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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
14.  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
15.  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
16.  Variation in risk of second primary cancer 
PMCID: PMC3255205  PMID: 22125335
17.  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
18.  Case–control study of markers of insulin resistance and endometrial cancer risk 
Endocrine-Related Cancer  2012;19(6):785-792.
Markers of insulin resistance such as the adiponectin:leptin ratio (A:L) and the homeostasis model assessment ratio (HOMA-IR) are associated with obesity and hyperinsulinemia, both established risk factors for endometrial cancer, and may therefore be informative regarding endometrial cancer risk. This study investigated the association between endometrial cancer risk and markers of insulin resistance, namely adiponectin, leptin, the A:L ratio, insulin, fasting glucose, and the HOMA-IR. We analyzed data from 541 incident endometrial cancer cases and 961 frequency age-matched controls in a population-based case–control study in Alberta, Canada from 2002 to 2006. Participants completed interview-administered questionnaires were assessed for anthropometric measures, and provided 8-h fasting blood samples either pre- or postoperatively. Blood was analyzed for concentrations of leptin, adiponectin, and insulin by immunoassay, and fasting plasma glucose levels were determined by fluorimetric quantitative determination. Compared with the lowest quartile, the highest quartile of insulin and HOMA-IR was associated with 64% (95% confidence intervals (CI): 1.12–2.40) and 72% (95% CI: 1.17–2.53) increased risks of endometrial cancer, respectively, and the highest quartile of adiponectin was associated with a 45% (95% CI: 0.37–0.80) decreased risk after multivariable adjustments. Null associations were observed between fasting glucose, leptin and A:L, and endometrial cancer risk. This population-based study provides evidence for a role of insulin resistance in endometrial cancer etiology and may provide one possible pathway whereby obesity increases the risk of this common cancer. Interventions aimed at decreasing both obesity and insulin resistance may decrease endometrial cancer risk.
PMCID: PMC3493985  PMID: 23033315
19.  The Alberta moving beyond breast cancer (AMBER) cohort study: a prospective study of physical activity and health-related fitness in breast cancer survivors 
BMC Cancer  2012;12:525.
Limited research has examined the association between physical activity, health-related fitness, and disease outcomes in breast cancer survivors. Here, we present the rationale and design of the Alberta Moving Beyond Breast Cancer (AMBER) Study, a prospective cohort study designed specifically to examine the role of physical activity and health-related fitness in breast cancer survivorship from the time of diagnosis and for the balance of life. The AMBER Study will examine the role of physical activity and health-related fitness in facilitating treatment completion, alleviating treatment side effects, hastening recovery after treatments, improving long term quality of life, and reducing the risks of disease recurrence, other chronic diseases, and premature death.
The AMBER Study will enroll 1500 newly diagnosed, incident, stage I-IIIc breast cancer survivors in Alberta, Canada over a 5 year period. Assessments will be made at baseline (within 90 days of surgery), 1 year, and 3 years consisting of objective and self-reported measurements of physical activity, health-related fitness, blood collection, lymphedema, patient-reported outcomes, and determinants of physical activity. A final assessment at 5 years will measure patient-reported data only. The cohort members will be followed for an additional 5 years for disease outcomes.
The AMBER cohort will answer key questions related to physical activity and health-related fitness in breast cancer survivors including: (1) the independent and interactive associations of physical activity and health-related fitness with disease outcomes (e.g., recurrence, breast cancer-specific mortality, overall survival), treatment completion rates, symptoms and side effects (e.g., pain, lymphedema, fatigue, neuropathy), quality of life, and psychosocial functioning (e.g., anxiety, depression, self-esteem, happiness), (2) the determinants of physical activity and health-related fitness including demographic, medical, social cognitive, and environmental variables, (3) the mediators of any observed associations between physical activity, health-related fitness, and health outcomes including biological, functional, and psychosocial, and (4) the moderators of any observed associations including demographic, medical, and biological/disease factors. Taken together, these data will provide a comprehensive inquiry into the outcomes, determinants, mechanisms, and moderators of physical activity and health-related fitness in breast cancer survivors.
PMCID: PMC3534483  PMID: 23153358
Breast cancer; Exercise; Physical activity; Cardiorespiratory fitness; Muscular strength; Lymphedema; Quality of life; Exercise determinants; Recurrence; Survival
20.  SNP-SNP Interactions Discovered by Logic Regression Explain Crohn's Disease Genetics 
PLoS ONE  2012;7(10):e43035.
