A risk prediction model for head and neck cancers incorporating lifestyle factors, HPV serology and genetic markers.

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 5254 controls from five 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.

Hormonal factors in association with lung cancer among Asian women: A pooled analysis from the International Lung Cancer Consortium.

Two thousand sixty-four lung cancer cases and 5342 controls were evaluated in this International Lung Cancer Consortium (ILCCO) pooled analysis on estrogen-related hormonal factors and lung cancer in Asian women. Random effect of study site and fixed effect of age, smoking status, comprehensive smoking index and family history of lung cancer were adjusted for in the multivariable logistic regression models. We found that late onset of menarche conferred elevated odds of lung cancer with adjusted odds ratio (OR) of 1.24 (95% confidence interval [CI] = 1.05, 1.45) for 17 years or older, compared to 14 years or younger. Late onset of menopause at 55 years old or older was associated with lung cancer with OR = 1.24 (95% CI = 1.02, 1.51). Nonnatural menopause was associated with an OR of 1.39 (95% CI = 1.13, 1.71). More live births showed reversed association with lung cancer (ORs of 5 or more live births: 0.71 (95% CI = 0.60, 0.84), compared to 0-2 live births (Ptrend < 0.001). A later first child delivery seemed associated with an increased susceptibility: OR of 21 to 25 years old: 1.23 (95% CI = 1.06, 1.40), 26 or older: 1.27 (95% CI = 1.06, 1.52), Ptrend = .010). The use of oral contraceptives appeared to be protective with an OR of 0.69 (95% CI = 0.57, 0.83). Stronger for adenocarcinoma than squamous cell carcinoma, these relationships were not clearly modified by smoking status, probably because of lower prevalence of smoking. This is a first and largest pooling study of lung cancer among Asian women and the results suggested potential roles of hormone-related pathways in the etiology of this disease.

Child abuse and neglect during the COVID-19 pandemic: An umbrella review.

BACKGROUND: During the COVID-19 pandemic, multiple child health experts postulated that the stay-at-home orders would negatively impact child abuse and neglect. OBJECTIVES: We aimed to examine the impact of the COVID-19 pandemic on child abuse and neglect in children ages 18 and under; and review author recommendations for future emergency lockdown procedures. METHODS: We completed a systematic search of articles across five databases. Review-level studies were included if they examined any abuse or neglect related outcomes in children and youth (e.g., injuries, case openings), and were published in English. We completed quality appraisals of each included article using the Health Evidence™ tool. We categorized the findings by data source including administrative and survey data, or other data sources. We also narratively summarized reported recommendations. RESULTS: In total, 11 reviews were included. Two reviews were of strong quality, 7 moderate, and 2 were weak. Overall, studies within reviews that reported from administrative data sources demonstrated decreased child abuse and neglect outcomes compared to before the pandemic. Studies using cross-sectional data demonstrated increases. Reviews with mixed results often reported increases in emotional, neglect and psychological abuse cases and decreases physical and sexual abuse cases. CONCLUSIONS: This study found consistent results across reviews; depending on the data source and study design, child abuse and neglect outcomes either increased or decreased during the COVID-19 pandemic. Future work should enhance data collection methods for surveillance and intervention of child abuse and neglect during public health emergencies when traditional mechanisms are limited, with an increased focus on the rigor of reporting.

Design and methodological considerations for biomarker discovery and validation in the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Program.

The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.

Accounting for EGFR Mutations in Epidemiologic Analyses of Non-Small Cell Lung Cancers: Examples Based on the International Lung Cancer Consortium Data.

BACKGROUND: Somatic EGFR mutations define a subset of non-small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. METHODS: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. RESULTS: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74-0.77) in the training and 0.77 (95% CI, 0.74-0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. CONCLUSIONS: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. IMPACT: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

Are Sink Drainage Systems a Reservoir for Hospital-Acquired Gammaproteobacteria Colonization and Infection? A Systematic Review.

