Global matters of epidemiology and the ethical challenges of addressing the health of populations.

PURPOSE: The American College of Epidemiology (ACE) held its 2022 Annual Meeting, September 8-11, with a conference theme of 'Pandemic of Misinformation: Building Trust in Epidemiology'. The ACE Ethics Committee hosted a symposium session in recognition of the global spotlight placed on epidemiology and public health due to the COVID-19 crisis. The ACE Ethics Committee invited previous Chairs of the Ethics Committee and current President of the International Epidemiological Association to present at the symposium session. This paper aims to highlight the ethical challenges presented during the symposium session. METHODS: Three speakers with diverse backgrounds representing expertize from the fields of ethics, epidemiology, public health, clinical trials, pharmacoepidemiology, statistics, law, and public policy, covering perspectives from the U.S., Europe, and Southeast Asia were selected to present on the ethical challenges in epidemiology and public health applying a global theme. Dr. D. Weed presented on 'Causation, Epidemiology and Ethics'; Dr. C.M. Pandey presented on the 'Ethical Challenges in the Practice of Digital Epidemiology'; and Dr. J. Acquavella presented on 'Departures from Scientific Objectivity: A Cause of Eroding Trust in Epidemiology.' RESULTS: The collective goal to improve the public's health was a mutually shared theme across the three distinct areas. We highlight the common ethical guidance and principle-based approaches that have served epidemiology and public health in framing and critical analysis of novel challenges, including autonomy, beneficence, justice, scientific integrity, duties to the profession and community, and developing and maintaining public trust; however, gaps remain in how best to address health inequalities and the novel emergence and pervasiveness of misinformation and disinformation that have impacted the health of the global community. We introduce an ethical framework of translational bioethics that places considerations of the social determinants of health at the forefront. CONCLUSIONS: The COVID-19 pandemic required an expedited public health response and, at the same time, placed the profession of epidemiology and public health, its system, and structures, under the microscope like never before. This article illustrates that revisiting our foundations in research and practice and orienting contemporary challenges using an ethical lens can assist in identifying and furthering the health of populations globally.

Commentary: On the reliability of causal claims.

Causal assessments in epidemiology are a complex process due to the many methods involved. The general scientific method lords over the process joined by study designs and statistical methods. Other methods include those that evaluate quality and bias along with the research synthesis methods such as the systematic narrative review, meta-analysis, and the criteria-based methods. When different investigators apply these methods to the same evidence and come up with different causal assessments, as described in the review by Goodman et al. in this issue, a key question becomes, how can the differences be explained? A prime candidate involves different methodologic choices. A deeper question emerges from this same situation: are the methods used for causal assessments reliable? Reliability is a hallmark of scientific practice. The methods used to make claims about causality should be reliable. Given the complexity of the causal assessment process, an objective evaluation of reliability is challenging but clearly worth the effort. Fortunately, Hill's criterion of analogy, much maligned in epidemiology, provides a clue. This commentary explores the issue of the reliability of causal claims using the Goodman et al. systematic review as its foil along with the claims by EPA, IARC, and ATSDR about the relationship between perchloroethylene and non-Hodgkin lymphoma, the claims Goodman et al. believe are wrong.

Does paraquat cause Parkinson's disease? A review of reviews.

To examine the extent to which a consensus exists in the scientific community regarding the relationship between exposure to paraquat and Parkinson's disease, a critical review of reviews was undertaken focusing on reviews published between 2006 and the present that offered opinions on the issue of causation. Systematic searches were undertaken of scientific databases along with searches of published bibliographies to identify English language reviews on the topic of paraquat and Parkinson's disease including those on the broader topic of environmental and occupational risk factors for Parkinson's disease. Of the 269 publications identified in the searches, there were twelve reviews, some with meta-analyses, that met the inclusion criteria. Information on methods used by the reviewers, if any, and source of funding was collected; the quality of the reviews was considered. No author of any published review stated that it has been established that exposure to paraquat causes Parkinson's disease, regardless of methods used and independent of funding source. A consensus exists in the scientific community that the available evidence does not warrant a claim that paraquat causes Parkinson's disease. Future research on this topic should focus on improving the quality of epidemiological studies including better exposure measures and identifying specific mechanisms of action. Future reviews of emerging evidence should be structured as systematic narrative reviews with meta-analysis if appropriate.

