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1.  Association Between Regular Aspirin Use and Circulating Markers of Inflammation: A Study Within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial 
Regular aspirin use may decrease cancer risk by reducing chronic inflammation. However, associations between aspirin use and circulating markers of inflammation have not been well-studied.
Serum levels of 78 inflammatory markers were measured in 1,819 55-74 year-old men and women in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Data were combined from 3 completed case-control studies and re-weighted to the PLCO screening arm. Self-reported aspirin and ibuprofen use (number of tablets taken per day/week/month) over the previous 12 months was collected at baseline. Associations between i) non-regular (<4 tablets/month), ii) low (1-4 tablets/week), iii) moderate (1 tablet/day) or iv) high (2+ tablets/day) regular aspirin or ibuprofen use and marker levels were assessed with weighted logistic regression.
Aspirin use was nominally associated with (ptrend across categories≤0.05) decreased levels of chemokine C-C motif ligand 15 (CCL15) (OR 0.5; 95%CI: 0.3-0.8; moderate versus non-regular use); soluble vascular endothelial growth factor receptor 2 (sVEGFR2) (OR 0.7; 95%CI: 0.4-1.0); soluble tumor necrosis factor receptor 1 (sTNFR1) (OR 0.6; 95%CI: 0.4-0.9) and increased levels of CCL13 (OR 1.3; 95%CI: 0.8-2.1); CCL17 (OR 1.1; 95%CI: 0.7-1.9) and interleukin 4 (IL-4) (OR 1.6; 95%CI: 0.9-2.8). Trends were not statistically significant following correction for multiple comparisons. Likewise, no statistically significant associations were observed between ibuprofen use and marker levels.
No significant associations were observed between regular aspirin use and the inflammatory markers assessed. Impact: Additional studies are needed to better understand the relationship between aspirin use, chronic inflammation and cancer risk.
PMCID: PMC4417370  PMID: 25713025
3.  Age-Stratified 5-Year Risks of Cervical Precancer among Women with Enrollment and Newly Detected HPV Infection 
It is unclear whether a woman's age influences her risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) upon detection of HPV. A large change in risk as women age would influence vaccination and screening policies. Among 972,029 women age 30-64 undergoing screening with Pap and HPV testing (Hybrid Capture 2, Qiagen, Germantown, MD, USA) at Kaiser Permanente Northern California (KPNC), we calculated age-specific 5-year CIN3+ risks among women with HPV infections detected at enrollment, and among women with “newly detected” HPV infections at their second screening visit. 57,899 women (6.0%) had an enrollment HPV infection. Among the women testing HPV negative at enrollment with a second screening visit, 16,724 (3.3%) had a newly detected HPV infection at their second visit. Both enrollment and newly detected HPV rates declined with age (p<.001). Women with enrollment vs. newly detected HPV infection had higher 5-year CIN3+ risks: 8.5% vs. 3.9%, (p<.0001). Risks did not increase with age but declined slightly from 30-34 years to 60-64 years: 9.4% vs. 7.4% (p=0.017) for enrollment HPV and 5.1% vs. 3.5% (p=0.014) for newly detected HPV. Among women age 30-64 in an established screening program, women with newly detected HPV infections were at lower risk than women with enrollment infections, suggesting reduced benefit vaccinating women at older ages. Although the rates of HPV infection declined dramatically with age, the subsequent CIN3+ risks associated with HPV infection declined only slightly. The CIN3+ risks among older women are sufficiently elevated to warrant continued screening through age 65.
PMCID: PMC4314342  PMID: 25136967
Human Papillomavirus (HPV); cancer prevention; cytology; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); age
5.  Body mass index, physical activity, and serum markers of inflammation, immunity, and insulin resistance 
Epidemiologic studies examining circulating levels of inflammatory markers in relation to obesity and physical inactivity may aid in our understanding of the role of inflammation in obesity-related cancers. However, previous studies on this topic have focused on a limited set of markers.
We evaluated associations between body mass index (BMI) and vigorous physical activity level, based on self-report, and serum levels of 78 inflammation-related markers. Markers were measured using a bead-based multiplex method among 1,703 men and women, ages 55–74 years and with no prior history of cancer at blood draw, selected for case-control studies nested within the Prostate, Lung, Ovarian, and Colorectal Cancer Screening Trial. Analyses were adjusted for age, sex, smoking, case-control study, physical activity, and BMI.
Twelve markers were positively associated with BMI after False Discovery Rate (FDR) correction. Odds ratios (ORs) and 95% confidence interval (CIs) for highest versus lowest levels of CCL2/MCP-1, CXCL5/ENA-78, sTNFR-II, CXCL10/IP-10, CXCL6/GCP2, CCL13/MCP-4, amylin, CRP, C-peptide, CCL19/MIP-3b, insulin, and leptin were 1.50 (1.14–1.98), 1.52 (1.12–2.05), 1.61 (1.17–2.20), 1.69 (1.25–2.28), 1.74 (1.24–2.44), 1.75 (1.22–2.50), 1.91 (1.31–2.78), 2.41 (1.36–4.25), 2.78 (1.83–4.24), 3.30 (2.28–4.78), 4.05 (2.51–6.55), 50.03 (19.87–125.99) per 5-kg/m2, respectively. Only CXCL12/SDF-1a was associated with physical activity (≥3 versus <1 hours/week; OR=3.28, 95% CI: 1.55–6.94) after FDR correction.
BMI was associated with a wide range of circulating markers involved in the inflammatory response.