In genome-wide association studies (GWAS), the association between each single nucleotide polymorphism (SNP) and a phenotype is assessed statistically. To further explore genetic associations in GWAS, we considered two specific forms of biologically plausible SNP-SNP interactions, ‘SNP intersection’ and ‘SNP union,’ and analyzed the Crohn's Disease (CD) GWAS data of the Wellcome Trust Case Control Consortium for these interactions using a limited form of logic regression. We found strong evidence of CD-association for 195 genes, identifying novel susceptibility genes (e.g., ISX, SLCO6A1, TMEM183A) as well as confirming many previously identified susceptibility genes in CD GWAS (e.g., IL23R, NOD2, CYLD, NKX2-3, IL12RB2, ATG16L1). Notably, 37 of the 59 chromosomal locations indicated for CD-association by a meta-analysis of CD GWAS, involving over 22,000 cases and 29,000 controls, were represented in the 195 genes, as well as some chromosomal locations previously indicated only in linkage studies, but not in GWAS. We repeated the analysis with two smaller GWASs from the Database of Genotype and Phenotype (dbGaP): in spite of differences of populations and study power across the three datasets, we observed some consistencies across the three datasets. Notable examples included TMEM183A and SLCO6A1 which exhibited strong evidence consistently in our WTCCC and both of the dbGaP SNP-SNP interaction analyses. Examining these specific forms of SNP interactions could identify additional genetic associations from GWAS. R codes, data examples, and a ReadMe file are available for download from our website:
PMCID: PMC3470545  PMID: 23071489
21.  Short-Term Erythropoietin Treatment Does Not Substantially Modulate Monocyte Transcriptomes of Patients with Combined Heart and Renal Failure 
PLoS ONE  2012;7(9):e41339.
Combined heart and renal failure is associated with high cardiovascular morbidity and mortality. Anti-oxidant and anti-inflammatory, non-hematopoietic effects of erythropoietin (EPO) treatment have been proposed. Monocytes may act as biosensors of the systemic environment. We hypothesized that monocyte transcriptomes of patients with cardiorenal syndrome (CRS) reflect the pathophysiology of the CRS and respond to short-term EPO treatment at a recommended dose for treatment of renal anemia.
Patients with CRS and anemia (n = 18) included in the EPOCARES trial were matched to healthy controls (n = 12). Patients were randomized to receive 50 IU/kg/week EPO or not. RNA from CD14+-monocytes was subjected to genome wide expression analysis (Illumina) at baseline and 18 days (3 EPO injections) after enrolment. Transcriptomes from patients were compared to healthy controls and effect of EPO treatment was evaluated within patients.
In CRS patients, expression of 471 genes, including inflammation and oxidative stress related genes was different from healthy controls. Cluster analysis did not separate patients from healthy controls. The 6 patients with the highest hsCRP levels had more differentially expressed genes than the 6 patients with the lowest hsCRP levels. Analysis of the variation in log2 ratios of all individual 18 patients indicated that 4 of the 18 patients were different from the controls, whereas the other 14 were quite similar. After short-term EPO treatment, every patient clustered to his or her own baseline transcriptome. Two week EPO administration only marginally affected expression profiles on average, however, individual gene responses were variable.
In stable, treated CRS patients with mild anemia, monocyte transcriptomes were modestly altered, and indicated imprints of inflammation and oxidative stress. EPO treatment with a fixed dose has hematopoietic effects, had no appreciable beneficial actions on monocyte transcription profiles, however, could also not be associated with undesirable transcriptional responses.
PMCID: PMC3434212  PMID: 22957013
22.  Impact of Insurance Type on Survivor-Focused and General Preventive Health Care Utilization in Adult Survivors of Childhood Cancer: The Childhood Cancer Survivor Study (CCSS) 
Cancer  2010;117(9):1966-1975.
Lack of health insurance is a key barrier to accessing care for chronic conditions and cancer screening. We examined the influence of insurance type (private, public, none) on survivor-focused and general preventive health care in adult survivors of childhood cancer.
The Childhood Cancer Survivor Study is a retrospective cohort study of childhood cancer survivors diagnosed between 1970–1986. Among 8425 adult survivors, the Relative Risk (RR), 95% confidence interval (CI) of receiving survivor-focused and general preventive health care were estimated for uninsured (n=1390) and publicly insured (n=640), comparing to privately insured (n=6395).
Uninsured survivors were less likely than privately insured to report a cancer-related (adjusted RR=0.83, 95% CI, 0.75–0.91) or a cancer center visit (adjusted RR=0.83, 95% CI, 0.71–0.98). Uninsured survivors had lower levels of utilization in all measures of care in comparison with privately insured. In contrast, publicly insured survivors were more likely to report a cancer-related (adjusted RR=1.22, 95% CI, 1.11–1.35) or a cancer center visit (adjusted RR=1.41, 95% CI, 1.18–1.70) than privately insured. While having a similar utilization level of general health examinations, publicly insured survivors were less likely to report Papanicolaou smear or dental examinations.
Among this large, socioeconomically diverse cohort, publicly insured survivors utilize survivor-focused health care at rates at least as high as survivors with private insurance. Uninsured survivors have lower utilization to both survivor-focused and general preventive health care.
PMCID: PMC3433164  PMID: 21509774
Childhood Cancer Survivors; Health Insurance; Health Care Access; Survivorship; Delivery of Health Care
23.  Occurrence of Multiple Subsequent Neoplasms in Long-Term Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2011;29(22):3056-3064.
