***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Genotype scores that predict relevant clinical outcomes may detect other disease features and help direct prevention efforts . We report data that vali date a previously established v1.0 smoking cessation quit success genotype score and describe striking differences in the score in individuals who display differing developmental trajectories of use of common addictive substances . In a cessation study , v1.0 genotype scores predicted ability to quit with P=0.00056 and area under receiver-operating characteristic curve 0.66 . About 43 % vs 13 % quit in the upper vs lower genotype score terciles . Latent class growth analyses of a developmentally assessed sample identified three latent classes based on substance use . Higher v1.0 scores were associated with ( a ) higher probabilities of participant membership in a latent class that displayed low use of common addictive substances during adolescence ( P=0.0004 ) and ( b ) lower probabilities of membership in a class that reported escalating use ( P=0.001 ) . These results indicate that : ( a ) we have identified genetic predictors of smoking cessation success , ( b ) genetic influences on quit success overlap with those that influence the rate at which addictive substance use is taken up during adolescence and ( c ) individuals at genetic risk for both escalating use of addictive substances and poor abilities to quit may provide especially urgent focus for prevention efforts Purpose : A new generation of molecularly targeted agents is entering the definitive stage of clinical evaluation . Many of these drugs benefit only a subset of treated patients and may be overlooked by the traditional , broad- eligibility approach to r and omized clinical trials . Thus , there is a need for development of novel statistical methodology for rapid evaluation of these agents . Experimental Design : We propose a new adaptive design for r and omized clinical trials of targeted agents in setting s where an assay or signature that identifies sensitive patients is not available at the outset of the study . The design combines prospect i ve development of a gene expression – based classifier to select sensitive patients with a properly powered test for overall effect . Results : Performance of the adaptive design , relative to the more traditional design , is evaluated in a simulation study . It is shown that when the proportion of patients  sensitive to the new drug is low , the adaptive design substantially reduces the chance of false rejection of effective new treatments . When the new treatment is broadly effective , the adaptive design has power to detect the overall effect similar to the traditional design . Formulas are provided to determine the situations in which the new design is advantageous . Conclusion : Development of a gene expression – based classifier to identify the subset of sensitive patients  can be prospect ively incorporated into a r and omized phase III design without compromising the ability to detect an overall effect The authors present results of a r and omized clinical trial of the efficacy of extended treatment with bupropion SR in producing longer term cigarette smoking cessation .  Adult smokers ( N = 362 ) received  open-label treatment  ( 11 weeks ) that combined relapse prevention training , bupropion SR , and nicotine patch followed by extended treatment ( 14 weeks ) with bupropion SR or matching placebo .  Abstinence percentages were relatively high ( week 11 : 52 % ; week 25 : bupropion , 42 % ; placebo , 38 % ; week 52 : bupropion , 33 % ; placebo , 34 % ) , but bupropion SR did not surpass placebo .  Gender and baseline craving level were identified as significant , independent moderators of treatment response . Men were more likely to abstain than women ( week 11 : 59 % vs. 43 % , p = .001 ; week 25 : 48 % vs. 31 % , p = .001 ; week 52 : 39 % vs. 27 % , p = .01 ) . Because most smokers suffer relapse with any current cessation treatment , the comparatively high abstinence percentages achieved in this trial are of interest Extending a previous finding of an association between functional genetic variation in the mu-opioid receptor gene and response to nicotine replacement therapy , we explored the role of genetic variants in two genes encoding mu-opioid-receptor-interacting proteins , namely ARRB2 and HINT1 . Participants were 374 smokers treated for nicotine dependence with either transdermal nicotine or nicotine nasal spray for 8 weeks in an open-label r and omized trial . In a logistic regression model controlling for OPRM1 genotype , treatment type , and other covariates , we found no significant main effect of ARRB2 genotype on abstinence at either end of treatment or 6-month follow-up . Participants with the HINT1 TT genotype had significantly higher abstinence rates at 6-month follow-up , but this may not be a pharmacogenetic effect , given that the participants were drug free during this time . Haplotype analysis did not reveal any significant associations for either gene . We found an interaction of ARRB2 and OPRM1 genotype on abstinence at 6 months that approached significance ; however , interpretation of this finding is limited by the small number of participants with the minor alleles for both genes . Although these data do not provide support for the role of genetic variation in these mu-opioid-receptor-interacting proteins and smoking cessation , further exploration of opioid pathway genes in larger prospect i ve pharmacogenetic trials may be warranted Stopping smoking is difficult even with treatment . Many patients prescribed pharmacologic treatments for smoking cessation experience side effects or lack of efficacy . We performed a pharmacogenetic study of the efficacy and tolerability of bupropion and transdermal nicotine ( TN ) , two treatments for smoking cessation . Sample s were drawn from two studies . In the first study ( Maintenance 1 , MT1 ) , 301 smokers received bupropion plus TN for 11 weeks , followed by 14 weeks of placebo or bupropion . In the second study ( MT2 ) , 276 smokers received bupropion and TN for 8 weeks . We focused on eight SNPs in the 15q24 region , which contains the genes for the nicotinic cholinergic receptor subunits CHRNA5 , CHRNA3 , and CHRNB4 , and has previously been implicated in nicotine addiction and smoking cessation . Analyses of baseline smoking quantity ( SQ ) identified an association between SQ and both the functional CHRNA5 SNP rs16969968 ( D398N ) and the CHRNA3 SNP rs1051730 ( Y215Y ) in a combined cohort containing MT1 and MT2 . An association between SQ and ethnicity was also identified in the combined cohort . Pharmacogenetic analysis showed a significant association between rs8192475 ( R37H ) in CHRNA3 and both higher craving after quitting and increased withdrawal symptoms over time in MT2 . Two markers for point prevalence abstinence , CHRNA5 SNP rs680244 and CHRNB4 SNP rs12914008 , were also identified in MT2 , with the strongest findings at week 52 . These results provide further support for the role of the CHRNA5/A3/B4 subunits in determining number of cigarettes smoked and response to smoking cessation therapy . © 2011 Wiley‐Liss , We conducted gender-stratified analyses on a systems-based c and i date gene study of 53 regions involved in nicotinic response and the brain — reward pathway in two r and omized clinical trials of smoking  cessation treatments ( placebo , bupropion , transdermal and nasal spray nicotine replacement therapy ) . We adjusted P-values for multiple correlated tests , and used a Bonferroni-corrected α-level of 5 × 10−4 to determine system-wide significance . Four single-nucleotide polymorphisms ( rs12021667 , rs12027267 , rs6702335 , rs12039988 ; r2>0.98 ) in erythrocyte membrane protein b and 4.1 ( EPB41 ) had a significant male-specific marginal association with smoking abstinence ( odds ratio (OR)=0.5 ; 95 % confidence interval ( CI ) : 0.3–0.6 ) at end of treatment ( adjusted P<6 × 10−5 ) . rs806365 in cannabinoid receptor 1 ( CNR1 ) had a significant male-specific gene – treatment interaction at 6-month follow-up ( adjusted P=3.9 × 10−5 ) ; within males using nasal spray , rs806365 was associated with a decrease in odds of abstinence ( OR=0.04 ; 95 % CI : 0.01–0.2 ) . While the role of CNR1 in substance abuse has been well studied , we report EPB41 for the first time in the nicotine literature Purpose : Many anticancer therapies benefit only a subset of treated patients and may be overlooked by the traditional broad eligibility approach to design phase III clinical trials . New biotechnologies such as microarrays can be used to identify the patients that are most likely to benefit from anticancer therapies .  