Advancing Biomarkers for Treatment of Smoking and Nicotine Dependence: An Overview.

The special issue on Biomarkers of Nicotine and Tobacco Dependence reviews the science for precision treatment of nicotine dependence and future opportunities for research on biomarkers for inclusion in tobacco product cessation and switching clinical trials to advance translation. This overview summarizes the articles contributed to the special issue by leading researcher in field of addiction.

Impact of National Institutes of Health and Food and Drug Administration Tobacco Research Funding: A Bibliometrics Analyses.

INTRODUCTION: Conduct bibliometric analyses documenting the output of National Institutes of Health (NIH) tobacco-related and Food and Drug Administration (FDA) tobacco regulatory science (FDA-TRS) research portfolios. AIMS AND METHODS: PubMed identifiers for publications between 2015 and 2020 citing tobacco funding by NIH and/or FDA were imported into NIH iCite generating measures of productivity and influence, including number of citations, journal, relative citation ratios (RCR), and comparison of research influence across Web of Science (WoS) disciplines. Coauthorship and measures of centrality among and between NIH and FDA-supported investigators gauged collaboration. RESULTS: Between FY 2015 and 2020, 8160 publications cited funding from NIH tobacco-related grants, 1776 cited FDA-TRS grants and 496 cited Common funding (ie, both NIH and FDA-TRS funding). The proportion of publications citing NIH grants declined while those citing FDA-TRS or Common funding rose significantly. Publications citing Common funding showed the highest influence (mean RCR = 2.52). Publications citing FDA-TRS funding displayed higher median RCRs than publications citing NIH funding in most WoS categories. Higher translational progress was estimated over time for FDA-TRS and Common publications compared to NIH publications. Authors citing Common funding scored highest across all collaboration measures. CONCLUSIONS: This study demonstrates the high bibliometric output of tobacco research overall. The rise in publications citing FDA-TRS and Common likely reflects increased funding for TRS research. Higher RCRs across WoS subject categories and trends towards human translation among FDA-TRS and Common publications indicate focus on research to inform regulation. This analysis suggests that FDA support for TRS has expanded the field of tobacco control resulting in sustained productivity, influence, and collaboration. IMPLICATIONS: This paper is the first effort to better describe the impact of tobacco research resulting from the addition of FDA funding for TRS in the past decade. The analysis provides impetus for further investigation into the publication topics and their focus which would offer insight into the specific evidence generated on tobacco control and regulation.

NIH Tobacco Research and the Emergence of Tobacco Regulatory Science.

INTRODUCTION: This study explores how the emergence of FDA-funded Tobacco Regulatory Science (TRS) research complements and perhaps influenced the direction of tobacco research supported by NIH. AIMS AND METHODS: New NIH- and FDA-funded tobacco projects awarded in fiscal years (FY) 2011-2020 were identified using internal NIH databases of awarded grants. Project abstracts and research aims were coded by the authors to characterize research domains and tobacco products studied. RESULTS: Between FY 2011 and 2020, NIH funded 1032 and FDA funded 322 new tobacco projects. For the years and grant activity codes studied, the number of new NIH tobacco projects declined while FDA's increased; combined the number of new projects held steady. Much of NIH research included smoking combustibles (43.7%). The most common products in FDA research were cigarettes (74.8%) and e-cigarettes/ENDS (48.1%). Most NIH (58.6%) and FDA (67.7%) projects included research on the determinants of tobacco use. Another area of apparent overlap was health effects (29.5% NIH and 30.1% FDA). Projects unique to NIH included treatment interventions (33.3%), disease pathology/progression (17.8%) and neurobiology (18.9%). A minority of both NIH and FDA projects included populations particularly vulnerable to tobacco product use. CONCLUSIONS: In total, support for new tobacco research supported by NIH and FDA combined remained steady for the time period covered, though there was a concomitant decline in NIH tobacco projects with the increase in FDA-funded TRS projects for the activity codes studied. Despite the apparent overlap in some areas, both NIH and FDA support research that is unique to their respective missions. IMPLICATIONS: NIH continues to support tobacco research that falls within and outside of FDA's regulatory authorities. This research still is needed not only to bolster the evidence base for regulatory decisions at the national and state levels, but also to advance a comprehensive scientific agenda that can inform multiple levels of influence on tobacco control, use and addiction. It will be important to continue monitoring FDA-funded TRS and NIH-funded tobacco research portfolios to ensure that the level of support for and focus of the research is sufficient to address the burden of tobacco-related morbidity and mortality.

