A review of the literature on contingency management in the treatment of substance use disorders, 2009-2014.

This report describes a systematic literature review of voucher and related monetary-based contingency management (CM) interventions for substance use disorders (SUDs) over 5.2years (November 2009 through December 2014). Reports were identified using the search engine PubMed, expert consultations, and published bibliographies. For inclusion, reports had to (a) involve monetary-based CM; (b) appear in a peer-reviewed journal; (c) include an experimental comparison condition; (d) describe an original study; (e) assess efficacy using inferential statistics; (f) use a research design allowing treatment effects to be attributed to CM. Sixty-nine reports met inclusion criteria and were categorized into 7 research trends: (1) extending CM to special populations, (2) parametric studies, (3) extending CM to community clinics, (4) combining CM with pharmacotherapies, (5) incorporating technology into CM, (6) investigating longer-term outcomes, (7) using CM as a research tool. The vast majority (59/69, 86%) of studies reported significant (p<0.05) during-treatment effects. Twenty-eight (28/59, 47%) of those studies included at least one follow-up visit after CM was discontinued, with eight (8/28, 29%) reporting significant (p<0.05) effects. Average effect size (Cohen's d) during treatment was 0.62 (95% CI: 0.54, 0.70) and post-treatment it was 0.26 (95% CI: 0.11, 0.41). Overall, the literature on voucher-based CM over the past 5years documents sustained growth, high treatment efficacy, moderate to large effect sizes during treatment that weaken but remain evident following treatment termination, and breadth across a diverse set of SUDs, populations, and settings consistent with and extending results from prior reviews.

Co-occurring risk factors for current cigarette smoking in a U.S. nationally representative sample.

INTRODUCTION: Relatively little has been reported characterizing cumulative risk associated with co-occurring risk factors for cigarette smoking. The purpose of the present study was to address that knowledge gap in a U.S. nationally representative sample. METHODS: Data were obtained from 114,426 adults (≥18years) in the U.S. National Survey on Drug Use and Health (years 2011-13). Multiple logistic regression and classification and regression tree (CART) modeling were used to examine risk of current smoking associated with eight co-occurring risk factors (age, gender, race/ethnicity, educational attainment, poverty, drug abuse/dependence, alcohol abuse/dependence, mental illness). RESULTS: Each of these eight risk factors was independently associated with significant increases in the odds of smoking when concurrently present in a multiple logistic regression model. Effects of risk-factor combinations were typically summative. Exceptions to that pattern were in the direction of less-than-summative effects when one of the combined risk factors was associated with generally high or low rates of smoking (e.g., drug abuse/dependence, age ≥65). CART modeling identified subpopulation risk profiles wherein smoking prevalence varied from a low of 11% to a high of 74% depending on particular risk factor combinations. Being a college graduate was the strongest independent predictor of smoking status, classifying 30% of the adult population. CONCLUSIONS: These results offer strong evidence that the effects associated with common risk factors for cigarette smoking are independent, cumulative, and generally summative. The results also offer potentially useful insights into national population risk profiles around which U.S. tobacco policies can be developed or refined.

Use of High-Nicotine/Tar-Yield (Full-Flavor) Cigarettes and Risk for Nicotine Dependence in Nationally Representative Samples of US Smokers.

INTRODUCTION: The present study examines whether use of machine-estimated high-nicotine/tar-yield (full-flavor) cigarettes predicts greater risk of nicotine dependence after controlling for the influence of potential confounding factors in US nationally representative samples. METHODS: Data were obtained from multiple years of the National Survey on Drug Use and Health (NSDUH). Nicotine dependence was measured by (1) the Nicotine Dependence Syndrome Scale and (2) latency to first cigarette after waking. Associations between use of high-nicotine/tar-yield cigarettes and risk for nicotine dependence were examined using multiple logistic regression. RESULTS: The odds of nicotine dependence were reliably greater among users of high- compared to lower-nicotine/tar-yield cigarettes even after adjusting for sociodemographic and other smoking characteristics (Ps < .0001). This relationship was (1) generally graded across differing nicotine/tar-yield cigarettes, (2) discernible across two definitions of nicotine dependence and multiple NSDUH survey years, and (3) observed among adult and adolescent smokers. CONCLUSION: Use of high-nicotine/tar-yield cigarettes is associated with increased odds of nicotine dependence, a relationship that has important tobacco regulatory implications. Whether the widespread marketing and availability of high-nicotine/tar-yield cigarettes is increasing risk of nicotine dependence among US smokers warrants further research. IMPLICATIONS: This study adds additional empirical evidence to the relation of machine measured high-yield cigarettes and likelihood of nicotine dependence, and draws some implications in regards to regulation.

