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Supplementary Tables 1-3 from A Sex-Specific Association between a 15q25 Variant and Upper Aerodigestive Tract Cancers

Background: The increasing incidence of oropharyngeal cancer in many developed countries has been attributed to human papillomavirus type 16 (HPV16) infections. Recently, HPV16 E6 serology has been identified as a promising early marker for oropharyngeal cancer. Therefore, characterization of HPV16 E6 seropositivity among individuals without cancer is warranted.Methods: A total of 4,666 controls were pooled from several studies of cancer and HPV seropositivity, all tested within the same laboratory. HPV16 E6 seropositive controls were classified as having (i) moderate [mean fluorescent intensity (MFI) ≥ 484 and Results: Thirty-two (0.7%) HPV16 E6 seropositive controls were identified; 17 (0.4%) with moderate and 15 (0.3%) with high seroreactivity. High HPV16 E6 seroreactivity was associated with former smoking [odds ratio (OR), 5.5; 95% confidence interval (CI), 1.2–51.8], and seropositivity against HPV16 L1 (OR, 4.8; 95% CI, 1.3–15.4); E2 (OR, 7.7; 95% CI, 1.4–29.1); multiple HPV16 proteins (OR, 25.3; 95% CI, 2.6–119.6 for three HPV16 proteins beside E6) and HPV33 E6 (OR, 17.7; 95% CI, 1.9–81.8). No associations were observed with moderate HPV16 E6 seroreactivity.Conclusions: High HPV16 E6 seroreactivity is rare among individuals without diagnosed cancer and was not explained by demographic factors.Impact: Some HPV16 E6 seropositive individuals without diagnosed HPV-driven cancer, especially those with seropositivity against other HPV16 proteins, may harbor a biologically relevant HPV16 infection. Cancer Epidemiol Biomarkers Prev; 24(4); 683–9. ©2015 AACR.

Supplemental Table 1. Study-specific definitions for categorization of tobacco and alcohol use.

Background: Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx, and esophagus) in women (OR = 1.24, P = 0.003) with little effect in men (OR = 1.04, P = 0.35).Methods: In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case–control studies.Results: rs16969968 was again associated with UADT cancers in women (OR = 1.21, 95% CI = 1.08–1.36, P = 0.001) and a similar lack of observed effect in men [OR = 1.02, 95% CI = 0.95–1.09, P = 0.66; P-heterogeneity (Phet) = 0.01]. In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR = 1.22, 95% CI = 1.12–1.34, P = 7 × 10−6) but not males (OR = 1.02, 95% CI = 0.97–1.08, P = 0.35; Phet = 6 × 10−4). There was little evidence for a sexdifference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (Phet = 0.86).Conclusions: This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers.Impact: Further research is warranted to elucidate the mechanisms underlying these observations. Cancer Epidemiol Biomarkers Prev; 20(4); 658–64. ©2011 AACR.

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers, and genetic markers. A total of 10,126 head and neck cancer cases and 5,254 controls from 5 North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC=0.94, 95%CI=0.92–0.95 in men and AUC=0.92, 95%CI=0.88–0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity, and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.

BACKGROUND: Hydroxyzine is indicated for the management of anxiety, skin and sleep disorders. In 2015, the European Medicines Agency (EMA) concluded that hydroxyzine was pro-arrhythmogenic and changes to the product information were implemented in Europe. This study aimed to evaluate their impact in Denmark, Scotland, England and the Netherlands.METHOD: Quarterly time series analyses measuring hydroxyzine initiation, discontinuation, and switching to other antihistamines, benzodiazepines and antidepressants in Denmark, England, Scotland and the Netherlands from 2009 to 2018. Data were analysed using interrupted time series regression.RESULTS: Hydroxyzine initiation in quarter one 2010 in Denmark, Scotland, England and the Netherlands per 100 000 was: 23.5, 91.5, 35.9 and 34.4 respectively. Regulatory action was associated with a significant: immediate fall in hydroxyzine initiation per 100 000 in England (-12.05, 95%CI -18.47 to -5.63) and Scotland (-19.01, 95%CI -26.99 to -11.02); change to a negative trend in hydroxyzine initiation per 100 000/quarter in England (-1.72, 95%CI -2.69 to -0.75) and Scotland (-2.38, 95%CI -3.32 to -1.44). Regulatory action was associated with a significant: immediate rise in hydroxyzine discontinuation per 100 000 in England (3850, 95%CI 440-7240). No consistent changes were observed in the Netherlands or Denmark. Regulatory action was associated with no switching to other antihistamines, benzodiazepines or antidepressants following hydroxyzine discontinuation in any country.CONCLUSION: The 2015 EMA regulatory action was associated with heterogeneous impact with reductions in hydroxyzine initiation varying by country. There was limited impact on discontinuation with no strong evidence suggesting unintended consequences of major switching to other antihistamines, benzodiazepines or antidepressants.

Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC., Genetic susceptibility loci for oropharyngeal cancer have been reported but these studies have not always examined human papillomavirus (HPV) status. Here, the authors perform genome-wide analysis taking into account HPV16 serology status and report two independent loci in the HLA region, suggesting the protective role of HLA variants against HPV infection.