A metaphor for epidemiology: The sea of person time.

Metaphors have had an important role to play in the theory and practice of epidemiology. Some well-known examples include "black boxes," the "web of causation," "shoe-leather epidemiology," the "ivory tower" and the ubiquitous "gold standard." Metaphors like these do not replace methods or principles but rather like memes can spark a creative response and thoughtful reflection. In this paper, I bring to the attention of epidemiologists a metaphor that originated forty years ago in a paper describing and explaining measures of disease incidence. The authors wrote about a "sea of population time" to represent how incident disease events-specifically, incidence density measures- occur in the two-dimensional space of person-time. A "sea of population time" or "sea of person time" seems ideally suited as a metaphor for creative and thoughtful development in epidemiology. The vast and varied characteristics of oceans provide a plethora of ideas that can potentially help us to think more deeply about the role and responsibilities of epidemiologists. As an example, consider the notion that epidemiologists' journey across this sea in their methodologically-laden and concept-heavy fishing boats searching for the causes of disease. At the same time, epidemiologists live in the sea itself subject to and thus at risk of all the same diseases that affect human populations. Storms on this imaginary sea could sink our boats causing us to rethink conceptual and methodological frameworks. Here I provide in lyric form examples that explore what might exist behind the sea of person time and on its shores.

Analogy in causal inference: rethinking Austin Bradford Hill's neglected consideration.

The purpose of this article was to rethink and resurrect Austin Bradford Hill's "criterion" of analogy as an important consideration in causal inference. In epidemiology today, analogy is either completely ignored (e.g., in many textbooks), or equated with biologic plausibility or coherence, or aligned with the scientist's imagination. None of these examples, however, captures Hill's description of analogy. His words suggest that there may be something gained by contrasting two bodies of evidence, one from an established causal relationship, the other not. Coupled with developments in the methods of systematic assessments of evidence-including but not limited to meta-analysis-analogy can be restructured as a key component in causal inference. This new approach will require that a collection-a library-of known cases of causal inference (i.e., bodies of evidence involving established causal relationships) be developed. This library would likely include causal assessments by organizations such as the International Agency for Research on Cancer, the National Toxicology Program, and the United States Environmental Protection Agency. In addition, a process for describing key features of a causal relationship would need to be developed along with what will be considered paradigm cases of causation. Finally, it will be important to develop ways to objectively compare a "new" body of evidence with the relevant paradigm case of causation. Analogy, along with all other existing methods and causal considerations, may improve our ability to identify causal relationships.

Meta-analysis of Egg Consumption and Risk of Coronary Heart Disease and Stroke.

The possible relationship between dietary cholesterol and cardiac outcomes has been scrutinized for decades. However, recent reviews of the literature have suggested that dietary cholesterol is not a nutrient of concern. Thus, we conducted a meta-analysis of egg intake (a significant contributor to dietary cholesterol) and risk of coronary heart disease (CHD) and stroke. A comprehensive literature search was conducted through August 2015 to identify prospective cohort studies that reported risk estimates for egg consumption in association with CHD or stroke. Random-effects meta-analysis was used to generate summary relative risk estimates (SRREs) for high vs low intake and stratified intake dose-response analyses. Heterogeneity was examined in subgroups where sensitivity and meta regression analyses were conducted based on increasing egg intake. A 12% decreased risk (SRRE = 0.88, 95% confidence interval [CI], 0.81-0.97) of stroke was observed in the meta-analysis of 7 studies of egg intake (high vs low; generally 1/d vs <2/wk), with little heterogeneity (p-H = 0.37, I2 = 7.50). A nonstatistically significant SRRE of 0.97 (95% CI, 0.88-1.07, p-H = 0.67, I2 = 0.00) was observed in the meta-analysis of 7 studies of egg consumption and CHD. No clear dose-response trends were apparent in the stratified intake meta-analyses or the meta regression analyses. Based on the results of this meta-analysis, consumption of up to one egg daily may contribute to a decreased risk of total stroke, and daily egg intake does not appear to be associated with risk of CHD. Key Teaching Points: • The role of egg consumption in the risk of stroke and coronary heart disease has come under scrutiny over many years. • A comprehensive meta-analysis of prospective cohort studies that reported risk estimates for egg consumption in association with CHD or stroke was performed on the peer-reviewed epidemiologic literature through August 2015. • Overall, summary associations indicate that intake of up to 1 egg daily may be associated with reduced risk of total stroke. • Overall, summary associations show no clear association between egg intake and increased or decreased risk of CHD. • Eggs are a relatively low-cost and nutrient-dense whole food that provides a valuable source of protein, essential fatty acids, antioxidants, choline, vitamins, and minerals.

