diabetes diagnosis, bladder cancer incidence in the diabetic cohort was 85.3 (95% CI 72.0–100.4) per 100,000 person-years and 66.1 (54.5–79.4) in the control cohort (aHR 1.30 [1.02–1.67], P = 0.03). This first-year increased bladder cancer risk was limited to those with the fewest physician visits 2 years before the index date (≤12 visits, aHR 2.14 [1.29–3.55], P = 0.003). After the first year, type 2 diabetes was not associated with bladder cancer.
The results suggest that early detection bias may account for an overestimation in previously reported increased risks of bladder cancer associated with type 2 diabetes.
PMCID: PMC3781560  PMID: 23990517
6.  Predictors of adherence to different types and doses of supervised exercise during breast cancer chemotherapy 
Exercise is beneficial for breast cancer patients during chemotherapy but adherence to different types and doses of exercise is a challenge. The purpose of this study was to examine predictors of adherence to different types and doses of exercise during breast cancer chemotherapy in a multicenter randomized controlled trial.
Breast cancer patients in Edmonton, Vancouver, and Ottawa, Canada receiving chemotherapy (N = 301) were randomized to a standard dose of 25–30 minutes of aerobic exercise (STAN), a higher dose of 50–60 minutes of aerobic exercise (HIGH), or a higher dose of 50–60 minutes of combined aerobic and resistance exercise (COMB). Predictors included demographic, medical, fitness, and quality of life variables. Exercise adherence was measured as the percentage of supervised exercise sessions completed.
Overall adherence to the supervised exercise sessions was 73% (SD = 24%). In a multivariate regression model, six independent predictors explained 26.4% (p < 0.001) of the variance in exercise adherence. Higher exercise adherence was achieved by breast cancer patients in Vancouver (p < 0.001), with fewer endocrine symptoms (p = 0.009), randomized to STAN (p = 0.009), with fewer exercise limitations (p = 0.009), receiving shorter chemotherapy protocols (p = 0.015), and with higher VO2peak (p = 0.017). Disease stage (p for interaction = 0.015) and body mass index (p for interaction = 0.030) interacted with group assignment to predict adherence. For disease stage, patients with stage I/IIa disease adhered equally well to all three exercise interventions whereas patients with stage IIb/III disease adhered better to the STAN intervention than the two higher dose exercise interventions. For body mass index, healthy weight patients adhered equally well to all three exercise interventions whereas overweight patients adhered best to STAN and worst to COMB; and obese patients adhered best to STAN and worst to HIGH.
Determinants of exercise adherence in breast cancer patients receiving chemotherapy are multidisciplinary and may vary by the exercise prescription.
PMCID: PMC4110703  PMID: 24997476
Adherence; Cancer treatment; Cancer survivors; Determinants; Physical activity
7.  Adaptation of an evidence-based intervention to promote colorectal cancer screening: a quasi-experimental study 
To accelerate the translation of research findings into practice for underserved populations, we investigated the adaptation of an evidence-based intervention (EBI), designed to increase colorectal cancer (CRC) screening in one limited English-proficient (LEP) population (Chinese), for another LEP group (Vietnamese) with overlapping cultural and health beliefs.
Guided by Diffusion of Innovations Theory, we adapted the EBI to achieve greater reach. Core elements of the adapted intervention included: small media (a DVD and pamphlet) translated into Vietnamese from Chinese; medical assistants distributing the small media instead of a health educator; and presentations on CRC screening to the medical assistants. A quasi-experimental study examined CRC screening adherence among eligible Vietnamese patients at the intervention and control clinics, before and after the 24-month intervention. The proportion of the adherence was assessed using generalized linear mixed models that account for clustering under primary care providers and also within-patient correlation between baseline and follow up.