The aims of the current review were to compare the efficacy of monotherapy with bendroflumethiazide vs. indapamide on mortality, cardiovascular outcomes, blood pressure, need for intensification of treatment and treatment withdrawal. Two authors independently screened the results of a literature search, assessed the risk of bias and extracted relevant data. Randomized clinical trials of hypertensive patients of at least a 1‐year duration were included. When there was disagreement, a third reviewer was consulted. Risk ratio (RR) and mean differences were used as measures of effect. Two trials comparing bendroflumethiazide against placebo, one comparing indapamide with placebo and three of short duration directly comparing indapamide and Bendroflumethiazide, were included. No statistically significant difference was found between indapamide and bendroflumethiazide for all deaths [RR 0.82; 95% confidence interval (CI) 0.57, 1.18], cardiovascular deaths (RR 0.82; 95% CI 0.55, 1.20), noncardiovascular deaths (0.81; 95% CI 0.54, 1.22), coronary events (RR 0.73; 95% CI 0.30, 1.79) or all cardiovascular events (RR 0.89; 95% CI 0.67, 1.18). Indapamide performed worse for stroke (RR 2.21; 95% CI 1.19, 4.11), even though a reduction in RR compared with placebo was observed in both groups. There was no statistically or clinically significant difference between indapamide and bendroflumethiazide in blood pressure reduction (mean absolute difference

The aim of this systematic review was to examine the literature on clinical taper angles achieved by dental students during crown preparation to determine the theoretical and clinically acceptable values identified in research studies. Medline, Embase, Web of Knowledge, the Cochrane Library, the British Dental Journal, and the Journal of the American Dental Association were searched to identify relevant studies. Studies were included if they were in vivo research on full crown preparations by dental students and published in English. Data extracted were country, year of publication, model selection and measurement methods, tests for reproducibility, tooth type, number of teeth assessed, and tapers achieved. The search resulted in 12 included articles from 11 countries published between 1978 and 2014 featuring a total of 2,306 preparations. In those studies, students failed to achieve ideal convergence angles (between 4° and 14°) but produced clinically acceptable results (between 10° and 20°). These findings should be taken into account when assessing dental students during their training programs.

With the aim to dissect the effect of adult height on head and neck cancer (HNC), we use the Mendelian randomization (MR) approach to test the association between genetic instruments for height and the risk of HNC. 599 single nucleotide polymorphisms (SNPs) were identified as genetic instruments for height, accounting for 16% of the phenotypic variation. Genetic data concerning HNC cases and controls were obtained from a genome-wide association study. Summary statistics for genetic association were used in complementary MR approaches: the weighted genetic risk score (GRS) and the inverse-variance weighted (IVW). MR-Egger regression was used for sensitivity analysis and pleiotropy evaluation. From the GRS analysis, one standard deviation (SD) higher height (6.9 cm; due to genetic predisposition across 599 SNPs) raised the risk for HNC (Odds ratio (OR), 1.14; 95% Confidence Interval (95%CI), 0.99–1.32). The association analyses with potential confounders revealed that the GRS was associated with tobacco smoking (OR = 0.80, 95% CI (0.69–0.93)). MR-Egger regression did not provide evidence of overall directional pleiotropy. Our study indicates that height is potentially associated with HNC risk. However, the reported risk could be underestimated since, at the genetic level, height emerged to be inversely associated with smoking.

Head and neck cancer (HNC) is a preventable malignancy that continues to cause substantial morbidity and mortality worldwide. Using data from the ARCAGE and Rome studies, we investigated the main predictors of survival after larynx, hypopharynx and oral cavity (OC) cancers. We used the Kaplan-Meier method to estimate overall survival, and Cox proportional models to examine the relationship between survival and sociodemographic and clinical characteristics. 604 larynx, 146 hypopharynx and 460 OC cancer cases were included in this study. Over a median follow-up time of 4.6 years, nearly 50% (n = 586) of patients died. Five-year survival was 65% for larynx, 55% for OC and 35% for hypopharynx cancers. In a multivariable analysis, we observed an increased mortality risk among older (≥71 years) versus younger (≤50 years) patients with larynx/hypopharynx combined (LH) and OC cancers [HR = 1.61, 95% CI 1.09-2.38 (LH) and HR = 2.12, 95% CI 1.35-3.33 (OC)], current versus never smokers [HR = 2.67, 95% CI 1.40-5.08 (LH) and HR = 2.16, 95% CI 1.32-3.54 (OC)] and advanced versus early stage disease at diagnosis [IV versus I, HR = 2.60, 95% CI 1.78-3.79 (LH) and HR = 3.17, 95% CI 2.05-4.89 (OC)]. Survival was not associated with sex, alcohol consumption, education, oral health, p16 expression, presence of HPV infection or body mass index 2 years before cancer diagnosis. Despite advances in diagnosis and therapeutic modalities, survival after HNC remains low in Europe. In addition to the recognized prognostic effect of stage at diagnosis, smoking history and older age at diagnosis are important prognostic indicators for HNC.

Objectives: \ud This study aimed at re-evaluating the strength and shape of the dose-response relationship between the combined (or joint) effect of intensity and duration of cigarette smoking and the risk of head and neck cancer (HNC). We explored this issue considering bivariate spline models, where smoking intensity and duration were treated as interacting continuous exposures.\ud \ud Materials and Methods: \ud We pooled individual-level data from 33 case-control studies (18,260 HNC cases and 29,844 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. In bivariate regression spline models, exposures to cigarette smoking intensity and duration (compared with never smokers) were modeled as a linear piecewise function within a logistic regression also including potential confounders. We jointly estimated the optimal knot locations and regression parameters within the Bayesian framework.\ud \ud Results: \ud For oral-cavity/pharyngeal (OCP) cancers, an odds ratio (OR) >5 was reached after 30 years in current smokers of ∼20 or more cigarettes/day. Patterns of OCP cancer risk in current smokers differed across strata of alcohol intensity. For laryngeal cancer, ORs >20 were found for current smokers of ≥20 cigarettes/day for ≥30 years. In former smokers who quit ≥10 years ago, the ORs were approximately halved for OCP cancers, and ∼1/3 for laryngeal cancer, as compared to the same levels of intensity and duration in current smokers.\ud \ud Conclusion: \ud Referring to bivariate spline models, this study better quantified the joint effect of intensity and duration of cigarette smoking on HNC risk, further stressing the need of smoking cessation policies.

