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1.  Twenty-Five Year Follow-Up of Childhood Wilms Tumor: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2011;57(7):1210-1216.
Background
Treatment cures over 90% of children with Wilms tumor (WT) who subsequently risk late morbidity and mortality. This study describes the 25-year outcomes of 5-year Wilms tumor survivors in the Childhood Cancer Survivor Study (CCSS).
Procedure
The CCSS, a multi-institutional retrospective cohort study, assessed Wilms tumor survivors (n=1256), diagnosed 1970 – 1986, for chronic health conditions, health status, health care utilization, socioeconomic status, subsequent malignant neoplasms (SMNs), and mortality compared to the US population and a sibling cohort (n=4023).
Results
The cumulative incidence of all and severe chronic health conditions was 65.4% and 24.2% at 25 years. Hazard Ratios [HR] were 2.0, 95% Confidence Interval [CI], 1.8-2.3 for grades 1 -4 and 4.7, 95% CI, 3.6-6.1 for grade 3-4, compared to sibling group. WT survivors reported more adverse general health status than the sibling group (Prevalence Ratio [PR] 1.7; 95% CI, 1.2–2.4), but mental health status, socioeconomic outcome, and health care utilization were similar. The cumulative incidence of SMN was 3.0% (95%CI, 1.9–4.0%) and of mortality was 6.1% (95%CI, 4.7-7.4%). Radiation exposure increased the likelihood of congestive heart failure (CHF) (no doxorubicin - HR 6.6; 95%CI, 1.6-28.3; doxorubicin ≤ 250 mg/m2 - HR 13.0; 95%CI, 1.9-89.7; doxorubicin > 250 mg/m2 - HR 18.3; 95%CI, 3.8-88.2), SMN (Standardized Incidence Ratio [SIR] 9.0; 95%CI, 3.9-17.7 with and 4.9; 95%CI, 1.8-10.6 without doxorubicin) and death.
Conclusion
Long-term survivors of WT treated from 1970 to 1986 are at increased risk of treatment related morbidity and mortality 25 years from diagnosis.
doi:10.1002/pbc.23090
PMCID: PMC4634648  PMID: 21384541
Wilms Tumor; late effects; survivorship
2.  Community-driven research on environmental sources of H. pylori infection in arctic Canada 
Gut Microbes  2014;5(5):606-617.
The role of environmental reservoirs in H. pylori transmission remains uncertain due to technical difficulties in detecting living organisms in sources outside the stomach. Residents of some Canadian Arctic communities worry that contamination of the natural environment is responsible for the high prevalence of H. pylori infection in the region. This analysis aims to estimate associations between exposure to potential environmental sources of biological contamination and prevalence of H. pylori infection in Arctic Canada.
Using data from 3 community-driven H. pylori projects in the Northwest and Yukon Territories, we estimated effects of environmental exposures on H. pylori prevalence, using odds ratios (OR) and 95% confidence intervals (CI) from multilevel logistic regression models to adjust for household and community effects. Investigated exposures include: untreated drinking water; livestock; dogs; cats; mice or mouse droppings in the home; cleaning fish or game.
Our analysis did not identify environmental exposures associated clearly with increased H. pylori prevalence, except any exposure to mice or mouse droppings (OR = 4.6, CI = 1.2–18), reported by 11% of participants. Our multilevel models showed H. pylori clustering within households, but environmental exposures accounted for little of this clustering; instead, much of it was accounted for by household composition (especially: having infected household members; number of children).
Like the scientific literature on this topic, our results do not clearly implicate or rule out environmental reservoirs of H. pylori; thus, the topic remains a priority for future research. Meanwhile, H. pylori prevention research should seek strategies for reducing direct transmission from person to person.
doi:10.4161/19490976.2014.969639
PMCID: PMC4615287  PMID: 25483330
Arctic; Canada; environmental exposures; epidemiology; Helicobacter pylori;  transmission
3.  Understanding HPV Vaccine Uptake Among Cambodian American Girls 
Journal of community health  2014;39(5):857-862.