Our study included two cross-sectional samples: 1,016 at baseline (604 in the intervention clinic and 412 in the control clinic) and 1,260 post-intervention (746 in the intervention and 514 in the control clinic), including appreciable overlaps between the two time points. Pre-post change in CRC screening over time, expressed as an odds ratio (OR) of CRC screening adherence by time, showed a marginally-significant greater increase in CRC screening adherence at the intervention clinic compared to the control clinic (the ratio of the two ORs = 1.42; 95% CI 0.95, 2.15). In the sample of patients who were non-adherent to CRC screening at baseline, compared to the control clinic, the intervention clinic had marginally-significant greater increase in FOBT (adjusted OR = 1.77; 95% CI 0.98, 3.18) and a statistically-significantly greater increase in CRC screening adherence (adjusted OR = 1.70; 95% CI 1.05, 2.75).
Theoretically guided adaptations of EBIs may accelerate the translation of research into practice. Adaptation has the potential to mitigate health disparities for hard-to-reach populations in a timely manner.
PMCID: PMC4226971  PMID: 24989083
Adaptation; Implementation; Evidence-based intervention
Journal of community health  2013;38(3):546-553.
Cambodian Americans have high rates of chronic hepatitis B virus (HBV) infection. However, only about one-half of Cambodian Americans have been serologically tested for HBV. We conducted a randomized controlled trial to evaluate the impact of a lay health worker (LHW) intervention on HBV testing and knowledge levels among Cambodian Americans. The study group included 250 individuals who participated in a community based survey in metropolitan Seattle and had not been tested for HBV. Experimental group participants received a LHW intervention addressing HBV and control group participants received a LHW intervention addressing physical activity. Trial participants completed a follow-up survey six months after randomization. Over four-fifths (82%) of randomized individuals participated in a LHW home visit and the follow-up survey response rate was 80%. Among participants with follow-up data, 22% of the experimental group and 3% of the control group reported HBV testing (p<0.001). The experimental and control group testing difference remained significant in an intent-to-treat analysis. The experimental group was significantly more likely than the control group to know that Cambodians have higher rates of HBV infection than whites, HBV cannot be spread by eating food prepared by an infected person, HBV cannot be spread by sharing chopsticks, and HBV cannot be spread by shaking hands. Our findings indicate LHW interventions are acceptable to Cambodian Americans and can positively impact both HBV testing and knowledge levels.
PMCID: PMC3633619  PMID: 23299978
Cambodian Americans; Hepatitis B Infection; Lay Health Workers
9.  Community Health Worker Hepatitis B Education for Cambodian American Men and Women 
Cambodian Americans have high rates of chronic hepatitis B virus (HBV) infection and liver cancer. There is very limited information about the utility of community health worker (CHW) approaches to cancer education for Asian American men. We have previously reported our positive findings from a trial of CHW education about HBV for Cambodian Americans who had never been tested for HBV. This report describes similarities and differences between the outcomes of our CHW HBV educational intervention among Cambodian American men and women.
The study group for this analysis included 87 individuals (39 men and 48 women) who were randomized to the experimental (HBV education) arm of our trial, participated in the CHW educational intervention, and provided follow-up data six months post-intervention. We examined HBV testing rates at follow-up, changes in HBV-related knowledge between baseline and follow-up, and barriers to HBV testing (that were reported to CHWs) by gender.
At follow-up, 15% of men and 31% of women reported they had received a HBV test (p=0.09). HBV-related knowledge levels increased significantly among both men and women. With respect to HBV testing barriers, women were more likely than men to cite knowledge deficits, and men were more likely than women to cite logistic issues.
Our study findings indicate that CHW interventions can positively impact knowledge among Cambodian American men, as well as women. They also suggest CHW interventions may be less effective in promoting the use of preventive procedures by Cambodian American men than women. Future CHW research initiatives should consider contextual factors that may differ by gender and, therefore, potentially influence the relative effectiveness of CHW interventions for men versus women.
PMCID: PMC3801266  PMID: 24083730
Cambodian Americans; Hepatitis B Infection; Liver Cancer; Community Health Workers
10.  Continuity of Care and Colorectal Cancer Screening by Vietnamese American Patients 
Colorectal cancer (CRC) screening rates among Asian Americans are 30–50% lower than among Whites. Using practice management and electronic medical records data from a community health center, we examined the association of CRC screening with continuity of care and comorbidity. These variables have not previously been studied in Asian American and limited-English proficient populations.