Studies have suggested that alcohol consumption is strongly related to reduced reporting of chronic widespread pain (CWP) and level of disability in people with CWP or fibromyalgia. Direction of causality has not been established, that is whether the association is due to people's health influencing their alcohol consumption or vice versa. UK Biobank recruited over 500,000 people aged 40 to 69 years, registered at medical practices nationwide. Participants provided detailed information on health and lifestyle factors including pain and alcohol consumption. Total units consumed per week were calculated for current drinkers. Information was also collected on changes in alcohol consumption and reasons for such changes. Analysis was performed with logistic regression expressed as odds ratios (ORs) with 95% confidence intervals, then adjusted for a large number of potential confounding factors (adjORs). In males who reported drinking the same as 10 years previously, there was a U-shaped relationship between amount drunk and odds of reporting CWP (nondrinkers CWP prevalence 2.4%, 19.1-32.1 units/wk 0.4%, >53.6 units/wk 1.0%; adjORs 2.53 95% confidence intervals [1.78-3.60] vs 1 vs 1.52 [1.05-2.20]). In females, there was a decrease in the proportion reporting CWP up to the modal category of alcohol consumption with no further change in those drinking more (nondrinkers CWP prevalence 3.4%, 6.4-11.2 units/wk 0.7%, >32.1 units/wk 0.7%; adjORs 2.11 [1.67-2.66] vs 1 vs 0.86 [0.54-1.39]). This large study has shown a clear relationship between alcohol consumption and reporting of pain even in people who had not reported changing consumption because of health concerns, after adjustment for potential confounding factors.

A key aspect of epidemiology is about understanding and exploring variations in disease. In order to do so it is important that the same definitions of disease occurrence are used, no matter where a study is being conducted, and that the same approach to measurement is taken. The epidemiologist needs to be aware of which measure to use in specific circumstances. Measuring disease occurrence is the basic activity of epidemiology, and the following section provides the background to choosing the most appropriate measure(s) of disease occurrence for the aims of the study. The term ‘disease’ can also be taken in this context to describe any personal attribute. Thus, the concepts described in this chapter apply equally well to assessing the occurrence of a symptom, the development of a particular disability, or the frequency of a medical intervention.

This chapter builds on the previous one on the analysis of descriptive epidemiological studies and illustrates statistical methods appropriate for analysis of analytical epidemiological studies. It mainly focuses on data obtained from case–control and cohort studies, but also considers other study designs presented in Chapter 6. There are also several practical examples to help with the analysis and interpretation of the results of analytical epidemiological studies. In practice, relatively little mathematical calculation is done without computers. In this chapter, however, formulae are presented for the main measures of effect together with worked examples. Indeed, when data are available in tabulated form, as opposed to raw data files, it is frequently an easy task to calculate the important measures ‘by hand’. The formulae presented will permit the reader, for example, to check or further explore data published by others.

Having conducted a specific study design, the task is then to use the information collected to provide an effect measure which quantifies the magnitude of the association between the exposure(s) of interest and the disease under study. Epidemiological studies, and in particular their subsequent analysis, are therefore aimed at quantifying the level of increased risk when exposed to a particular factor, as this chapter explains. The effect measure which can be obtained to quantify the strength of the association, varies according to the type of study conducted. Just because there is a relationship between exposure and disease (even a strong one) does not mean that the relationship is causal.

Epidemiology can be considered as a suite of methodologies designed to inform on aspects of health and disease in human populations. They have been designed to cope with the variability between people in the risk for diseases and their course and response to treatments. There are many aspects of epidemiological study that are challenging and the successful study requires attention to the design, conduct of the study, and analysis of the data generated. There is another view of epidemiology, which is that it is a tool for studying diseases as they occur in human populations. The focus can also be on diagnosis, outcome, and results of interventions, as well as on causes. This broader definition allows a greater scope for the kinds of question that can be addressed both by those studying the health of populations and by those whose main focus is the study of disease in patient groups.

Although epidemiological studies are increasingly based on the analysis of existing data sets (including linked data sets), many studies still require primary data collection. Such data may come from patient questionnaires, interviews, abstraction from records, and/or the results of tests and measures such as weight or blood test results. The next stage is to analyse the data gathered from individual subjects to provide the answers required. Before commencing with the statistical analysis of any data set, the data themselves must be prepared in a format so that the detailed statistical analysis can achieve its goals. Items to be considered include the format the data are initially collected in and how they are transferred to an appropriate electronic form. This chapter explores how errors are minimized and the quality of the data set ensured. These tasks are not trivial and need to be planned as part of a detailed study methodology.

In comparing rates between populations, it is important that one is comparing ‘like with like’. One population may be considerably older than a population to which it is compared and therefore it would not be surprising that mortality rates were higher. Instead it is more useful to make comparisons taking account of differences in characteristics such as age or gender. The same considerations apply to examining disease rates over time in a given population. If the characteristics of the population change over time (e.g. the population gets older), this needs to be considered. To formulate hypotheses, the rate of a disease under study in a population may be compared with the rate in other populations, or in the same population at difierent time points. If the rates vary significantly between populations or are changing within a population, then this provides impetus for investigating the reasons underlying these differences or changes.

Although the definition of measures of disease occurrence, such as incidence and prevalence, may be relatively straightforward, there will be issues of how to operationalize these. The solutions will depend on what systems exist in the location of study such as clinical records, a prospective registration system. Alternatively, if there are no such systems, then alternative solutions will need to be investigated. This could include a proxy measure of disease or could involve undertaking one or more surveys to identify prevalence or new onset cases. Overall, the decision would need to be made on the basis of specific needs relating to an individual project where actual incidence data were not available, to ascertain whether an alternative (proxy) measure may be suitable.

