Health effects associated with chewing tobacco: a Burden of Proof study.

Chewing tobacco use poses serious health risks; yet it has not received as much attention as other tobacco-related products. This study synthesizes existing evidence regarding the health impacts of chewing tobacco while accounting for various sources of uncertainty. We conducted a systematic review and meta-analysis of chewing tobacco and seven health outcomes, drawing on 103 studies published from 1970 to 2023. We use a Burden of Proof meta-analysis to generate conservative risk estimates and find weak-to-moderate evidence that tobacco chewers have an increased risk of stroke, lip and oral cavity cancer, esophageal cancer, nasopharynx cancer, other pharynx cancer, and laryngeal cancer. We additionally find insufficient evidence of an association between chewing tobacco and ischemic heart disease. Our findings highlight a need for policy makers, researchers, and communities at risk to devote greater attention to chewing tobacco by both advancing tobacco control efforts and investing in strengthening the existing evidence base.

Health effects associated with exposure to secondhand smoke: a Burden of Proof study.

Despite a gradual decline in smoking rates over time, exposure to secondhand smoke (SHS) continues to cause harm to nonsmokers, who are disproportionately children and women living in low- and middle-income countries. We comprehensively reviewed the literature published by July 2022 concerning the adverse impacts of SHS exposure on nine health outcomes. Following, we quantified each exposure-response association accounting for various sources of uncertainty and evaluated the strength of the evidence supporting our analyses using the Burden of Proof Risk Function methodology. We found all nine health outcomes to be associated with SHS exposure. We conservatively estimated that SHS increases the risk of ischemic heart disease, stroke, type 2 diabetes and lung cancer by at least around 8%, 5%, 1% and 1%, respectively, with the evidence supporting these harmful associations rated as weak (two stars). The evidence supporting the harmful associations between SHS and otitis media, asthma, lower respiratory infections, breast cancer and chronic obstructive pulmonary disease was weaker (one star). Despite the weak underlying evidence for these associations, our results reinforce the harmful effects of SHS on health and the need to prioritize advancing efforts to reduce active and passive smoking through a combination of public health policies and education initiatives.

The Global, Regional, and National Burden of Adult Lip, Oral, and Pharyngeal Cancer in 204 Countries and Territories: A Systematic Analysis for the Global Burden of Disease Study 2019.

Importance: Lip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning. Objective: To analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates. Evidence Review: The incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019. Findings: In 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia. Conclusions and Relevance: In this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

The Burden of Proof studies: assessing the evidence of risk.

Exposure to risks throughout life results in a wide variety of outcomes. Objectively judging the relative impact of these risks on personal and population health is fundamental to individual survival and societal prosperity. Existing mechanisms to quantify and rank the magnitude of these myriad effects and the uncertainty in their estimation are largely subjective, leaving room for interpretation that can fuel academic controversy and add to confusion when communicating risk. We present a new suite of meta-analyses-termed the Burden of Proof studies-designed specifically to help evaluate these methodological issues objectively and quantitatively. Through this data-driven approach that complements existing systems, including GRADE and Cochrane Reviews, we aim to aggregate evidence across multiple studies and enable a quantitative comparison of risk-outcome pairs. We introduce the burden of proof risk function (BPRF), which estimates the level of risk closest to the null hypothesis that is consistent with available data. Here we illustrate the BPRF methodology for the evaluation of four exemplar risk-outcome pairs: smoking and lung cancer, systolic blood pressure and ischemic heart disease, vegetable consumption and ischemic heart disease, and unprocessed red meat consumption and ischemic heart disease. The strength of evidence for each relationship is assessed by computing and summarizing the BPRF, and then translating the summary to a simple star rating. The Burden of Proof methodology provides a consistent way to understand, evaluate and summarize evidence of risk across different risk-outcome pairs, and informs risk analysis conducted as part of the Global Burden of Diseases, Injuries, and Risk Factors Study.

Health effects associated with vegetable consumption: a Burden of Proof study.

Previous research suggests a protective effect of vegetable consumption against chronic disease, but the quality of evidence underlying those findings remains uncertain. We applied a Bayesian meta-regression tool to estimate the mean risk function and quantify the quality of evidence for associations between vegetable consumption and ischemic heart disease (IHD), ischemic stroke, hemorrhagic stroke, type 2 diabetes and esophageal cancer. Increasing from no vegetable consumption to the theoretical minimum risk exposure level (306-372 g daily) was associated with a 23.2% decline (95% uncertainty interval, including between-study heterogeneity: 16.4-29.4) in ischemic stroke risk; a 22.9% (13.6-31.3) decline in IHD risk; a 15.9% (1.7-28.1) decline in hemorrhagic stroke risk; a 28.5% (-0.02-51.4) decline in esophageal cancer risk; and a 26.1% (-3.6-48.3) decline in type 2 diabetes risk. We found statistically significant protective effects of vegetable consumption for ischemic stroke (three stars), IHD (two stars), hemorrhagic stroke (two stars) and esophageal cancer (two stars). Including between-study heterogeneity, we did not detect a significant association with type 2 diabetes, corresponding to a one-star rating. Although current evidence supports increased efforts and policies to promote vegetable consumption, remaining uncertainties suggest the need for continued research.