Do Socioeconomic Risk Factors for Cigarette Smoking Extend to Smokeless Tobacco Use?

INTRODUCTION: Individuals with lower socioeconomic status (SES) are at increased risk for cigarette smoking. Less research has been conducted characterizing the relationship between SES and risk of using of other tobacco products. The present study examined SES as a risk factor for smokeless tobacco (ST) use in a US nationally representative sample, utilizing data from the 2012 National Survey on Drug Use and Health. METHODS: Odds were generated for current cigarette smoking and ST use among adults (≥18 years) based on SES markers (educational attainment, income, blue-collar employment, and unemployment) after controlling for the influence of demographics and other substance dependence. RESULTS: Odds of current cigarette smoking increased as a graded, inverse function of educational attainment as well as lower income and being unemployed. Odds of current ST use also increased as a function of lower educational attainment, although not in the linear manner seen with cigarette smoking. Odds of ST use but not cigarette smoking also increased with blue-collar employment. In contrast to patterns seen with cigarette smoking, ST use did not change in relation to income or unemployment. CONCLUSIONS: Markers of SES are significantly associated with odds of cigarette smoking and ST use, but which indicators are predictive and the shape of their relationship to use differs across the two tobacco products.

A literature review on prevalence of gender differences and intersections with other vulnerabilities to tobacco use in the United States, 2004-2014.

This report describes results from a systematic literature review examining gender differences in U.S. prevalence rates of current use of tobacco and nicotine delivery products and how they intersect with other vulnerabilities to tobacco use. We searched PubMed on gender differences in tobacco use across the years 2004-2014. For inclusion, reports had to be in English, in a peer-reviewed journal or federal government report, report prevalence rates for current use of a tobacco product in males and females, and use a U.S. nationally representative sample. Prevalence rates were generally higher in males than in females across all products. This pattern remained stable despite changes over time in overall prevalence rates. Gender differences generally were robust when intersecting with other vulnerabilities, although decreases in the magnitude of gender differences were noted among younger and older users, and among educational levels and race/ethnic groups associated with the highest or lowest prevalence rates. Overall, these results document a pervasive association of gender with vulnerability to tobacco use that acts additively with other vulnerabilities. These vulnerabilities should be considered whenever formulating tobacco control and regulatory policies.

Vulnerability to smokeless tobacco use among those dependent on alcohol or illicit drugs.

INTRODUCTION: Individuals dependent on alcohol or illicit drugs are vulnerable to cigarette smoking and related adverse health outcomes. Less research has been conducted regarding whether these same groups are vulnerable to smokeless tobacco (ST) use. The goal of this study is to examine vulnerability to ST use among individuals with other drug dependence. METHODS: Utilizing the most recent (2011) National Survey on Drug Use and Health (NDSUH), we determined odds ratios (ORs) for current cigarette smoking and ST use among those with current alcohol, cocaine, heroin, and marijuana dependence, adjusting for relevant sociodemographic characteristics. Vulnerability to cigarette smoking was assessed to confirm that alcohol and illicit drug dependence were associated with increased smoking in these data sets, as shown in prior studies. Identical analyses were completed in the 2009 and 2010 NSDUH to assess generality. RESULTS: Odds for current cigarette smoking were increased for each category of dependence (p < .0005): alcohol (OR with 99% CI = 3.30 [2.58, 4.21]), cocaine (OR = 4.50 [1.53, 13.20]), heroin (OR = 7.84 [1.92, 32.03]), and marijuana (OR = 3.55 [2.59, 4.88]). Odds for current ST use were also increased among those with alcohol dependence (OR = 1.56 [1.06, 2.30], p = .003) but not illicit drug dependence. Generality of the findings was confirmed in the 2009 and 2010 NSDUH. CONCLUSIONS: Consistent with earlier reports, alcohol and illicit drug dependence are associated with robust increases in risk for cigarette smoking. In the case of alcohol dependence, but not illicit drug dependence, this vulnerability also extends to ST use.

