Publications by authors named "Thomas J White"

30 Publications

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

Prev Med 2016 11 8;92:36-46. Epub 2016 Aug 8.

Vermont Center of Behavior & Health, University of Vermont, United States; Departments of Psychiatry, University of Vermont, United States; Psychological Science, University of Vermont, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ypmed.2016.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385000PMC
November 2016

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

Prev Med 2016 11 21;92:110-117. Epub 2016 Feb 21.

Vermont Center on Tobacco Regulatory Science, University of Vermont, United States.

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.
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http://dx.doi.org/10.1016/j.ypmed.2016.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992654PMC
November 2016

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

Transl Issues Psychol Sci 2016 Jun;2(2):128-152

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074560PMC
http://dx.doi.org/10.1037/tps0000067DOI Listing
June 2016

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

Health Place 2016 05 22;39:153-9. Epub 2016 Apr 22.

Vermont Center on Tobacco Regulatory Science, University of Vermont, Burlington, VT, USA.

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.
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http://dx.doi.org/10.1016/j.healthplace.2016.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874850PMC
May 2016

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

Nicotine Tob Res 2016 06 7;18(6):1424-30. Epub 2015 Nov 7.

Vermont Center on Behavior and Health, University of Vermont, Burlington, VT; Department of Psychiatry, University of Vermont, Burlington, VT; Department of Psychology, University of Vermont, Burlington, VT

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.
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http://dx.doi.org/10.1093/ntr/ntv252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906263PMC
June 2016

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

Nicotine Tob Res 2016 May 26;18(5):869-73. Epub 2015 Oct 26.

Vermont Center on Behavior and Health, University of Vermont, Burlington, VT; Department of Psychiatry, University of Vermont, Burlington, VT; Department of Psychology, University of Vermont, Burlington, VT

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.
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http://dx.doi.org/10.1093/ntr/ntv199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900232PMC
May 2016

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

Drug Alcohol Depend 2015 Sep 17;154:300-3. Epub 2015 Jul 17.

Vermont Center on Behavior and Health, University of Vermont, United States; Department of Psychiatry, University of Vermont, United States; Department of Psychology, University of Vermont, United States.

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.
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http://dx.doi.org/10.1016/j.drugalcdep.2015.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752816PMC
September 2015

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

Prev Med 2015 Nov 26;80:89-100. Epub 2015 Jun 26.

Dana Medical Library, University of Vermont, USA.

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.
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http://dx.doi.org/10.1016/j.ypmed.2015.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592404PMC
November 2015

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

Exp Clin Psychopharmacol 2015 Apr 2;23(2):97-108. Epub 2015 Mar 2.

Vermont Center on Behavior and Health.

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.
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http://dx.doi.org/10.1037/a0038810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388785PMC
April 2015

Examining educational attainment, prepregnancy smoking rate, and delay discounting as predictors of spontaneous quitting among pregnant smokers.

Exp Clin Psychopharmacol 2014 Oct 28;22(5):384-91. Epub 2014 Jul 28.

Vermont Center on Behavior and Health, Department of Psychiatry, University of Vermont.

We investigated three potential predictors (educational attainment, prepregnancy smoking rate, and delay discounting [DD]) of spontaneous quitting among pregnant smokers. These predictors were examined alone and in combination with other potential predictors using study-intake assessments from controlled clinical trials examining the efficacy of financial incentives for smoking cessation and relapse prevention. Data from 349 pregnant women (231 continuing smokers and 118 spontaneous quitters) recruited from the greater Burlington, VT, area contributed to this secondary analysis, including psychiatric/sociodemographic characteristics, smoking characteristics, and performance on a computerized DD task. Educational attainment, smoking rate, and DD values were each significant predictors of spontaneous quitting in univariate analyses. A model examining those three predictors together retained educational attainment as a main effect and revealed a significant interaction of DD and smoking rate (i.e., DD was a significant predictor at lower but not higher smoking rates). A final model considering all potential predictors, included education, the interaction of DD and smoking rate, and five additional predictors (i.e., stress ratings, the belief that smoking during pregnancy will "greatly harm my baby," age of smoking initiation, marital status, and prior quit attempts during pregnancy). The study presented here contributes new knowledge on predictors of spontaneous quitting among pregnant smokers with substantive practical implications for reducing smoking during pregnancy.
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http://dx.doi.org/10.1037/a0037492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180793PMC
October 2014

Examining vulnerability to smokeless tobacco use among adolescents and adults meeting diagnostic criteria for major depressive disorder.

