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1.  Ventral Striatum/Nucleus Accumbens Activation to Smoking-Related Pictorial Cues in Smokers and Nonsmokers: A Functional Magnetic Resonance Imaging Study 
Biological psychiatry  2005;58(6):488-494.
Converging evidence from several theories of the development of incentive-sensitization to smoking-related environmental stimuli suggests that the ventral striatum plays an important role in the processing of smoking-related cue reactivity.
Twenty-six healthy right-handed volunteers (14 smokers and 12 nonsmoking controls) underwent functional magnetic resonance imaging (fMRI) during which neutral and smoking-related images were presented. Region of interest analyses were performed within the ventral striatum/nucleus accumbens (VS/NAc) for the contrast between smoking-related (SR) and nonsmoking related neutral (N) cues.
Group activation for SR versus N cues was observed in smokers but not in nonsmokers in medial orbitofrontal cortex, superior frontal gyrus, anterior cingulate cortex, and posterior fusiform gyrus using whole-brain corrected Z thresholds and in the ventral VS/NAc using uncorrected Z-statistics (smokers Z = 3.2). Region of interest analysis of signal change within ventral VS/NAc demonstrated significantly greater activation to SR versus N cues in smokers than controls.
This is the first demonstration of greater VS/NAc activation in addicted smokers than nonsmokers presented with smoking-related cues using fMRI. Smokers, but not controls, demonstrated activation to SR versus N cues in a distributed reward signaling network consistent with cue reactivity studies of other drugs of abuse.
PMCID: PMC4439461  PMID: 16023086
Nucleus accumbens; smoking; nicotine; tobacco; cue reactivity; fMRI
2.  Influence of a Dopamine Pathway Additive Genetic Efficacy Score on Smoking Cessation: Results from Two Randomized Clinical Trials of Bupropion 
Addiction (Abingdon, England)  2013;108(12):10.1111/add.12325.
To evaluate associations of treatment and an ‘additive genetic efficacy score’ (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled in two randomized clinical trials of smoking cessation therapies.
Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support.
Two Hospital-affiliated clinics (Study 1), and two University-affiliated clinics (Study 2).
N=792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.
Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 Variable Number of Tandem Repeats polymorphism [DRD4 VNTR], SLC6A3 3' VNTR) analyzed both separately and as part of an AGES, time to first lapse, and point prevalence abstinence at end of treatment.
Significant associations of the AGES (hazard ratio = 1.10, 95% Confidence Interval [CI] = 1.06–1.14], p=0.0099) and of the DRD4 VNTR (HR = 1.29, 95%CI 1.17–1.41, p=0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β [SE]=−0.18 [0.07], p=0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo.
A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.
PMCID: PMC3834197  PMID: 23941313
Bupropion; genetic; pharmacogenetic analysis; randomized clinical trial; first lapse
3.  Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: Analysis of pooled data from two clinical trials 
We analyzed pooled data from two comparable randomized placebo-controlled clinical trials of bupropion pharmacotherapy for smoking cessation for which data on DRD2 Taq1A genotype were available. A total of 722 smokers across the two trials were randomized to 10 weeks of sustained-release bupropion hydrochloride or placebo. General estimating equation analysis demonstrated a significant gene × drug interaction (B=0.87, SE=0.34, p=.009). Smokers with the A2/A2 genotype using bupropion were more than three times as likely, relative to placebo, to be abstinent at end of treatment (35.2% vs. 15.1%; OR=3.25, 95% CI 2.00–5.28) and at 6 months of follow-up (26.7% vs. 12.2%; OR=2.81, 95% CI 1.66–4.77), which was attenuated by 12 months (16.3% vs. 10.7%; OR=1.70, 95% CI 0.95–3.05). We found no significant benefit of bupropion relative to placebo on smoking cessation outcomes at any time point in participants with A1/A1 or A1/A2 genotypes. These data suggest that bupropion may be effective for smoking cessation only in a subgroup of smokers with the DRD2 Taq1 A2/A2 genotype.
PMCID: PMC2128730  PMID: 18058343
4.  Opioid antagonists for smoking cessation 
The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking.
To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone.
Search methods
We searched the Cochrane Tobacco Addiction Group Specialised Register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using ’Narcotic antagonists’ and smoking terms in April 2013. We also contacted investigators, when possible, for information on unpublished studies.
Selection criteria
We considered randomised controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence.