A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment.

The International Agency for Research on Cancer (IARC) published a monograph in 2015 concluding that glyphosate is "probably carcinogenic to humans" (Group 2A) based on limited evidence in humans and sufficient evidence in experimental animals. It was also concluded that there was strong evidence of genotoxicity and oxidative stress. Four Expert Panels have been convened for the purpose of conducting a detailed critique of the evidence in light of IARC's assessment and to review all relevant information pertaining to glyphosate exposure, animal carcinogenicity, genotoxicity, and epidemiologic studies. Two of the Panels (animal bioassay and genetic toxicology) also provided a critique of the IARC position with respect to conclusions made in these areas. The incidences of neoplasms in the animal bioassays were found not to be associated with glyphosate exposure on the basis that they lacked statistical strength, were inconsistent across studies, lacked dose-response relationships, were not associated with preneoplasia, and/or were not plausible from a mechanistic perspective. The overall weight of evidence from the genetic toxicology data supports a conclusion that glyphosate (including GBFs and AMPA) does not pose a genotoxic hazard and therefore, should not be considered support for the classification of glyphosate as a genotoxic carcinogen. The assessment of the epidemiological data found that the data do not support a causal relationship between glyphosate exposure and non-Hodgkin's lymphoma while the data were judged to be too sparse to assess a potential relationship between glyphosate exposure and multiple myeloma. As a result, following the review of the totality of the evidence, the Panels concluded that the data do not support IARC's conclusion that glyphosate is a "probable human carcinogen" and, consistent with previous regulatory assessments, further concluded that glyphosate is unlikely to pose a carcinogenic risk to humans.

Glyphosate epidemiology expert panel review: a weight of evidence systematic review of the relationship between glyphosate exposure and non-Hodgkin's lymphoma or multiple myeloma.

We conducted a systematic review of the epidemiologic literature for glyphosate focusing on non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) - two cancers that were the focus of a recent review by an International Agency for Research on Cancer Working Group. Our approach was consistent with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews. We evaluated each relevant study according to a priori criteria for study quality: adequacy of study size, likelihood of confounding, potential for other biases and adequacy of the statistical analyses. Our evaluation included seven unique studies for NHL and four for MM, all but one of which were case control studies for each cancer. For NHL, the case-control studies were all limited by the potential for recall bias and the lack of adequate multivariate adjustment for multiple pesticide and other farming exposures. Only the Agricultural Health (cohort) Study met our a priori quality standards and this study found no evidence of an association between glyphosate and NHL. For MM, the case control studies shared the same limitations as noted for the NHL case-control studies and, in aggregate, the data were too sparse to enable an informed causal judgment. Overall, our review did not find support in the epidemiologic literature for a causal association between glyphosate and NHL or MM.

Red Meat and Colorectal Cancer: A Quantitative Update on the State of the Epidemiologic Science.