Cervical cancer incidence rates vary substantially among racial/ethnic groups in the United States (US) with women of Southeast Asian descent having the highest rates. Up to 70% of cervical cancers could be prevented by widespread use of the human papillomavirus (HPV) vaccine. However, there is a lack of information about HPV vaccine uptake among Southeast Asian girls in the US. We conducted a telephone survey of Cambodian women with daughters who were age-eligible for HPV vaccination. Survey items addressed HPV vaccination barriers, facilitators, and uptake. Our study group included 86 Cambodian mothers who lived in the Seattle metropolitan area. The proportions of survey participants who reported their daughter had initiated and completed the HPV vaccine series were only 29% and 14%, respectively. Higher levels of vaccine uptake were significantly associated with mothers having heard about the HPV vaccine from a health professional and having received a recent Pap test. Commonly cited barriers to HPV vaccination included lack of knowledge about the HPV vaccine, not having received a physician recommendation for HPV vaccination, and thinking the HPV vaccine is unnecessary in the absence of health problems. Linguistically and culturally appropriate HPV educational programs should be developed and implemented in Cambodian American communities. These programs should aim to enhance understanding of disease prevention measures, increase knowledge about the HPV vaccine, and empower women to ask their daughters’ doctors for HPV vaccination.
doi:10.1007/s10900-014-9844-8
PMCID: PMC4134757  PMID: 24532309
Cambodian American; HPV; Vaccination
4.  Resistance-Associated NS5A Variants of Hepatitis C Virus Are Susceptible to Interferon-Based Therapy 
PLoS ONE  2015;10(9):e0138060.
Background & Aims
The presence of resistance-associated variants (RAVs) of hepatitis C virus (HCV) attenuates the efficacy of direct acting antivirals (DAAs). The objective of this study was to characterize the susceptibility of RAVs to interferon-based therapy.
Methods
Direct and deep sequencing were performed to detect Y93H RAV in the NS5A region. Twenty nine genotype 1b patients with detectable RAV at baseline were treated by a combination of simeprevir, pegylated interferon and ribavirin. The longitudinal changes in the proportion of Y93H RAV during therapy and at breakthrough or relapse were determined.
Results
By direct sequencing, Y93H RAV became undetectable or decreased in proportion at an early time point during therapy (within 7 days) in 57% of patients with both the Y93H variant and wild type virus at baseline when HCV RNA was still detectable. By deep sequencing, the proportion of Y93H RAV against Y93 wild type was 52.7% (5.8%– 97.4%) at baseline which significantly decreased to 29.7% (0.16%- 98.3%) within 7 days of initiation of treatment (p = 0.023). The proportion of Y93H RAV was reduced in 21 of 29 cases (72.4%) and a marked reduction of more than 10% was observed in 14 cases (48.7%). HCV RNA reduction was significantly greater for Y93H RAV (-3.65±1.3 logIU/mL/day) than the Y93 wild type (-3.35±1.0 logIU/mL/day) (p<0.001).
Conclusion
Y93H RAV is more susceptible to interferon-based therapy than the Y93 wild type.
doi:10.1371/journal.pone.0138060
PMCID: PMC4569333  PMID: 26368554
5.  Genetic Polymorphisms of IL28B and PNPLA3 Are Predictive for HCV Related Rapid Fibrosis Progression and Identify Patients Who Require Urgent Antiviral Treatment with New Regimens 
PLoS ONE  2015;10(9):e0137351.
The assessment of individual risk of fibrosis progression in patients with chronic hepatitis C is an unmet clinical need. Recent genome-wide association studies have highlighted several genetic alterations as predictive risk factors of rapid fibrosis progression in chronic hepatitis C. However, most of these results require verification, and whether the combined use of these genetic predictors can assess the risk of fibrosis progression remains unclear. Therefore, genetic risk factors associated with fibrosis progression were analyzed in 176 chronic hepatitis C patients who did not achieve sustained virological response by interferon-based therapy and linked to the fibrosis progression rate (FPR). FPR was determined in all patients by paired liver biopsy performed before and after therapy (mean interval: 6.2 years). Mean FPR in patients with IL28B (rs8099917) TG/GG and PNPLA3 (rs738409) CG/GG were significantly higher than in those with IL28B TT (FPR: 0.144 vs. 0.034, P < 0.001) and PNPLA3 CC (FPR: 0.10 vs. 0.018, P = 0.005), respectively. IL28B TG/GG [hazard ratio (HR): 3.9, P = 0.001] and PNPLA3 CG/GG (HR: 3.1, P = 0.04) remained independent predictors of rapid fibrosis progression upon multivariate analysis together with average alanine aminotransferase after interferon therapy ≥40 IU/l (HR: 4.2, P = 0.002). Based on these data, we developed a new clinical score predicting the risk of fibrosis progression (FPR-score). The FPR-score identified subgroups of patients with a low (FPR: 0.005), intermediate (FPR: 0.103, P < 0.001), and high (FPR: 0.197, P < 0.001) risk of fibrosis progression. In conclusion, IL28B and PNPLA3 genotypes are associated with rapid fibrosis progression, and the FPR-score identifies patients who has a high risk of fibrosis progression and require urgent antiviral treatment.