Data collection and analysis
We extracted data in duplicate on the study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. Abstinence at end of treatment was a secondary outcome. We extracted cotinine- or carbon monoxide-verified abstinence where available. Where appropriate, we performed meta-analysis, pooling risk ratios using a Mantel-Haenszel fixed-effect model.
Main results
Eight trials of naltrexone met inclusion criteria for meta-analysis of long-term cessation. One trial used a factorial design so five trials compared naltrexone versus placebo and four trials compared naltrexone plus nicotine replacement therapy (NRT) versus placebo plus NRT. Results from 250 participants in one long-term trial remain unpublished. No significant difference was detected between naltrexone and placebo (risk ratio (RR) 1.00; 95% confidence interval (CI) 0.66 to 1.51, 445 participants), or between naltrexone and placebo as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30, 768 participants). The estimate was similar when all eight trials were pooled (RR 0.97; 95% CI 0.76 to 1.24, 1213 participants). In a secondary analysis of abstinence at end of treatment, there was also no evidence of any early treatment effect, (RR 1.03; 95% CI 0.88 to 1.22, 1213 participants). No trials of naloxone or buprenorphine reported abstinence outcomes.
Authors’ conclusions
Based on data from eight trials and over 1200 individuals, there was no evidence of an effect of naltrexone alone or as an adjunct to NRT on long-term smoking abstinence, with a point estimate strongly suggesting no effect and confidence intervals that make a clinically important effect of treatment unlikely. Although further trials might narrow the confidence intervals they are unlikely to be a good use of resources.
PMCID: PMC4038652  PMID: 23744347
Buprenorphine [therapeutic use]; Naloxone [therapeutic use]; Naltrexone [therapeutic use]; Narcotic Antagonists [*therapeutic use]; Randomized Controlled Trials as Topic; Smoking [*drug therapy]; Smoking Cessation [*methods]; Tobacco Use Cessation Products; Humans
5.  Systematic review and meta-analysis of opioid antagonists for smoking cessation 
BMJ Open  2014;4(3):e004393.
This meta-analysis sought to evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. Post-treatment abstinence was examined as a secondary outcome and effects on withdrawal symptoms, craving and reduced consumption were also explored.
The search strategy for this meta-analysis included clinical trials (published and unpublished data) in the Cochrane Tobacco Addiction Group Specialized Register and MEDLINE.
Adult smokers.
We included randomised trials comparing opioid antagonists to placebo or an alternative therapy for smoking cessation and reported data on abstinence for a minimum of 6 months.
Primary and secondary outcome measures
Outcomes included smoking abstinence at long-term follow-up (primary); abstinence at end of treatment (secondary); and effects on withdrawal, craving and smoking consumption (exploratory).
8 trials with a total of 1213 participants were included. Half the trials examined the benefit of adding naltrexone versus placebo to nicotine replacement therapy (NRT). There was no significant difference between naltrexone and placebo alone (relative risk (RR) 1.00; 95% CI 0.66 to 1.51) or as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30), with an overall pooled estimate of RR 0.97; 95% CI 0.76 to 1.24. Findings for naltrexone effects on withdrawal, craving and reduced smoking were equivocal.
The findings indicate no beneficial effect of naltrexone alone or as an adjunct to NRT on short-term or long-term smoking abstinence. While further trials may narrow the confidence limits, they are unlikely to appreciably alter the conclusion.
PMCID: PMC3963070  PMID: 24633528
opioid antagonists ; smoking cessation; tobacco; smoking abstinence; naltrexone
6.  Pharmacogenetics of Smoking Cessation in General Practice: Results From the Patch II and Patch in Practice Trials 
Nicotine & Tobacco Research  2011;13(3):157-167.
Cigarette smoking remains the leading cause of preventable death worldwide. However, the efficacy of available first-line therapies remains low, particularly in primary care practice where most smokers seek and receive treatment. These observations reinforce the notion that ‘one size fits all’ smoking cessation therapies may not be optimal. Therefore, a translational research effort was launched by the Imperial Cancer Research Fund (later Cancer Research UK) General Practice Research Group, who led a decade-long research enterprise that examined the influence of pharmacological hypothesis-driven research into genetic influences on drug response for smoking cessation with transdermal nicotine replacement therapy in general practice.
New and previously published smoking cessation genetic association results of 30 candidate gene polymorphisms genotyped for participants in two transdermal nicotine replacement clinical trials based in UK general practices, which employed an intention to analyze approach.
By this high bar, one of the polymorphisms (COMT rs4680) was robust to correction for multiple comparisons. Moreover, future research directions are outlined; and lessons learned as well as best-practice models for designing, analyzing, and translating results into clinical practice are proposed.
