Wang-Yen Lee

OBJECTIVE: To evaluate the association of nicotinic acetylcholine receptor single nucleotide polymorphism with 7-day point prevalence abstinence in randomized clinical trials of smoking cessation therapies in individuals grouped by pharmacotherapy randomization to inform the development of personalized smoking cessation therapy. MATERIALS AND METHODS: We quantified association of four SNPs at three nAChRs with abstinence in eight randomized clinical trials. Participants were 2633 outpatient treatment-seeking, self-identified European ancestry individuals smoking at least 10 cigarettes/day, recruited through advertisement, prescribed pharmacotherapy, and provided with behavioral therapy. Interventions included nicotine replacement therapy, bupropion, varenicline, placebo, or combined NRT and bupropion, and five modes of group and individual behavioral therapy. Outcome measures tested in multivariate logistic regression were end of treatment and 6 month abstinence, with demographic, behavioral, and genetic covariates. RESULTS: 'Risk' alleles previously associated with smoking heaviness were significantly associated with reduced abstinence in the PLA pharmacotherapy group at 6MO [for rs588765, odds ratio 0.41 ], and at end of treatment and at 6MO [for rs1051730, 0.42 and 0.31 ], and with increased abstinence in the NRT PG at 6MO [for rs588765, 2.07 and for rs1051730, 2.54 ]. We observed significant heterogeneity in rs1051730 effects between PGs. CONCLUSION: chr15q25.1 nAChR SNP risk alleles for smoking heaviness significantly increase relapse with PLA treatment and significantly increase abstinence with NRT. These SNP-PG associations require replication in independent samples for validation, and testing in larger sample sizes to evaluate whether similar effects occur in other PGs. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.

We utilized a cohort of 828 treatment-seeking self-identified white cigarette smokers to rank candidate gene single nucleotide polymorphisms associated with the Fagerström Test for Nicotine Dependence, a measure of nicotine dependence which assesses quantity of cigarettes smoked and time- and place-dependent characteristics of the respondent's smoking behavior. A total of 1123 SNPs at 55 autosomal candidate genes, nicotinic acetylcholine receptors and genes involved in dopaminergic function, were tested for association to baseline FTND scores adjusted for age, depression, education, sex, and study site. SNP P-values were adjusted for the number of transmission models, the number of SNPs tested per candidate gene, and their intragenic correlation. DRD2, SLC6A3, and NR4A2 SNPs with adjusted P-values <0.10 were considered sufficiently noteworthy to justify further genetic, bioinformatic, and literature analyses. Each independent signal among the top-ranked SNPs accounted for ∼1% of the FTND variance in this sample. The DRD2 SNP appears to represent a novel association with nicotine dependence. The SLC6A3 SNPs have previously been shown to be associated with SLC6A3 transcription or dopamine transporter density in vitro, in vivo, and ex vivo. Analysis of SLC6A3 and NR4A2 SNPs identified a statistically significant gene-gene interaction, consistent with in vitro evidence that the NR4A2 protein product regulates SLC6A3 transcription. A community cohort of N=175 multiplex ever-smoking pedigrees provided nominal evidence for association with the FTND at these top ranked SNPs, uncorrected for multiple comparisons. © 2009 Nature Publishing Group All rights reserved.

Although the efficacy of pharmacotherapy for tobacco dependence has been previously demonstrated, there is substantial variability among individuals in treatment response. We performed a systems-based candidate gene study of 1295 single nucleotide polymorphisms in 58 genes within the neuronal nicotinic receptor and dopamine systems to investigate their role in smoking cessation in a bupropion placebo-controlled randomized clinical trial. Putative functional variants were supplemented with tagSNPs within each gene. We used global tests of main effects and treatment interactions, adjusting the P-values for multiple correlated tests. An SNP in the 3′ UTR region of the β2 nicotinic acetylcholine receptor subunit has an impact on abstinence rates at the end of treatment and after a 6-month follow-up period. This latter P-value is also significant with adjustment for the number of genes tested. Independent of treatment at 6-month follow-up, individuals carrying the minor allele have substantially decreased the odds of quitting. Effect of estimates indicate that the treatment is more effective for individuals with the wild-type compared with individuals carrying the minor allele, although this difference is only suggestive. Furthermore, this SNP demonstrated a role in the time to relapse and an impact on withdrawal symptoms at target quit date. Overall, while our results indicate strong evidence for CHRNB2 in ability to quit smoking, these results require replication in an independent sample. © 2008 The Author.

Pragmatic theological realism (PTR) urges us to take up the realist aim of theology or the goal of truth although we have good reason to think that the goal can neither be attained nor approximated. Rescher contends that pursuing an unreachable goal can be rational on pragmatic grounds so long as pursuing the unreachable goal yields indirect benefits. I have blocked this attempt at providing a pragmatic justification for the realist aim of PTR on precisely the same pragmatic grounds: since there is a competing alternative to PTR and the alternative can provide whatever indirect benefits PTR can offer while being less risky than it is, prudential reasoning favours the alternative to PTR. This undermines the pragmatic case for the realist aim of theology since the instrumentalist alternative does not aim at the truth.

Pragmatic Scientific Realism (PSR) urges us to take up the realist aim or the goal of truth although we have good reason to think that the goal can neither be attained nor approximated. While Newton-Smith thinks that pursuing what we know we cannot achieve is clearly irrational, Rescher disagrees and contends that pursuing an unreachable goal can be rational on pragmatic grounds—if in pursuing the unreachable goal one can get indirect benefits. I have blocked this attempt at providing a pragmatic justification for the realist aim of PSR on precisely the same pragmatic grounds—since there is a competing alternative to PSR, and the alternative can provide whatever indirect benefits PSR can offer while being less risky than it is, prudential reasoning favours the alternative to PSR. This undermines the pragmatic case for the realist aim of science since the instrumentalist alternative does not aim at the truth.

According to Hitchcock and Sober’s argument from overfitting for weak predictivism, the fact that a theory accurately predicts a portion of its data is evidence that it has been formulated by balancing simplicity and goodness-of-fit rather than overfitting data. The core argument consists of two likelihood inequalities. In this paper I show that there is a surprising accommodation-friendly implication in their argument, and contend that it is beset by a substantial difficulty, namely, there is no good reason to think that their second likelihood inequality is true

Lipton contends that the no-miracle argument is illegitimate, because it fails to adduce new evidence beyond that cited by scientists for their theories. The debate on this issue between Lipton and Psillos has focussed on whether there is a construal of the no-miracle argument in relation to first-order scientific inferences that can yield new evidence. I move away from this focus without taking sides, and argue that the no-miracle argument, on its two popular interpretations, is as legitimate, cogent, and useful an inductive argument for scientific realism as first-order scientific inferences to the best explanation even if it does not add to scientific evidence