Current Incentives for Scientists Lead to Underpowered Studies with Erroneous Conclusions

This is the final version of the article. Available from Public Library of Science via the DOI in this record.We can regard the wider incentive structures that operate across science, such as the priority given to novel findings, as an ecosystem within which scientists strive to maximise their fitness (i.e., publication record and career success). Here, we develop an optimality model that predicts the most rational research strategy, in terms of the proportion of research effort spent on seeking novel results rather than on confirmatory studies, and the amount of research effort per exploratory study. We show that, for parameter values derived from the scientific literature, researchers acting to maximise their fitness should spend most of their effort seeking novel results and conduct small studies that have only 10%-40% statistical power. As a result, half of the studies they publish will report erroneous conclusions. Current incentive structures are in conflict with maximising the scientific value of research; we suggest ways that the scientific ecosystem could be improved.Funding: Medical Research Council and the University of Bristol (grant number MC_UU_12013/6).Received by MRM. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Natural Environment Research Council (grant number NE/L011921/1).Received by ADH. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. MRM is a member of the UK Centre for Tobacco and Alcohol Studies, a UKCRC Public Health Research: Centre of Excellence. Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and the National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledge

The Association of Cigarette Smoking With Depression and Anxiety: A Systematic Review

BACKGROUND: Many studies report a positive association between smoking and mental illness. However, the literature remains mixed regarding the direction of this association. We therefore conducted a systematic review evaluating the association of smoking and depression and/or anxiety in longitudinal studies. METHODS: Studies were identified by searching PubMed, Scopus, and Web of Science and were included if they: (1) used human participants, (2) were longitudinal, (3) reported primary data, (4) had smoking as an exposure and depression and/or anxiety as an outcome, or (5) had depression and/or anxiety as the exposure and smoking as an outcome. RESULTS: Outcomes from 148 studies were categorized into: smoking onset, smoking status, smoking heaviness, tobacco dependence, and smoking trajectory. The results for each category varied substantially, with evidence for positive associations in both directions (smoking to later mental health and mental health to later smoking) as well as null findings. Overall, nearly half the studies reported that baseline depression/anxiety was associated with some type of later smoking behavior, while over a third found evidence that a smoking exposure was associated with later depression/anxiety. However, there were few studies directly supporting a bidirectional model of smoking and anxiety, and very few studies reporting null results. CONCLUSIONS: The literature on the prospective association between smoking and depression and anxiety is inconsistent in terms of the direction of association most strongly supported. This suggests the need for future studies that employ different methodologies, such as Mendelian randomization (MR), which will allow us to draw stronger causal inferences. Implications: We systematically reviewed longitudinal studies on the association of different aspects of smoking behavior with depression and anxiety. The results varied considerably, with evidence for smoking both associated with subsequent depression and anxiety, and vice versa. Few studies supported a bidirectional relationship, or reported null results, and no clear patterns by gender, ethnicity, clinical status, length to follow-up, or diagnostic test. Suggesting that despite advantages of longitudinal studies, they cannot alone provide strong evidence of causality. Therefore, future studies investigating this association should employ different methods allowing for stronger causal inferences to be made, such as MR

Investigating possible causal effects of externalizing behaviors on tobacco initiation: A Mendelian randomization analysis

Observational studies suggest childhood externalizing disorders are associated with increased smoking and earlier initiation. However, causality cannot be inferred from observational data alone. The current study uses two-sample MR to examine the causal relationship between externalizing behaviors and tobacco use. Single nucleotide polymorphisms (SNPs) associated with aggression were obtained from the Early Life Epidemiology Consortium (mean age 8), ADHD from the Integrative Psychiatric Research and Psychiatric Genomics Consortiums (age range 6–18), and tobacco initiation and age of onset from the Tobacco and Genetics Consortium. SNPs were combined using the inverse variance weighted approach, weighted median approach, and MR-Egger regression. There was no clear evidence of an effect of aggression on tobacco initiation or age of onset for childhood aggression (initiation: β −0.002, 95% CI −0.005, 0.001, P = 0.286; age: β −0.001 95% CI −0.002, 0.000, P = 0.310) or adolescent aggression (initiation: β −0.001, 95% CI −0.006, 0.003, P = 0.610; age: β 0.000, 95% CI 0.000, 0.001, P = 0.183)]. However, there was some evidence of an association of ADHD on tobacco initiation (OR 1.23, 95% CI 1.10, 1.35, P = 0.016), although no clear evidence of an effect of ADHD on age of onset (OR = 1.022, 95% CI 0.992, 1.052, P = 0.215). Our results provide some evidence that genetic risk of childhood ADHD is causally related to increased risk of tobacco initiation; however, the causal estimate is relatively small. We found no clear evidence that genetic risk of childhood aggression is causally related to the risk of tobacco initiation or age of onset