This cross-sectional analysis identified serum markers could be considered in future studies aimed at understanding the underlying mechanisms linking inflammation with obesity and obesity-related cancers.
PMCID: PMC4257882  PMID: 25249326
6.  Cigarette Smoking and Variations in Systemic Immune and Inflammation Markers 
A comprehensive characterization of the effects of cigarette smoke on systemic soluble immune/inflammatory markers may provide insight into the mechanisms through which smoking causes disease.
Levels of 78 inflammation, immune, and metabolic markers were measured using multiplex immune assays in 1819 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) participants aged 55 to 74 years from three existing nested case-control studies. These data were made representative of the entire PLCO screening arm through reweighting with weights estimated in logistic regression models. We assessed associations between smoking status, cigarettes smoked per day, and time since quitting with dichotomized marker levels using adjusted weighted logistic regression models.
Current smoking was associated with 10 inflammation markers after correcting for multiple testing, encompassing several components of the immune/inflammation response. Levels of seven of these markers (interleukin [IL]-15, IL-1RA, IL-1β, IL-16, stem cell factor, soluble interleukin 6 receptor, and soluble vascular endothelial growth factor receptor 3) were lower among current smokers (n = 414) when compared with never smokers (n = 548), with odds ratios (ORs) ranging from 0.44 to 0.27, while levels of CC motif ligand (CCL)/thymus and activation regulated chemokine (CCL17/TARC) (OR = 4.08, 95% confidence interval [CI] = 2.01 to 8.25), CCL11/EOTAXIN (OR = 2.57, 95% CI = 1.45 to 4.55), and C-reactive protein (CRP) (OR = 2.54, 95% CI = 1.29 to 4.98) were elevated. These markers were not associated with cigarettes per day among current smokers, but there were trends in IL-15, IL-1RA, IL-1β, CCL17/TARC, CCL11/EOTAXIN, and CRP levels across categories of years since quitting smoking.
Smoking is associated with a broad range of alterations in systemic immune and inflammation marker levels among older, long-term smokers. Smoking cessation may result in marker levels reverting back to those of never smokers over time.
PMCID: PMC4200029  PMID: 25274579
Cancer research  2014;74(19):5553-5560.
Some retrospective studies suggest an association between infection with GB-virus C (GBV-C) and non-Hodgkin lymphoma (NHL). We evaluated this association prospectively in a nested case-control study within the U.S. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Cases (N=658) and controls (N=1,316) were individually-matched by age, sex, race/ethnicity, timing of study entry and sample selection. Pre-diagnostic PLCO serum samples were tested for GBV-C RNA (as a measure of active infection) and E2 antibody (active or resolved infection). Logistic regression was used to estimate odds ratios (ORs) for the association between GBV-C and NHL overall and NHL subtypes. Twelve cases (1.8%) and 7 controls (0.5%) were GBV-C RNA positive. GBV-C RNA positivity was associated with NHL overall (OR=3.43, 95% CI=1.35-8.71) and, based on small numbers, diffuse large B-cell lymphoma (OR=5.31, 95% CI=1.54-18.36). The association with NHL persisted when the interval between testing and selection was greater than 4 years (OR=6.00, 95% CI= 1.21-29.73). In contrast, E2 antibody-positivity was not associated with NHL risk (OR=1.08, 95% CI=0.74-1.58). Our study demonstrates that GBV-C infection precedes development of NHL. GBV-C infection may play an etiologic role in a small proportion of NHL cases, perhaps by causing chronic immune stimulation or impaired immunosurveillance.
PMCID: PMC4184918  PMID: 25115299
8.  Tumor-based case-control studies of infection and cancer: muddling the when and where of molecular epidemiology 
We describe the “tumor-based case-control” study as a type of epidemiologic study used to evaluate associations between infectious agents and cancer. These studies assess exposure using diseased tissues from affected individuals (i.e., evaluating tumor tissue in studying cancer cases), but they must utilize non-diseased tissues to assess control subjects, who do not have the disease of interest. This approach can lead to exposure misclassification in two ways. First, concerning the “when” of exposure assessment, retrospective assessment of tissues may not accurately measure exposure at the key earlier timepoint (i.e., during the etiologic window). Second, concerning the “where” of exposure assessment, use of different tissues in cases and controls can have different accuracy for detecting the exposure (i.e., differential exposure misclassification). We present an example concerning the association of human papillomavirus with various cancers, where tumor-based case-control studies likely overestimate risk associated with infection. In another example, we illustrate how tumor-based case-control studies of Helicobacter pylori and gastric cancer underestimate risk. Tumor-based case-control studies can demonstrate infection within tumor cells, providing qualitative information regarding disease etiology. However, measures of association calculated in tumor-based case-control studies are prone to over- or under-estimating the relationship between infections and subsequent cancer risk.
PMCID: PMC4184938  PMID: 25063520
infections; cancer etiology; study design; methodology
9.  Reassurance Against Future Risk of Precancer and Cancer Conferred by a Negative Human Papillomavirus Test 
Primary human papillomavirus (HPV) testing (without concurrent Pap tests) every 3 years is under consideration in the United States as an alternative to the two recommended cervical cancer screening strategies: primary Pap testing every 3 years, or concurrent Pap and HPV testing (“cotesting”) every 5 years. Using logistic regression and Weibull survival models, we estimated and compared risks of cancer and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) for the three strategies among 1011092 women aged 30 to 64 years testing HPV-negative and/or Pap-negative in routine screening at Kaiser Permanente Northern California since 2003. All statistical tests were two sided. Three-year risks following an HPV-negative result were lower than 3-year risks following a Pap-negative result (CIN3+ = 0.069% vs 0.19%, P < .0001; Cancer = 0.011% vs 0.020%, P < .0001) and 5-year risks following an HPV-negative/Pap-negative cotest (CIN3+ = 0.069% vs 0.11%, P < .0001; Cancer = 0.011% vs 0.014%, P = .21). These findings suggest that primary HPV testing merits consideration as another alternative for cervical screening.