Exp Clin Psychopharmacol 2014 Aug 30;22(4):316-22. Epub 2014 Jun 30.

Vermont Center on Behavior and Health and Department of Psychiatry, University of Vermont.

Smoking prevalence is unevenly distributed in the U.S. population, with those with mental illness, other substance use disorders, and lower socioeconomic status being especially vulnerable. Less research has been conducted on the association between these same vulnerabilities and smokeless tobacco (ST) use. The present study examined cigarette and ST use among adolescents and adults who met diagnostic criteria for major depressive disorder in the National Survey on Drug Use and Health (NSDUH). Utilizing the most recent (2011) NSDUH, we compared odds for current cigarette smoking and ST use among adolescents and adults meeting criteria for past-year major depressive disorder to the general population, after adjusting for potential confounding influences of sociodemographic and other substance use characteristics. Analyses were conducted to examine sex as a moderator of the relation between major depressive disorder and tobacco use. Odds for current cigarette smoking among those classified with major depressive disorder were increased among adolescents (OR = 1.33, 95% CI [1.05, 1.69], p = .021) and adults (OR = 1.70, 95% CI [1.47, 1.97], p < .0005), and odds for current ST use did not differ among adolescents (OR = 0.90, 95% CI [0.54, 1.49], p = .678) and were lower among adults (OR = 0.68, 95% CI [0.51, 0.91], p = .010). Sex was not a significant moderator in adolescents or adults. Major depressive disorder is associated with increased risk for smoking but not ST use among adolescents and adults further demonstrating heterogeneity in predictors of vulnerability to use of different tobacco products.
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http://dx.doi.org/10.1037/a0037291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124457PMC
August 2014

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

Nicotine Tob Res 2014 Feb 30;16(2):216-23. Epub 2013 Sep 30.

Department of Psychiatry, University of Vermont, Burlington, VT;

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.
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http://dx.doi.org/10.1093/ntr/ntt150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880236PMC
February 2014

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

Curr Atheroscler Rep 2011 Oct;13(5):396-404

Celera Corporation, 1401 Harbor Bay Parkway, Alameda, CA 94502, USA.

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.
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http://dx.doi.org/10.1007/s11883-011-0198-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165136PMC
October 2011

Targets of balancing selection in the human genome.

Mol Biol Evol 2009 Dec 27;26(12):2755-64. Epub 2009 Aug 27.

Department of Molecular Biology and Genetics, Cornell University, USA.

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.
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http://dx.doi.org/10.1093/molbev/msp190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782326PMC
December 2009

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

PLoS Genet 2009 Aug 7;5(8):e1000592. Epub 2009 Aug 7.

Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA.

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.
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http://dx.doi.org/10.1371/journal.pgen.1000592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714078PMC
August 2009

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

PLoS Genet 2008 May 30;4(5):e1000083. Epub 2008 May 30.

Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.

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.
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http://dx.doi.org/10.1371/journal.pgen.1000083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2377339PMC
May 2008

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

Nature 2008 Feb;451(7181):994-7

Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA.

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.
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http://dx.doi.org/10.1038/nature06611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923434PMC
February 2008

Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials.

J Am Coll Cardiol 2008 Jan;51(4):435-43

Celera, Inc., Alameda, California 94502, USA.

Objectives: We asked whether 35 genetic polymorphisms, previously found to be associated with cardiovascular disease, were associated with myocardial infarction (MI) in the CARE (Cholesterol and Recurrent Events) trial and with coronary heart disease (CHD) in the WOSCOPS (West of Scotland Coronary Prevention Study) trial and whether the risk associated with these polymorphisms could be reduced by pravastatin treatment.