Proportionally more deleterious genetic variation in European than in African populations.

Quantifying the number of deleterious mutations per diploid human genome is of crucial concern to both evolutionary and medical geneticists. Here we combine genome-wide polymorphism data from PCR-based exon resequencing, comparative genomic data across mammalian species, and protein structure predictions to estimate the number of functionally consequential single-nucleotide polymorphisms (SNPs) carried by each of 15 African American (AA) and 20 European American (EA) individuals. We find that AAs show significantly higher levels of nucleotide heterozygosity than do EAs for all categories of functional SNPs considered, including synonymous, non-synonymous, predicted 'benign', predicted 'possibly damaging' and predicted 'probably damaging' SNPs. This result is wholly consistent with previous work showing higher overall levels of nucleotide variation in African populations than in Europeans. EA individuals, in contrast, have significantly more genotypes homozygous for the derived allele at synonymous and non-synonymous SNPs and for the damaging allele at 'probably damaging' SNPs than AAs do. For SNPs segregating only in one population or the other, the proportion of non-synonymous SNPs is significantly higher in the EA sample (55.4%) than in the AA sample (47.0%; P < 2.3 x 10(-37)). We observe a similar proportional excess of SNPs that are inferred to be 'probably damaging' (15.9% in EA; 12.1% in AA; P < 3.3 x 10(-11)). Using extensive simulations, we show that this excess proportion of segregating damaging alleles in Europeans is probably a consequence of a bottleneck that Europeans experienced at about the time of the migration out of Africa.

Evolutionary processes acting on candidate cis-regulatory regions in humans inferred from patterns of polymorphism and divergence.

Analysis of polymorphism and divergence in the non-coding portion of the human genome yields crucial information about factors driving the evolution of gene regulation. Candidate cis-regulatory regions spanning more than 15,000 genes in 15 African Americans and 20 European Americans were re-sequenced and aligned to the chimpanzee genome in order to identify potentially functional polymorphism and to characterize and quantify departures from neutral evolution. Distortions of the site frequency spectra suggest a general pattern of selective constraint on conserved non-coding sites in the flanking regions of genes (CNCs). Moreover, there is an excess of fixed differences that cannot be explained by a Gamma model of deleterious fitness effects, suggesting the presence of positive selection on CNCs. Extensions of the McDonald-Kreitman test identified candidate cis-regulatory regions with high probabilities of positive and negative selection near many known human genes, the biological characteristics of which exhibit genome-wide trends that differ from patterns observed in protein-coding regions. Notably, there is a higher probability of positive selection in candidate cis-regulatory regions near genes expressed in the fetal brain, suggesting that a larger portion of adaptive regulatory changes has occurred in genes expressed during brain development. Overall we find that natural selection has played an important role in the evolution of candidate cis-regulatory regions throughout hominid evolution.

Genetic testing for early detection of individuals at risk of coronary heart disease and monitoring response to therapy: challenges and promises.

Coronary heart disease (CHD) often presents suddenly with little warning. Traditional risk factors are inadequate to identify the asymptomatic high-risk individuals. Early identification of patients with subclinical coronary artery disease using noninvasive imaging modalities would allow the early adoption of aggressive preventative interventions. Currently, it is impractical to screen the entire population with noninvasive coronary imaging tools. The use of relatively simple and inexpensive genetic markers of increased CHD risk can identify a population subgroup in which benefit of atherosclerotic imaging modalities would be increased despite nominal cost and radiation exposure. Additionally, genetic markers are fixed and need only be measured once in a patient's lifetime, can help guide therapy selection, and may be of utility in family counseling.

Natural selection on protein-coding genes in the human genome.