PMCID: PMC4111283  PMID: 25038467
11.  Circulating Inflammation Markers and Prospective Risk for Lung Cancer 
Despite growing recognition of an etiologic role for inflammation in lung carcinogenesis, few prospective epidemiologic studies have comprehensively investigated the association of circulating inflammation markers with lung cancer.
We conducted a nested case–control study (n = 526 lung cancer patients and n = 592 control subjects) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Control subjects were matched to lung cancer case patients on age, sex, follow-up time (median = 2.9 years), randomization year, and smoking (pack-years and time since quitting). Serum levels of 77 inflammation markers were measured using a Luminex bead-based assay. Conditional logistic regression and weighted Cox models were used to estimate odds ratios (ORs) and cumulative risks, respectively.
Of 68 evaluable markers, 11 were statistically significantly associated with lung cancer risk (P trend across marker categories < .05), including acute-phase proteins (C-reactive protein [CRP], serum amyloid A [SAA]), proinflammatory cytokines (soluble tumor necrosis factor receptor 2 [sTNFRII]), anti-inflammatory cytokines (interleukin 1 receptor antagonist [IL-1RA]), lymphoid differentiation cytokines (interleukin 7 [IL-7]), growth factors (transforming growth factor alpha [TGF-A]), and chemokines (epithelial neutrophil-activating peptide 78 [ENA 78/CXCL5], monokine induced by gamma interferon [MIG/CXCL9], B cell–attracting chemokine 1 [BCA-1/CXCL13], thymus activation regulated chemokine [TARC/CCL17], macrophage-derived chemokine [MDC/CCL22]). Elevated marker levels were associated with increased lung cancer risk, with odds ratios comparing the highest vs the lowest group ranging from 1.47 (IL-7) to 2.27 (CRP). For IL-1RA, elevated levels were associated with decreased lung cancer risk (OR = 0.71; 95% confidence interval = 0.51 to 1.00). Associations did not differ by smoking, lung cancer histology, or latency. A cross-validated inflammation score using four independent markers (CRP, BCA-1/CXCL13, MDC/CCL22, and IL-1RA) provided good separation in 10-year lung cancer cumulative risks among former smokers (quartile [Q] 1 = 1.1% vs Q4 = 3.1%) and current smokers (Q1 = 2.3% vs Q4 = 7.9%) even after adjustment for smoking.
Some circulating inflammation marker levels are associated with prospective lung cancer risk.
PMCID: PMC3888091  PMID: 24249745
12.  Prevalence of and Risk Factors for Oral Human Papillomavirus Among Young Women in Costa Rica 
The Journal of Infectious Diseases  2013;208(10):1643-1652.
Background. Little is known about the epidemiology of oral human papillomavirus (HPV) in Latin America.
Methods. Women (N = 5838) aged 22–29 in the control and vaccine arms of an HPV-16/18 vaccine trial in Costa Rica had oral, cervical, and anal specimens collected. Samples were tested for alpha mucosal HPV types (SPF10/LiPA25 version 1); a subset of oral samples (n = 500) was tested for cutaneous HPV types in the genera alpha, beta, gamma, mu, and nu.
Results. In the control arm (n = 2926), 1.9% of women had an oral alpha mucosal HPV detected, 1.3% had carcinogenic HPV, and 0.4% had HPV-16; similar patterns for non-16/18 HPV types were observed in the vaccine arm. Independent risk factors for any oral alpha mucosal HPV among women in the control arm included marital status (adjusted odds ratio [AOR], 3.2; 95% confidence interval [CI], 1.8–5.7 for single compared to married/living as married), number of sexual partners (AOR, 2.4; 95% CI, 1.0–6.1 for ≥4 partners compared to 0–1 partners), chronic sinusitis (AOR, 3.1; 95% CI, 1.5–6.7), and cervical HPV infection (AOR, 2.6; 95% CI, 1.4–4.6). Detection of beta HPV was common (18.6%) and not associated with sexual activity.
Conclusions. Unlike cutaneous HPV types, alpha mucosal HPV types were uncommon in the oral region and were predominately associated with sexual behavior.
Clinical Trials Registration. NCT00128661.
PMCID: PMC3805238  PMID: 24014882
human papillomavirus vaccine; HPV; oropharynx cancer; Costa Rica; Guanacaste; oral HPV DNA
13.  A migrant study of pubertal timing and tempo in British-Bangladeshi girls at varying risk for breast cancer 
Earlier menarche is related to subsequent breast cancer risk, yet international differences in the age and tempo of other pubertal milestones and their relationships with body mass index (BMI) are not firmly established in populations at differing risk for breast cancer. We compared age and tempo of adrenarche, thelarche, pubarche, and menarche in a migrant study of Bangladeshi girls to the United Kingdom (UK) and assessed whether differences by migration were explained by differences in BMI.