The results and lessons learned from this general practice-based pharmacogenetic research programme provide transportable insights at the transition to the second generation of pharmacogenetic and genomic investigations of smoking cessation and its translation to primary care.
PMCID: PMC3107615  PMID: 21330274
7.  Sex differences in TTC12/ANKK1 haplotype associations with daily tobacco smoking in Black and White Americans 
Nicotine & Tobacco Research  2010;12(3):251-262.
The 11q23.1 genomic region has been associated with nicotine dependence in Black and White Americans.
By conducting linkage disequilibrium analyses of 7 informative single nucleotide polymorphisms (SNPs) within the tetratricopeptide repeat domain 12 (TTC12)/ankyrin repeat and kinase containing 1 (ANKK1)/dopamine (D2) receptor gene cluster, we identified haplotype block structures in 270 Black and 368 White (n = 638) participants, from the Baltimore Epidemiologic Catchment Area cohort study, spanning the TTC12 and ANKK1 genes consisting of three SNPs (rs2303380–rs4938015–rs11604671). Informative haplotypes were examined for sex-specific associations with daily tobacco smoking initiation and cessation using longitudinal data from 1993–1994 and 2004–2005 interviews.
There was a Haplotype × Sex interaction such that Black men possessing the GTG haplotype who were smokers in 1993–2004 were more likely to have stopped smoking by 2004–2005 (55.6% GTG vs. 22.0% other haplotypes), while Black women were less likely to have quit smoking if they possessed the GTG (20.8%) versus other haplotypes (24.0%; p = .028). In Whites, the GTG haplotype (vs. other haplotypes) was associated with lifetime history of daily smoking (smoking initiation; odds ratio = 1.6; 95% CI = 1.1–2.4; p = .013). Moreover, there was a Haplotype × Sex interaction such that there was higher prevalence of smoking initiation with GTG (77.6%) versus other haplotypes (57.0%; p = .043).
In 2 different ethnic American populations, we observed man–woman variation in the influence of the rs2303380–rs4938015–rs11604671 GTG haplotype on smoking initiation and cessation. These results should be replicated in larger cohorts to establish the relationship among the rs2303380–rs4938015–rs11604671 haplotype block, sex, and smoking behavior.
PMCID: PMC2825103  PMID: 20133381
8.  Association of CHRNA5-A3-B4 SNP rs2036527 with smoking cessation therapy response in African American smokers 
Associations between CHRNA5-A3-B4 variants and smoking behaviors exist, however the association with smoking abstinence is less understood, particularly among African Americans. In 1295 African Americans enrolled in two clinical trials, we investigated the association between CHRNA5-A3-B4 and smoking abstinence. Rs2056527[A] was associated with lower abstinence with active pharmacotherapy (during-treatment: OR=0.42&P<0.001; end of treatment (EOT): OR=0.55&P=0.004), or with nicotine gum alone (during-treatment: OR=0.31&P<0.001; EOT: OR=0.51&P=0.02), but not significantly with bupropion, although similar directions and magnitudes were observed (during-treatment: OR=0.54&P=0.05; EOT: OR=0.59&P=0.08). Additionally, rs588765[T] was associated with abstinence with gum during treatment (OR=2.31&P<0.01). Rs16969968 occurred at a low frequency and was not consistently associated with abstinence. CHRNA5-A3-B4 variants were not associated with tobacco consumption and adjustments for smoking behaviors did not alter the associations with smoking abstinence. Together, our data suggest that in African Americans CHRNA5-A3-B4 variants are not associated with baseline smoking, but can influence smoking abstinence during active pharmacotherapy.
PMCID: PMC4111775  PMID: 24733007
African Americans; CHRNA5-A3-B4; Smoking cessation; Nicotine; Bupropion; Tobacco Consumption
9.  Effects of Nicotine Deprivation and Replacement on BOLD-fMRI Response to Smoking Cues as a Function of DRD4 VNTR Genotype 
Nicotine & Tobacco Research  2014;16(7):939-947.
Reactivity to smoking cues is an important factor in the motivation to smoke and has been associated with the dopamine receptor 4 variable number tandem repeat (DRD4 exon III VNTR) polymorphism. However, little is known about the associated neural mechanisms.