Designing a study ‘on paper’ is no guarantee it will work; for example, individuals agree to be recruited or the method of data acquisition is acceptable and provides the data in the format and quality required. For this reason it is, especially when planning large/expensive studies, to test the feasibility of the different components in separate small-scale studies. Alternatively, or in addition it may be useful to do a pilot study, which reproduces the planned methods for the proposed full study, to test ‘the whole system’. A successful pilot study enhances the likelihood of grant success; indeed, grant-awarding bodies will often expect to see evidence that they have been conducted.

The preceding chapters have focused on the generation of scientific evidence using epidemiological studies. Here the emphasis is on bringing together evidence (evidence synthesis) to inform future research and health policies. The chapter considers levels and quality of scientific evidence and describes in detail how to conduct a systematic review. It reviews the ways of summarizing and evaluating evidence from epidemiological studies. Summary of evidence is needed in everyday clinical practice and for public health. We live in a time of information overload, and it is impossible to read all the available scientific journals, even on a narrow scientific topic. Simply using search terms such as ‘cancer’ will result in millions of results in Google Scholar or PubMed (a service of the US National Library of Medicine®) database. Given the ever-increasing volume of medical literature and time constraints, summary of evidence plays a big role in decision-making.

A key issue in epidemiology is to choose an appropriate study design. The design chosen will depend on the question of interest and some designs will offer clear advantages over others. However, other factors such as current state of knowledge will be important. The decision will be based not only on methodological but also on practical considerations, including the resources available, and the speed with which a result is required. For example, the most appropriate study may be too expensive or take too long to provide an answer. In such circumstances a compromise will need to be made—to undertake a study which can be conducted within the budget and time available, and which delivers information that is suitable for addressing the question of interest.

Primary data collection is challenging and with increasing electronic data capture in routine healthcare and other aspects of life, it is possible to address several epidemiological questions by robust analysis of such ‘secondary data’. There are considerable advantages in terms of scope, size, and speed of study to be balanced against the quality and depth of using primary data. Even when such direct contact is not required, there is often the need to extract necessary information from individual subject records such as medical files. There is often no alternative source of information, although the greater digitization of information is changing that scenario with the potential that the availability of such information might preclude the need for primary data.

The most important aspect that will influence the validity of any epidemiological study is the careful selection of the subjects for investigation. Separate issues relate to the sampling of subjects for disease status in case–control studies, and sampling by exposure status in cohort studies. In simplest terms, the issues are who should be the cases and, given that, who should be the controls. Thus, in each instance the needs are to identify the sampling frame and then what should be the process for selecting the specific sample or subsamples needed for study. In addition to consideration of who to study, other factors such as how to identify and verify plus the size of the planned study are all topics to be addressed.

Validity in respect of information that is collected in an epidemiological study is a measure of how accurate the data collected are, relative to an underlying truth. Classical approaches aim to ensure that the approach is both sensitive (low false negatives) and specific (low false positives) as, for example, in determining the presence or absence of a disease. A modified approach is needed where the value of an attribute is collected. Underpinning both these approaches is the need to consider what is the test of the underlying truth. The reader may already be aware of the application of validity tests in assessing the performance of diagnostic and screening tests. It is conventional to evaluate this performance in terms of the two indicators, sensitivity and specificity.

This chapter reviews the options for population selection in undertaking investigations aimed at estimating the occurrence of a disease. In terms of measuring disease occurrence, an important issue will be determining the appropriate target population. The choice will depend on being able to access the population, how representative it is, the size of the population, and the population data accuracy. It will not always be possible to use an ‘ideal’ population, there will be different options and the advantages and disadvantages of each will need to be determined. The same principles apply, however, if the object of the study is to investigate the occurrence of a risk factor, such as cigarette smoking, or other human attributes.

There are several major ethical issues that face an epidemiological study. There is always the challenge in studying free-living individuals in the modern society, of balancing the needs for robust methods with individual freedoms. The key concerns reflect ensuring an appropriate consent process, maintaining confidentiality, and minimizing any negative consequences for a participant. The most commonly collected information for an epidemiological study come either from material already available in databases, material such as hard copies of records that can have key data items extracted, or data that is gathered directly from the subject. Occasionally a limited physical examination is undertaken. Much less often, there is a requirement to take samples of biological fluid such as blood and urine, or to undergo simple investigations such as electrocardiography or plain radiography, but even such investigations are typically associated with trivial risk to health.

Epidemiological studies can only show associations they cannot prove that a link is causative. Even in the bias free study with minimal confounding, a strong association does not mean that, for example, the presence of the risk factor has a direct biological link to the disease in question. There are several tests that can be used to increase the confidence that an association has biological meaning and needs to be considered. It is interesting always to differentiate factors that are on the ‘path’ to disease but not the underlying cause. The appropriateness of all these steps is dependent on the validity of the association.

There are two major reasons to maximize participation in an epidemiological study. Firstly, low participation can lead to bias and secondly, inadequate numbers recruited can limit the power of the study. All other things being equal, lower participation will increase the influence of non-response bias in a study. However, it should be noted that even in studies with high participation there exists a possibility of selection bias if non-participants are markedly different from participants in aspects that are key to the conditions being studied. There are several ways of boosting participation which should be embedded into the study design from the start, since chasing up to increase participation is resource-expensive.

Epidemiological studies can be very expensive, especially from large populations with multicentre recruitment. The researcher will need to ensure that there are adequate resources, allowing for the fact that things will not always go to plan, but making sure that the research is value for money. What is considered a reasonable cost will also depend on how strong the rationale is for conducting the study. Although in theory the study design influences the costs, in practice the resources available will often constrain the methodological choices. Costing an epidemiological study accurately at the start is vital. There are several ways to maximize the use of resources to ensure the study is efficient.