Effects of first exposure to plain cigarette packaging on smoking behaviour and attitudes: a randomised controlled study.

Published onlineJournal ArticleRandomized Controlled TrialResearch Support, Non-U.S. Gov'tBACKGROUND: Plain packaging requires tobacco products to be sold in packs with a standard shape, method of opening and colour, leaving the brand name in a standard font and location. We ran a randomised controlled trial to investigate the impact of plain packaging on smoking behaviour and attitudes. METHODS: In a parallel group randomised trial design, 128 daily smokers smoked cigarettes from their usual UK brand, or a plain Australian brand that was closely matched to their usual UK brand for 24 hours. Primary outcomes were number of cigarettes smoked and volume of smoke inhaled per cigarette. Secondary outcomes were self-reported ratings of motivation to quit, cigarette taste, experience of using the pack, experience of smoking, attributes of the pack, perceptions of the health warning, changes in smoking behaviour, and views on plain packaging. RESULTS: There was no evidence that pack type had an effect on either of the primary measures (ps > 0.279). However, smokers using plain cigarette packs rated the experience of using the pack more negatively (-0.52, 95% CI -0.82 to -0.22, p = 0.001), rated the pack attributes more negatively (-1.59, 95% CI -1.80 to -1.39, p < 0.001), and rated the health warning as more impactful (+0.51, 95% CI 0.24 to 0.78, p < 0.001). CONCLUSIONS: Plain cigarette packs reduce ratings of the experience of using the cigarette pack, and ratings of the pack attributes, and increase the self-perceived impact of the health warning, but do not change smoking behaviour, at least in the short term. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52982308. Registered 27 June 2013.UK Clinical Research CollaborationMR

Longitudinal associations of social cognition and substance use in childhood and early adolescence: findings from the Avon Longitudinal Study of Parents and Children

Substance use is associated with impaired social cognition. Experimental studies have shown that acute intoxication of alcohol, tobacco, and cannabis decreases the performance in non-verbal, social communication and theory of mind tasks. However, in epidemiological studies the temporal direction of this association has gone relatively unstudied. We investigated both directions of association within an adolescent birth cohort: the association of social cognition with subsequent substance use, and the association of early substance use with subsequent social cognition. We used data from the Avon Longitudinal Study of Parents and Children, a UK birth cohort. Logistic regression indicated that poor childhood non-verbal communication was associated with decreased odds of adolescent alcohol (OR 0.70, 95% 0.54-0.91), tobacco (OR 0.62, 95% CI 0.47-0.83), and cannabis use (OR 0.62, 95% CI 0.46-0.83). Early adolescent substance use was associated with increased odds of poor social communication (alcohol: OR 1.46, 95% CI 0.99-2.14; tobacco: OR 1.95, 95% CI 1.33-2.86) and poor social reciprocity (alcohol: OR 1.57, 95% CI 1.18-2.09; tobacco: OR 1.92, 95% CI 1.43-2.58; cannabis: OR 1.54, 95% CI 1.16-2.05). Overall, the relationship between social cognition and substance use was different in each temporal direction. Poor non-verbal communication in childhood appeared protective against later substance use, while adolescent substance use was associated with decreased social cognitive performance