Non-treatment-seeking Caucasian smokers completed overnight abstinence and viewed smoking and neutral cues during 2 separate functional magnetic resonance imaging scans while wearing either a nicotine or placebo patch (order randomized) and were genotyped for the DRD4 VNTR. We conducted mixed-effects repeated-measures analyses of variance (within-subject factor: nicotine or placebo patch; between-subject factor: DRD4 long [L: ≥1 copy of ≥7 repeats] or short [S: 2 copies ≤6 repeats] genotype) of 6 a priori regions of interest.
Relative to neutral cues, smoking cues elicited greater activity in bilateral ventral striatum and left amygdala during nicotine replacement and deactivation in these regions during nicotine deprivation. A patch × DRD4 interaction was observed in the left amygdala, an area associated with appetitive reinforcement and relapse risk, such that S allele carriers demonstrated greater activation on active patch than on placebo patch.
Brain systems associated with reward salience may become primed and overreactive at nicotine replacement doses intended for the first step of smoking cessation and may become inhibited during nicotine withdrawal in DRD4 S but not in DRD4 L carriers. These findings are consistent with the role of these regions in drug reinforcement and suggest a differential influence of nicotine replacement on amygdala activation in the association of incentive salience with smoking stimuli across DRD4 genotypes.
PMCID: PMC4072897  PMID: 24659022
10.  Association of the DRD2 gene Taq1A polymorphism and smoking behavior: A meta-analysis and new data 
Nicotine & Tobacco Research  2009;11(1):64-76.
Many studies have investigated the association of the dopamine type-2 receptor (DRD2) Taq1A polymorphism with tobacco use and cigarette smoking behaviors, but findings remain equivocal. There is a biological basis for considering that this association differs by sex, and differences in subpopulations might explain some of the contradictory evidence.
Our a priori hypothesis was that the association of the DRD2 Taq1A polymorphism with smoking behavior would be more prominent in females than males. We therefore investigated the strength of evidence for an association between the DRD2 Taq1A polymorphism and smoking behavior in a large sample of females and used meta-analytic techniques to synthesize existing published data and explore the role of sex in explaining any heterogeneity between studies.
We did not observe any strong evidence of association between the DRD2 Taq1A polymorphism and smoking behavior, including smoking initiation, smoking persistence, and smoking rate, either in our female sample or in our meta-analysis of 29 studies, comprising 28 published studies and the data from the present study. Metaregression suggested an association between the proportion of male participants in a study and the individual study effect size, indicating a larger effect size with a greater proportion of male participants for smoking initiation and smoking persistence. This effect did not appear to be due to the inclusion of the data from the present study.
Available evidence does not support an association between the DRD2 Taq1A polymorphism and smoking behavior. Contrary to our a priori hypothesis, we found evidence of a stronger association in males than in females.
PMCID: PMC3203402  PMID: 19246443
11.  Genetic variation in the serotonin pathway and smoking cessation with nicotine replacement therapy: New data from the Patch in Practice trial and pooled analyses 
Drug and alcohol dependence  2008;98(0):77-85.
The serotonin pathway has been implicated in nicotine dependence and may influence smoking cessation. Therefore, 792 cigarette smokers from the Patch in Practice trial were genotyped for the tryptophan hydroxylase (TPH1 A779C), serotonin transporter (SLC6A4 5-HTTLPR), and 5-HT1A (HTR1A C-1019G) polymorphisms. Cox regression analysis did not demonstrate significant effects of any of the three genotypes on relapse to smoking: TPH1 (Reference AA; AC: hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.78, 1.24, p = 0.90; CC: HR 0.93, 95% CI 0.73, 1.18, p = 0.55); 5-HTTLPR (Reference LL; SL: HR 1.01, 95% CI 0.85, 1.20, p = 0.90; SS: HR 1.13, 95% CI 0.91, 1.39, p = 0.27); HTR1A (Reference CC; CG: HR 1.04, 95% CI 0.86, 1.25, p = 0.70; GG: HR 1.01, 95% CI 0.82, 1.24, p = 0.93). Moreover, pooled analyses of data from all three extant pharmacogenetic NRT trials (N= 1398) found no significant effect of 5-HTTLPR genotype on continuous abstinence at 12-week (Reference LL; SL: odds ratio (OR) = 1.25, 95% CI 0.89, 1.74, p = 0.19; SS: OR= 1.31, 95% CI 0.86, 1.98, p = 0.21) or 26-week follow-up (Reference LL; SL: OR= 0.93, 95% CI 0.64, 1.33, p = 0.68; SS: OR= 1.00, 95% CI 0.63, 1.58, p = 1.00). These data do not support a statistically or clinically significant moderating effect of these specific 5-HT pathway genetic variants on smoking cessation. However, the possibility remains that other variants in these or other 5-HT genes may influence NRT efficacy for smoking cessation in treatment seeking smokers.
