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1.  Emerging technologies for HIV prevention for MSM: What we’ve learned, and ways forward 
The field of technology-enabled HIV research and prevention has emerged in the past 10 years as an exciting, dynamic field that offers great potential to help bring HIV prevention efforts to scale in key risk communities. Evolutions in technologies and in HIV epidemics suggest mutual opportunities to reach most at risk populations in novel ways. New technologies cannot completely replace interventions and services currently delivered by people. However, we suggest that emerging technologies hold promise to bring services to scale and produce efficiencies in reaching rural populations of MSM, connecting with populations who aren’t reached in current urban outreach efforts, and providing services or research surveys that can be described algorithmically. Further, the types of technologies (e.g., internet-based, smartphone-based, text messaging) should be matched with both the content to be delivered, and the technology usage patterns of target populations. We suggest several key principles and lessons learned that comprise a framework in which to consider the opportunities of technologies and HIV prevention and research. Future directions include improvement of data quality in online surveying, better characterization of biases, developing improved sampling approaches, working with funders to ensure compatibility of funding mechanisms and online research proposals, and promoting consensus approaches to the duplication and presentation of research and program evaluation results from online research. Given current calls for comprehensive packages of prevention services for MSM, effective prevention might require an intentional combination of technology-enabled prevention services to achieve scale, and strategic use of personally-delivered package components in cases where non-algorithmic services, such as individualized counseling, are needed.
PMCID: PMC3670990  PMID: 23673879
technology; MSM; HIV prevention
2.  Adaptation of the African couples HIV testing and counseling model for men who have sex with men in the United States: an application of the ADAPT-ITT framework 
SpringerPlus  2014;3:249.
To respond to the need for new HIV prevention services for men who have sex with men (MSM) in the United States, and to respond to new data on the key role of main partnerships in US MSM epidemics, we sought to develop a new service for joint HIV testing of male couples. We used the ADAPT-ITT framework to guide our work. From May 2009 to July 2013, a multiphase process was undertaken to identify an appropriate service as the basis for adaptation, collect data to inform the adaptation, adapt the testing service, develop training materials, test the adapted service, and scale up and evaluate the initial version of the service. We chose to base our adaptation on an African couples HIV testing service that was developed in the 1980s and has been widely disseminated in low- and middle-income countries. Our adaptation was informed by qualitative data collections from MSM and HIV counselors, multiple online surveys of MSM, information gathering from key stakeholders, and theater testing of the adapted service with MSM and HIV counselors. Results of initial testing indicate that the adapted service is highly acceptable to MSM and to HIV counselors, that there are no evident harms (e.g., intimate partner violence, relationship dissolution) associated with the service, and that the service identifies a substantial number of HIV serodiscordant male couples. The story of the development and scale-up of the adapted service illustrates how multiple public and foundation funding sources can collaborate to bring a prevention adaptation from concept to public health application, touching on research, program evaluation, implementation science, and public health program delivery. The result of this process is an adapted couples HIV testing approach, with training materials and handoff from academic partners to public health for assessment of effectiveness and consideration of the potential benefits of implementation; further work is needed to optimally adapt the African couples testing service for use with male–female couples in the United States.
PMCID: PMC4035496  PMID: 24877036
HIV; AIDS; Prevention; Testing; Counseling; MSM; Couples; Adaptation; ADAPT-ITT
3.  Attitudes toward couples-based HIV counseling and testing among MSM in Cape Town, South Africa 
AIDS and behavior  2013;17(0 1):43-50.
Couples-based voluntary HIV counseling and testing (CVCT) allows couples to receive their HIV test results together and has been demonstrated to be effective in reducing HIV transmission, increasing and sustaining condom use, and reducing sexual risk-taking among at-risk heterosexual couples. However, the acceptability of CVCT among MSM has yet to be evaluated in an African setting. The results from seven focus group discussions and twenty-nine in-depth interviews conducted in Cape Town, South Africa exhibit overwhelmingly high acceptance of CVCT. Participants were attracted to the counseling components of the service, stating that these would allow for the couple to increase their commitment and to explore methods of how to effectively reduce their risk of acquiring or transmitting HIV in the presence of a trained counselor. These results suggest CVCT would be highly welcomed and could work to fill the significant lack of services available and accessible to MSM couples in Cape Town.
PMCID: PMC3529975  PMID: 22961498
CVCT; MSM; HIV testing; Couples
4.  Comprehensive Analysis of Copy Number Variation in Monozygotic Twins Discordant for Bipolar Disorder or Schizophrenia 
Schizophrenia research  2013;146(0):289-290.