After obtaining IRB approval, we extracted data in 2009 on age-eligible Vietnamese patients who had one or more clinic visits in the prior 24 months. Our analysis examined associations between CRC screening (per current US Preventive Services Task Force guidelines) and clinic site, demographics, insurance status, continuity of care, comorbidities, and provider characteristics.
We identified a total of 1,016 eligible patients (604 at Clinic 1 and 412 at Clinic 2). Adherence to CRC screening was lower for patients who were male; lacked insurance; had only one medical visit in the past 12 months; and had no assigned primary care provider. Our multivariable models showed higher screening rates among patients who were female; had public health insurance; and had more than one medical visit in the past 12 months, regardless of “high” or “low” continuity of care.
We found no association between higher continuity of care and CRC screening. Additional primary care systems research is needed to guide cancer screening interventions for limited-English proficient patients.
PMCID: PMC3856709  PMID: 21133636
Colorectal cancer; screening; Vietnamese Americans
11.  A Cross-border Comparison of Hepatitis B Testing Among Chinese Residing in Canada and the United States 
The Western Pacific region has the highest level of endemic hepatitis B virus (HBV) infection in the world, with the Chinese representing nearly one-third of infected persons globally. HBV carriers are potentially infectious to others and have an increased risk of chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Studies from the U.S. and Canada demonstrate that immigrants, particularly from Asia, are disproportionately affected by liver cancer.
Given the different health care systems in Seattle and Vancouver, two geographically proximate cities, we examined HBV testing levels and factors associated with testing among Chinese residents of these cities.
We surveyed Chinese living in areas of Seattle and Vancouver with relatively high proportions of Chinese residents. In-person interviews were conducted in Cantonese, Mandarin, or English. Our bivariate analyses consisted of the chi-square test, with Fisher’s Exact test as necessary. We then performed unconditional logistic regression, first examining only the city effect as the sole explanatory variable of the model, then assessing the adjusted city effect in a final main-effects model that was constructed through backward selection to select statistically significant variables at alpha = 0.05.
Survey cooperation rates for Seattle and Vancouver were 58% and 59%, respectively. In Seattle, 48% reported HBV testing, whereas in Vancouver, 55% reported testing. HBV testing in Seattle was lower than in Vancouver, with a crude odds ratio of 0.73 (95% CI = 0.56, 0.94). However after adjusting for demographic, health care access, knowledge, and social support variables, we found no significant differences in HBV testing between the two cities. In our logistic regression model, the odds of HBV testing were greatest when the doctor recommended the test, followed by when the employer asked for the test.
Findings from this study support the need for additional research to examine the effectiveness of clinic-based and workplace interventions to promote HBV testing among immigrants to North America.
PMCID: PMC3856895  PMID: 19640196
Asian and Pacific Islanders; chronic hepatitis B; liver cancer; prevention clinic
12.  Maternal Exposure to Bisphenol-A and Fetal Growth Restriction: A Case-Referent Study 
We conducted a case-referent study of the effect of exposure to bisphenol-A on fetal growth in utero in full-term, live-born singletons in Alberta, Canada. Newborns <10 percentile of expected weight for gestational age and sex were individually matched on sex, maternal smoking and maternal age to referents with weight appropriate to gestational age. Exposure of the fetus to bisphenol-A was estimated from maternal serum collected at 15–16 weeks of gestation. We pooled sera across subjects for exposure assessment, stratified on case-referent status and sex. Individual 1:1 matching was maintained in assembling 69 case and 69 referent pools created from 550 case-referent pairs. Matched pools had an equal number of aliquots from individual women. We used an analytical strategy conditioning on matched set and total pool-level values of covariates to estimate individual-level effects. Pools of cases and referents had identical geometric mean bisphenol-A concentrations (0.5 ng/mL) and similar geometric standard deviations (2.3–2.5). Mean difference in concentration between matched pools was 0 ng/mL, standard deviation: 1 ng/mL. Stratification by sex and control for confounding did not suggest bisphenol-A increased fetal growth restriction. Our analysis does not provide evidence to support the hypothesis that bisphenol-A contributes to fetal growth restriction in full-term singletons.
PMCID: PMC3881152  PMID: 24336026
BPA; endocrine disruption; small for gestation age; birth weight; epidemiology
13.  Physical Activity among Cambodian Americans: An Exploratory Study 
Journal of community health  2012;37(5):1040-1048.