The development and validation of a human screening model of tobacco abstinence

INTRODUCTION: Given the low efficacy of smoking cessation methods, an experimental medicine model indicating smoking abstinence would be of great benefit to the development of new treatments. Hence the sensitivity of cognitive tasks and ambulatory craving measures to smoking abstinence were investigated. METHODS: Cognitive tasks and ambulatory ratings of craving were assessed for sensitivity to acute abstinence (experiment 1), and nicotine replacement therapy administration (NRT) (experiment 2). RESULTS: In experiment 1 go/no-go performance was improved (Mean Difference [MD] -0.99, 95% CI: -1.90 to -0.08) and craving was lower (Regression Coefficient [RC] -33.39, 95% CI: -39.96 to -26.82) in satiated compared with abstinent smokers. There was no clear evidence that N-back (MD 0.64, 95% CI: -0.42 to 2.51), delay discounting (MD 0.01, 95% CI: 0.001 to 0.005) or dot probe performance (MD 0.61, 95% CI: -0.87 to 1.54) were sensitive to acute abstinence. In experiment 2 go/no-go performance was improved (MD 1.12, 95% CI: 0.16-2.08) and craving was lower (RC -18.59, 95% CI: -24.63 to -12.55) smokers abstinent overnight receiving NRT compared with placebo. There was no clear evidence that N-back (MD -0.25, 95% CI: -1.45 to 0.94), delay discounting (MD 0.01, 95% CI: -0.002 to 0.004) or dot probe performance (MD -0.49, 95% CI: -1.61 to -0.64) were sensitive to NRT. CONCLUSIONS: Findings from two experiments converge to suggest that abstinence in smokers reliably increases ambulatory craving assessments and, to a lesser extent, decreases go/no-go task performance. These findings can be utilized in the development of an experimental medicine model to test novel treatments for smoking cessation

Plain packaging of cigarettes and smoking behavior: study protocol for a randomized controlled study.

Published onlineComparative StudyJournal ArticleRandomized Controlled TrialResearch Support, Non-U.S. Gov'tBACKGROUND: Previous research on the effects of plain packaging has largely relied on self-report measures. Here we describe the protocol of a randomized controlled trial investigating the effect of the plain packaging of cigarettes on smoking behavior in a real-world setting. METHODS/DESIGN: In a parallel group randomization design, 128 daily cigarette smokers (50% male, 50% female) will attend an initial screening session and be assigned plain or branded packs of cigarettes to smoke for a full day. Plain packs will be those currently used in Australia where plain packaging has been introduced, while branded packs will be those currently used in the United Kingdom. Our primary study outcomes will be smoking behavior (self-reported number of cigarettes smoked and volume of smoke inhaled per cigarette as measured using a smoking topography device). Secondary outcomes measured pre- and post-intervention will be smoking urges, motivation to quit smoking, and perceived taste of the cigarettes. Secondary outcomes measured post-intervention only will be experience of smoking from the cigarette pack, overall experience of smoking, attributes of the cigarette pack, perceptions of the on-packet health warnings, behavior changes, views on plain packaging, and the rewarding value of smoking. Sex differences will be explored for all analyses. DISCUSSION: This study is novel in its approach to assessing the impact of plain packaging on actual smoking behavior. This research will help inform policymakers about the effectiveness of plain packaging as a tobacco control measure. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52982308 (registered 27 June 2013).British Heart FoundationCancer Research UKESRCMRCNIHRUK Clinical Research Collaboratio

Behavioral tasks sensitive to acute abstinence and predictive of smoking cessation success: A systematic review and meta-analysis