PMCID: PMC4439462  PMID: 18562131
Smoking cessation; Tryptophan hydroxylase; Serotonin transporter; 5-HT1A receptor; Nicotine replacement therapy; Pharmacogenetics
12.  A cost-effectiveness analysis of genetic testing of the DRD2 Taq1A polymorphism to aid treatment choice for smoking cessation 
We conducted a cost-effectiveness analysis of genetic testing for smoking cessation, based on data available from the published pharmacogenetic studies of nicotine replacement therapy and bupropion, and a previous cost-effectiveness analysis of smoking cessation treatments. We use multiparameter evidence synthesis methods to combine evidence on cessation by genotype with evidence on cessation irrespective of genotype (which can be written as a function of genotype-specific parameters). Our intention was to explore the most cost-effective approach to prescribing smoking cessation pharmacotherapy, given the hypothetical availability of a test based on a single-gene variant that has been reported to predict treatment response. We considered four types of treatment: nicotine replacement therapy (NRT) pharmacotherapy, bupropion SR pharmacotherapy, combination NRT and bupropion, and standard care as the control. Two scenarios were investigated, one in which the control represented brief advice and the other in which the control represented individual counseling. Strategies that either do not test for dopamine D2 receptor (DRD2) genotype (each individual receives the same treatment), or do test for DRD2 genotype (treatment allocated according to genotype), were evaluated. Our results indicated that the most cost-effective strategy in our hypothetical example of a single-gene test to aid prescription of smoking cessation pharmacotherapy is to prescribe both NRT and bupropion regardless of genotype, as a first-line treatment for smoking cessation. We conclude that it should not be assumed that genetic tailoring will necessarily be more cost-effective than applying the current “one-size-fits-all” model of pharmacotherapy for smoking cessation. In addition, single-gene tests are unlikely to be cost-effective, partly because the predictive value of these tests is likely to be modest.
PMCID: PMC2257987  PMID: 18188764
13.  Publication and other reporting biases in cognitive sciences: detection, prevalence and prevention 
Trends in cognitive sciences  2014;18(5):235-241.
Recent systematic reviews and empirical evaluations of the cognitive sciences literature suggest that publication and other reporting biases are prevalent across diverse domains of cognitive science. This review summarizes the various forms of publication and reporting biases and other questionable research practices, and overviews the available methods for probing into their existence. We discuss the available empirical evidence for the presence of such biases across the neuroimaging, animal, other pre-clinical, psychological, clinical trials, and genetics literature in the cognitive sciences. We also highlight emerging solutions (from study design to data analyses and reporting) to prevent bias and improve the fidelity in the field of cognitive science research.
PMCID: PMC4078993  PMID: 24656991
publication bias; reporting bias; cognitive sciences; neuroscience; bias
14.  Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation 
This randomized, double-blinded, placebo-controlled trial examined genetic influences on treatment response to sustained-release bupropion for smoking cessation. Smokers of European ancestry (N=291), who were randomized to receive bupropion or placebo (12 weeks) plus counseling, were genotyped for the dopamine D2 receptor (DRD2-Taq1A), dopamine transporter (SLC6A3 3′ VNTR), and cytochrome P450 2B6 (CYP2B6 1459 C→T) polymorphisms. Main outcome measures were cotinine-verified point prevalence of abstinence at end of treatment and at 2-, 6-, and 12-month follow-ups post quit date. Using generalized estimating equations, we found that bupropion, compared with placebo, was associated with significantly greater odds of abstinence at all time points (all p values<.01). We found a significant DRD2 × bupropion interaction (B=1.49, SE=0.59, p=.012) and a three-way DRD2 × bupropion × craving interaction on 6-month smoking cessation outcomes (B=−0.45, SE=0.22, p=.038), such that smokers with the A2/A2 genotype demonstrated the greatest craving reduction and the highest abstinence rates with bupropion. Furthermore, there was a significant DRD2 × CYP2B6 interaction (B=1.43, SE=0.56, p=.01), such that individuals with the DRD2-Taq1 A2/A2 genotype demonstrated a higher odds of abstinence only if they possessed the CYP2B6 1459 T/T or C/T genotype. Because the sample size of this study was modest for pharmacogenetic investigations, the results should be interpreted with caution. Although these results require replication, the data suggest preliminarily that the DRD2-Taq1A polymorphism may influence treatment response to bupropion for smoking cessation and, further, that exploration of gene × gene and gene × craving interactions in future, larger studies may provide mechanistic insights into the complex pharmacodynamics of bupropion.