doi:10.1371/journal.pone.0137351
PMCID: PMC4564246  PMID: 26352693
6.  Non-cancer Related Mortality Risks in Adult Survivors of Pediatric Malignancies: The Childhood Cancer Survivor Study 
Purpose
We sought to identify factors, other than cancer-related treatment and presence/severity of chronic health conditions, which may be associated with late mortality risk among adult survivors of pediatric malignancies.
Methods
Using the Childhood Cancer Survivor Study cohort and a case-control design, 445 participants who died from causes other than cancer recurrence/progression or non-health related events were compared with 7162 surviving participants matched for primary diagnosis, age at baseline questionnaire, time from diagnosis to baseline questionnaire, and time at-risk. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for overall/cause-specific mortality. Independent measures included number/severity of chronic conditions, medical care, health-related behaviors, and health perceptions/concerns.
Results
Adjusting for education, income, chemotherapy/radiation exposures, and number/severity of chronic health conditions, an increased risk for all-cause mortality was associated with exercising fewer than 3 days/week (OR=1.72, CI:1.27 – 2.34), being underweight (OR=2.58, CI:1.55 – 4.28), increased medical-care utilization (p<0.001), and self-reported fair to poor health (p<0.001). Physical activity was associated with a higher risk of death among males (OR=3.26, CI: 1.90 – 5.61) reporting no exercise compared to those who exercised ≥3 times per week. Ever consuming alcohol was associated with a reduced risk of all-cause (OR=0.61, CI: 0.41–0.89) and other non-external causes of death (OR=0.40, CI: 0.20–0.79). Concerns/worries about future health (OR=1.54, CI: 1.10–2.71) were associated with increased all-cause mortality.
Conclusions
Factors independent of cancer treatment and chronic health conditions modify the risk of death among adult survivors of pediatric cancer.
Implications for Cancer Survivors
Continued cohort observation may inform interventions to reduce mortality.
doi:10.1007/s11764-014-0353-7
PMCID: PMC4127349  PMID: 24719269
mortality risk; childhood cancer; surveillance; cancer survivorship
7.  The Sedentary Time and Activity Reporting Questionnaire (STAR-Q): Reliability and Validity Against Doubly Labeled Water and 7-Day Activity Diaries 
American Journal of Epidemiology  2014;180(4):424-435.
We determined measurement properties of the Sedentary Time and Activity Reporting Questionnaire (STAR-Q), which was designed to estimate past-month activity energy expenditure (AEE). STAR-Q validity and reliability were assessed in 102 adults in Alberta, Canada (2009–2011), who completed 14-day doubly labeled water (DLW) protocols, 7-day activity diaries on day 15, and the STAR-Q on day 14 and again at 3 and 6 months. Three-month reliability was substantial for total energy expenditure (TEE) and AEE (intraclass correlation coefficients of 0.84 and 0.73, respectively), while 6-month reliability was moderate. STAR-Q-derived TEE and AEE were moderately correlated with DLW estimates (Spearman's ρs of 0.53 and 0.40, respectively; P < 0.001), and on average, the STAR-Q overestimated TEE and AEE (median differences were 367 kcal/day and 293 kcal/day, respectively). Body mass index-, age-, sex-, and season-adjusted concordance correlation coefficients (CCCs) were 0.24 (95% confidence interval (CI): 0.07, 0.36) and 0.21 (95% CI: 0.11, 0.32) for STAR-Q-derived versus DLW-derived TEE and AEE, respectively. Agreement between the diaries and STAR-Q (metabolic equivalent-hours/day) was strongest for occupational sedentary time (adjusted CCC = 0.76, 95% CI: 0.64, 0.85) and overall strenuous activity (adjusted CCC = 0.64, 95% CI: 0.49, 0.76). The STAR-Q demonstrated substantial validity for estimating occupational sedentary time and strenuous activity and fair validity for ranking individuals by AEE.