Available data indicate that Asian Americans as a group have lower levels of physical activity than non-Latino whites. However, few studies have focused on physical activity among Asian American sub-groups. Our objectives were to describe levels of physical activity, as well as individual and environmental correlates of physical activity among Cambodian Americans.
We conducted a telephone survey of Cambodians living in three geographic areas (Central California, Northern California, and the Pacific Northwest) during 2010. Physical activity levels were assessed using the International Physical Activity Questionnaire (IPAQ) short version. Survey items addressed demographic characteristics, knowledge about the health benefits of physical activity, social norms and supports with respect to physical activity, the availability of neighbourhood recreational facilities, and neighbourhood characteristics.
Our study group included 222 individuals. Only 12% of the study group reported low levels of physical activity, 40% reported moderate levels, and 48% reported high levels. Physical activity was strongly associated with the availability of neighborhood recreational facilities such as parks, but not with neighborhood characteristics such as heavy traffic.
Our results suggest that a majority of Cambodian Americans are adherent to current physical activity guidelines. Neighborhood recreational facilities that provide opportunities for leisure-time physical activity are associated with higher levels of physical activity in Cambodian communities. Future research should assess the reliability and validity of the IPAQ in a Cambodian American study group.
PMCID: PMC3437005  PMID: 22183889
Cambodian Americans; Physical activity
14.  Heterogeneity and event dependence in the analysis of sickness absence 
Sickness absence (SA) is an important social, economic and public health issue. Identifying and understanding the determinants, whether biological, regulatory or, health services-related, of variability in SA duration is essential for better management of SA. The conditional frailty model (CFM) is useful when repeated SA events occur within the same individual, as it allows simultaneous analysis of event dependence and heterogeneity due to unknown, unmeasured, or unmeasurable factors. However, its use may encounter computational limitations when applied to very large data sets, as may frequently occur in the analysis of SA duration.
To overcome the computational issue, we propose a Poisson-based conditional frailty model (CFPM) for repeated SA events that accounts for both event dependence and heterogeneity. To demonstrate the usefulness of the model proposed in the SA duration context, we used data from all non-work-related SA episodes that occurred in Catalonia (Spain) in 2007, initiated by either a diagnosis of neoplasm or mental and behavioral disorders.
As expected, the CFPM results were very similar to those of the CFM for both diagnosis groups. The CPU time for the CFPM was substantially shorter than the CFM.
The CFPM is an suitable alternative to the CFM in survival analysis with recurrent events, especially with large databases.
PMCID: PMC3852331  PMID: 24040880
Sickness absence; Survival analysis; Conditional frailty model; Poisson regression; Mental disorders; Neoplasms
15.  Nonadherence to Oral Mercaptopurine and Risk of Relapse in Hispanic and Non-Hispanic White Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2012;30(17):2094-2101.
Systemic exposure to mercaptopurine (MP) is critical for durable remissions in children with acute lymphoblastic leukemia (ALL). Nonadherence to oral MP could increase relapse risk and also contribute to inferior outcome in Hispanics. This study identified determinants of adherence and described impact of adherence on relapse, both overall and by ethnicity.
Patients and Methods
A total of 327 children with ALL (169 Hispanic; 158 non-Hispanic white) participated. Medication event-monitoring system caps recorded date and time of MP bottle openings. Adherence rate, calculated monthly, was defined as ratio of days of MP bottle opening to days when MP was prescribed.