PMCID: PMC2039873  PMID: 17654295
15.  The serotonin transporter 5-HTTLPR polymorphism and treatment response to nicotine patch: Follow-up of a randomized controlled trial 
In this follow-up of a randomized placebo-controlled clinical trial of nicotine replacement transdermal patch for smoking cessation, 741 smokers of European ancestry who were randomized to receive active patch or placebo patch were genotyped for the serotonin transporter gene-linked polymorphic region. The study setting was a primary care research network in Oxfordshire, United Kingdom. The primary outcome measures were biochemically verified sustained abstinence from cigarette smoking at end of treatment and 24-week follow-up. The main effect of genotype was not associated with sustained abstinence from smoking at either end of treatment (SL: p=.33; SS: p=.81) or 24-week follow-up (SL: p=.05; SS: p=.21), and we found no evidence for a genotype×treatment interaction effect. In summary, despite the theoretically important contribution of serotonin neurotransmission to smoking cessation, the serotonin transporter gene was not associated with treatment response to nicotine patch for smoking cessation in this primary care–based trial.
PMCID: PMC2031912  PMID: 17365753
17.  No association between germline variation in catechol-O-methyltransferase and colorectal cancer survival in postmenopausal women 
Menopause (New York, N.Y.)  2014;21(4):415-420.
Sex-steroid hormones play a role in colorectal cancer (CRC) development, but little is known about their influence on tumor progression and metastasis. Because catechol-O-methyltransferase activity (COMT; 22q11.21) is an important component of estrogen-mediated carcinogenesis, we hypothesized that germline variation in COMT may be associated with CRC survival.
We identified 10 single-nucleotide polymorphisms (SNPs) that tagged variation across both isoforms of COMT in 2,458 women with CRC from the Nurses’ Health Study (NHS), Postmenopausal Hormones Supplementary Study to the Colon Cancer Family Registry (PMH-CCFR), VITamins And Lifestyle (VITAL) Study, and Women’s Health Initiative (WHI). All four studies participate in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO).
Over a median follow-up of 7 years across all studies, there were 799 deaths, including 566 from CRC. Accounting for multiple comparisons, no associations between the SNPs and CRC-specific or overall survival reached statistical significance, including the well-characterized Val108/158Met polymorphism (rs4680; hazard ratio per minor allele [HR], 1.04; 95% confidence interval [CI], 0.92–1.17 for CRC-specific survival and 1.01; 0.90–1.14 for overall survival).
In this large study of women with CRC, we found no evidence that common inherited variation in COMT is associated with survival-time after diagnosis.
PMCID: PMC3865220  PMID: 23880798
18.  Clinical Interpretation and Implications of Whole-Genome Sequencing 
Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.
To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.
An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.
Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.
Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95%CI, 0.40-0.64), and reclassified 69%of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).
In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.
PMCID: PMC4119063  PMID: 24618965
19.  Teaching tobacco dependence treatment and counseling skills during medical school: rationale and design of the Medical Students helping patients Quit tobacco (MSQuit) group randomized controlled trial 
Contemporary clinical trials  2014;37(2):284-293.
Physician-delivered tobacco treatment using the 5As is clinically recommended, yet its use has been limited. Lack of adequate training and confidence to provide tobacco treatment are cited as leading reasons for limited 5A use. Tobacco dependence treatment training while in medical school is recommended, but is minimally provided. The MSQuit trial (Medical Students helping patients Quit tobacco) aims to determine if a multi-modal and theoretically-guided tobacco educational intervention will improve tobacco dependence treatment skills (i.e. 5As) among medical students.
10 U.S. medical schools were pair-matched and randomized in a group-randomized controlled trial to evaluate whether a multi-modal educational (MME) intervention compared to traditional education (TE) will improve observed tobacco treatment skills. MME is primarily composed of TE approaches (i.e. didactics) plus a 1st year web-based course and preceptor-facilitated training during a 3rd year clerkship rotation. The primary outcome measure is an objective score on an Objective Structured Clinical Examination (OSCE) tobacco-counseling smoking case among 3rd year medical students from schools who implemented the MME or TE.