Included were groups of Bangladeshi (n =168), British-Bangladeshi (n =174) and white British (n =54) girls, aged 5 to 16 years. Interviewer-administered questionnaires obtained pubertal staging; height and weight were measured. Salivary dehydroepiandrosterone-sulfate concentrations >400 pg/ml defined adrenarche. Median ages of pubertal milestones and hazard ratios (HR) with 95% confidence intervals (CI) were estimated from Weibull survival models.
In all three groups, adrenarche occurred earliest, followed by thelarche, pubarche, and finally menarche. Neither median age at adrenarche (Bangladeshi = 7.2, British-Bangladeshi = 7.4, white British = 7.1; P-trend = 0.70) nor at menarche (Bangladeshi = 12.5, British-Bangladeshi = 12.1, white British = 12.6; P-trend = 0.70) differed across groups. In contrast, median age at thelarche (Bangladeshi = 10.7, British-Bangladeshi = 9.6, white British = 8.7; P-trend <0.01) occurred earlier among girls living in the UK. Compared with Bangladeshi girls, HRs (95% CI) for earlier thelarche were 1.6 (1.1 to 2.4) for British-Bangladeshi girls and 2.6 (1.5 to 4.4) for white British girls (P-trend <0.01), but were attenuated after adjustment for BMI (British-Bangladeshi = 1.1 (0.7 to 1.8), white British = 1.7(1.0 to 3.1); P-trend =0.20).
Thelarche occurred earlier, but puberty progressed slower with increasing exposure to the UK environment; differences were partially explained by greater BMI. The growth environment might account for much of the ethnic differences in pubertal development observed across and within countries.
PMCID: PMC4303203  PMID: 25398700
Long-term breast cancer trends in incidence in the United States (US) show rising ER positive rates and falling ER negative rates. We hypothesized that these divergent trends reflect etiologic heterogeneity and that comparable trends should be observed in other countries with similar risk factor profiles. We, therefore, analyzed invasive female breast cancers in Denmark, a country with similar risk factors as the US. We summarized the overall trend in age-standardized rates with the estimated annual percentage change (EAPC) statistic (1993–2010) and used age-period-cohort models to estimate age-specific EAPCs, cohort rate ratios (CRRs), and projections for future time periods (2011–2018). In Denmark, the overall rate of ER positive cancers rose between 1993 and 2010 by 3·0%/year (95% CI: 2·8 to 3·3%/yr) while the overall rate of ER negative cancers fell by 2·1%/year (95% CI: −2·5 to −1·6%/yr). The ER positive rate increased fastest among postmenopausal women and the ER negative rate decreased fastest among premenopausal women, reflecting that cohorts born after 1944 were at relatively higher risk of ER positive tumors and lower risk of ER negative tumors. If current trends continue, ER positive cancers will increase at least 13% by 2018 in Denmark, ER negative cancers will fall 15% by 2018, and breast cancer overall will increase at least 7% by 2018. Divergent ER-specific trends are consistent with distinct etiologic pathways. If trends in known risk factors are responsible, the Danish and US experience may foreshadow a common pattern worldwide.
PMCID: PMC3749265  PMID: 23616071
Breast cancer; Estrogen receptor; Epidemiology; Age-period-cohort models
15.  Childhood Environment Influences Adrenarcheal Timing among First-Generation Bangladeshi Migrant Girls to the UK 
PLoS ONE  2014;9(10):e109200.
Adrenarche is a key early life event that marks middle childhood at approximately 7 years of age. Earlier work with British-Bangladeshi migrant women suggested that environmental conditions experienced before adrenarche influence adult reproductive function. We therefore investigated whether Bangladeshi children who migrate to the United Kingdom (UK) reach adrenarche earlier than non-migrants in Bangladesh or the United Kingdom.
Methods and Findings
Healthy girls, aged 5–16 years, were recruited from schools in Sylhet, Bangladesh and London, England comprising four groups: Sylhetis (n = 165), first-generation migrants to the United Kingdom (n = 42), second-generation girls (n = 162), and British girls of European origin (n = 50). Anthropometric measurements were collected together with questionnaire data for migration and socioeconomic characteristics. Saliva samples were assayed for dehydroepiandrosterone (DHEAS) using enzyme-linked immunosorbent assays. Multiple linear regressions tested for group differences in anthropometric and socioeconomic variables and DHEAS levels. Median ages at adrenarche (DHEAS>400 pg/ml) were estimated using Weibull regression models for parametric survival analysis. Hazard ratios for reaching adrenarche earlier and 95% confidence intervals (CI), both unadjusted and adjusted for anthropometric variables, were estimated from the survival analyses. First-generation migrants had a median age at adrenarche (5.3 years) that was significantly earlier than Sylheti (7.2), second-generation (7.4), and European (7.1) girls. In univariate analyses, first-generation girls reached adrenarche significantly earlier than Sylhetis [HR (CI): 2.8 (1.4–5.5]. In multivariate models, first generation girls still reached adrenarche earlier than Sylhetis after adjusting for height [HR(CI): 1.9 (0.9–4.1)] and weight [HR(CI):1.7 (0.8–3.8)], but these results were attenuated.
We suggest that rapid catch-up growth experienced by first generation girls during early childhood may explain their advanced adrenarche. The environmental conditions leading to an earlier adrenarche, as well as the health implications of this early transition, merit further exploration.
PMCID: PMC4195659  PMID: 25309977
16.  Cross-protective vaccine efficacy of the bivalent HPV vaccine against HPV31 is associated with humoral immune responses 
Human Vaccines & Immunotherapeutics  2013;9(7):1399-1406.