Host-agent-vector-environment measures for electronic cigarette research used in NIH grants.

OBJECTIVE: The purpose of this study is to describe the focus and comprehensiveness of domains measured in e-cigarette research. METHODS: A portfolio analysis of National Institutes of Health grants focusing on e-cigarette research and funded between the fiscal years 2007 and 2015 was conducted. Grant proposals were retrieved using a government database and coded using the Host-Agent-Vector-Environment (HAVE) model as a framework to characterise the measures proposed. Eighty-one projects met the criteria for inclusion in the analysis. RESULTS: The primary HAVE focus most commonly found was Host (73%), followed by Agent (21%), Vector (6%) and Environment (0%). Intrapersonal measures and use trajectories were the most common measures in studies that include Host measures (n=59 and n=51, respectively). Product composition was the most common area of measurement in Agent studies (n=24), whereas Marketing (n=21) was the most common (n=21) area of Vector measurement. When Environment measures were examined as secondary measures in studies, they primarily focused on measuring Peer, Occupation and Social Networks (n=18). Although all studies mentioned research on e-cigarettes, most (n=52; 64%) did not specify the type of e-cigarette device or liquid solution under study. CONCLUSIONS: This analysis revealed a heavy focus on Host measures (73%) and a lack of focus on Environment measures. The predominant focus on Host measures may have the unintended effect of limiting the evidence base for tobacco control and regulatory science. Further, a lack of specificity about the e-cigarette product under study will make comparing results across studies and using the outcomes to inform tobacco policy difficult.

NIH electronic cigarette workshop: developing a research agenda.

BACKGROUND: Electronic cigarettes (e-cigarettes) represent an emerging public health issue. These devices deliver nicotine along with other constituents, including flavorants, via an inhalable aerosol. Their uptake is rapidly increasing in both adults and youths, primarily among current smokers. Public debate is increasing on how these devices should be regulated and used, yet only limited peer-reviewed research exists. To develop a informed policy for e-cigarettes, their effects on human behavior, physiology, and health need to be understood. PURPOSE: This paper describes proceedings from a National Institutes of Health-sponsored workshop, which was held in November 2013, to identify research needs related to the effects of e-cigarettes. Discussion topics included e-cigarette risks and abuse potential; the potential role for e-cigarettes in harm reduction and smoking cessation; unintended consequences of e-cigarette use, such as becoming a gateway to conventional cigarettes; and dual use of both e-cigarettes and conventional cigarettes. RESULTS AND CONCLUSIONS: The research needs identified by the workshop participants included the following: standards to measure the contents and emissions of e-cigarettes; biomarkers of exposure; physiological effects of e-cigarettes on tissues and organ systems, including pulmonary and cardiovascular; information on e-cigarette users, how the devices are used, and identification of the best tools to assess these measures; factors that drive use and influence patterns of use; and appropriate methods for evaluating a potential role for e-cigarettes in smoking or nicotine cessation. To understand fully the challenges and the opportunities that e-cigarettes represent, expertise will be needed in basic, behavioral, translational, and clinical sciences.

Gene-environment interplay in common complex diseases: forging an integrative model­recommendations from an NIH workshop.

Although it is recognized that many common complex diseases are a result of multiple genetic and environmental risk factors, studies of gene-environment interaction remain a challenge and have had limited success to date. Given the current state-of-the-science, NIH sought input on ways to accelerate investigations of gene-environment interplay in health and disease by inviting experts from a variety of disciplines to give advice about the future direction of gene-environment interaction studies. Participants of the NIH Gene-Environment Interplay Workshop agreed that there is a need for continued emphasis on studies of the interplay between genetic and environmental factors in disease and that studies need to be designed around a multifaceted approach to reflect differences in diseases, exposure attributes, and pertinent stages of human development. The participants indicated that both targeted and agnostic approaches have strengths and weaknesses for evaluating main effects of genetic and environmental factors and their interactions. The unique perspectives represented at the workshop allowed the exploration of diverse study designs and analytical strategies, and conveyed the need for an interdisciplinary approach including data sharing, and data harmonization to fully explore gene-environment interactions. Further, participants also emphasized the continued need for high-quality measures of environmental exposures and new genomic technologies in ongoing and new studies.