After 53,394 person-days of monitoring, adherence declined from 94.7% (month 1) to 90.2% (month 6; P < .001). Mean adherence over 6 months was significantly lower among Hispanics (88.4% v 94.8%; P < .001), patients age ≥ 12 years (85.8% v 93.1%; P < .001), and patients from single-mother households (80.6% v 93.1%; P = .001). A progressive increase in relapse was observed with decreasing adherence (reference: adherence ≥ 95%; 94.9% to 90%: hazard ratio [HR], 4.1; 95% CI,1.2 to 13.5; P = .02; 89.9% to 85%: HR, 4.0; 95% CI, 1.0 to 15.5; P = .04; < 85%: HR. 5.7; 95% CI, 1.9 to 16.8; P = .002). Cumulative incidence of relapse (± standard deviation) was higher among Hispanics (16.5% ± 4.0% v 6.3% ± 2.2%; P = .02). Association between Hispanic ethnicity and relapse (HR, 2.6; 95% CI, 1.1 to 6.1; P = .02) became nonsignificant (HR, 1.8; 95% CI, 0.6 to 5.2; P = .26) after adjusting for adherence and socioeconomic status. At adherence rates ≥ 90%, Hispanics continued to demonstrate higher relapse, whereas at rates < 90%, relapse risk was comparable to that of non-Hispanic whites.
Lower adherence to oral MP increases relapse risk. Ethnic difference in relapse risk differs by level of adherence—an observation currently under investigation.
PMCID: PMC3601449  PMID: 22564992
16.  Assessing SNP-SNP Interactions among DNA Repair, Modification and Metabolism Related Pathway Genes in Breast Cancer Susceptibility 
PLoS ONE  2013;8(6):e64896.
Genome-wide association studies (GWASs) have identified low-penetrance common variants (i.e., single nucleotide polymorphisms, SNPs) associated with breast cancer susceptibility. Although GWASs are primarily focused on single-locus effects, gene-gene interactions (i.e., epistasis) are also assumed to contribute to the genetic risks for complex diseases including breast cancer. While it has been hypothesized that moderately ranked (P value based) weak single-locus effects in GWASs could potentially harbor valuable information for evaluating epistasis, we lack systematic efforts to investigate SNPs showing consistent associations with weak statistical significance across independent discovery and replication stages. The objectives of this study were i) to select SNPs showing single-locus effects with weak statistical significance for breast cancer in a GWAS and/or candidate-gene studies; ii) to replicate these SNPs in an independent set of breast cancer cases and controls; and iii) to explore their potential SNP-SNP interactions contributing to breast cancer susceptibility. A total of 17 SNPs related to DNA repair, modification and metabolism pathway genes were selected since these pathways offer a priori knowledge for potential epistatic interactions and an overall role in breast carcinogenesis. The study design included predominantly Caucasian women (2,795 cases and 4,505 controls) from Alberta, Canada. We observed two two-way SNP-SNP interactions (APEX1-rs1130409 and RPAP1-rs2297381; MLH1-rs1799977 and MDM2-rs769412) in logistic regression that conferred elevated risks for breast cancer (Pinteraction<7.3×10−3). Logic regression identified an interaction involving four SNPs (MBD2-rs4041245, MLH1-rs1799977, MDM2-rs769412, BRCA2-rs1799943) (Ppermutation = 2.4×10−3). SNPs involved in SNP-SNP interactions also showed single-locus effects with weak statistical significance, while BRCA2-rs1799943 showed stronger statistical significance (Pcorrelation/trend = 3.2×10−4) than the others. These single-locus effects were independent of body mass index. Our results provide a framework for evaluating SNPs showing statistically weak but reproducible single-locus effects for epistatic effects contributing to disease susceptibility.
PMCID: PMC3670937  PMID: 23755158
17.  Identification of a Breast Cancer Susceptibility Locus at 4q31.22 Using a Genome-Wide Association Study Paradigm 
PLoS ONE  2013;8(5):e62550.
More than 40 single nucleotide polymorphisms (SNPs) for breast cancer susceptibility were identified by genome-wide association studies (GWASs). However, additional SNPs likely contribute to breast cancer susceptibility and overall genetic risk, prompting this investigation for additional variants. Six putative breast cancer susceptibility SNPs identified in a two-stage GWAS that we reported earlier were replicated in a follow-up stage 3 study using an independent set of breast cancer cases and controls from Canada, with an overall cumulative sample size of 7,219 subjects across all three stages. The study design also encompassed the 11 variants from GWASs previously reported by various consortia between the years 2007–2009 to (i) enable comparisons of effect sizes, and (ii) identify putative prognostic variants across studies. All SNP associations reported with breast cancer were also adjusted for body mass index (BMI). We report a strong association with 4q31.22-rs1429142 (combined per allele odds ratio and 95% confidence interval = 1.28 [1.17–1.41] and Pcombined = 1.5×10−7), when adjusted for BMI. Ten of the 11 breast cancer susceptibility loci reported by consortia also showed associations in our predominantly Caucasian study population, and the associations were independent of BMI; four FGFR2 SNPs and TNRC9-rs3803662 were among the most notable associations. Since the original report by Garcia-Closas et al. 2008, this is the second study to confirm the association of 8q24.21-rs13281615 with breast cancer outcomes.