Background: We investigated the role of antibody responses as potential mechanism for the cross-protective vaccine-efficacies (VE) observed from randomized clinical trials of the HPV16/18 bivalent vaccine.
Results: HPV31 cases had lower HPV16 antibody levels than controls (OR4th quartile compared with 1st quartile = 0.63; 95%CI: 0.36–1.08; p-trend = 0.03). HPV31 cases were also less likely to have detectable HPV31 neutralization, and HPV16 avidity than controls. No statistically significant differences by HPV18 antibody or HPV45 neutralization were observed among HPV45 cases and controls. Protection against HPV58 was not associated with any of the markers, confirming the specificity of our findings.
Methods: Samples are from three-dose HPV vaccine recipients from the Costa Rica HPV16/18 vaccine trial. Women with a new HPV31, HPV45, or HPV58 infections over four years of follow-up were compared with randomly selected control women—with no new infection with HPV31/45/58—with respect to HPV16 and HPV18 antibody, HPV31, HPV45, and HPV58 neutralization, and HPV16 avidity.
Conclusions: High HPV16 levels and avidity, and the ability to neutralize HPV31 were associated with protection against newly detected HPV31 infections, suggesting that the partial VE demonstrated for HPV31 is likely to be mediated at least in part through antibodies induced by HPV16/18 vaccination.
PMCID: PMC3974884  PMID: 23571174
HPV vaccine; humoral; immune response; cross-protection; mechanisms for protection
17.  Comparison of Algorithm-based Estimates of Occupational Diesel Exhaust Exposure to Those of Multiple Independent Raters in a Population-based Case–Control Study 
Annals of Occupational Hygiene  2012;57(4):470-481.
Algorithm-based exposure assessments based on patterns in questionnaire responses and professional judgment can readily apply transparent exposure decision rules to thousands of jobs quickly. However, we need to better understand how algorithms compare to a one-by-one job review by an exposure assessor. We compared algorithm-based estimates of diesel exhaust exposure to those of three independent raters within the New England Bladder Cancer Study, a population-based case–control study, and identified conditions under which disparities occurred in the assessments of the algorithm and the raters.
Occupational diesel exhaust exposure was assessed previously using an algorithm and a single rater for all 14 983 jobs reported by 2631 study participants during personal interviews conducted from 2001 to 2004. Two additional raters independently assessed a random subset of 324 jobs that were selected based on strata defined by the cross-tabulations of the algorithm and the first rater’s probability assessments for each job, oversampling their disagreements. The algorithm and each rater assessed the probability, intensity and frequency of occupational diesel exhaust exposure, as well as a confidence rating for each metric. Agreement among the raters, their aggregate rating (average of the three raters’ ratings) and the algorithm were evaluated using proportion of agreement, kappa and weighted kappa (κw). Agreement analyses on the subset used inverse probability weighting to extrapolate the subset to estimate agreement for all jobs. Classification and Regression Tree (CART) models were used to identify patterns in questionnaire responses that predicted disparities in exposure status (i.e., unexposed versus exposed) between the first rater and the algorithm-based estimates.
For the probability, intensity and frequency exposure metrics, moderate to moderately high agreement was observed among raters (κw = 0.50–0.76) and between the algorithm and the individual raters (κw = 0.58–0.81). For these metrics, the algorithm estimates had consistently higher agreement with the aggregate rating (κw = 0.82) than with the individual raters. For all metrics, the agreement between the algorithm and the aggregate ratings was highest for the unexposed category (90–93%) and was poor to moderate for the exposed categories (9–64%). Lower agreement was observed for jobs with a start year <1965 versus ≥1965. For the confidence metrics, the agreement was poor to moderate among raters (κw = 0.17–0.45) and between the algorithm and the individual raters (κw = 0.24–0.61). CART models identified patterns in the questionnaire responses that predicted a fair-to-moderate (33–89%) proportion of the disagreements between the raters’ and the algorithm estimates.
The agreement between any two raters was similar to the agreement between an algorithm-based approach and individual raters, providing additional support for using the more efficient and transparent algorithm-based approach. CART models identified some patterns in disagreements between the first rater and the algorithm. Given the absence of a gold standard for estimating exposure, these patterns can be reviewed by a team of exposure assessors to determine whether the algorithm should be revised for future studies.
PMCID: PMC3629988  PMID: 23184256
case–control; diesel exhaust; expert judgement; exposure assessment
18.  A general binomial regression model to estimate standardized risk differences from binary response data 
Statistics in medicine  2012;32(5):808-821.
Estimates of absolute risks and risk differences are necessary for evaluating the clinical and population impact of biomedical research findings. We have developed a linear-expit regression model (LEXPIT) to incorporate linear and nonlinear risk effects to estimate absolute risk from studies of a binary outcome. The LEXPIT is a generalization of both the binomial linear and logistic regression models. The coefficients of the LEXPIT linear terms estimate adjusted risk differences, while the exponentiated nonlinear terms estimate residual odds ratios. The LEXPIT could be particularly useful for epidemiological studies of risk association, where adjustment for multiple confounding variables is common. We present a constrained maximum likelihood estimation algorithm that ensures the feasibility of risk estimates of the LEXPIT model and describe procedures for defining the feasible region of the parameter space, judging convergence, and evaluating boundary cases. Simulations demonstrate that the methodology is computationally robust and yields feasible, consistent estimators. We applied the LEXPIT model to estimate the absolute five-year risk of cervical precancer or cancer associated with different Pap and human papillomavirus test results in 167,171 women undergoing screening at Kaiser Permanente Northern California. The LEXPIT model found an increased risk due to abnormal Pap test in HPV-negative that was not detected with logistic regression. Our R package blm provides free and easy-to-use software for fitting the LEXPIT model.