Copy number variation plays a clear role in the etiology of many psychiatric disorders, particularly schizophrenia. We performed array-CGH to look for copy number variants between five pairs of monozygotic twins discordant for bipolar disorder or schizophrenia. Our study found no differences in copy number variants between the sets of twins. Although alluring, realistic accounting for heterogeneity and chimerism highlight the technological limitations in studying monozygotic twins discordant for psychiatric disorders.
PMCID: PMC3650833  PMID: 23507357
schizophrenia; bipolar disorder; monozygotic twin; discordant; genetics; copy number variation; structural variation
5.  Sexual risk behaviour and viral suppression among HIV-infected adults receiving medical care in the United States 
AIDS (London, England)  2014;28(8):1203-1211.
To describe the prevalence and association of sexual risk behaviours and viral suppression among HIV-infected adults in the United States.
Cross-sectional analysis of weighted data from a probability sample of HIV-infected adults receiving outpatient medical care. The facility and patient response rates were 76 and 51%, respectively.
We analysed 2009 interview and medical record data. Sexual behaviours were self-reported in the past 12 months. Viral suppression was defined as all viral load measurements in the medical record during the past 12 months less than 200 copies/ml.
An estimated 98 022 (24%) HIV-infected adults engaged in unprotected vaginal or anal sex; 50 953 (12%) engaged in unprotected vaginal or anal sex with at least one partner of negative or unknown HIV status; 23 933 (6%) did so while not virally suppressed. Persons who were virally suppressed were less likely than persons who were not suppressed to engage in vaginal or anal sex [prevalence ratio, 0.88; 95% confidence interval (CI), 0.82–0.93]; unprotected vaginal or anal sex (prevalence ratio, 0.85; 95% CI, 0.73–0.98); and unprotected vaginal or anal sex with a partner of negative or unknown HIV status (prevalence ratio, 0.79; 95% CI, 0.64–0.99).
The majority of HIV-infected adults receiving medical care in the U.S. did not engage in sexual risk behaviours that have the potential to transmit HIV, and of the 12% who did, approximately half were not virally suppressed. Persons who were virally suppressed were less likely than persons who were not suppressed to engage in sexual risk behaviours.
PMCID: PMC4004641
antiretroviral therapy; HIV-infected persons; sexual behaviour; unsafe sex; viral load
6.  The Potential for Elimination of Racial-Ethnic Disparities in HIV Treatment Initiation in the Medicaid Population among 14 Southern States 
PLoS ONE  2014;9(4):e96148.
The purpose of this study was to explore the racial and ethnic disparities in initiation of antiretroviral treatment (ARV treatment or ART) among HIV-infected Medicaid enrollees 18–64 years of age in 14 southern states which have high prevalence of HIV/AIDS and high racial disparities in HIV treatment access and mortality.
We used Medicaid claims data from 2005 to 2007 for a retrospective cohort study. We compared frequency variances of HIV treatment uptake among persons of different racial- ethnic groups using univariate and multivariate methods. The unadjusted odds ratio was estimated through multinomial logistic regression. The multinomial logistic regression model was repeated with adjustment for multiple covariates.
Of the 23,801 Medicaid enrollees who met criteria for initiation of ARV treatment, only one third (34.6%) received ART consistent with national guideline treatment protocols, and 21.5% received some ARV medication, but with sub-optimal treatment profiles. There was no significant difference in the proportion of people who received ARV treatment between black (35.8%) and non-Hispanic whites (35.7%), but Hispanic/Latino persons (26%) were significantly less likely to receive ARV treatment.
Overall ARV treatment levels for all segments of the population are less than optimal. Among the Medicaid population there are no racial HIV treatment disparities between Black and White persons living with HIV, which suggests the potential relevance of Medicaid to currently uninsured populations, and the potential to achieve similar levels of equality within Medicaid for Hispanic/Latino enrollees and other segments of the Medicaid population.
PMCID: PMC4000218  PMID: 24769625
7.  HIV testing among United States high school students at the state and national level, Youth Risk Behavior Survey 2005–2011 
SpringerPlus  2014;3:202.
Human immunodeficiency virus (HIV) remains an important public health issue and CDC recommends routine HIV screening for Americans aged 13–64. Adolescents and young adults are disproportionately affected compared to the overall population. We analyzed self-reported HIV testing and related risk behaviors at the state and national level among youths who had sexual intercourse, with a focus on state level differences.
This study used the state and national Youth Risk Behaviors Surveys 2005–2011. It included a total of 59,793 national-level observations and 39,421 state-level observations of US high school students, of which respectively 28,177 and 13,916 reported ever having sexual intercourse.
The outcome of interest was having ever been tested for HIV. The risk behaviors were condom use at last intercourse, number of sexual partners in lifetime, age at first intercourse, ever forced sexual intercourse, and ever illegal injection drug use. Analyses performed included logistic regression and t-test analyses.