Increasing rates of antimicrobial-resistant organisms have focused attention on sink drainage systems as reservoirs for hospital-acquired Gammaproteobacteria colonization and infection. We aimed to assess the quality of evidence for transmission from this reservoir. We searched 8 databases and identified 52 studies implicating sink drainage systems in acute care hospitals as a reservoir for Gammaproteobacterial colonization/infection. We used a causality tool to summarize the quality of evidence. Included studies provided evidence of co-occurrence of contaminated sink drainage systems and colonization/infection, temporal sequencing compatible with sink drainage reservoirs, some steps in potential causal pathways, and relatedness between bacteria from sink drainage systems and patients. Some studies provided convincing evidence of reduced risk of organism acquisition following interventions. No single study provided convincing evidence across all causality domains, and the attributable fraction of infections related to sink drainage systems remains unknown. These results may help to guide conduct and reporting in future studies.

Germline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer.

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.

The relationship between body-mass index and overall survival in non-small cell lung cancer by sex, smoking status, and race: A pooled analysis of 20,937 International lung Cancer consortium (ILCCO) patients.

INTRODUCTION: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC). METHODS: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses. RESULTS: Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; pinteraction = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (pinteraction = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (pinteraction<0.001) and obese categories (pinteraction = 0.004) relative to the normal-BMI category, when compared to male ever-smokers. CONCLUSION: Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.

Nicotine dependence as a risk factor for upper aerodigestive tract (UADT) cancers: A mediation analysis.

PURPOSE: This study investigated nicotine dependence as an independent risk factor for upper aerodigestive tract (UADT) cancers, including lung and head and neck cancers (HNC). The study aimed to isolate the direct effect of nicotine dependence, independent of tobacco smoking. METHODS: A case-control study with a total of 4957 participants was conducted in Ontario, Canada, of which 2964 categorized as either current or former smokers were used in the analysis. Nicotine dependence of ever-smokers (2360 UADT cases and 604 controls) was measured using the Fagerström Test for Nicotine Dependence. Using mediation analyses and adjusted logistic regression models, we decomposed the direct effect of nicotine dependence and the mediated effect of smoking duration to quantify the risks of lung and HNC. The role of human papillomavirus (HPV) and cancer subtypes were assessed. RESULTS: Most individual nicotine dependence behaviours showed positive associations with lung cancer with approximately 1.8 to 3.5-fold risk increase, and to lesser extent with 1.4 to 2.3-fold risk for HNC. Nicotine dependence is partially accountable for increased risks of lung cancer (OR = 1.20, 95%CI = 1.13-1.28) and HNC (1.12, 95%CI = 1.04-1.19). Nicotine dependence had a greater effect on the risk of HPV-negative oropharyngeal cancer (OR = 3.06, 95%CI = 1.65-5.66) in comparison to HPV-positive oropharyngeal cancer (OR = 1.05, 95%CI = 0.67-1.65). The direct effects of nicotine dependence remained significant after accounting for cumulative tobacco exposures. CONCLUSION: Nicotine dependence increases the risks of lung and HNC cancers after accounting for tobacco smoking, suggesting potential toxic effects of nicotine. These results are informative for the safety consideration of nicotine exposures.

Risk factors for serious outcomes associated with influenza illness in high- versus low- and middle-income countries: Systematic literature review and meta-analysis.

AIM: To determine factors associated with a serious outcome (hospital admission or severe outcome: critical care or death) and associated with illness caused by laboratory-confirmed influenza, with a specific interest in low- and middle-income countries (LMIC). METHOD: Databases were searched on 11 March 2016 for reports of influenza and factors associated with mortality or morbidity in humans, with no language restrictions. Pooled risks were estimated using random-effects models. RESULTS: Despite the heterogeneity of results across studies, known risk factors for serious disease were associated with both hospital admission and severe outcomes (critical care and/or death). In LMIC, but not in high income countries (HIC), pregnant women, people with HIV/AIDS and children < 5 years old (compared with older children) were at increased risk of a severe outcome. Also, although all patients with neurological conditions were at higher risk of severe outcomes than those without, children were at higher risk than adults and children who lived in a LMIC were at significantly higher risk than those living in HIC. Adults were more likely than children to suffer a severe outcome if they had diabetes or a hematologic condition, were obese or had liver disease. Asthma is a risk factor for hospital admission but not for severe outcomes. CONCLUSION: Known risk factors for serious disease remain important predictors of hospital admission and severe outcomes with few differences between HIC and LMIC countries. These differences likely reflect differences in health-seeking behaviours and health services, but high heterogeneity between studies limits conclusions about the effect size.