The potential relationship between red meat consumption and colorectal cancer (CRC) has been the subject of scientific debate. Given the high degree of resulting uncertainty, our objective was to update the state of the science by conducting a systematic quantitative assessment of the epidemiologic literature. Specifically, we updated and expanded our previous meta-analysis by integrating data from new prospective cohort studies and conducting a broader evaluation of the relative risk estimates by specific intake categories. Data from 27 independent prospective cohort studies were meta-analyzed using random-effects models, and sources of potential heterogeneity were examined through subgroup and sensitivity analyses. In addition, a comprehensive evaluation of potential dose-response patterns was conducted. In the meta-analysis of all cohorts, a weakly elevated summary relative risk was observed (1.11, 95% CI: 1.03-1.19); however, statistically significant heterogeneity was present. In general, summary associations were attenuated (closer to the null and less heterogeneous) in models that isolated fresh red meat (from processed meat), adjusted for more relevant factors, analyzed women only, and were conducted in countries outside of the United States. Furthermore, no clear patterns of dose-response were apparent. In conclusion, the state of the epidemiologic science on red meat consumption and CRC is best described in terms of weak associations, heterogeneity, an inability to disentangle effects from other dietary and lifestyle factors, lack of a clear dose-response effect, and weakening evidence over time. KEY TEACHING POINTS: •The role of red meat consumption in colorectal cancer risk has been widely contested among the scientific community.•In the current meta-analysis of red meat intake and colorectal cancer, we comprehensively examined associations by creating numerous sub-group stratifications, conducting extensive sensitivity analyses, and evaluating dose-response using several different methods.•Overall, all summary associations were weak in magnitude with no clear dose-response patterns.•Interpretation of findings from epidemiologic studies investigating diet and health outcomes involves numerous methodological considerations, such as accurately measuring food intake, dietary pattern differences across populations, food definitions, outcome classifications, bias and confounding, multicollinearity, biological mechanisms, genetic variation in metabolizing enzymes, and differences in analytical metrics and statistical testing parameters.

Meta-Analysis of Long-Chain Omega-3 Polyunsaturated Fatty Acids (LCω-3PUFA) and Prostate Cancer.

We conducted a systematic review and meta-analysis to estimate the potential association between LCω-3PUFAs and prostate cancer (PC). A comprehensive literature search was performed through 2013 to identify prospective studies that examined dietary intakes of long-chain omega-3 polyunsaturated fatty acids (LCω-3PUFA) or blood biomarkers of LCω-3PUFA status and risk of PC. Random-effects meta-analyses were conducted to generate summary relative risk estimates (SRREs) for LCω-3PUFAs and total PC, and by stage and grade. Subgroup analyses were also conducted for specific fatty acids and other study characteristics. Twelve self-reported dietary intake and 9 biomarker studies from independent study populations were included in the analysis, with 446,243 and 14,897 total participants, respectively. No association between LCω-3PUFAs and total PC was observed (SRRE = 1.00, 95% CI: 0.93-1.09) for the dietary intake studies (high vs. low LCω-3PUFAs category comparison) or for the biomarker studies (SRRE of 1.07, 95% CI: 0.94-1.20). In general, most summary associations for the dietary intake studies were in the inverse direction, whereas the majority of summary associations for the biomarker studies were in the positive direction, but all were weak in magnitude. The results from this meta-analysis do not support an association between LCω-3PUFAs and PC.

Evidence-based mapping of design heterogeneity prior to meta-analysis: a systematic review and evidence synthesis.