Childhood cancer survivors experience an increased incidence of subsequent neoplasms (SNs). Those surviving the first SN (SN1) remain at risk to develop multiple SNs. Because SNs are a common cause of late morbidity and mortality, characterization of rates of multiple SNs is needed.
Patients and Methods
In a total of 14,358 5-year survivors of childhood cancer diagnosed between 1970 and 1986, analyses were carried out among 1,382 survivors with an SN1. Cumulative incidence of second subsequent neoplasm (SN2), either malignant or benign, was calculated.
A total of 1,382 survivors (9.6%) developed SN1, of whom 386 (27.9%) developed SN2. Of those with SN2, 153 (39.6%) developed more than two SNs. Cumulative incidence of SN2 was 46.9% (95% CI, 41.6% to 52.2%) at 20 years after SN1. The cumulative incidence of SN2 among radiation-exposed survivors was 41.3% (95% CI, 37.2% to 45.4%) at 15 years compared with 25.7% (95% CI, 16.5% to 34.9%) for those not treated with radiation. Radiation-exposed survivors who developed an SN1 of nonmelanoma skin cancer (NMSC) had a cumulative incidence of subsequent malignant neoplasm (SMN; ie, malignancies excluding NMSC) of 20.3% (95% CI, 13.0% to 27.6%) at 15 years compared with only 10.7% (95% CI, 7.2% to 14.2%) for those who were exposed to radiation and whose SN1 was an invasive SMN (excluding NMSC).
Multiple SNs are common among aging survivors of childhood cancer. SN1 of NMSC identifies a population at high risk for invasive SMN. Survivors not exposed to radiation who develop multiple SNs represent a population of interest for studying genetic susceptibility to neoplasia.
PMCID: PMC3157966  PMID: 21709189
24.  Analytical Validation of Serum Proteomic Profiling for Diagnosis of Prostate Cancer: Sources of Sample Bias 
Clinical Chemistry  2007;54(1):44-52.
This report and a companion report describe a validation of the ability of serum proteomic profiling via SELDI-TOF mass spectrometry to detect prostatic cancer. Details of this 3-stage process have been described. This report describes the development of the algorithm and results of the blinded test for stage 1.
We derived the decision algorithm used in this study from the analysis of serum samples from patients with prostate cancer (n = 181) and benign prostatic hyperplasia (BPH) (n = 143) and normal controls (n = 220). We also derived a validation test set from a separate, geographically diverse set of serum samples from 42 prostate cancer patients and 42 controls without prostate cancer. Aliquots were subjected to randomization and blinded analysis, and data from each laboratory site were subjected to the decision algorithm and decoded.
Using the data collected from the validation test set, the decision algorithm was unsuccessful in separating cancer from controls with any predictive utility. Analysis of the experimental data revealed potential sources of bias.
The ability of the decision algorithm to successfully differentiate between prostate cancer, BPH, and control samples using data derived from serum protein profiling was compromised by bias.
PMCID: PMC3354530  PMID: 17981926
25.  Survivors of Childhood Cancer Have Increased Risk for Gastrointestinal Complications Later in Life 
Gastroenterology  2011;140(5):1464-1471.e1.
Background & Aims
Children who receive cancer therapy experience numerous acute gastrointestinal (GI) toxicities. However, the long-term GI consequences have not been extensively studied. We evaluated the incidence of adverse long-term GI outcomes and identified treatment-related risk factors.
Upper GI, hepatic, and lower GI adverse outcomes were assessed in cases randomly selected from participants in the Childhood Cancer Survivor Study, a study of 14,358 survivors of childhood cancer who were diagnosed between 1970 and 1986; data were compared with those from siblings. The median age at cancer diagnosis was 6.8 years (0–21.0 years), the median age at outcome assessment was 23.2 years (5.6–48.9 years) for survivors and 26.6 years (1.8–56.2 years) for siblings. Rates of self-reported, late complications of the GI tract (occurred 5 or more years after cancer diagnosis) were determined and associated with patient characteristics and cancer treatments, adjusting for age, sex, and race; data were compared with those from siblings.
Compared with siblings, survivors had increased risk for late-onset complications of the upper GI tract (relative risk [RR]=1.8; 95% confidence interval [CI], 1.6–2.0), liver (RR=2.1; 95% CI, 1.8–2.5), and lower GI tract (RR=1.9; 1.7–2.2). The RR for requiring colostomy, ileostomy, or liver biopsy, or for developing liver cirrhosis were 5.6 (95% CI, 2.4–13.1), 24.1 (95% CI, 7.5–77.8), and 8.9 (95% CI, 2.0–40.0), respectively. Older age at diagnosis, intensified therapy, abdominal radiation, and abdominal surgery increased the risk of certain GI complications.
Individuals who received therapy for cancer during childhood have an increased risk of developing GI complications later in life.
PMCID: PMC3081911  PMID: 21315721
tumor; chemotherapy; side effect; toxicity; pediatric

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