Health effects associated with consumption of unprocessed red meat: a Burden of Proof study.

Characterizing the potential health effects of exposure to risk factors such as red meat consumption is essential to inform health policy and practice. Previous meta-analyses evaluating the effects of red meat intake have generated mixed findings and do not formally assess evidence strength. Here, we conducted a systematic review and implemented a meta-regression-relaxing conventional log-linearity assumptions and incorporating between-study heterogeneity-to evaluate the relationships between unprocessed red meat consumption and six potential health outcomes. We found weak evidence of association between unprocessed red meat consumption and colorectal cancer, breast cancer, type 2 diabetes and ischemic heart disease. Moreover, we found no evidence of an association between unprocessed red meat and ischemic stroke or hemorrhagic stroke. We also found that while risk for the six outcomes in our analysis combined was minimized at 0 g unprocessed red meat intake per day, the 95% uncertainty interval that incorporated between-study heterogeneity was very wide: from 0-200 g d-1. While there is some evidence that eating unprocessed red meat is associated with increased risk of disease incidence and mortality, it is weak and insufficient to make stronger or more conclusive recommendations. More rigorous, well-powered research is needed to better understand and quantify the relationship between consumption of unprocessed red meat and chronic disease.

Health effects associated with smoking: a Burden of Proof study.

As a leading behavioral risk factor for numerous health outcomes, smoking is a major ongoing public health challenge. Although evidence on the health effects of smoking has been widely reported, few attempts have evaluated the dose-response relationship between smoking and a diverse range of health outcomes systematically and comprehensively. In the present study, we re-estimated the dose-response relationships between current smoking and 36 health outcomes by conducting systematic reviews up to 31 May 2022, employing a meta-analytic method that incorporates between-study heterogeneity into estimates of uncertainty. Among the 36 selected outcomes, 8 had strong-to-very-strong evidence of an association with smoking, 21 had weak-to-moderate evidence of association and 7 had no evidence of association. By overcoming many of the limitations of traditional meta-analyses, our approach provides comprehensive, up-to-date and easy-to-use estimates of the evidence on the health effects of smoking. These estimates provide important information for tobacco control advocates, policy makers, researchers, physicians, smokers and the public.

Estimating health care delivery system value for each US state and testing key associations.

OBJECTIVE: To estimate health care systems' value in treating major illnesses for each US state and identify system characteristics associated with value. DATA SOURCES: Annual condition-specific death and incidence estimates for each US state from the Global Burden Disease 2019 Study and annual health care spending per person for each state from the National Health Expenditure Accounts. STUDY DESIGN: Using non-linear meta-stochastic frontier analysis, mortality incidence ratios for 136 major treatable illnesses were regressed separately on per capita health care spending and key covariates such as age, obesity, smoking, and educational attainment. State- and year-specific inefficiency estimates were extracted for each health condition and combined to create a single estimate of health care delivery system value for each US state for each year, 1991-2014. The association between changes in health care value and changes in 23 key health care system characteristics and state policies was measured. DATA COLLECTION/EXTRACTION METHODS: Not applicable. PRINCIPAL FINDINGS: US state with relatively high spending per person or relatively poor health-outcomes were shown to have low health care delivery system value. New Jersey, Maryland, Florida, Arizona, and New York attained the highest value scores in 2014 (81 [95% uncertainty interval 72-88], 80 [72-87], 80 [71-86], 77 [69-84], and 77 [66-85], respectively), after controlling for health care spending, age, obesity, smoking, physical activity, race, and educational attainment. Greater market concentration of hospitals and of insurers were associated with worse health care value (p-value ranging from <0.01 to 0.02). Higher hospital geographic density and use were also associated with worse health care value (p-value ranging from 0.03 to 0.05). Enrollment in Medicare Advantage HMOs was associated with better value, as was more generous Medicaid income eligibility (p-value 0.04 and 0.01). CONCLUSIONS: Substantial variation in the value of health care exists across states. Key health system characteristics such as market concentration and provider density were associated with value.

Cost-effectiveness of HPV vaccination in 195 countries: A meta-regression analysis.