The effect of strict adherence to a high-fiber, high-fruit and -vegetable, and low-fat eating pattern on adenoma recurrence.

Individual differences in dietary intake are thought to account for substantial variation in cancer incidence. However, there has been a consistent lack of effect for low-fat, high-fiber dietary interventions and risk of colorectal cancer. These inconsistencies may reflect the multistage process of cancer as well as the range and timing of dietary change. Another potential reason for the lack of effect is poor dietary adherence among participants in these trials. The authors examined the effect of strict adherence to a low-fat, high-fiber, high-fruit and -vegetable intervention over 4 years among participants (n = 1,905) in the US Polyp Prevention Trial (1991-1998) on colorectal adenoma recurrence. There was a wide range of individual variation in the level of compliance among intervention participants. The most adherent participants, defined as "super compliers" (n = 210), consistently reported that they met or exceeded each of the 3 dietary goals at all 4 annual visits. Multivariate logistic regression models were used to estimate the association between dietary adherence and adenoma recurrence. The authors observed a 35% reduced odds of adenoma recurrence among super compliers compared with controls (odds ratio = 0.65, 95% confidence interval: 0.47, 0.92). Findings suggest that high compliance with a low-fat, high-fiber diet is associated with reduced risk of adenoma recurrence.

The Scientific Foundation for personal genomics: recommendations from a National Institutes of Health-Centers for Disease Control and Prevention multidisciplinary workshop.

The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed.

Predictors of sustained smoking cessation: a prospective analysis of chronic smokers from the alpha-tocopherol Beta-carotene cancer prevention study.

OBJECTIVES: Because US smoking rates have not declined during the past decade, there is a renewed need to identify factors associated with smoking cessation. Using a nested case-control design, we explored the association between ability to sustain cessation over an extended period and demographic, smoking, medical, and behavioral variables. METHODS: We selected a sample of 1379 sustained quitters (abstinent from smoking for at least 40 months) and 1388 relapsers (abstinent for more than 8 months before relapse) from participants in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, a nutritional intervention study involving Finnish men aged 50 to 69 years at baseline. Contingency table and multiple regression analyses were used to evaluate potential differences between the 2 groups on baseline variables. RESULTS: Compared with sustained quitters, relapsers were more likely to report symptoms of emotional distress and higher levels of nicotine dependence, to drink more alcohol, and to report more medical conditions. CONCLUSIONS: Factors associated with both tobacco use and comorbid conditions impact an individual's ability to maintain long-term smoking cessation. Understanding the underlying mechanisms of action and potential common pathways among these factors may help to improve smoking cessation therapies.

Adherence to the polyp prevention trial dietary intervention is associated with a behavioral pattern of adherence to nondietary trial requirements and general health recommendations.

This study investigated the factors associated with success in meeting the dietary goals of the Polyp Prevention Trial (PPT), a 4-y low-fat, high-fiber, high-fruit/vegetable dietary intervention. The PPT provided a rare opportunity to assess factors in long-term adherence to a dietary pattern that required changes to multiple aspects rather than a single aspect of diet. Demographics, health indicators, and dietary intake were assessed at baseline and annually for 4 y of follow-up. Participants (n=833) received dietary and behavioral counseling to support adherence to trial dietary goals. We assessed the association of baseline variables and trial participation with success in meeting dietary goals. Participant adherence to the intervention goals was significantly associated with never smoking, no history of weight gain, and consumption of less fat and more fiber, fruits, and vegetables at trial baseline. Successful participants were also more educated and married, whereas those with the poorest adherence were older. In addition, successful participants demonstrated greater participation throughout the trial, including attendance at counseling sessions, completion of dietary records, and contacts with staff. Of particular interest were the behavioral and demographic characteristics that distinguished the subset of participants who achieved most or all dietary intervention goals across all 4 study years who we termed Super Compliers. These individuals also were more likely to adhere to social norms for healthy lifestyles and demonstrated greater adherence to other aspects of trial participation.