Objective The aim of this study was to validate the clinical use of the modified Huddart and Bodenham scoring system for the measurement of maxillary arch constriction in children born with cleft lip and/or palate. Design The study design consisted of a reliability assessment between clinical and study model scoring. Setting The study was carried out in cleft clinics at three hospital-based orthodontic units. Participants A total of 53 subjects were recruited when attending routine clinic appointments and gave informed consent to participate. Intervention The modified Huddart and Bodenham scoring system was applied to study models for 53 subjects by all examiners; whereas, one examiner scored 53 subjects clinically, the other two examiners scored 25 and 28 subjects, respectively, on two occasions at least 1 month apart. Main Outcome Measure Reliability of modified Huddart and Bodenham scoring clinically and on study models was compared. Results When scoring clinically with the modified Huddart and Bodenham index on two occasions, the intraexaminer and interexaminer intraclass correlation coefficients (ICC) indicated a high level of repeatability and reliability (ICC range, 0.941 to 0.989). The Bland-Altman plots did not show any areas of systematic bias. The ICC between clinical and model scores for each examiner ranged between 0.923 and 0.959. The Bland-Altman plots did not show any areas of systematic bias. The ICC between clinical and model scores for each examiner ranged between 0.923 and 0.959. Canines had lower reliability than molars and incisors. Conclusions There was excellent intraexaminer and interexaminer agreement both on study models and in the intraoral scoring using the modified Huddart and Bodenham index. In addition, there was a high degree of correlation between study model and clinical scores using this index.

The International Head and Neck Cancer Epidemiology (INHANCE) consortium is a collaboration of research groups leading large epidemiology studies to improve the understanding of the causes and mechanisms of head and neck cancer. The consortium includes investigators of 35 studies who have pooled their data on 25 500 patients with head and neck cancer (i.e., cancers of the oral cavity, oropharynx, hypopharynx, and larynx) and 37 100 controls. The INHANCE analyses have confirmed that tobacco use and alcohol intake are key risk factors of these diseases and have provided precise estimates of risk and dose response, the benefit of quitting, and the hazard of smoking even a few cigarettes per day. Other risk factors include short height, lean body mass, low education and income, and a family history of head and neck cancer. Risk factors are generally similar for oral cavity, pharynx, and larynx, although the magnitude of risk may vary. Some major strengths of pooling data across studies include more precise estimates of risk and the ability to control for potentially confounding factors and to examine factors that may interact with each other. The INHANCE consortium provides evidence of the scientific productivity and discoveries that can be obtained from data pooling projects. © 2015 John Wiley & Sons A/S.

Objectives HPV16-positive oropharyngeal cancer (OPC) patients experience better outcomes compared to HPV16-negative patients. Currently, strategies for treatment de-escalation are based on HPV status, smoking history and disease stage. However, the appropriate cut-point for smoking and the role of other non-clinical factors in OPC survival remains uncertain. Materials and Methods We examined factors associated with OPC outcome in 321 patients recruited in a large European multi-center study. Seropositivity for HPV16 E6 was used as a marker of HPV16 positive cancer. Hazard ratios (HR) and confidence intervals (CI) were estimated using Cox proportional models adjusted for potential confounders. Results Overall 5-year survival following OPC diagnosis was 50%. HPV16-positive OPC cases were at significantly lower risk of death (aHR = 0.51, 95% CI: 0.32–0.80). A significant effect on OPC survival was apparent for female sex (aHR 0.50: 95% CI: 0.29–0.85) and being underweight at diagnosis (aHR: 2.41, 95% CI: 1.38–4.21). A 10 pack year smoking history was not associated with overall survival. Higher stage at diagnosis appeared as the only factor significantly associated with OPC recurrence (aHR: 4.88, 95% CI: 2.12–11.21). Conclusion This study confirms that HPV16 status is an independent prognostic factor for OPC survival while female sex lowers risk of death and being underweight at diagnosis increases the risk of death. Smoking was not an independent predictor of OPC survival.

Objectives To investigate the link between self-reported oral health and arthritis in the Scottish population using data from the Scottish Health Survey. Material and Methods Data were available from 2008 to 2013 on self-reported arthritis, oral health conditions and oral hygiene habits from the Scottish Health Survey. Arthritis was defined in this survey by self-reported long standing illness, those who reported having arthritis, rheumatism and/or fibrositis. Oral conditions were defined by self-reported bleeding gums, toothache, biting difficulties and/or edentulousness. Oral hygiene habits were defined by self-reported brushing teeth and/or using dental floss on daily basis. Logistic regression was used for statistical analysis adjusted for age, gender, qualification, smoking and body mass index. Results Prevalence of self-reported arthritis was 9.3% (95% confidence interval [CI] = 9.03 to 9.57). Those who reported having bleeding gums (adjusted odds ratio [OR] = 1.63; 95% CI = 1.35 to 1.96), toothache (OR = 1.32; 95% CI = 1.16 to 1.5), biting difficulties (OR = 1.95; 95% CI = 1.62 to 2.34), and being edentulous (OR = 1.22; 95% CI = 1.08 to 1.37) had an increased risk of arthritis. Brushing teeth (OR = 1.25; 95% CI = 0.74 to 2.12), and using dental floss (OR = 1.11; 95% CI = 0.89 to 1.39) were not associated with arthritis. Conclusions Self-reported oral conditions were associated with increased risk of self-reported arthritis. Oral hygiene habits were not associated with self-reported arthritis. Further investigation is required to assess the causal association between oral hygiene, oral disease and arthritis.