PMCID: PMC3661567  PMID: 23717390
18.  Long-term Fruit and Vegetable Change in Worksites: Seattle 5 A Day Follow-up 
To evaluate long-term change in fruit and vegetable intake following a group randomized trial of worksites.
Medium-sized blue-collar businesses in the Seattle metropolitan area were recruited. Intake was assessed using serial cross-sectional samples of current workforce at 3 time points. The multilevel 18-month intervention involved partnership with the companies. Long-term follow-up was at 4.4 years postbaseline. Statistical analysis used general linear models, adjusting for worksite random effects.
Initially, 45 worksites were randomized, with 29 agreeing to participate in a new study. Fruits and vegetable intake increased, with larger sustained changes in the intervention worksites, resulting in a long-term differential change of 0.25 servings per day, 95% confidence interval (0.09 to 0.40).
Intervention sustained small effects at 4 years, including 2 years with no contact. Although effects were not large, this low-intensity intervention approach could provide an important public health model.
PMCID: PMC3658284  PMID: 20604696
Intervention evaluation studies; behavior change persistence; food; fruits and vegetables; long-term effects
19.  HPV Vaccination Uptake among Cambodian Mothers 
Journal of Cancer Education  2012;27(1):145-148.
Women of Southeast Asian descent have higher cervical cancer incidence rates than any other group. Widespread use of HPV vaccination could prevent up to 70% of cervical cancers. There is little published information addressing HPV vaccination uptake among Asian Americans. We conducted a survey of Cambodian women with daughters who were age-eligible for HPV vaccination. Survey items addressed HPV vaccination barriers, facilitators, and uptake. Only 26% of the survey participants reported any of their age-eligible daughters had received vaccination, and only 40% reported a previous physician recommendation for vaccination. Higher levels of vaccine uptake were strongly associated with having received a doctor's recommendation for vaccination (P<0.001) and having asked a doctor for vaccination (p=0.002). HPV vaccine uptake was relatively low in our Cambodian study group. Educational initiatives should encourage health care providers who serve Cambodian families to recommend HPV vaccination and empower Cambodian mothers to ask their daughters' doctors for vaccination.
PMCID: PMC3224678  PMID: 21861237
20.  Impact of Colon Cancer Screening on Family History Phenotype 
Epidemiology (Cambridge, Mass.)  2012;23(2):308-310.
If effective cancer screening is more common in people with a family history of cancer, the relationship between family history and cancer incidence may become distorted.
To assess the impact of screening on the association between colorectal cancer family history and risk of colorectal cancer, we developed a model to simulate screening patterns in those with and without a family history.
The introduction of screening reduces the apparent risk of colorectal cancer associated with family history in subsequent generations. This reduction becomes more pronounced as the difference in the uptake of screening between those with a family history and those without becomes larger.
A result of effective screening is that observed family history of colorectal cancer may no longer match inherited risk, and observed family history may fail to be a strong risk factor. This may have implications for exposure-disease relationships if screening is differentially associated with the exposure.
PMCID: PMC3299289  PMID: 22252410
Cambodian Americans have an elevated risk of liver cancer. This health disparity is attributable to high rates of hepatitis B virus (HBV) infection. Our study examined factors associated with HBV testing among Cambodian men and women.
A population-based survey was conducted in the Seattle area. The Health Behavior Framework guided our survey instrument development. We attempted to interview a man and a woman in each household.
The sample included 300 men and 367 women. About one-half of the male (45%) and female (54%) respondents had been tested for HBV. Two factors were independently associated with testing among men and women: a doctor had recommended testing and had asked a doctor for testing. Knowing that someone who looks and feels healthy can spread HBV was independently associated with testing among men.