PMCID: PMC3982929  PMID: 22865328
Absolute risk; Binomial regression; Constrained maximization; Logistic regression; Risk difference
19.  Five-year risk of recurrence following treatment of CIN2, CIN3, or AIS: performance of HPV and Pap cotesting in post-treatment management 
Journal of lower genital tract disease  2013;17(5 0 1):S78-S84.
After excisional treatment, CIN2+ can recur. It is not clear how many negative post-treatment Pap or cotest results are needed to assure adequate safety against CIN2+, prior to return to extended retesting intervals.
We observed 5-year risks of CIN2+, and outcomes for 3 follow-up management strategies after treatment (Pap alone, HPV alone, and cotesting) for 3273 women aged 25 and older who were treated for CIN2, CIN3, or AIS between 2003–2010 at Kaiser Permanente Northern California.
Five-year risks of recurrent CIN2+ after treatment varied both by antecedent screening test result and the histology of the treated lesion. The risk ranged from 5% for CIN2 preceded by HPV-positive/ASC-US or LSIL to 16% for CIN3/AIS preceded by AGC/ASC-H/HSIL+ (p<0.0001). However, after post-treatment negative tests, risks were lowered and similar regardless of antecedent screening test and histology of treated disease. The 5-year recurrent CIN2+ risk associated with a negative post-treatment cotest (2.4%) was lower than that of an HPV-negative test alone (3.7%, p=0.3) or Pap-negative result alone (4.2%, p=0.1). Two negative post-treatment tests of each kind conferred slightly lower 5-year CIN2+ risk than one (Pap-negative: 2.7% vs. 4.2%, p=0.2; HPV-negative: 2.7% vs. 3.7%, p=0.7; HPV-negative/Pap-negative: 1.5% vs. 2.4%, p=0.8). The 5-year CIN2+ risk associated with 2 negative cotests of 1.5% (95%CI 0.3% to 7.2%) approached the 0.68% risk associated with a negative Pap test during routine screening.
Women with antecedent AGC/ASC-H/HSIL+ Pap results or those treated with CIN3/AIS had a substantial risk of developing CIN2+ after treatment. Based on the principle of “benchmarking to implicit risk thresholds”, after negative test results following treatment, no subgroup of women achieved risk sufficiently low risk to return to 5-year routine screening. However, negative cotests after treatment provided more reassurance against recurrent CIN2+ than either negative Pap tests or HPV tests alone.
PMCID: PMC3616418  PMID: 23519309
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelialneoplasia (CIN); Hybrid Capture 2 (HC2); post-treatment; test of cure
20.  Benchmarking CIN3+ risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines 
Journal of lower genital tract disease  2013;17(5 0 1):S28-S35.
In 2012, the United States Preventive Services Task Force (USPSTF) and a consensus of 25 organizations endorsed concurrent cytology and HPV testing (“cotesting”) for cervical cancer screening. Past screening and management guidelines were implicitly based on risks defined by Pap-alone, without consideration of HPV test results. To promote management that is consistent with accepted practice, new guidelines incorporating cotesting should aim to achieve equal management of women at equal risk of cervical intraepithelial neoplasia grade 3 and cancer (CIN3+).
We estimated cumulative 5-year risks of CIN3+ for 965,360 women aged 30–64 undergoing cotesting at Kaiser Permanente Northern California 2003–2010. We calculated the implicit risk thresholds for Pap-alone and applied them for new management guidance on HPV and Pap cotesting, citing 2 examples: HPV-positive/ASC-US and HPV-negative/Pap-negative. We call this guidance process “benchmarking”.
LSIL, for which immediate colposcopy is prescribed, carries 5-year CIN3+ risk of 5.2%, suggesting that test results with similar risks should be managed with colposcopy. Similarly, ASC-US (2.6% risk) is managed with 6–12 month follow-up and Pap-negative (0.26% risk) is managed with 3-year follow-up. The 5-year CIN3+ risk for women with HPV-positive/ASC-US was 6.8% (95%CI 6.2% to 7.6%). This is greater than the 5.2% risk implicitly leading to referral to colposcopy, consistent with current management recommendations that HPV-positive/ASC-US should be referred for immediate colposcopy. The 5-year CIN3+ risk for women with HPV-negative/Pap-negative was 0.08% (95%CI 0.07% to 0.09%), far below the 0.26% implicitly required for a 3-year return and justifying a longer (e.g., 5-year) return.
Using the principle of “equal management of equal risks,” benchmarking to implicit risk thresholds based on Pap-alone can be used to achieve safe and consistent incorporation of cotesting.
PMCID: PMC3616419  PMID: 23519302
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2)
21.  Five-year risk of CIN3+ and cervical cancer for women who test Pap-negative, but are HPV-positive 
Journal of lower genital tract disease  2013;17(5 0 1):S56-S63.
Current US guidelines for cotesting recommend that the large numbers of women who test Pap-negative, but HPV-positive, return in 1 year, and those who remain HPV-positive or have LSIL (or worse) Pap be referred for colposcopy. However, the performance of these guidelines in routine clinical practice has not been evaluated.