HIV testing was positively associated with HIV-related risk behaviors among sexually active high school students. However, HIV testing remained relatively low (22%) between 2005 and 2011, even for those engaging in risk behaviors. Results differed among the only 7 states that monitored HIV testing through YRBS, most commonly with respect to HIV testing and condom use.
Routine HIV testing is critical for early identification of HIV, which was set as a priority in a recent Executive Order. Our data suggest further efforts are needed to achieve widespread uptake of HIV testing among high school students. Furthermore, differences observed across states likely reflect different needs and should be followed up closely by states. Finally, having accurate data that reflects the reality of youths’ lives is crucial for efficient prevention planning. Thus, more states should consider collecting HIV testing data to evaluate uptake of HIV testing among youth.
PMCID: PMC4024479  PMID: 24855587
HIV testing; Adolescent; High school; Risk behavior; YRBS
8.  Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders 
Nature neuroscience  2013;16(9):1228-1237.
Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We show here that the enrichment of a rare Chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enables the detection of association between TOP3β and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3β revealed that this topoisomerase is a component of cytosolic messenger ribonucleoproteins (mRNPs) and is catalytically active on RNA. The recruitment of TOP3β to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome (FXS). Thus, we uncover a novel role for TOP3β in mRNA metabolism and provide several lines of evidence implicating it in neurodevelopmental disorders.
PMCID: PMC3986889  PMID: 23912948
9.  Use of a Google Map Tool Embedded in an Internet Survey Instrument: Is it a Valid and Reliable Alternative to Geocoded Address Data? 
JMIR Research Protocols  2014;3(2):e24.
Men who have sex with men (MSM) in the United States are at high risk for human immunodeficiency virus (HIV) and poor HIV related outcomes. Maps can be used to identify, quantify, and address gaps in access to HIV care among HIV-positive MSM, and tailor intervention programs based on the needs of patients being served.
The objective of our study was to assess the usability of a Google map question embedded in a Web-based survey among Atlanta-based, HIV-positive MSM, and determine whether it is a valid and reliable alternative to collection of address-based data on residence and last HIV care provider.
Atlanta-based HIV-positive MSM were recruited through Facebook and from two ongoing studies recruiting primarily through venue-based sampling or peer referral (VBPR). Participants were asked to identify the locations of their residence and last attended HIV care provider using two methods: (1) by entering the street address (gold standard), and (2) “clicking” on the locations using an embedded Google map. Home and provider addresses were geocoded, mapped, and compared with home and provider locations from clicked map points to assess validity. Provider location error values were plotted against home location error values, and a kappa statistic was computed to assess agreement in degree of error in identifying residential location versus provider location.
The median home location error across all participants was 0.65 miles (interquartile range, IQR, 0.10, 2.5 miles), and was lower among Facebook participants (P<.001), whites (P<.001), and those reporting higher annual household income (P=.04). Median home location error was lower, although not statistically significantly, among older men (P=.08) and those with higher educational attainment (P=.05). The median provider location error was 0.32 miles (IQR, 0.12, 1.2 miles), and did not vary significantly by age, recruitment method, race, income, or level of educational attainment. Overall, the kappa was 0.20, indicating poor agreement between the two error measures. However, those recruited through Facebook had a greater level of agreement (κ=0.30) than those recruited through VBPR methods (κ=0.16), demonstrating a greater level of consistency in using the map question to identify home and provider locations for Facebook-recruited individuals.
Most participants were able to click within 1 mile of their home address and their provider’s office, and were not always able to identify the locations on a map consistently, although some differences were observed across recruitment methods. This map tool may serve as the basis of a valid and reliable tool to identify residence and HIV provider location in the absence of geocoded address data. Further work is needed to improve and compare map tool usability with the results from this study.
PMCID: PMC4004146  PMID: 24726954
HIV; geographic mapping; survey; validity; reliability
10.  Genes, environments, and developmental GEWIS: Methods for a multi-site study of early substance abuse 
The importance of including developmental and environmental measures in genetic studies of human pathology is widely acknowledged, but few empirical studies have been published. Barriers include the need for longitudinal studies that cover relevant developmental stages and for samples large enough to deal with the challenge of testing gene-environment-development interaction. A solution to some of these problems is to bring together existing data sets that have the necessary characteristics. As part of the NIDA-funded Gene-Environment-Development Initiative (GEDI) our goal is to identify exactly which genes, which environments, and which developmental transitions together predict the development of drug use and misuse. Four data sets were used whose common characteristics include (1) general population samples including males and females; (2) repeated measures across adolescence and young adulthood; (3) assessment of nicotine, alcohol and cannabis use and addiction; (4) measures of family and environmental risk; and (5) consent for genotyping DNA from blood or saliva. After quality controls, 2,962 individuals provided over 15,000 total observations. In the first gene-environment analyses, of alcohol misuse and stressful life events, some significant gene-environment and gene-development effects were identified. We conclude that in some circumstances, already-collected data sets can be combined for gene-environment and gene-development analyses. This greatly reduces the cost and time needed for this type of research. However, care must be taken to ensure careful matching across studies and variables.