Cost-effectiveness analysis (CEA) is a well-known, but resource intensive, method for comparing the costs and health outcomes of health interventions. To build on available evidence, researchers are developing methods to transfer CEA across settings; previous methods do not use all available results nor quantify differences across settings. We conducted a meta-regression analysis of published CEAs of human papillomavirus (HPV) vaccination to quantify the effects of factors at the country, intervention, and method-level, and predict incremental cost-effectiveness ratios (ICERs) for HPV vaccination in 195 countries. We used 613 ICERs reported in 75 studies from the Tufts University's Cost-Effectiveness Analysis (CEA) Registry and the Global Health CEA Registry, and extracted an additional 1,215 one-way sensitivity analyses. A five-stage, mixed-effects meta-regression framework was used to predict country-specific ICERs. The probability that HPV vaccination is cost-saving in each country was predicted using a logistic regression model. Covariates for both models included methods and intervention characteristics, and each country's cervical cancer burden and gross domestic product per capita. ICERs are positively related to vaccine cost, and negatively related to cervical cancer burden. The mean predicted ICER for HPV vaccination is 2017 US$4,217 per DALY averted (95% uncertainty interval (UI): US$773-13,448) globally, and below US$800 per DALY averted in 64 countries. Predicted ICERs are lowest in Sub-Saharan Africa and South Asia, with a population-weighted mean ICER across 46 countries of US$706 per DALY averted (95% UI: $130-2,245), and across five countries of US$489 per DALY averted (95% UI: $90-1,557), respectively. Meta-regression analyses can be conducted on CEA, where one-way sensitivity analyses are used to quantify the effects of factors at the intervention and method-level. Building on all published results, our predictions support introducing and expanding HPV vaccination, especially in countries that are eligible for subsidized vaccines from GAVI, the Vaccine Alliance, and Pan American Health Organization.

(18)F-FDG PET/CT-positive internal mammary lymph nodes: pathologic correlation by ultrasound-guided fine-needle aspiration and assessment of associated risk factors.

OBJECTIVE: Metastatic breast cancer in internal mammary (IM) lymph nodes is associated with a poor prognosis. This study correlates (18)F-FDG PET/CT-positive IM lymph nodes with ultrasound-guided fine-needle aspiration (FNA) cytopathologic results and determines risk factors for IM node positivity on PET/CT. MATERIALS AND METHODS: For this retrospective study, a database search was performed to identify patients referred for whole-body (18)F-FDG PET/CT for initial staging or restaging of breast cancer from January 1, 2005, through December 31, 2010. The radiology reports and images were reviewed for patients with (18)F-FDG-avid IM lymph nodes on PET/ CT and correlated with the cytopathologic results from FNA of selected PET/CT-positive IM lymph nodes. The patients with positive IM nodes on PET/CT who underwent PET/CT for initial staging were compared against age-matched and tumor size-matched patients to identify risk factors for IM node positivity on PET/CT. RESULTS: One hundred ten of 1259 patients (9%) had an (18)F-FDG-avid IM lymph node on PET/CT. Twenty-five patients underwent ultrasound-guided FNA of a suspicious IM node, and 20 IM lymph nodes (80%) were cytologically proven metastases from the primary breast malignancy. High tumor grade, the presence of lymphovascular invasion (LVI), and triple receptor-negative hormonal receptor status were found to be significant risk factors for IM node positivity on PET/CT (p < 0.05). CONCLUSION: Although fewer than 10% of breast cancer patients have positive IM nodes on (18)F-FDG PET/CT performed for initial staging or restaging, a positive IM node indicates a very high likelihood of malignant involvement on ultrasound-guided FNA. The presences of high tumor grade, LVI, or triple receptor-negative status are risk factors for IM node positivity on (18)F-FDG PET/CT.

Positron emission mammography: correlation of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status and 18F-FDG.

OBJECTIVE: The study objective was to assess the correlation between (18)F-FDG uptake values on positron emission mammography (PEM), expressed as maximum uptake value and lesion-to-background ratio, and receptor status (i.e., estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]), tumor histology, and tumor grade. We also evaluated for the correlation between maximum uptake value on PEM and maximum uptake value on a whole-body PET/CT. MATERIALS AND METHODS: We retrospectively reviewed our database for patients with newly diagnosed breast cancer who were referred for PEM between June 2007 and September 2009. A subset of patients also underwent a whole-body PET/CT scan. The original pathology reports were reviewed to establish the histologic type, grade, and receptor status. RESULTS: The study involved 98 patients with 100 lesions. ER-negative tumors and PR-negative tumors had significantly higher mean lesion-to-background ratio than did their respective receptor-positive tumors (p = 0.02). Triple-negative tumors (i.e., ER-negative, PR-negative, and HER2-negative tumors) had statistically higher mean lesion-to-background ratio than did ER-positive PR-positive HER2-negative tumors (p = 0.04). Infiltrating ductal carcinomas had significantly higher PEM FDG uptake values than did infiltrating lobular carcinomas (p = 0.02-0.04). Breast tumors with higher histologic grade also had significantly higher PEM FDG uptake values than did those with lower grade (p = 0.03 and p < 0.001). A moderately high correlation (0.76-0.79) was seen between whole-body PET/CT and PEM uptake values. CONCLUSION: This study shows a correlation between PEM FDG uptake values and the prognostic factors that have been shown to predict breast cancer survival.