doi:10.1093/aje/kwu150
PMCID: PMC4128771  PMID: 25038920
motor activity; physical activity; reproducibility of results; sedentary lifestyle; questionnaires; validation studies
8.  Estimating the risk for late effects of therapy in children newly diagnosed with standard risk acute lymphoblastic leukemia using an historical cohort: A report from the Childhood Cancer Survivor Study 
The Lancet. Oncology  2014;15(8):841-851.
Summary
Background
Pediatric acute lymphoblastic leukemia (ALL) therapy has evolved such that the risk for late effects in ALL survivors treated on contemporary protocols is likely different from that observed in survivors treated in prior eras. We estimated the risk for late effects in children with standard-risk ALL treated in the current era using data from similarly treated members of the Childhood Cancer Survivor Study (CCSS) cohort.
Methods
The CCSS is a multi-centre North American study of five-year survivors of childhood cancer diagnosed between 1970 and1986. Cohort members were eligible for this analysis if they were aged 1·0–9·9 years at the time of ALL diagnosis and received therapy consistent with contemporary standard-risk ALL protocols. Outcomes were compared to a sibling cohort (n=2788) and the general United States population.
Findings
556/5980 cohort members treated for ALL met the inclusion criteria. After a median follow up of 18·4 years (range 0·0–33·0) from cohort entry, 28/556 (5%) had died (standardized mortality ratio, 3·5; 95% CI, 2·3–5·0). Sixteen deaths were due to causes other than ALL recurrence. Among 556 survivors, six (1%) developed a subsequent malignant neoplasm (standardized incidence ratio, 2·6; 95% CI, 1·0–5·7). 107 subjects in each group would need to be followed for one year in order to observe one extra chronic health condition in the ALL group compared to the sibling group (95% CI, 81–193). 415 subjects in each group would need to be followed for one year to observe one extra severe, life-threatening or fatal condition in the ALL group (95% CI, 376–939) Survivors did not differ from siblings in their educational attainment, rate of marriage or independent living.
Interpretation
Overall, the expected prevalence of adverse long-term outcomes among children treated for standard risk ALL on contemporary protocols is low, but regular care from a knowledgeable primary care practitioner is warranted.
Funding
National Cancer Institute, Cancer Center Support, American Lebanese-Syrian Associated Charities, Cancer Research Switzerland.
doi:10.1016/S1470-2045(14)70265-7
PMCID: PMC4142216  PMID: 24954778
9.  Evaluating the Auto-MODS Assay, a Novel Tool for Tuberculosis Diagnosis for Use in Resource-Limited Settings 
Journal of Clinical Microbiology  2014;53(1):172-178.
There is an urgent need for simple, rapid, and affordable diagnostic tests for tuberculosis (TB) to combat the great burden of the disease in developing countries. The microscopic observation drug susceptibility assay (MODS) is a promising tool to fill this need, but it is not widely used due to concerns regarding its biosafety and efficiency. This study evaluated the automated MODS (Auto-MODS), which operates on principles similar to those of MODS but with several key modifications, making it an appealing alternative to MODS in resource-limited settings. In the operational setting of Chiang Rai, Thailand, we compared the performance of Auto-MODS with the gold standard liquid culture method in Thailand, mycobacterial growth indicator tube (MGIT) 960 plus the SD Bioline TB Ag MPT64 test, in terms of accuracy and efficiency in differentiating TB and non-TB samples as well as distinguishing TB and multidrug-resistant (MDR) TB samples. Sputum samples from clinically diagnosed TB and non-TB subjects across 17 hospitals in Chiang Rai were consecutively collected from May 2011 to September 2012. A total of 360 samples were available for evaluation, of which 221 (61.4%) were positive and 139 (38.6%) were negative for mycobacterial cultures according to MGIT 960. Of the 221 true-positive samples, Auto-MODS identified 212 as positive and 9 as negative (sensitivity, 95.9%; 95% confidence interval [CI], 92.4% to 98.1%). Of the 139 true-negative samples, Auto-MODS identified 135 as negative and 4 as positive (specificity, 97.1%; 95% CI, 92.8% to 99.2%). The median time to culture positivity was 10 days, with an interquartile range of 8 to 13 days for Auto-MODS. Auto-MODS is an effective and cost-sensitive alternative diagnostic tool for TB diagnosis in resource-limited settings.