We estimated cumulative 5-year risks of CIN3+ for 32,374 women aged 30–64 with HPV-positive/Pap-negative cotest results at Kaiser Permanente Northern California during 2003–2010.
The 5-year CIN3+ risk following an HPV-positive/Pap-negative cotest result, which was found in 3.6% of women, was 4.5% (95%CI 4.2%–4.8%). The 5-year cancer risk was 0.34% (95%CI 0.26% to 0.45%) and half of the cases were adenocarcinoma. Overall, 47% of the women remained HPV-positive upon return (median 415 days after baseline), a percentage that varied little over ages 30–64. At the return following a baseline HPV-positive/Pap-negative result, almost every repeat cotest result predicted greater subsequent 5-year CIN3+ risk than the same cotest result had at baseline (HPV-positive/LSIL: 9.2% vs. 6.1%, p=0.01; HPV-positive/ASC-US: 7.9% vs. 6.8%, p=0.2; HPV-positive/Pap-negative: 7.4% vs. 4.5%, p<0.0001; HPV-negative/LSIL: 1.7% vs. 2.0%, p=0.8; HPV-negative/ASC-US: 2.9% vs. 0.43%, p=0.0005; HPV-negative/Pap-negative: 0.93% vs. 0.08%, p<0.0001).
Using the principle of “equal management of equal risks”, HPV-positive/Pap-negative women had subsequent CIN3+ risk consistent with risk thresholds for a 1-year return. However, upon returning in approximately 1 year, about one-half of women will be referred for colposcopy due to continued HPV positivity or Pap abnormality. Clinicians should keep in mind that cotest results at the return following a baseline HPV-positive/Pap-negative finding are riskier than the same baseline cotest results in the general population, supporting intensified clinical management of return cotests.
PMCID: PMC3616446  PMID: 23519306
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); prospective cohort
22.  Five-year risk of CIN3+ and cervical cancer for women with HPV-positive and HPV-negative high-grade Pap results 
Journal of lower genital tract disease  2013;17(5 0 1):S50-S55.
High-grade Pap results (e.g., AGC, ASC-H, and HSIL) predict high cancer risks, resulting in referral to colposcopy without HPV triage. However, new guidelines recommending cotesting for women 30 and older imply that clinicians will often receive the HPV test result concurrently for high-grade Pap results. We examined whether HPV testing provides useful risk stratification in this context.
From a cohort of 965,360 women age 30–64 undergoing cotesting at Kaiser Permanente Northern California, we estimated 5-year risks of cervical cancer and CIN3+ for AGC (2,074 women), ASC-H (1,647 women), and HSIL (2,019 women) according to HPV test results.
HPV positivity of AGC Pap results was 25% and decreased with age (30–34: 44% vs. 60–64: 17%, p<0.0001), while HPV-positivity of ASC-H and HSIL were much higher (71% and 94% respectively) and decreased less with age. Even for these high-grade Pap results, 5-year CIN3+ risks differed substantially between HPV-positive and HPV-negative women (AGC: 33% vs. 0.93%, p<0.0001; ASC-H: 25% vs. 3.5%, p<0.0001; HSIL: 49% vs. 30%, p=0.006). However, except for AGC, cervical cancer risks differed less between HPV-positive and HPV-negative women (AGC: 9.0% vs. 0.37%, p<0.0001; ASC-H: 2.5% vs. 2.1%, p=0.8; HSIL: 6.6% vs. 6.8%, p=0.7).
The risks of CIN3+ for HPV-negative high-grade Pap results were lower than for HPV-positive high-grade Pap results, especially for AGC. However, by the principle of “equal management of equal risks”, all HPV-negative high-grade Pap results had cancer risks high enough to warrant colposcopy, confirming that there is no current role for HPV triage of high-grade Pap results.
PMCID: PMC3616447  PMID: 23519305
Human Papillomavirus (HPV); cancer prevention; baseline; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); screening guidelines; HSIL; AGC; ASC-H
23.  Estimating 5-year risk of CIN3+ to guide the management of women aged 21–24 
Journal of lower genital tract disease  2013;17(5 0 1):S64-S68.
Current US national guidelines recommend beginning screening at age 21 using Pap tests only, with cotesting starting at age 30. To inform the management of Pap test abnormalities among women aged 21–24, who have extremely low cancer risks, we compared risks of CIN3+ for women aged 21–24 versus 25–29 or 30–64.
We estimated 5-year risks of CIN3+ for Pap test results, with HPV triage of ASC-US, for 133,947 women aged 21–24, compared with 135,382 women age 25–29 and 965,360 women age 30–64, between 2003–2010 at Kaiser Permanente Northern California.
There were 3 cancers diagnosed during follow-up in women aged 21–24. Following high-grade Pap results (0.6% of Pap results), 5-year CIN3+ risks for women aged 21–24 were comparable to those aged 25–29 and 30–64 (AGC: 6.9% vs. 14% vs. 8.5%, p=0.8; ASC-H: 16% vs. 24% vs. 18%, p=0.8; HSIL: 28% vs. 28% vs. 47%, p=0.4). Following LSIL, 5-year CIN3+ risk was lower for ages 21–24 (3.0%) than ages 25–29 (5.0%, p=0.01) or ages 30–64 (5.2%, p=0.0002). Although 5-year CIN3+ risk for HPV-negative/ASC-US was similar across all 3 groups (0.57% vs. 0.59% vs. 0.43%, p=1), risk for HPV-positive/ASC-US was lower for age 21–24 (4.4%) than 25–29 (7.1%, p<0.0001) or 30–64 (6.8%, p<0.0001).