Comparisons of DNA polymorphism within species to divergence between species enables the discovery of molecular adaptation in evolutionarily constrained genes as well as the differentiation of weak from strong purifying selection. The extent to which weak negative and positive darwinian selection have driven the molecular evolution of different species varies greatly, with some species, such as Drosophila melanogaster, showing strong evidence of pervasive positive selection, and others, such as the selfing weed Arabidopsis thaliana, showing an excess of deleterious variation within local populations. Here we contrast patterns of coding sequence polymorphism identified by direct sequencing of 39 humans for over 11,000 genes to divergence between humans and chimpanzees, and find strong evidence that natural selection has shaped the recent molecular evolution of our species. Our analysis discovered 304 (9.0%) out of 3,377 potentially informative loci showing evidence of rapid amino acid evolution. Furthermore, 813 (13.5%) out of 6,033 potentially informative loci show a paucity of amino acid differences between humans and chimpanzees, indicating weak negative selection and/or balancing selection operating on mutations at these loci. We find that the distribution of negatively and positively selected genes varies greatly among biological processes and molecular functions, and that some classes, such as transcription factors, show an excess of rapidly evolving genes, whereas others, such as cytoskeletal proteins, show an excess of genes with extensive amino acid polymorphism within humans and yet little amino acid divergence between humans and chimpanzees.

Assessing the evolutionary impact of amino acid mutations in the human genome.

Quantifying the distribution of fitness effects among newly arising mutations in the human genome is key to resolving important debates in medical and evolutionary genetics. Here, we present a method for inferring this distribution using Single Nucleotide Polymorphism (SNP) data from a population with non-stationary demographic history (such as that of modern humans). Application of our method to 47,576 coding SNPs found by direct resequencing of 11,404 protein coding-genes in 35 individuals (20 European Americans and 15 African Americans) allows us to assess the relative contribution of demographic and selective effects to patterning amino acid variation in the human genome. We find evidence of an ancient population expansion in the sample with African ancestry and a relatively recent bottleneck in the sample with European ancestry. After accounting for these demographic effects, we find strong evidence for great variability in the selective effects of new amino acid replacing mutations. In both populations, the patterns of variation are consistent with a leptokurtic distribution of selection coefficients (e.g., gamma or log-normal) peaked near neutrality. Specifically, we predict 27-29% of amino acid changing (nonsynonymous) mutations are neutral or nearly neutral (|s|<0.01%), 30-42% are moderately deleterious (0.01%<|s|<1%), and nearly all the remainder are highly deleterious or lethal (|s|>1%). Our results are consistent with 10-20% of amino acid differences between humans and chimpanzees having been fixed by positive selection with the remainder of differences being neutral or nearly neutral. Our analysis also predicts that many of the alleles identified via whole-genome association mapping may be selectively neutral or (formerly) positively selected, implying that deleterious genetic variation affecting disease phenotype may be missed by this widely used approach for mapping genes underlying complex traits.

Targets of balancing selection in the human genome.

Balancing selection is potentially an important biological force for maintaining advantageous genetic diversity in populations, including variation that is responsible for long-term adaptation to the environment. By serving as a means to maintain genetic variation, it may be particularly relevant to maintaining phenotypic variation in natural populations. Nevertheless, its prevalence and specific targets in the human genome remain largely unknown. We have analyzed the patterns of diversity and divergence of 13,400 genes in two human populations using an unbiased single-nucleotide polymorphism data set, a genome-wide approach, and a method that incorporates demography in neutrality tests. We identified an unbiased catalog of genes with signatures of long-term balancing selection, which includes immunity genes as well as genes encoding keratins and membrane channels; the catalog also shows enrichment in functional categories involved in cellular structure. Patterns are mostly concordant in the two populations, with a small fraction of genes showing population-specific signatures of selection. Power considerations indicate that our findings represent a subset of all targets in the genome, suggesting that although balancing selection may not have an obvious impact on a large proportion of human genes, it is a key force affecting the evolution of a number of genes in humans.

A scan for positively selected genes in the genomes of humans and chimpanzees.