Low levels of HBV testing remain a public health problem among Cambodians. Interventions should improve patient-provider communication by encouraging providers who serve Cambodians to recommend HBV testing, as well as by empowering Cambodians to ask for testing.
PMCID: PMC3282163  PMID: 22002705
Cambodian Americans; Hepatitis B Testing; Immigrant Health; Liver Cancer
22.  Germline DNA Copy Number Aberrations Identified as Potential Prognostic Factors for Breast Cancer Recurrence 
PLoS ONE  2013;8(1):e53850.
Breast cancer recurrence (BCR) is a common treatment outcome despite curative-intent primary treatment of non-metastatic breast cancer. Currently used prognostic and predictive factors utilize tumor-based markers, and are not optimal determinants of risk of BCR. Germline-based copy number aberrations (CNAs) have not been evaluated as determinants of predisposition to experience BCR. In this study, we accessed germline DNA from 369 female breast cancer subjects who received curative-intent primary treatment following diagnosis. Of these, 155 experienced BCR and 214 did not, after a median duration of follow up after breast cancer diagnosis of 6.35 years (range = 0.60–21.78) and 8.60 years (range = 3.08–13.57), respectively. Whole genome CNA genotyping was performed on the Affymetrix SNP array 6.0 platform. CNAs were identified using the SNP-Fast Adaptive States Segmentation Technique 2 algorithm implemented in Nexus Copy Number 6.0. Six samples were removed due to poor quality scores, leaving 363 samples for further analysis. We identified 18,561 CNAs with ≥1 kb as a predefined cut-off for observed aberrations. Univariate survival analyses (log-rank tests) identified seven CNAs (two copy number gains and five copy neutral-loss of heterozygosities, CN-LOHs) showing significant differences (P<2.01×10−5) in recurrence-free survival (RFS) probabilities with and without CNAs.We also observed three additional but distinct CN-LOHs showing significant differences in RFS probabilities (P<2.86×10−5) when analyses were restricted to stratified cases (luminal A, n = 208) only. After adjusting for tumor stage and grade in multivariate analyses (Cox proportional hazards models), all the CNAs remained strongly associated with the phenotype of BCR. Of these, we confirmed three CNAs at 17q11.2, 11q13.1 and 6q24.1 in representative samples using independent genotyping platforms. Our results suggest further investigations on the potential use of germline DNA variations as prognostic markers in cancer-associated phenotypes.
PMCID: PMC3547038  PMID: 23342018
23.  Hyperglycemia is a significant prognostic factor of hepatocellular carcinoma after curative therapy 
AIM: To evaluate whether metabolic factors are related to distant recurrence of hepatocellular carcinoma (HCC) and survival after curative treatment.
METHODS: This retrospective study included 344 patients whose HCC was treated curatively by radiofrequency ablation (RFA) therapy. The mean age was 67.6 years and the mean observation period was 4.04 years. The etiological background of liver disease was hepatitis B virus infection in 30, hepatitis C virus infection in 278, excessive alcohol drinking in 9, and other in 27 patients. The Child-Pugh classification grade was A (n = 307) or B (n = 37). The number of HCC nodules was one in 260, two in 61, and three in 23 patients. For surveillance of HCC recurrence after curative therapy with RFA, patients were radiologically evaluated every 3 mo. Factors associated with distant recurrence of HCC or survival were studied.