BACKGROUND: Assessment of design heterogeneity conducted prior to meta-analysis is infrequently reported; it is often presented post hoc to explain statistical heterogeneity. However, design heterogeneity determines the mix of included studies and how they are analyzed in a meta-analysis, which in turn can importantly influence the results. The goal of this work is to introduce ways to improve the assessment and reporting of design heterogeneity prior to statistical summarization of epidemiologic studies. METHODS: In this paper, we use an assessment of sugar-sweetened beverages (SSB) and type 2 diabetes (T2D) as an example to show how a technique called 'evidence mapping' can be used to organize studies and evaluate design heterogeneity prior to meta-analysis.. Employing a systematic and reproducible approach, we evaluated the following elements across 11 selected cohort studies: variation in definitions of SSB, T2D, and co-variables, design features and population characteristics associated with specific definitions of SSB, and diversity in modeling strategies. RESULTS: Evidence mapping strategies effectively organized complex data and clearly depicted design heterogeneity. For example, across 11 studies of SSB and T2D, 7 measured diet only once (with 7 to 16 years of disease follow-up), 5 included primarily low SSB consumers, and 3 defined the study variable (SSB) as consumption of either sugar or artificially-sweetened beverages. This exercise also identified diversity in analysis strategies, such as adjustment for 11 to 17 co-variables and a large degree of fluctuation in SSB-T2D risk estimates depending on variables selected for multivariable models (2 to 95% change in the risk estimate from the age-adjusted model). CONCLUSIONS: Meta-analysis seeks to understand heterogeneity in addition to computing a summary risk estimate. This strategy effectively documents design heterogeneity, thus improving the practice of meta-analysis by aiding in: 1) protocol and analysis planning, 2) transparent reporting of differences in study designs, and 3) interpretation of pooled estimates. We recommend expanding the practice of meta-analysis reporting to include a table that summarizes design heterogeneity. This would provide readers with more evidence to interpret the summary risk estimates.

The role of red and processed meat in colorectal cancer development: a perspective.

This paper is based on a workshop held in Oslo, Norway in November 2013, in which experts discussed how to reach consensus on the healthiness of red and processed meat. Recent nutritional recommendations include reducing intake of red and processed meat to reduce cancer risk, in particular colorectal cancer (CRC). Epidemiological and mechanistic data on associations between red and processed meat intake and CRC are inconsistent and underlying mechanisms are unclear. There is a need for further studies on differences between white and red meat, between processed and whole red meat and between different types of processed meats, as potential health risks may not be the same for all products. Better biomarkers of meat intake and of cancer occurrence and updated food composition databases are required for future studies. Modifying meat composition via animal feeding and breeding, improving meat processing by alternative methods such as adding phytochemicals and improving our diets in general are strategies that need to be followed up.

A systematic review of multivitamin-multimineral use and cardiovascular disease and cancer incidence and total mortality.

Multivitamin-multimineral (MVM) supplements are the most frequently used dietary supplements in the United States, with one third or more of the population using at least one daily. However, the health-related implications of MVM use are unclear. Thus, we systematically reviewed and summarized the prospective studies of MVM supplementation and all-cause and cause-specific mortality, as well as cardiovascular disease (CVD) and cancer incidence, to critically evaluate the current evidence on this topic. We included studies of generally healthy adult populations that evaluated multivitamin (the most commonly used dietary supplement) and/or multimineral supplement use or simultaneous use of 3 or more vitamins and minerals. We did not evaluate individual supplements. A total of 12 cohort studies and 3 primary prevention randomized controlled trials met our inclusion criteria. The majority of the studies were conducted in the United States (n = 11), and the remaining were conducted in European countries (n = 3) and Japan (n = 1). Although between-study methodological variation was present, most relative risks hovered closely around or slightly below the null value. No clear patterns of associations by study country, gender, smoking status, or frequency of use were observed. Based upon the available scientific evidence to date, supplementation with MVMs does not appear to increase all-cause mortality, cancer incidence or mortality, or CVD incidence or mortality and may provide a modest protective benefit.

Evidence mapping: methodologic foundations and application to intervention and observational research on sugar-sweetened beverages and health outcomes.