Since the divergence of humans and chimpanzees about 5 million years ago, these species have undergone a remarkable evolution with drastic divergence in anatomy and cognitive abilities. At the molecular level, despite the small overall magnitude of DNA sequence divergence, we might expect such evolutionary changes to leave a noticeable signature throughout the genome. We here compare 13,731 annotated genes from humans to their chimpanzee orthologs to identify genes that show evidence of positive selection. Many of the genes that present a signature of positive selection tend to be involved in sensory perception or immune defenses. However, the group of genes that show the strongest evidence for positive selection also includes a surprising number of genes involved in tumor suppression and apoptosis, and of genes involved in spermatogenesis. We hypothesize that positive selection in some of these genes may be driven by genomic conflict due to apoptosis during spermatogenesis. Genes with maximal expression in the brain show little or no evidence for positive selection, while genes with maximal expression in the testis tend to be enriched with positively selected genes. Genes on the X chromosome also tend to show an elevated tendency for positive selection. We also present polymorphism data from 20 Caucasian Americans and 19 African Americans for the 50 annotated genes showing the strongest evidence for positive selection. The polymorphism analysis further supports the presence of positive selection in these genes by showing an excess of high-frequency derived nonsynonymous mutations.

Rural tobacco use across the United States: How rural and urban areas differ, broken down by census regions and divisions.

This project compared urban/rural differences in tobacco use, and examined how such differences vary across regions/divisions of the U.S. Using pooled 2012-2013 data from the National Survey on Drug Use and Health (NSDUH), we obtained weighted prevalence estimates for the use of cigarettes, menthol cigarettes, chewing tobacco, snuff, cigars, and pipes. NSDUH also provides information on participants' residence: rural vs. urban, and Census region and division. Overall, use of cigarettes, chew, and snuff were higher in rural, compared to urban areas. Across all tobacco products, urban/rural differences were particularly pronounced in certain divisions (e.g., the South Atlantic). Effects did not appear to be fully explained by differences in poverty. Going beyond previous research, these findings show that urban/rural differences vary across different types of tobacco products, as well as by division of the country. Results underscore the need for regulatory efforts that will reduce health disparities.

A Review of the Literature on Remote Monitoring Technology in Incentive-Based Interventions for Health-Related Behavior Change.

Use of technology (e.g., Internet, cell phones) to allow remote implementation of incentives interventions for health-related behavior change is growing. To our knowledge, there has yet to be a systematic review of this literature reported. The present report provides a systematic review of the controlled studies where technology was used to remotely implement financial incentive interventions targeting substance use and other health behaviors published between 2004 and 2015. For inclusion in the review, studies had to use technology to remotely accomplish one of the following two aims alone or in combination: (a) monitor the target behavior, or (b) deliver incentives for achieving the target goal. Studies also had to examine financial incentives (e.g., cash, vouchers) for health-related behavior change, be published in peer-reviewed journals, and include a research design that allowed evaluation of the efficacy of the incentive intervention relative to another condition (e.g., non-contingent incentives, treatment as usual). Of the 39 reports that met inclusion criteria, 18 targeted substance use, 10 targeted medication adherence or home-based health monitoring, and 11 targeted diet, exercise, or weight loss. All 39 (100%) studies used technology to facilitate remote monitoring of the target behavior, and 26 (66.7%) studies also incorporated technology in the remote delivery of incentives. Statistically significant intervention effects were reported in 71% of studies reviewed. Overall, the results offer substantial support for the efficacy of remotely implemented incentive interventions for health-related behavior change, which have the potential to increase the cost-effectiveness and reach of this treatment approach.

Evaluation of the paraoxonases as candidate genes for stroke: Gln192Arg polymorphism in the paraoxonase 1 gene is associated with increased risk of stroke.