doi:10.1128/JCM.01946-14
PMCID: PMC4290917  PMID: 25378569
10.  Correction: Improving Google Flu Trends Estimates for the United States through Transformation 
PLoS ONE  2015;10(4):e0122939.
doi:10.1371/journal.pone.0122939
PMCID: PMC4405189  PMID: 25897857
11.  Dermcidin expression is associated with disease progression and survival among breast cancer patients 
Improved diagnostic screening has led to earlier detection of many tumors, but screening may still miss many aggressive tumor types. Proteomic and genomic profiling studies of breast cancer samples have identified tumor markers that may help improve screening for more aggressive, rapidly growing breast cancers. To identify potential blood-based biomarkers for the early detection of breast cancer, we assayed serum samples via matrix-assisted laser desorption ionization–time of flight mass spectrometry from a rat model of mammary carcinogenesis. We found elevated levels of a fragment of the protein dermcidin (DCD) to be associated with early progression of N-methylnitrosourea-induced breast cancer, demonstrating significance at weeks 4 (p = 0.045) and 5 (p = 0.004), a time period during which mammary pathologies rapidly progress from ductal hyperplasia to adenocarcinoma. The highest serum concentrations were observed in rats bearing palpable mammary carcinomas. Increased DCD was also detected with immunoblotting methods in 102 serum samples taken from women just prior to breast cancer diagnosis. To validate these findings in a larger population, we applied a 32-gene in vitro DCD response signature to a dataset of 295 breast tumors and assessed correlation with intrinsic breast cancer subtypes and overall survival. The DCD-derived gene signature was significantly associated with subtype (p < 0.001) and poorer overall survival [HR (95 % CI) = 1.60 (1.01–2.51), p = 0.044]. In conclusion, these results present novel evidence that DCD levels may increase in early carcinogenesis, particularly among more aggressive forms of breast cancer.
doi:10.1007/s10549-014-2880-3
PMCID: PMC4403631  PMID: 24562771
Dermcidin; Breast cancer; Serum; Microenvironment
12.  Hyaluronan Synthase 3 Variant and Anthracycline-Related Cardiomyopathy: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2014;32(7):647-653.
Purpose
The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed.
Patients and Methods
By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease.
Results
By using a matched case-control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 × 10−7). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m2) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09).
Conclusion
Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) –induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.
doi:10.1200/JCO.2013.50.3557
PMCID: PMC3927733  PMID: 24470002
13.  Telomere Content and Risk of Second Malignant Neoplasm in Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
PURPOSE
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.
EXPERIMENTAL DESIGN
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1158/1078-0432.CCR-13-2076
PMCID: PMC3944671  PMID: 24277454
telomere; second malignant neoplasm; risk; childhood cancer
14.  Treatment variation in patients diagnosed with early stage breast cancer in Alberta from 2002 to 2010: a population-based study 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/s12913-015-0680-z
PMCID: PMC4308832  PMID: 25609420
Breast cancer; Population-based; Radiotherapy; Surgery
15.  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.
doi:10.1371/journal.pone.0109209
PMCID: PMC4281210  PMID: 25551391
17.  Study design and methods for the Breast Cancer and Exercise Trial in Alberta (BETA) 
BMC Cancer  2014;14:919.