Background: Identification of genetic polymorphisms associated with CHD may improve assessment of CHD risk and understanding of disease pathophysiology.

Methods: We tested the association between genotype and recurrent MI in the CARE study and between genotype and primary CHD in the WOSCOPS trial using regression models that adjusted for conventional risk factors: Cox proportional hazards models for the CARE study and conditional logistic regression models for a nested case-control study of the WOSCOPS trial.

Results: We found that Trp719Arg (rs20455) in KIF6 was associated with coronary events. KIF6 encodes kinesin-like protein 6, a member of the molecular motor superfamily. In placebo-treated patients, carriers of the KIF6 719Arg allele (59.4% of the CARE trial cohort) had a hazard ratio of 1.50 (95% confidence interval [CI] 1.05 to 2.15) in the CARE trial and an odds ratio of 1.55 (95% CI 1.14 to 2.09) in the WOSCOPS trial. Among carriers, the absolute risk reduction by pravastatin was 4.89% (95% CI 1.81% to 7.97%) in the CARE trial and 5.49% (95% CI 3.52% to 7.46%) in the WOSCOPS trial.

Conclusions: In both the CARE and the WOSCOPS trials, carriers of the KIF6 719Arg allele had an increased risk of coronary events, and pravastatin treatment substantially reduced that risk.
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http://dx.doi.org/10.1016/j.jacc.2007.05.057DOI Listing
January 2008

A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.

Am J Hum Genet 2007 Feb 21;80(2):273-90. Epub 2006 Dec 21.

Celera, Alameda, CA 94502, USA.

We performed a multitiered, case-control association study of psoriasis in three independent sample sets of white North American individuals (1,446 cases and 1,432 controls) with 25,215 genecentric single-nucleotide polymorphisms (SNPs) and found a highly significant association with an IL12B 3'-untranslated-region SNP (rs3212227), confirming the results of a small Japanese study. This SNP was significant in all three sample sets (odds ratio [OR](common) 0.64, combined P [Pcomb]=7.85x10(-10)). A Monte Carlo simulation to address multiple testing suggests that this association is not a type I error. The coding regions of IL12B were resequenced in 96 individuals with psoriasis, and 30 additional IL12B-region SNPs were genotyped. Haplotypes were estimated, and genotype-conditioned analyses identified a second risk allele (rs6887695) located approximately 60 kb upstream of the IL12B coding region that exhibited association with psoriasis after adjustment for rs3212227. Together, these two SNPs mark a common IL12B risk haplotype (OR(common) 1.40, Pcomb=8.11x10(-9)) and a less frequent protective haplotype (OR(common) 0.58, Pcomb=5.65x10(-12)), which were statistically significant in all three studies. Since IL12B encodes the common IL-12p40 subunit of IL-12 and IL-23, we individually genotyped 17 SNPs in the genes encoding the other chains of these cytokines (IL12A and IL23A) and their receptors (IL12RB1, IL12RB2, and IL23R). Haplotype analyses identified two IL23R missense SNPs that together mark a common psoriasis-associated haplotype in all three studies (OR(common) 1.44, Pcomb=3.13x10(-6)). Individuals homozygous for both the IL12B and the IL23R predisposing haplotypes have an increased risk of disease (OR(common) 1.66, Pcomb=1.33x10(-8)). These data, and the previous observation that administration of an antibody specific for the IL-12p40 subunit to patients with psoriasis is highly efficacious, suggest that these genes play a fundamental role in psoriasis pathogenesis.
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http://dx.doi.org/10.1086/511051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785338PMC
February 2007

DAPK1 variants are associated with Alzheimer's disease and allele-specific expression.

Hum Mol Genet 2006 Sep 17;15(17):2560-8. Epub 2006 Jul 17.

Celera Diagnostics, Alameda, CA 94502, USA.