MSQuit is the first randomized to evaluate whether a tobacco treatment educational intervention implemented during medical school will improve medical students’ tobacco treatment skills. We hypothesize that the MME intervention will better prepare students in tobacco dependence treatment as measured by the OSCE. If a comprehensive tobacco treatment educational learning approach is effective, while also feasible and acceptable to implement, then medical schools may substantially influence skill development and use of the 5As among future physicians.
PMCID: PMC4048818  PMID: 24486635
tobacco dependence treatment and counseling; 5As; medical school education; medical students; tobacco control; group randomized controlled trial
20.  Relationship Between Amounts of Daily Cigarette Consumption and Abdominal Obesity Moderated by CYP2A6 Genotypes in Chinese Male Current Smokers 
Cigarette smoking is an important risk factor for abdominal obesity. However, the degree to which the CYP2A6 genotype moderates the relationship between smoking and abdominal obesity has not been established.
This study aims to investigate whether or not the relationship between smoking quantity and abdominal obesity is influenced by CYP2A6 genotypes.
Nine hundred fifty-four male current smokers were selected. A venous specimen was collected to test serum cotinine and CYP2A6 genotype, and all smokers were divided into heavy (>15 cigarettes/day) and light smokers (≤15 cigarettes/day).
Heavy smoking increased the risk of abdominal obesity (odds ratio (OR)=1.57; 95% CI, 1.13–2.19) compared with light smoking. Furthermore, heavy smoking had a positive interactive effect with CYP2A6 poor metabolizer genotype on abdominal obesity (OR=3.90; 95% CI, 1.25– 12.18). Moreover, CYP2A6 poor metabolizer genotypes were associated with slower nicotine metabolism.
Heavy smoking may increase the risk of abdominal obesity—particularly in smokers with CYP2A6 poor metabolizer genotypes.
PMCID: PMC4114962  PMID: 22160797
Cigarette smoking; CYP2A6 genotypes; Abdominal obesity; Interaction
21.  Interaction between heavy smoking and CYP2A6 genotypes on type 2 diabetes and its possible pathways 
To explore the interactions between smoking and CYP2A6 genotypes on type 2 diabetes (T2DM) as well as potential pathways for smoking in causing T2DM.
Cross-sectional study.
A total of 1344 smokers with complete data from a community-based T2DM survey in Guangzhou and Zhuhai of China from July 2006 to June 2007 were interviewed with a structured questionnaire about socio-demographic status and daily cigarette consumption. Serum glucose, insulin, and cotinine were measured after an overnight fast. Subjects were genotyped for CYP2A6 and classified, according to genotype, into normal, intermediate, slow, or poor nicotine metabolizers based on prior knowledge of CYP2A6 allele associations with nicotine C-oxidation rate. Abdominal obesity was defined as a waist-to-hip ratio ≥0.90 for males or ≥0.85 for females. Type 2 diabetic patients (n=154) were diagnosed according to WHO 1999 criteria. Chi-square tests, multivariate logistic regression models, and a structural equation model were used in this study.
Multivariate analysis indicated that, compared with light smoking, heavy smoking significantly increased the risk of T2DM (odds ratio (OR)=1.75, 95% CI=1.01–3.05). There were significant interactions between heavy smoking and slow CYP2A6 (OR=5.12, 95% CI=1.08–24.23) and poor CYP2A6 metabolizer genotypes (OR=8.54, 95% CI=1.28–57.02) on T2DM. Structural equation modeling indicated that CYP2A6 moderation of smoking quantity risk on T2DM was mediated by the effects on serum cotinine, abdominal obesity, insulin resistance, and insulin secretion.
Heavy smoking was significantly associated with T2DM, and this association was moderated by CYP2A6 genotype and mediated by serum cotinine, abdominal obesity, insulin resistance, and insulin secretion.
PMCID: PMC4112659  PMID: 21964962
22.  Pharmacogenetic Smoking Cessation Intervention in a Health Care Setting: A Pilot Feasibility Study 
Nicotine & Tobacco Research  2012;15(2):518-526.
There is increasing evidence that response to pharmacological treatment for nicotine dependence may be moderated by genetic polymorphisms. However, the feasibility, acceptability, and impact of genetically tailoring treatment in real-world clinical settings are unknown.
We conducted a multiphased, mixed-methods feasibility study with current smokers to develop and evaluate a patient-centered, theoretically grounded personalized medicine treatment protocol. The initial research phase included formative work to develop intervention materials. The second phase included a randomized pilot trial to evaluate the intervention. Trial participants (n = 36) were genotyped for ANKK1 rs1800497 and were randomized to receive genetic feedback (GF) plus standard behavioral counseling (BC) for smoking cessation or BC without GF. All participants received genetically tailored pharmacotherapy (nicotine patch or bupropion).