BACKGROUND AND PURPOSE: The paraoxonases are involved in protecting low-density lipoprotein (LDL) from lipid oxidation. Paraoxonase 1 (PON1) was implicated in susceptibility to coronary artery disease and stroke in previous studies. We evaluated, in a comprehensive way, all 3 paraoxonase genes for association with stroke observed in the Cholesterol and Recurrent Events (CARE) trial. METHODS: Over 2500 subjects enrolled in the CARE trial were genotyped for 14 single nucleotide polymorphisms, including 7 newly identified in this study, in the 3 paraoxonase genes. RESULTS: A glutamine (Gln)/arginine (Arg) polymorphism at amino acid residue 192 in PON1 was significantly associated with stroke (P=0.003 in multivariate analysis, including age, sex, LDL, hypertension, diabetes, smoking, and pravastatin treatment as covariates). The odds ratios were 2.28 (95% CI, 1.38 to 3.79) for Gln/Arg heterozygotes and 2.47 (95% CI, 1.18 to 5.19) for Arg/Arg homozygotes compared with Gln/Gln homozygotes. These results are consistent with 2 of 3 other published studies. In combined analysis of all 4 studies, the association between Gln192Arg SNP and stroke was highly significant (chi2(8df)=45.58, P<0.000001). Sequence analysis of the PON1 gene from seventy stroke cases revealed a novel nonsense mutation at codon 32 in one stroke case, which was not detected in over 2500 unaffected individuals. Polymorphisms in the PON2 and PON3 genes were not associated with stroke. CONCLUSIONS: These results suggest that Gln192Arg genotype is an important risk factor for stroke.

Examination of a recommended algorithm for eliminating nonsystematic delay discounting response sets.

PURPOSE: To examine (1) whether use of a recommended algorithm (Johnson and Bickel, 2008) improves upon conventional statistical model fit (R(2)) for identifying nonsystematic response sets in delay discounting (DD) data, (2) whether removing such data meaningfully effects research outcomes, and (3) to identify participant characteristics associated with nonsystematic response sets. METHODS: Discounting of hypothetical monetary rewards was assessed among 349 pregnant women (231 smokers and 118 recent quitters) via a computerized task comparing $1000 at seven future time points with smaller values available immediately. Nonsystematic response sets were identified using the algorithm and conventional statistical model fit (R(2)). The association between DD and quitting was analyzed with and without nonsystematic response sets to examine whether the inclusion or exclusion impacts this relationship. Logistic regression was used to examine whether participant sociodemographics were associated with nonsystematic response sets. RESULTS: The algorithm excluded fewer cases than the R(2) method (14% vs. 16%), and was not correlated with logk as is R(2). The relationship between logk and the clinical outcome (spontaneous quitting) was unaffected by exclusion methods; however, other variables in the model were affected. Lower educational attainment and younger age were associated with nonsystematic response sets. CONCLUSIONS: The algorithm eliminated data that were inconsistent with the nature of discounting and retained data that were orderly. Neither method impacted the smoking/DD relationship in this data set. Nonsystematic response sets are more likely among younger and less educated participants, who may need extra training or support in DD studies.

Does impulsiveness moderate response to financial incentives for smoking cessation among pregnant and newly postpartum women?

We examined whether impulsiveness moderates response to financial incentives for cessation among pregnant smokers. Participants were randomized to receive financial incentives delivered contingent on smoking abstinence or to a control condition wherein incentives were delivered independent of smoking status. The study was conducted in two steps: First, we examined associations between baseline impulsiveness and abstinence at late pregnancy and 24-weeks-postpartum as part of a planned prospective study of this topic using data from a recently completed, randomized controlled clinical trial (N = 118). Next, to increase statistical power, we conducted a second analysis collapsing results across that recent trial and two prior trials involving the same study conditions (N = 236). Impulsivity was assessed using a delay discounting (DD) of hypothetical monetary rewards task in all three trials and Barratt Impulsiveness Scale (BIS) in the most recent trial. Neither DD nor BIS predicted smoking status in the single or combined trials. Receiving abstinence-contingent incentives, lower baseline smoking rate, and a history of quit attempts prepregnancy predicted greater odds of antepartum abstinence across the single and combined trials. No variable predicted postpartum abstinence across the single and combined trials, although a history of antepartum quit attempts and receiving abstinence-contingent incentives predicted in the single and combined trials, respectively. Overall, this study provides no evidence that impulsiveness as assessed by DD or BIS moderates response to this treatment approach while underscoring a substantial association of smoking rate and prior quit attempts with abstinence across the contingent incentives and control treatment conditions.