Factors associated with patients' perceptions of health care providers' communication behavior.

We examined patients' ratings of communication with health care providers by sociodemographic characteristics, health care access, and health status. Data were from a national, population-based survey, the 2003 Health Information National Trends Survey (HINTS). The survey was administered to 6,369 adults from a representative sample of U.S. households. Linear regression analysis was conducted using SUDAAN. None of the sociodemographic variables were significantly associated with patients' ratings of providers' communication behavior in the linear model. Ratings of health care providers' communication behavior, however, were significantly higher among respondents with health insurance (p = 0.007) and those with a usual source of health care from whom they consistently sought care (p < 0.001). Ratings of provider communication were significantly lower among respondents who perceived their general health to be fair or poor (p < 0.001) and among those respondents with greater depressive symptoms (p < 0.001). Differences in patient ratings of health care providers' communication by health care access and health status suggest the potential for disparities in health outcomes.

Inflammatory cytokine gene polymorphisms, nonsteroidal anti-inflammatory drug use, and risk of adenoma polyp recurrence in the polyp prevention trial.

BACKGROUND: Pro- and anti-inflammatory cytokine genes may be important in the maintenance and progression of colorectal cancer. It is possible that single-nucleotide polymorphisms in inflammatory genes may play a role in chronic colonic inflammation and development of colorectal adenomas. Furthermore, common variants in cytokine genes may modify the anti-inflammatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in the prevention of colorectal cancer. METHODS: We examined the association between cytokine gene polymorphisms and risk of recurrent adenomas among 1,723 participants in the Polyp Prevention Trial. We used logistic regression to calculate odds ratios (OR) for the association between genotype, NSAID use, and risk of adenoma recurrence. RESULTS: Cytokine gene polymorphisms were not statistically significantly associated with risk of adenoma recurrence in our study. We observed statistically significant interactions between NSAID use, IL-10 -1082 G>A genotype, and risk of adenoma recurrence (P = 0.01) and multiple adenoma recurrence (P = 0.01). Carriers of the IL-10 -1082 G>A variant allele who were non-NSAID users had a statistically significant decreased risk of multiple adenoma recurrence (OR, 0.43; 95% confidence interval, 0.24-0.77) as well as a nonsignificant 30% decreased risk of any adenoma recurrence. In contrast, NSAID users who were carriers of the IL-10 -1082 G>A variant allele were at an increased risk of any adenoma recurrence (OR, 1.55; 95% confidence interval, 1.00-2.43). CONCLUSION: These findings suggest that individuals who are carriers of the IL-10 -1082 G>A variant allele may not benefit from the chemoprotective effect of NSAIDs on adenoma polyp recurrence.

Systems and individual factors associated with smoking status: evidence from HINTS.

OBJECTIVES: To examine the association of health care access/use, trust of physician advice, and depressive symptoms with the ability to sustain smoking cessation. METHODS: Data from a nationally representative sample were used to compare current smokers (n = 1246), sustained quitters (n = 1502), and never smokers (n = 3277). RESULTS: Sustained quitters reported fewer depressive symptoms (OR = 0.92) and were more likely to have health insurance (OR = 1.75) and a usual source of care (OR= 1.40) that they had seen within the last year (OR = 2.16) and that they were more likely to trust (OR = 1.40). CONCLUSIONS: Identification of these factors may inform providers' efforts to target and assist in smoking cessation.

Internet sales of tobacco: heading off the new E-pidemic.

Tobacco vendors are a growing presence on the internet. We describe the business appeal of the internet to tobacco retailers, including interviews with industry insiders that reveal the marketing goals and strategies of tobacco companies and highlight the potential future risks to tobacco control efforts. In countering these tactics, tobacco control advocates should not limit themselves to legal and regulatory remedies, but should also use the power of the internet to their own advantage. We suggest methods to combat the growing number of sites devoted to tobacco sales. These strategies could be used to limit both consumer access to, and sales effectiveness of, these sites.