BACKGROUND AND AIMS: Performance on cognitive tasks may be sensitive to acute smoking abstinence and may also predict whether quit attempts fail. Our aim was to conduct a systematic review and meta-analysis to identify cognitive tasks sensitive to acute abstinence and predictive of smoking cessation success. METHODS: Embase, Medline, PsycInfo and Web of Science were searched up to March 2016. Studies were included if they enrolled adults and assessed smoking using used a quantitative measure. Studies were combined in a random effects meta-analysis. RESULTS: We included 42 acute abstinence studies and 13 cessation studies. There was evidence for an effect of abstinence on delay discounting [d = 0.26, 95% CI 0.07 to 0.45, p = 0.005], response inhibition [d = 0.48, 95% CI 0.26 to 0.70, p < 0.001], mental arithmetic [d = 0.38, 95% CI 0.06 to 0.70, p = 0.018], and recognition memory [d = 0.46, 95% CI 0.23 to 0.70, p < 0.001]. In contrast performance on the Stroop [d =0 .17, 95% CI -0.17 to 0.51, p = 0.333] and smoking Stroop [d = 0.03, 95% CI -0.11 to 0.17, p = 0.675] task was not influenced by abstinence. We found only weak evidence for an effect of acute abstinence on dot probe task performance [d = 0.15, 95% CI -0.01 to 0.32, p = 0.072]. The design of the cessation studies was too heterogeneous to permit meta-analysis. CONCLUSIONS: Compared with satiated smokers, acutely abstinent smokers display higher delay discounting, lower response inhibition, impaired arithmetic, and recognition memory performance. However, reaction time measures of cognitive bias appear to be unaffected by acute tobacco abstinence. Conclusions about cognitive tasks that predict smoking cessation success were limited by methodological inconsistencies

Emotional bias training as a treatment for anxiety and depression: evidence from experimental medicine studies in healthy and medicated samples.

BACKGROUND: Anxiety and depression are leading causes of disability worldwide, yet individuals are often unable to access appropriate treatment. There is a need to develop effective interventions that can be delivered remotely. Previous research has suggested that emotional processing biases are a potential target for intervention, and these may be altered through brief training programs. METHODS: We report two experimental medicine studies of emotional bias training in two samples: individuals from the general population (n = 522) and individuals currently taking antidepressants to treat anxiety or depression (n = 212). Participants, recruited online, completed four sessions of EBT from their own home. Mental health and cognitive functioning outcomes were assessed at baseline, immediately post-training, and at 2-week follow-up. RESULTS: In both studies, our intervention successfully trained participants to perceive ambiguous social information more positively. This persisted at a 2-week follow-up. There was no clear evidence that this change in emotional processing transferred to improvements in symptoms in the primary analyses. However, in both studies, there was weak evidence for improved quality of life following EBT amongst individuals with more depressive symptoms at baseline. No clear evidence of transfer effects was observed for self-reported daily stress, anhedonia or depressive symptoms. Exploratory analyses suggested that younger participants reported greater treatment gains. CONCLUSIONS: These studies demonstrate the effectiveness of delivering a multi-session online training program to promote lasting cognitive changes. Given the inconsistent evidence for transfer effects, EBT requires further development before it can be considered as a treatment for anxiety and depression

Investigating causality in associations between smoking initiation and schizophrenia using Mendelian randomization

Smoking is strongly associated with schizophrenia. Although it has been widely assumed that this reflects self-medication, recent studies suggest that smoking may be a risk factor for schizophrenia. We performed two-sample bi-directional Mendelian randomization using summary level genomewide association data from the Tobacco And Genetics Consortium and Psychiatric Genomics Consortium. Variants associated with smoking initiation and schizophrenia were combined using an inverse-variance weighted fixed-effects approach. We found evidence consistent with a causal effect of smoking initiation on schizophrenia risk (OR 1.73, 95% CI 1.30-2.25, p < 0.001). However, after relaxing the p-value threshold to include variants from more than one gene and minimize the potential impact of pleiotropy, the association was attenuated (OR 1.03, 95% CI 0.97-1.09, p = 0.32). There was little evidence in support of a causal effect of schizophrenia on smoking initiation (OR 1.01, 95% CI 0.98-1.04, p = 0.32). MR Egger regression sensitivity analysis indicated no evidence for pleiotropy in the effect of schizophrenia on smoking initiation (intercept OR 1.01, 95% CI 0.99-1.02, p = 0.49). Our findings provide little evidence of a causal association between smoking initiation and schizophrenia, in either direction. However, we cannot rule out a causal effect of smoking on schizophrenia related to heavier, lifetime exposure, rather than initiation.Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and the National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. Support from the Medical Research Council (MC_UU_12013/6, MR/M006727/1) is also gratefully acknowledged. Stephen Burgess is supported by a fellowship from the Wellcome Trust (100114)