The intervention was feasible to implement and was acceptable to participants based on satisfaction ratings and objective measures of participation. There was no evidence that the GF resulted in adverse psychological outcomes (e.g., depression, fatalism, reduced perceived control over quitting, differential motivation for quitting) based on quantitative or qualitative outcomes.
Study results suggest that it is feasible to offer treatment within a health care setting that includes genetically tailored pharmacotherapy and doing so had no apparent adverse psychological impacts. Further evaluation of pharmacogenetically tailored smoking cessation interventions appears warranted.
PMCID: PMC3611995  PMID: 22949583
23.  Chronic psychosocial stressors and salivary biomarkers in emerging adults 
Psychoneuroendocrinology  2011;37(8):1158-1170.
We investigated whole saliva as a source of biomarkers to distinguish individuals who have, and who have not, been chronically exposed to severe and threatening life difficulties. We evaluated RNA and DNA metrics, expression of 37 candidate genes, and cortisol release in response to the Trier Social Stress Test, as well as clinical characteristics, from 48 individuals stratified on chronic exposure to psychosocial stressors within the last year as measured by the Life Events and Difficulties Schedule. Candidate genes were selected based on their differential gene expression ratio in circulating monocytes from a published genome-wide analysis of adults experiencing different levels of exposure to a chronic stressor.
In univariate analyses, we observed significantly decreased RNA integrity (RIN) score (P = 0.04), and reduced expression of glucocorticoid receptor-regulated genes (Ps < 0.05) in whole saliva RNA from individuals exposed to chronic stressors, as compared to those with no exposure. In those exposed, we observed significantly decreased BMI (P < 0.001), increased ever-smoking and increased lifetime alcohol abuse or dependence (P ≤ 0.03), and a reduction of cortisol release. In post hoc multivariate analyses including clinical and biospecimen-derived variables, we consistently observed significantly decreased expression of IL8 (Ps < 0.05) in individuals exposed, with no significant association to RIN score. Alcohol use disorders, tobacco use, a reduced acute stress response and decreased salivary IL8 gene expression characterize emerging adults chronically exposed to severe and threatening psychosocial stressors.
PMCID: PMC3774595  PMID: 22172638
Human; Saliva; Gene expression; IL8; qPCR
24.  PharmGKB Summary - Very Important Pharmacogene Information for Cytochrome P-450, Family 2, Subfamily A, polypeptide 6 (CYP2A6) 
Pharmacogenetics and genomics  2012;22(9):695-708.
PMCID: PMC3413746  PMID: 22547082
CYP2A6; inter-individual variation; pharmacokinetics; genetic polymorphisms; drug metabolism; drug efficacy
25.  Potential Reporting Bias in fMRI Studies of the Brain 
PLoS ONE  2013;8(7):e70104.
Functional magnetic resonance imaging (fMRI) studies have reported multiple activation foci associated with a variety of conditions, stimuli or tasks. However, most of these studies used fewer than 40 participants.
After extracting data (number of subjects, condition studied, number of foci identified and threshold) from 94 brain fMRI meta-analyses (k = 1,788 unique datasets) published through December of 2011, we analyzed the correlation between individual study sample sizes and number of significant foci reported. We also performed an analysis where we evaluated each meta-analysis to test whether there was a correlation between the sample size of the meta-analysis and the number of foci that it had identified. Correlation coefficients were then combined across all meta-analyses to obtain a summary correlation coefficient with a fixed effects model and we combine correlation coefficients, using a Fisher’s z transformation.
Principal Findings
There was no correlation between sample size and the number of foci reported in single studies (r = 0.0050) but there was a strong correlation between sample size and number of foci in meta-analyses (r = 0.62, p<0.001). Only studies with sample sizes <45 identified larger (>40) numbers of foci and claimed as many discovered foci as studies with sample sizes ≥45, whereas meta-analyses yielded a limited number of foci relative to the yield that would be anticipated from smaller single studies.
These results are consistent with possible reporting biases affecting small fMRI studies and suggest the need to promote standardized large-scale evidence in this field. It may also be that small studies may be analyzed and reported in ways that may generate a larger number of claimed foci or that small fMRI studies with inconclusive, null, or not very promising results may not be published at all.
PMCID: PMC3723634  PMID: 23936149

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