RESULTS: Inadequate maintenance of blood glucose in diabetic patients was associated with higher incidence of distant recurrence. The 1-, 2-, and 3-year recurrence rates were significantly higher in diabetic patients with inadequate maintenance of blood glucose compared with the others: 50.6% vs 26.8%, 83.5% vs 54.4%, and 93.8% vs 73.0%, respectively (P = 0.0001). Inadequate maintenance of blood glucose was an independent predictor of distant recurrence [adjusted relative risk 1.97 (95%CI, 1.33-2.91), (P = 0.0007)] after adjustment for other risk factors, such as number of HCC nodules [2.03 (95%CI, 1.51-2.73), P < 0.0001] and initial level of serum alpha fetoprotein (AFP) [1.43 (95%CI, 1.04-1.97), P = 0.028]. Obesity was not an independent predictor of recurrence. The incidence of distant recurrence did not differ between diabetic patients with adequate maintenance of blood glucose and non-diabetic patients. Among 232 patients who had HCC recurrence, 138 had a second recurrence. The 1-, 2-, and 3-year rates of second recurrence were significantly higher in diabetic patients with inadequate maintenance of blood glucose than in the others: 9.0% vs 5.9%, 53.1% vs 24.3%, and 69.6% vs 42.3%, respectively (P = 0.0021). Inadequate maintenance of blood glucose in diabetic patients [1.99 (95%CI, 1.23-3.22), P = 0.0049] and presence of multiple HCC nodules [1.53 (95%CI, 1.06-2.22), P = 0.024] were again significantly associated with second HCC recurrence. Inadequate maintenance of blood glucose in diabetic patients was also a significant predictor of poor survival [2.77 (95%CI, 1.38-5.57), P = 0.0046] independent of excessive alcohol drinking [6.34 (95%CI, 1.35-29.7), P = 0.019], initial level of serum AFP [3.40 (95%CI, 1.88-6.18), P < 0.0001] and Child-Pugh classification grade B [2.24 (95%CI, 1.12-4.46), P = 0.022]. Comparing diabetic patients with inadequate maintenance of blood glucose vs the others, the 1-, 2-, and 3-year survival rates were significantly lower in diabetic patients with inadequate maintenance of blood glucose: 92% vs 99%, 85% vs 96%, and 70% vs 92%, respectively (P = 0.0003).
CONCLUSION: Inadequate maintenance of blood glucose in diabetic patients is a significant risk factor for recurrence of HCC and for poor survival after curative RFA therapy.
PMCID: PMC3547569  PMID: 23345948
Hyperglycemia; Hepatocellular carcinoma; Recurrence; Radio frequency ablation; Survival
24.  Variation in risk of second primary cancer 
PMCID: PMC3255205  PMID: 22125335
25.  Diabetes Mellitus in Long-Term Survivors of Childhood Cancer: Increased Risk Associated with Radiation Therapy A Report for the Childhood Cancer Survivor Study (CCSS) 
Archives of internal medicine  2009;169(15):1381-1388.
Childhood cancer survivors are at increased risk of morbidity and mortality. To further characterize this risk, this study aimed to compare the prevalence of diabetes mellitus (DM) in childhood cancer survivors and their siblings.
Participants included 8599 survivors in the Childhood Cancer Survivor Study (CCSS), a retrospectively ascertained North American cohort of long-term survivors who were diagnosed 1970–1986, and 2936 randomly selected siblings of CCSS survivors. The main outcome was self-reported DM.
Survivors and siblings had mean ages of 31.5 years (range, 17.0–54.1) and 33.4 years (range, 9.6–58.4), respectively. DM was reported in 2.5% of survivors and 1.7% of siblings. Adjusting for body mass index (BMI), age, sex, race/ethnicity, household income, and insurance, survivors were 1.8 times more likely to report DM (95% confidence interval [CI], 1.3–2.5; P<0.001) than siblings, with survivors who received total body irradiation (odds ratio [OR], 12.6; 95% CI, 6.2–25.3; P<0.001), abdominal irradiation (OR, 3.4; 95% CI, 2.3–5.0; P<0.001) and cranial irradiation (OR, 1.6; 95% CI 1.0–2.3; P=0.03) at increased risk. In adjusted models, increased risk of DM was associated with: total body irradiation (OR 7.2; 95% CI, 3.4–15.0; P<0.001); abdominal irradiation (OR 2.7; 95% CI, 1.9–3.8; P<0.001); alkylating agents (OR 1.7; 95% CI, 1.2–2.3; P<0.01); and younger age at diagnosis (0–4 years; OR 2.4; 95% CI 1.3–4.6; P<0.01).
Childhood cancer survivors treated with total body or abdominal irradiation have an increased risk of diabetes that appears unrelated to BMI or physical inactivity.
PMCID: PMC3529471  PMID: 19667301
Childhood cancer survivor; diabetes mellitus; abdominal radiation; total body irradiation

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