Periodontal disease (PdD) has been shown to be related to other systemic diseases. However, to assess this relationship, large epidemiologic studies are required. Such studies need validated self-report measures. The aim of this systematic review is to assess the validity of self-reported measures in the diagnosis of PdD.The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Medline, Embase, and Google Scholar were searched up to January 2016. Two periodontal journals were searched manually. Two reviewers independently made selected studies and extracted data. All disagreements were resolved after discussion with a third reviewer. Risk of bias was evaluated. Sensitivity, specificity, diagnostic odds ratio, and 95% confidence interval (CI) were calculated. Of 933 papers found, 11 were selected for the review. All studies, except two, had acceptable quality. Four comparable studies were selected for meta-analysis.Study size ranged from 114 to 1,426 participants. Sensitivity and specificity ranged from 4% to 93% and 58% to 94%, respectively. Diagnostic odds ratio was 1.4 (95% CI: 0.9 to 2.2) for the question on bleeding gums and 11.7 (95% CI: 4.1 to 33.4) for the question on tooth mobility. Heterogeneity was low for most questions except those on painful gums and tooth mobility.Self-reported PdD has acceptable validity and can be used for surveillance of PdD in large epidemiologic studies. However, there is a need for large, well-designed diagnostic studies.

Objectives Dentures are worn by around 20% of the population, yet if they become displaced they may enter the gastrointestinal or respiratory system, sometimes with grave consequences. The aim of this study was to review recent published literature in order to identify the epidemiology of patients and characteristics of swallowed and aspirated dental prostheses, and propose strategies to minimise these risks. Material and Methods A fifteen year retrospective of published case series and case reports was carried out. Photographs, radiographs and descriptions of the dental prostheses were gathered, as well as the patient’s presenting complaint, the anatomical site where the denture was caught and the procedure required to remove the denture. Results Ninety one separate events of swallowed or aspirated dentures were identified from 83 case reports and series from 28 countries. Average age was 55 years, and these were 74% male. Photographs were retrieved for 49 of these dentures. Clasps were present in 25 of the dentures. There was no significant difference between clasped and unclasped dentures for perforation rates, need for open surgery and spontaneously passed dentures. Conclusions We discuss the implications of this study regarding denture designs, specifically the importance of using a radiopaque acrylic, using clasps when required even if there is a risk of aspiration, advising patients to return if a denture is loose or damaged, and finally that all patients who wear a denture are at risk of aspiration and swallowing events, and associated morbidity and mortality.

Background Aspirin and other NSAIDs are widely used as analgesics and the former is a preventative agent for vascular events. It is unclear whether their long-term use affects cancer risk. Data on the chemopreventative role of these drugs on the mortality in patients with upper aerodigestive tract cancer (UADT) are insufficient. The aim of this study was to investigate the effect of aspirin and other NSAIDs on survival in UADT cancer patients. Methods An observational cohort study of patients with UADT cancer was undertaken using Primary Care Clinical Informatics Unit (PCCIU) database of electronic medical records in Scotland. Information was available on all prescriptions of aspirin and other NSAIDs before and after diagnosis. The main outcome measure was all-cause mortality. Cox regression was used for statistical data analysis. Results There were 2392 patients diagnosed with UADT cancer between 1996 and 2010. Mean age of patients was 66 years (SD 12) and most were male (63%). Median survival in head and neck (HNC) patients was 94 months, while median survival in oesophageal cancer patients was 10 months. For HNC improved survival was observed with aspirin prescription (ever vs never hazard ratio (HR) 0.56 95% Confidence Interval (CI) 0.44, 0.71), there was no association with Cyclooxygenase 2 Inhibitors (COX-2) prescriptions. Improved survival was observed with other NSAIDs prescription (ever vs never HR 0.74 95% CI 0.60, 0.90). For oesophageal cancer patients, improved survival was observed with aspirin prescriptions (ever vs never HR 0.54 95% CI 0.45, 0.64), COX-2 prescriptions (HR 0.78 95% CI 0.62, 0.98) and other NSAIDs (HR 0.67 95% CI 0.56, 0.80). Conclusions Aspirin and other NSAIDs prescriptions after diagnosis are associated with a reduced all-cause mortality in UADT cancer patients.

Introduction: Biobank-type studies are typically large but have very low participation rates. It has been suggested that these studies may provide biased estimates of prevalence but are likely to provide valid estimates of association. We test these hypotheses using data collected on pain in a large Biobank study in the United Kingdom. Methods: UK Biobank recruited 503,325 persons aged 40–69 years (participation rate 5.5%). Participants completed questionnaires, including pain, lifestyle and environment factors. As a comparison, we used both a large population study of pain (MUSICIAN: n = 8847, aged: 40–69 years) conducted 2008–2009 and the National Child Development study (NCDS) which recruited all persons in Great Britain born during one week of 1958 and followed them up at age 44 years ( n = 9377). Results: ‘Any pain’ (UK Biobank 61.0%; MUSICIAN 63.9%), chronic pain (42.9%, 52.2%) and site-specific musculoskeletal pain (back 26.2%, 29.7%; shoulder/neck 23.3%, 25.3%) were generally similar in UK Biobank and MUSICIAN. The prevalence of chronic pain and most regional musculoskeletal pains in UK Biobank were all within 2% of that in NCDS. Conclusion: UK Biobank has provided estimates of the prevalence of pain which are similar to those from previous large-scale studies, although a formal comparison of the estimates cannot be made. It has also confirmed known associations with the reporting of pain. Despite its very low participation rate, such a study provides the opportunity to investigate novel exposure–pain relationships and investigate rarer exposures and characteristics to further our knowledge of the epidemiology of pain.