Genetic factors play an important role in the etiology of late-onset Alzheimer's disease (LOAD). We tested gene-centric single nucleotide polymorphisms (SNPs) on chromosome 9 and identified two SNPs in the death-associated protein kinase, DAPK1, that show significant association with LOAD. SNP rs4878104 was significantly associated with LOAD in our discovery case-control sample set (WU) and replicated in each of two initial validation case-control sample sets (P<0.05, UK1, SD). The risk-allele frequency of this SNP showed a similar direction in three other case-control sample sets. A meta-analysis of the six sample sets combined, totaling 2012 cases and 2336 controls, showed an allelic P-value of 0.0016 and an odds ratio (OR) of 0.87 (95%CI: 0.79-0.95). Minor allele homozygotes had a consistently lower risk than major allele homozygotes in the discovery and initial two replication sample sets, which remained significant in the meta-analysis of all six sample sets (OR=0.7, 95%CI: 0.58-0.85), whereas the risk for heterozygous subjects was not significantly different from that of major allele homozygotes. A second SNP, rs4877365, which is in high linkage disequilibrium with rs4878104 (r2=0.64), was also significantly associated with LOAD (meta P=0.0017 in the initial three sample sets). Furthermore, DAPK1 transcripts show differential allelic gene expression, and both rs4878104 and rs4877365 were significantly associated with DAPK1 allele-specific expression (P=0.015 to <0.0001). These data suggest that genetic variation in DAPK1 modulates susceptibility to LOAD.
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http://dx.doi.org/10.1093/hmg/ddl178DOI Listing
September 2006

Genome-based biomarkers for adverse drug effects, patient enrichment and prediction of drug response, and their incorporation into clinical trial design.

Per Med 2006 May;3(2):177-185

Celera Genomics, Inc. & Celera Diagnostics, 45 W. Gude Drive, Rockville, MD 20850, USA.

Classic examples of pharmacogenomic biomarkers for drug efficacy include genetic variation in the drug target (including its expression level) and drug metabolizing enzymes (DMEs). Recent US FDA approvals of tests for cytochrome P450 2D6/2C9 and uridine diphosphate glucuronsyltransferase (UGT)1A1 have given regulatory endorsement to biomarkers that can improve drug safety by identifying individuals at risk for drug toxicity. Markers that predict risk for disease can identify patients who will have a greater than average benefit from therapy. This creates a new opportunity to enrich clinical trials with patients who are likely to have more events and to achieve earlier drug approval. Markers that predict for risk of cardiovascular, thrombotic and liver diseases may also identify a subset of individuals at substantially elevated risk for adverse drug effects. The adaptive clinical trial design provides a mechanism for incorporating genomic information during clinical trials, while providing sufficient time for diagnostic product development and co-registration with a new drug application.
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http://dx.doi.org/10.2217/17410541.3.2.177DOI Listing
May 2006

A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.

Am J Hum Genet 2006 Jan 15;78(1):78-88. Epub 2005 Nov 15.

Celera Diagnostics, Alameda, CA, USA.

Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.
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http://dx.doi.org/10.1086/498851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1380225PMC
January 2006

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

Stroke 2005 Nov 20;36(11):2346-50. Epub 2005 Oct 20.

Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, NJ 08543-5400, USA.

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.
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http://dx.doi.org/10.1161/01.STR.0000185703.88944.7dDOI Listing
November 2005

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

Nature 2005 Oct;437(7062):1153-7

Department of Biological Statistics and Computational Biology, 101 Biotechnology Building, Cornell University, Ithaca, New York 14853, USA.

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.
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http://dx.doi.org/10.1038/nature04240DOI Listing
October 2005

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

PLoS Biol 2005 Jun 3;3(6):e170. Epub 2005 May 3.

Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.

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.
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http://dx.doi.org/10.1371/journal.pbio.0030170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1088278PMC
June 2005

Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family.

Proc Natl Acad Sci U S A 2004 Nov 26;101(44):15688-93. Epub 2004 Oct 26.

Celera Diagnostics, Alameda, CA 94502, USA.