However , due to the high-dimensional nature of the genomic data , developing a reliable classifier by the time the definitive phase III trail is design ed may not be feasible . Experimental Design : Previously , Freidlin and Simon ( Clinical Cancer Research , 2005 ) introduced the adaptive signature design that combines a prospect i ve development of a sensitive patient classifier and a properly powered test for overall effect in a single pivotal trial . In this article , we propose a cross-validation extension of the adaptive signature design that optimizes the efficiency of both the classifier development and the validation components of the design . Results : The new design is evaluated through simulations and is applied to data from a r and omized breast cancer trial . Conclusion : The cross-validation approach is shown to considerably improve the performance of the adaptive signature design . We also describe approaches to the estimation of the treatment effect for the identified sensitive sub population . Clin Cancer Res ; 16(2 ) ; INTRODUCTION We evaluated chr6q25.3 organic cation transporter gene ( SLC22A1 , SLC22A2 , SLC22A3 ) variation and response to smoking cessation therapies . The corresponding proteins are low-affinity transporters of choline , acetylcholine and monoamines , and smoking cessation pharmacotherapies expressed in multiple tissues . METHODS We selected 7 common polymorphisms for mega-regression analysis . We assessed additive model association of polymorphisms with 7-day point prevalence abstinence overall and by assigned pharmacotherapy at end of treatment and at 6 months among European-ancestry participants of 7 r and omized controlled trials adjusted for demographic , population genetic , and trial covariates . RESULTS Initial results were obtained in 6 trials with 1,839 participants . Nominally statistically significant associations of 2 SLC22A2 polymorphisms were observed : ( 1 ) with rs316019 at 6 months , overall ( [ c.808T > G ; p . Ser270Ala ] , OR = 1.306 , 95 % CI = 1.034 - 1.649 , p = .025 ) , and among those r and omized to nicotine replacement therapy ( NRT ) ( OR = 1.784 , 95 % CI = 1.072 - 2.970 , p = .026 ) ; and ( 2 ) with rs316006 ( c.1502 - 529A > T ) among those r and omized to varenicline ( OR = 1.420 , 95 % CI = 1.038 - 1.944 , p = .028 , OR = 1.362 , 95 % CI = 1.001 - 1.853 , p = .04 ) at end of treatment and 6 months . Individuals r and omized to NRT from a seventh trial were genotyped for rs316019 ; rs316019 was associated with a nominally statistically significant effect on abstinence overall at 6 months among 2,233 participants ( OR = 1.249 , 95 % CI = 1.007 - 1.550 , p = .043 ) . CONCLUSIONS The functional OCT2 Ser270Ala polymorphism is nominally statistically significantly associated with abstinence among European-ancestry treatment-seeking smokers after adjustments for pharmacotherapy , demographics , population genetics , and without adjustment for multiple testing of 7 SNPs . Replication of these preliminary findings in additional r and omized controlled trials of smoking cessation therapies and from multiple continental population s would describe another pharmacogenetic role for SLC22A2/OCT2 INTRODUCTION The α4β2 nicotinic receptor is of central importance in tobacco dependence , while the homomeric α7 receptor may also play a role . In this c and i date gene study , we examine the association between 8 single nucleotide polymorphisms ( SNPs ) in genes coding for nicotinic acetylcholine receptor subunits α4 ( rs1044396 , rs2273504 , rs2236196 , and rs2273502 ) , α7 ( rs2133965 and rs4779969 ) , and β2 ( rs2072660 and rs2072661 ) and smoking abstinence in a cohort of quitters enrolled in a clinical trial of behavioral support . METHODS Data were obtained from the " Patch in Practice " study , involving 925 smokers in the United Kingdom . All participants were given an 8 
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AUTHORS ' CONCLUSIONS We did not identify widespread differential treatment effects of pharmacotherapy based on genotype .
Some genotype groups within certain ethnic groups may benefit more from NRT or may benefit less from the combination of bupropion with NRT .
Although we found evidence of superior NRT efficacy for NMR slow versus normal metabolisers , because of the lack of heterogeneity between NMR groups , we can not conclude that NRT is more effective for slow metabolisers .