BACKGROUND: Although smoking and HPV infection are recognized as important risk factors for oropharyngeal cancer, how their joint exposure impacts on oropharyngeal cancer risk is unclear. Specifically, whether smoking confers any additional risk to HPV-positive oropharyngeal cancer is not understood.METHODS: Using HPV serology as a marker of HPV-related cancer, we examined the interaction between smoking and HPV16 in 459 oropharyngeal (and 1445 oral cavity and laryngeal) cancer patients and 3024 control participants from two large European multi-centre studies. Odds ratios and credible intervals [CrI], adjusted for potential confounders, were estimated using Bayesian logistic regression.RESULTS: Both smoking [odds ratio (OR [CrI]: 6.82 [4.52, 10.29]) and HPV seropositivity (OR [CrI]: 235.69 [99.95, 555.74]) were independently associated with oropharyngeal cancer. The joint association of smoking and HPV seropositivity was consistent with that expected on the additive scale (synergy index [CrI]: 1.32 [0.51, 3.45]), suggesting they act as independent risk factors for oropharyngeal cancer.CONCLUSIONS: Smoking was consistently associated with increase in oropharyngeal cancer risk in models stratified by HPV16 seropositivity. In addition, we report that the prevalence of oropharyngeal cancer increases with smoking for both HPV16-positive and HPV16-negative persons. The impact of smoking on HPV16-positive oropharyngeal cancer highlights the continued need for smoking cessation programmes for primary prevention of head and neck cancer.

Background: The increasing incidence of oropharyngeal cancer in many developed countries has been attributed to human papillomavirus type 16 (HPV16) infections. Recently, HPV16 E6 serology has been identified as a promising early marker for oropharyngeal cancer. Therefore, characterization of HPV16 E6 seropositivity among individuals without cancer is warranted. Methods: A total of 4,666 controls were pooled from several studies of cancer and HPV seropositivity, all tested within the same laboratory. HPV16 E6 seropositive controls were classified as having (i) moderate [mean fluorescent intensity (MFI) ≥ 484 and Results: Thirty-two (0.7%) HPV16 E6 seropositive controls were identified; 17 (0.4%) with moderate and 15 (0.3%) with high seroreactivity. High HPV16 E6 seroreactivity was associated with former smoking [odds ratio (OR), 5.5; 95% confidence interval (CI), 1.2–51.8], and seropositivity against HPV16 L1 (OR, 4.8; 95% CI, 1.3–15.4); E2 (OR, 7.7; 95% CI, 1.4–29.1); multiple HPV16 proteins (OR, 25.3; 95% CI, 2.6–119.6 for three HPV16 proteins beside E6) and HPV33 E6 (OR, 17.7; 95% CI, 1.9–81.8). No associations were observed with moderate HPV16 E6 seroreactivity. Conclusions: High HPV16 E6 seroreactivity is rare among individuals without diagnosed cancer and was not explained by demographic factors. Impact: Some HPV16 E6 seropositive individuals without diagnosed HPV-driven cancer, especially those with seropositivity against other HPV16 proteins, may harbor a biologically relevant HPV16 infection. Cancer Epidemiol Biomarkers Prev; 24(4); 683–9. ©2015 AACR.

Toporcov, Tatiana Natasha Znaor, Ariana Zhang, Zuo-Feng Yu, Guo-Pei Winn, Deborah M Wei, Qingyi Vilensky, Marta Vaughan, Thomas Thomson, Peter Talamini, Renato Szeszenia-Dabrowska, Neonila Sturgis, Erich M Smith, Elaine Shangina, Oxana Schwartz, Stephen M Schantz, Stimson Rudnai, Peter Richiardi, Lorenzo Ramroth, Heribert Purdue, Mark P Olshan, Andrew F Eluf-Neto, Jose Muscat, Joshua Moyses, Raquel Ajub Morgenstern, Hal Menezes, Ana McClean, Michael Matsuo, Keitaro Mates, Dana Macfarlane, Tatiana V Lissowska, Jolanta Levi, Fabio Lazarus, Philip La Vecchia, Carlo Lagiou, Pagona Koifman, Sergio Kjaerheim, Kristina Kelsey, Karl Holcatova, Ivana Herrero, Rolando Healy, Claire Hayes, Richard B Franceschi, Silvia Fernandez, Leticia Fabianova, Eleonora Daudt, Alexander W Curioni, Otavio Alberto Maso, Luigino Dal Curado, Maria Paula Conway, David I Chen, Chu Castellsague, Xavier Canova, Cristina Cadoni, Gabriella Brennan, Paul Boccia, Stefania Antunes, Jose Leopoldo Ferreira Ahrens, Wolfgang Agudo, Antonio Boffetta, Paolo Hashibe, Mia Lee, Yuan-Chin Amy Filho, Victor Wunsch eng FIRCA TW01500/TW/FIC NIH HHS/ K07CA104231/CA/NCI NIH HHS/ P01CA068384/CA/NCI NIH HHS/ P30ES010126/ES/NIEHS NIH HHS/ P50CA90388/CA/NCI NIH HHS/ R01CA048996/CA/NCI NIH HHS/ R01CA100264/CA/NCI NIH HHS/ R01CA30022/CA/NCI NIH HHS/ R01CA51845/CA/NCI NIH HHS/ R01CA61188/CA/NCI NIH HHS/ R01DA11386/DA/NIDA NIH HHS/ R01DE012609/DE/NIDCR NIH HHS/ R01DE11979/DE/NIDCR NIH HHS/ R01DE13110/DE/NIDCR NIH HHS/ R01DE13158/DE/NIDCR NIH HHS/ R01ES11740/ES/NIEHS NIH HHS/ R03CA113157/CA/NCI NIH HHS/ R03CA77954/CA/NCI NIH HHS/ R03DE016611/DE/NIDCR NIH HHS/ R21ES011667/ES/NIEHS NIH HHS/ T32CA09142/CA/NCI NIH HHS/ U01CA96134/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England 2015/01/24 06:00 Int J Epidemiol. 2015 Feb;44(1):169-85. doi: 10.1093/ije/dyu255. Epub 2015 Jan 22.; International audience; BACKGROUND: Increasing incidence of head and neck cancer (HNC) in young adults has been reported. We aimed to compare the role of major risk factors and family history of cancer in HNC in young adults and older patients. METHODS: We pooled data from 25 case-control studies and conducted separate analyses for adults 45 years old ('older adults', 17700 cases and 22 704 controls). Using logistic regression with studies treated as random effects, we estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The young group of cases had a higher proportion of oral tongue cancer (16.0% in women; 11.0% in men) and unspecified oral cavity / oropharynx cancer (16.2%; 11.1%) and a lower proportion of larynx cancer (12.1%; 16.6%) than older adult cases. The proportions of never smokers or never drinkers among female cases were higher than among male cases in both age groups. Positive associations with HNC and duration or pack-years of smoking and drinking were similar across age groups. However, the attributable fractions (AFs) for smoking and drinking were lower in young when compared with older adults (AFs for smoking in young women, older women, young men and older men, respectively, = 19.9% (95% CI=9.8%, 27.9%), 48.9% (46.6%, 50.8%), 46.2% (38.5%, 52.5%), 64.3% (62.2%, 66.4%); AFs for drinking=5.3% (-11.2%, 18.0%), 20.0% (14.5%, 25.0%), 21.5% (5.0%, 34.9%) and 50.4% (46.1%, 54.3%). A family history of early-onset cancer was associated with HNC risk in the young [OR=2.27 (95% CI=1.26, 4.10)], but not in the older adults [OR=1.10 (0.91, 1.31)]. The attributable fraction for family history of early-onset cancer was 23.2% (8.60% to 31.4%) in young compared with 2.20% (-2.41%, 5.80%) in older adults. CONCLUSIONS: Differences in HNC aetiology according to age group may exist. The lower AF of cigarette smoking and alcohol drinking in young adults may be due to the reduced length of exposure due to the lower age. Other characteristics, such as those that are inherited, may play a more important role in HNC in young adults compared with older adults.