BACKGROUND: Evidence maps are a new method that systematically characterize the range of research activity in broad topic areas and are used to guide research priority setting, systematic reviews, and meta-analyses. OBJECTIVE: We expanded evidence mapping methods by demonstrating their usefulness as a tool for organizing epidemiologic research on sugar-sweetened beverage (SSB) intake and health outcomes: obesity, type 2 diabetes, metabolic syndrome, and coronary heart disease/stroke. DESIGN: We performed a search of the PubMed, Scopus, and Cochrane databases and a hand search of references. Studies selected were reviews and longitudinal studies (intervention and cohort) published between 1 January 1966 and 31 October 2012. RESULTS: We identified and mapped 77 studies (18 review and 59 primary research articles); most of the research focused on obesity (n = 47). For all outcomes, >30% (n = 18) of the primary research studies we identified were not referenced in published reviews. We found considerable variability among primary research studies of SSBs and the 4 health outcomes in terms of designs, definitions of SSBs, and definitions of outcomes, which renders these studies difficult to interpret collectively. For example, we counted 14 different definitions of weight/obesity in 29 observational cohort studies, and ≤6 studies reported the use of the same outcome measure. CONCLUSIONS: Establishing field standards in the study of SSB intake and health outcomes would facilitate interpretation across research studies and thereby increase the utility of systematic reviews/meta-analyses and ultimately the efficiency of research efforts. Rapid publication of new data suggests the need for regular updates and caution when reading reviews.

The quality of nutrition and cancer reviews: a systematic assessment.

The methodological quality of published reviews of nutrition and cancer (2008-2009) and of the carcinogenicity of acrylamide (1999-2009) was systematically assessed. Each review was examined with respect to four characteristics: whether the purpose of the review was explicitly stated, whether a methods section (detailing the methods used to "weigh" the evidence) was included, whether "weight of evidence" methods were described elsewhere in the paper (e.g., in the discussion), and finally, whether references to recognized "weight of evidence" methods were included. In this study, ninety per cent of a systematically selected sample of recent reviews on nutrition and cancer published in 2008-2009 and 74% of reviews on acrylamide on cancer published in 1999-2009 were found to be methodologically troublesome or frankly unsound. Failure of peer review and editorial oversight are possible explanations, suggesting a broad lack of concern about this issue in the scientific community. If peer reviewers in the nutrition and cancer community do not require "weight of evidence" methods, then these methods may not appear in the published reviews. Similarly, if journal editors (or editorial policies) do not require methods sections in literature reviews, then these sections may not appear. The prerogative of the author(s) seems the most likely determinant of whether a systematic approach is used or not in nutrition and cancer reviews.

A weight-of-evidence review of colorectal cancer in pesticide applicators: the agricultural health study and other epidemiologic studies.

OBJECTIVE: To systematically evaluate epidemiologic studies on pesticides and colon cancer and rectal cancer in agricultural pesticide applicator populations using a transparent "weight-of-evidence" (WOE) methodological approach. METHODS: Twenty-nine (29) publications from the Agricultural Health Study (AHS) and 13 additional epidemiologic studies were identified that reported data for pesticide applicators and/or specific pesticide compounds and colorectal, colon, or rectal cancer. The AHS evaluated pesticide applicators as well as dose-response associations for specific pesticide compounds, whereas the large majority of non-AHS evaluated applicators but did not analyze specific compounds or dose-response trends. This WOE assessment of 153 different pesticide-outcome pairs emphasized several key evidentiary features: existence of statistically significant relative risks, magnitude of observed associations, results from the most reliable exposure assessments, and evidence of convincing dose-response relationships (i.e., those monotonically increasing, with statistically significant trend tests). RESULTS: Occupation as a pesticide applicator or pesticide application as a farming-related function was not associated with increasing the risk of colon or rectal cancer. Deficits of colon or rectal cancer were observed across most studies of pesticide applicators. After applying the WOE methodology to the epidemiologic studies of specific pesticide compounds and colon or rectal cancer, a number of pesticide-outcome pairs were identified and evaluated further based on positive statistical associations. Of these, only two-aldicarb and colon cancer and imazethapyr and proximal colon cancer-appears to warrant further discussion regarding a possible causal relationship, although the epidemiologic data are limited. For the remainder, a lack of a clear dose-response trend, inconsistencies in associations between exposure metrics and comparison groups, imprecise associations, variable participation rates for analyses of specific compounds, and the reliance upon data from one study (the AHS) limit interpretation regarding risk. CONCLUSION: The available epidemiologic evidence does not support a causal relationship between occupation as a pesticide applicator or specific pesticide exposures and colon or rectal cancer.