Although several genes have been implicated in the development of the early-onset autosomal dominant form of Alzheimer's disease (AD), the genetics of late-onset AD (LOAD) is complex. Loci on several chromosomes have been linked to the disease, but so far only the apolipoprotein E gene has been consistently shown to be a risk factor. We have performed a large-scale single-nucleotide polymorphism (SNP)-based association study, across the region of linkage on chromosome 12, in multiple case-control series totaling 1,089 LOAD patients and 1,196 control subjects and report association with SNPs in the glyceraldehyde-3-phosphate dehydrogenase (GAPD) gene. Subsequent analysis of GAPD paralogs on other chromosomes demonstrated association with two other paralogs. A significant association between LOAD and a compound genotype of the three GAPD genes was observed in all three sample sets. Individually, these SNPs make differential contributions to disease risk in each of the casecontrol series, suggesting that variants in functionally similar genes may account for series-to-series heterogeneity of disease risk. Our observations raise the possibility that GAPD genes are AD risk factors, a hypothesis that is consistent with the role of GAPD in neuronal apoptosis.
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http://dx.doi.org/10.1073/pnas.0403535101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC524264PMC
November 2004

Inferring nonneutral evolution from human-chimp-mouse orthologous gene trios.

Science 2003 Dec;302(5652):1960-3

Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.

Even though human and chimpanzee gene sequences are nearly 99% identical, sequence comparisons can nevertheless be highly informative in identifying biologically important changes that have occurred since our ancestral lineages diverged. We analyzed alignments of 7645 chimpanzee gene sequences to their human and mouse orthologs. These three-species sequence alignments allowed us to identify genes undergoing natural selection along the human and chimp lineage by fitting models that include parameters specifying rates of synonymous and nonsynonymous nucleotide substitution. This evolutionary approach revealed an informative set of genes with significantly different patterns of substitution on the human lineage compared with the chimpanzee and mouse lineages. Partitions of genes into inferred biological classes identified accelerated evolution in several functional classes, including olfaction and nuclear transport. In addition to suggesting adaptive physiological differences between chimps and humans, human-accelerated genes are significantly more likely to underlie major known Mendelian disorders.
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http://dx.doi.org/10.1126/science.1088821DOI Listing
December 2003

Phylogeography of the fungal pathogen Histoplasma capsulatum.

Mol Ecol 2003 Dec;12(12):3383-401

Department of Plant and Microbial Biology, 321 Koshland Hall, University of California, Berkeley, CA 94720, USA.

Until recently, Histoplasma capsulatum was believed to harbour three varieties, var. capsulatum (chiefly a New World human pathogen), var. duboisii (an African human pathogen) and var. farciminosum (an Old World horse pathogen), which varied in clinical manifestations and geographical distribution. We analysed the phylogenetic relationships of 137 individuals representing the three varieties from six continents using DNA sequence variation in four independent protein-coding genes. At least eight clades were idengified: (i) North American class 1 clade; (ii) North American class 2 clade; (iii) Latin American group A clade; (iv) Latin American group B clade; (v) Australian clade; (vi) Netherlands (Indonesian?) clade; (vii) Eurasian clade and (viii) African clade. Seven of eight clades represented genetically isolated groups that may be recognized as phylogenetic species. The sole exception was the Eurasian clade which originated from within the Latin American group A clade. The phylogenetic relationships among the clades made a star phylogeny. Histoplasma capsulatum var. capsulatum individuals were found in all eight clades. The African clade included all of the H. capsulatum var. duboisii individuals as well as individuals of the other two varieties. The 13 individuals of var. farciminosum were distributed among three phylogenetic species. These findings suggest that the three varieties of Histoplasma are phylogenetically meaningless. Instead we have to recognize the existence of genetically distinct geographical populations or phylogenetic species. Combining DNA substitution rates of protein-coding genes with the phylogeny suggests that the radiation of Histoplasma started between 3 and 13 million years ago in Latin America.
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http://dx.doi.org/10.1046/j.1365-294x.2003.01995.xDOI Listing
December 2003
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