Delahaye-Sourdeix, Manon Anantharaman, Devasena Timofeeva, Maria N Gaborieau, Valerie Chabrier, Amelie Vallee, Maxime P Lagiou, Pagona Holcatova, Ivana Richiardi, Lorenzo Kjaerheim, Kristina Agudo, Antonio Castellsague, Xavier Macfarlane, Tatiana V Barzan, Luigi Canova, Cristina Thakker, Nalin S Conway, David I Znaor, Ariana Healy, Claire M Ahrens, Wolfgang Zaridze, David Szeszenia-Dabrowska, Neonilia Lissowska, Jolanta Fabianova, Eleonora Mates, Ioan Nicolae Bencko, Vladimir Foretova, Lenka Janout, Vladimir Curado, Maria Paula Koifman, Sergio Menezes, Ana Wunsch-Filho, Victor Eluf-Neto, Jose Boffetta, Paolo Fernandez Garrote, Leticia Polesel, Jerry Lener, Marcin Jaworowska, Ewa Lubinski, Jan Boccia, Stefania Rajkumar, Thangarajan Samant, Tanuja A Mahimkar, Manoj B Matsuo, Keitaro Franceschi, Silvia Byrnes, Graham Brennan, Paul McKay, James D eng 1R03DE020116/DE/NIDCR NIH HHS/ R01CA092039 05/05S1/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural 2015/04/04 06:00 J Natl Cancer Inst. 2015 Apr 2;107(5). pii: djv037. doi: 10.1093/jnci/djv037. Print 2015 May.; International audience; Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10(-10)) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust association between a truncating BRCA2 variant and UADT cancer risk suggests that treatment strategies orientated towards BRCA2 mutations may warrant further investigation in UADT tumors.

The aim of this study was to examine the link between AS and periodontitis.Medline, Embase, AMED, CINAHL, Web of Science and Google Scholar were searched to identify eligible studies that were selected and reviewed independently by at least two authors.Six case-control studies were included in the review. Study size ranged from 90 to 40 926 participants. The prevalence of periodontitis ranged from 38% to 88% in AS patients and from 26% to 71% in controls. As there was low-level heterogeneity (I(2) = 13%), using fixed effects analysis the overall pooled estimate of the odds ratios for periodontitis was 1.85 (95% CI 1.72, 1.98). There was no evidence of publication bias.The results led to the need for a further large study with sufficient statistical power to detect the desired effect size, taking into account potential confounding factors and using validated measures of AS and periodontitis.

To determine the prevalence and factors associated with hypotonia.Systematic review and meta-analysis.A search strategy was developed along with inclusion criteria and run in MEDLINE and EMBASE (published from 2002 to August 2012) databases to reveal all studies on the prevalence of hypodontia or associated factors. A hand search of reference lists and a Google search aimed to improve the sensitivity of the literature search.All studies on the prevalence of hypodontia or associated factors published from 2002 onwards were included. Abstracts of non-English papers were also analyzed.All potential articles were checked against the inclusion criteria independently, and in duplicate by two investigators. A checklist was used to assess the quality of selected studies.Prevalence of hypodontia, excluding third molars.The overall prevalence of hypodontia was found to be 6.4% (95% CI: 5.7, 7.2). There was a statistically significant difference in the prevalence of hypodontia by continent (Q = 34.18, P0.001). Prevalence of hypodontia was the highest in Africa: 13.4% (95% CI: 9.7, 18.0), followed by Europe (7% CI: 6.0-8.0%), Asia (6.3% CI: 4.4, 9.1) and Australia (6.3% CI: 5.3, 7.4) with a lower prevalence in North America (5.0% CI: 4.1-5.9) and Latin America and Caribbean (4.4% CI: 3.2-6.1). Females were found to have a higher prevalence than males (combined OR 1.22; 95% CI: 1.14, 1.30). The most commonly affected teeth were mandibular second premolars followed by maxillary lateral incisors and maxillary second premolars. The prevalence of mild, moderate and severe hypodontia was found to be 81.6, 14.3 and 3.1% respectively.There was a high variation in the prevalence of hypodontia between the studies. African populations were found to have a higher risk for tooth agenesis and there was an increased risk for females to have hypodontia than males.