The Cost-Effectiveness Analysis of Teleglaucoma Screening Device.

Glaucoma is the leading cause of irreversible vision loss and costs the American economy $2.9 billion. Teleglaucoma remotely detects glaucoma improving access to ophthalmic care in rural areas. It helps manage glaucoma more efficiently to preserve vision and reduce healthcare costs. A cost-effectiveness analysis was conducted using healthcare provider or third-party payer perspective within rural Canada. The study population were patients at-risk of glaucoma which includes those with diabetes and/or hypertension, family history of glaucoma, adults older than 50 years, and concurrent ocular conditions in rural Alberta. Markov modelling was used to model glaucoma health states. Effectiveness was measured in Quality-Adjusted Life Years (QALYs) and costs were used in Canadian dollars. Using TreeAge Pro 2009, incremental cost-effectiveness ratios (ICER) were developed in dollars per QALYs. Deterministic and probabilistic sensitivity analyses were performed to assess the factors affecting cost-effectiveness. Teleglaucoma had a 20% increase in ophthalmologist-referral rate; it reduced patient travel times by 61 hours and physician wait times by 30% in comparison to in-person examination (standard of care). Teleglaucoma costs $872 per patient screened which was 80% less than in-person examination. Teleglaucoma had a greater incremental effectiveness providing an additional 0.12 QALY per patient examination. It was more sensitive (86.5%) and less specific (78.6%) than in-person examination. Teleglaucoma was more cost-effective than in-person examination with an ICER of-$27,460/QALY. This indicated that teleglaucoma will save $27, 460 for each additional QALY gained. Long term benefits showed teleglaucoma prevents 24% cases of glaucoma blindness after 30 years. Teleglaucoma demonstrated improved health outcomes, as well as, cost benefits. It increases access to ophthalmic care and improves healthcare service efficiency, specifically in rural areas. Teleglaucoma is more cost-effective than current in-person examination and can improve the quality of life in glaucoma patients.

The effectiveness of teleglaucoma versus in-patient examination for glaucoma screening: a systematic review and meta-analysis.

BACKGROUND: Glaucoma is the leading cause of irreversible visual impairment in the world affecting 60.5 million people worldwide in 2010, which is expected to increase to approximately 79.6 million by 2020. Therefore, glaucoma screening is important to detect, diagnose, and treat patients at the earlier stages to prevent disease progression and vision loss. Teleglaucoma uses stereoscopic digital imaging to take ocular images, which are transmitted electronically to an ocular specialist. The purpose is to synthesize literature to evaluate teleglaucoma, its diagnostic accuracy, healthcare system benefits, and cost-effectiveness. METHODS: A systematic search was conducted to help locate published and unpublished studies. Studies which evaluate teleglaucoma as a screening device for glaucoma were included. A meta-analysis was conducted to provide estimates of diagnostic accuracy, diagnostic odds ratio, and the relative percentage of glaucoma cases detected. The improvements to healthcare service quality and cost data were assessed. RESULTS: Of 11237 studies reviewed, 45 were included. Our results indicated that, teleglaucoma is more specific and less sensitive than in-person examination. The pooled estimates of sensitivity was 0.832 [95% CI 0.770, 0.881] and specificity was 0.790 [95% CI 0.668, 0.876]. The relative odds of a positive screen test in glaucoma cases are 18.7 times more likely than a negative screen test in a non-glaucoma cases. Additionally, the mean cost for every case of glaucoma detected was $1098.67 US and of teleglaucoma per patient screened was $922.77 US. CONCLUSION: Teleglaucoma can accurately discriminate between screen test results with greater odds for positive cases. It detects more cases of glaucoma than in-person examination. Both patients and the healthcare systems benefit from early detection, reduction in wait and travel times, increased specialist referral rates, and cost savings. Teleglaucoma is an effective screening tool for glaucoma specifically for remote and under-services communities.