Women aged 21–24 had almost zero cancer risk, and positive Pap test results predicted low CIN3+ risk except for the 0.6% of Pap results that were high-grade. The generally low risk supports conservative management of women aged 21–24.
PMCID: PMC3616448  PMID: 23519307
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); young women
24.  Follow-up testing post-colposcopy: Five-year risk of CIN2+ after a colposcopic diagnosis of CIN1 or less 
Journal of lower genital tract disease  2013;17(5 0 1):S69-S77.
The majority of women referred for colposcopy are not diagnosed with CIN2+ but, nonetheless, are typically asked to return much sooner than their next routine screening interval in 3-5 years. An important question is how many subsequent negative Pap results, or negative Pap and HPV cotest results, are needed prior to returning to an extended retesting interval.
We estimated 5-year risks of CIN2+ for 3 follow-up management strategies after colposcopy (Pap-alone, HPV-alone and cotesting) for 20,319 women aged 25 and older screened from 2003-2010 at Kaiser Permanente Northern California who were referred for colposcopy but for whom CIN2+ was not initially diagnosed (i.e., “Women with CIN1/negative colposcopy”).
Screening results immediately antecedent to CIN1/negative colposcopy influenced subsequent 5-year CIN2+ risk: women with an antecedent HPV-positive/ASC-US or LSIL Pap had a lower risk (10%) than those with antecedent ASC-H (16%, p<0.0001) or HSIL+ (24%, p<0.0001). For women with an antecedent HPV-positive/ASC-US or LSIL, a single negative cotest approximately 1 year post-colposcopy predicted lower subsequent 5-year risk of CIN2+ (1.1%) than 2 sequential negative HPV tests (1.8%, p=0.3) or 2 sequential negative Pap results (4.0%, p<0.0001). For those with an antecedent ASC-H or HSIL+ Pap, 1 negative cotest after 1 year predicted lower subsequent 5-year risk of CIN2+ (2.2%) than 1 negative HPV test (4.4%, p=0.4) or 1 negative Pap (7.0%, p=0.06); insufficient data existed to calculate risk after sequential negative cotests for women with high grade antecedent cytology.
After CIN1/negative colposcopy followed by negative post-colposcopy tests, women did not achieve sufficiently low CIN2+ risk to return to 5-year routine screening. For women with antecedent HPV-positive/ASC-US or LSIL, a single negative post-colposcopy cotest reduced risk to a level consistent with a 3-year return. For women with antecedent ASC-H or HSIL+, no single negative test result sufficed to reduce risk to a level consistent with a 3-year return.
For women with CIN1/negative colposcopy and antecedent HPV-positive/ASC-US or LSIL, a single negative post-colposcopy cotest reduced risk to a level consistent with a 3-year return.
PMCID: PMC3616505  PMID: 23519308
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); colposcopy
25.  Five-year risk of CIN3+ and cervical cancer for women with HPV testing of ASC-US Pap results 
Journal of lower genital tract disease  2013;17(5 0 1):S36-S42.
New screening guidelines recommend that HPV-negative/ASC-US results be considered as equivalent to HPV-negative/Pap-negative results, leading to rescreening in 5 years. However, despite ample research data, the routine clinical performance of HPV testing of women with ASC-US has not been adequately documented.
We estimated 5-year risks of CIN3+ and cancer for 2 groups between 2003-2010 at Kaiser Permanente Northern California: 27,050 women aged 30-64 who underwent HPV and Pap cotesting and had an ASC-US Pap result, and 12,209 women aged 25-29 who underwent HPV triage of ASC-US.
Five-year risks of CIN3+ and of cancer for women aged 30-64 testing HPV-negative/ASC-US and for 923,152 women testing Pap-negative alone were similar although statistically distinguishable (CIN3+: 0.43% vs. 0.26% (p=0.001); Cancer: 0.050% vs. 0.025% (p=0.1, respectively)). The cancer risk increase for HPV-negative/ASC-US versus Pap-negative alone was confined to women aged 60-64 (0.26% vs. 0.035%, p=0.3). Five-year risks of CIN3+ and of cancer for women with HPV-negative/ASC-US were substantially higher than those for women testing HPV-negative/Pap-negative (CIN3+: 0.43% vs. 0.08% (p<0.0001); Cancer: 0.050% vs. 0.011% (p=0.003, respectively)). For women aged 30-64 testing HPV-positive/ASC-US, 5-year risks of CIN3+ and cancer were slightly higher than for the 9,374 women with LSIL (CIN3+: 6.8 % vs. 5.2% (p=0.0007); Cancer: 0.41% vs. 0.16% (p=0.04)). Similar patterns were seen for women aged 25-29.
Women with HPV-negative/ASC-US had similar risk as women testing Pap-negative alone, but had higher risk than women testing HPV-negative/Pap-negative. Based on the principle of “equal management of equal risks”, our findings support equal management of women with HPV-negative/ASC-US and those with Pap-negative alone, except for exiting women from screening because cancer risks at ages 60-64 may be higher for HPV-negative/ASC-US. Our findings also support managing HPV-positive/ASC-US and LSIL similarly.
Women testing HPV-negative/ASC-US have similar risk of CIN3+ or cancer as women testing Pap-negative alone, but have higher risk than women testing HPV-negative/Pap-negative.
PMCID: PMC3616508  PMID: 23519303
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); ASC-US

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