Background
Exercise has favorable effects on biomarkers associated with a lower risk of breast cancer, however it is unclear if higher doses of exercise provide additional effects. No clinical trial has systematically examined how different exercise volumes influence the mechanisms underlying breast cancer etiology. The Breast Cancer and Exercise Trial in Alberta (BETA) - a follow-up study to the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial - is examining how a one-year, high versus moderate volume aerobic exercise intervention influences several biomechanisms hypothesized to influence breast cancer risk in a group of postmenopausal women. Secondary aims are to compare intervention effects on psychosocial and quality of life outcomes as well as understand exercise adherence at 12 and 24 months, and maintenance of all study outcomes at 24 months.
Methods/Design
The BETA Trial is a two-center, two-armed randomized controlled exercise intervention trial conducted in 400 previously inactive, postmenopausal women aged 50–74 years, in Alberta, Canada. Participants were randomly assigned to a one-year aerobic exercise intervention of either high volume (300 minutes/week) or moderate volume (150 minutes/week). Blood draws and accelerometry were performed at baseline, six and 12 months. Baseline and 12-month measurements were taken of adiposity (including dual energy X-ray absorptiometry and computed tomography scans), physical fitness, dietary intake, self-reported physical activity and sedentary behavior, quality of life, perceived stress, happiness, sleep, and determinants of exercise adherence. Exercise maintenance was assessed and all study measurements were repeated at 24 months. Blood will be analyzed for endogenous estrogens, insulin resistance indicators, and inflammatory markers.
Discussion
The BETA Trial will compare the impact of a high versus moderate volume of aerobic exercise on a variety of biological, physiological, and psychological outcomes of relevance to postmenopausal women. A tightly controlled exercise intervention and objective outcome measurements are methodological strengths. The BETA Trial will inform future prevention initiatives by assessing adherence to a high volume of exercise over 12 months by postmenopausal women, and the ability of these women to maintain activity over the longer-term. The ultimate objective is to inform public health guidelines for reducing breast cancer risk through physical activity.
Trial registration
Clinical Trials Registration Number: NCT01435005
doi:10.1186/1471-2407-14-919
PMCID: PMC4364325  PMID: 25480020
Breast cancer; Physical activity; Adiposity; Estrogens; Insulin resistance; Inflammation; Quality of life
18.  Modifiable Risk Factors and Major Cardiac Events Among Adult Survivors of Childhood Cancer 
Journal of Clinical Oncology  2013;31(29):3673-3680.
Purpose
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.
Results
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).
Conclusion
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.
doi:10.1200/JCO.2013.49.3205
PMCID: PMC3804290  PMID: 24002505
19.  Detection Bias and Overestimation of Bladder Cancer Risk in Type 2 Diabetes 
Diabetes Care  2013;36(10):3070-3075.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc13-0045
PMCID: PMC3781560  PMID: 23990517
20.  Predictors of adherence to different types and doses of supervised exercise during breast cancer chemotherapy 
Background
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.
Methods
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.
Results
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.
Conclusions
Determinants of exercise adherence in breast cancer patients receiving chemotherapy are multidisciplinary and may vary by the exercise prescription.
doi:10.1186/s12966-014-0085-0
PMCID: PMC4110703  PMID: 24997476
Adherence; Cancer treatment; Cancer survivors; Determinants; Physical activity
21.  Adaptation of an evidence-based intervention to promote colorectal cancer screening: a quasi-experimental study 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1186/1748-5908-9-85
PMCID: PMC4226971  PMID: 24989083
Adaptation; Implementation; Evidence-based intervention
22.  EVALUATION OF A HEPATITIS B LAY HEALTH WORKER INTERVENTION FOR CAMBODIAN AMERICANS 
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.
doi:10.1007/s10900-012-9649-6
PMCID: PMC3633619  PMID: 23299978
Cambodian Americans; Hepatitis B Infection; Lay Health Workers
23.  Community Health Worker Hepatitis B Education for Cambodian American Men and Women 
Background
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.
Methods
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.
Results
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.
Discussion
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
24.  Continuity of Care and Colorectal Cancer Screening by Vietnamese American Patients 
Background
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.
Methods
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.
Results
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.
Conclusions
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
25.  A Cross-border Comparison of Hepatitis B Testing Among Chinese Residing in Canada and the United States 
Background
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.
Purpose
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.
Methods
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.
Results
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.
Discussion
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

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