PMCID: PMC3609892  PMID: 23461817
11.  Estrogen metabolism within the lung and its modulation by tobacco smoke 
Carcinogenesis  2012;34(4):909-915.
Although estrogen and the enzymes responsible for its metabolism have been detected within the lung, the ability of this tissue to metabolize estrogen has not been demonstrated previously. The goal of this study was to characterize the profile of estrogen metabolites within the murine lung and to determine the effect of tobacco smoke exposure on metabolite levels. Use of liquid chromatography–tandem mass spectrometry led to the detection of three estrogens (E1, E2 and E3) and five estrogen metabolites (2-OHE1, 4-OHE1, 4-OHE2, 2-OMeE1 and 2-OMeE2) within the perfused lung, with 4-OHE1 being the most abundant species. Levels of 4-OHEs, carcinogenic derivatives produced primarily by cytochrome P450 1B1 (Cyp1b1), were 2-fold higher in females than males. Deletion of Cyp1b1 in females led to a dramatic reduction (21-fold) in 4-OHEs, whereas levels of 2-OHE1 and the putative protective estrogen metabolite 2-OMeE2 were increased (2.4- and 5.0-fold, respectively) (P = 0.01). Similar quantitative differences in estrogen metabolite levels were observed between Cyp1b1 null and wild-type males. Exposure of female mice to tobacco smoke for 8 weeks (2h per day, 5 days per week) increased the levels of 4-OHE1 (4-fold) and 2-OHE2 (2-fold) within the lung while reducing the total concentration of 2-OMeEs to 70% of those of unexposed controls. These data suggest that tobacco smoke accelerates the production of 4-OHEs within the lung; carcinogenic metabolites that could potentially contribute to lung tumor development. Thus, inhibition of CYP1B1 may represent a promising strategy for the prevention and treatment of lung cancer.
PMCID: PMC3616670  PMID: 23276798
12.  Safety and Acceptability of Couples HIV Testing and Counseling for US Men Who Have Sex with Men: A Randomized Prevention Study 
We tested a couples HIV testing and counseling (CHTC) intervention with male couples in Atlanta by randomizing eligible couples to receive either CHTC or separate individual voluntary HIV counseling and testing (iVCT). To evaluate the acceptability and safety of CHTC, main outcomes were satisfaction with the intervention and the proportions of couples reporting intimate partner violence (IPV) and relationship dissolution after the service. The results indicated that the service was very acceptable to men (median 7-item index of satisfaction was 34 for CHTC and 35 for iVCT, P = .4). There was no difference in either incident IPV (22% versus 17% for CHTC and iVCT, respectively, P = .6) or relationship dissolution (42% versus 51% for CHTC and iVCT, respectively, P = .5). Based on the preliminary data, CHTC is safe for male couples, and it is equally acceptable to iVCT for men who have main partners.
PMCID: PMC3954957  PMID: 23995295
HIV; testing services; male couples; men who have sex with men
13.  Questions about DISC1 as a Genetic Risk Factor for Schizophrenia 
Molecular psychiatry  2013;18(10):1050-1052.
PMCID: PMC3967792  PMID: 24056909
Genomics; disrupted in schizophrenia 1; DISC1; replication
14.  Detecting Large Copy Number Variants Using Exome Genotyping Arrays In a Large Swedish Schizophrenia Sample 
Molecular psychiatry  2013;18(11):1178-1184.
Although copy number variants (CNVs) are important in genomic medicine, CNVs have not been systematically assessed for many complex traits. Several large rare CNVs increase risk for schizophrenia (SCZ) and autism and often demonstrate pleiotropic effects; however, their frequencies in the general population and other complex traits are unknown. Genotyping large numbers of samples is essential for progress. Large cohorts from many different diseases are being genotyped using exome-focused arrays designed to detect uncommon or rare protein-altering sequence variation. Although these arrays were not designed for CNV detection, the hybridization intensity data generated in each experiment could, in principle, be used for gene-focused CNV analysis. Our goal was to evaluate the extent to which CNVs can be detected using data from one particular exome array (the Illumina Human Exome Bead Chip). We genotyped 9, 100 Swedish subjects (3, 962 cases with SCZ and 5, 138 controls) using both standard GWAS arrays and exome arrays. In comparison to CNVs detected using GWAS arrays, we observed high sensitivity and specificity for detecting genic CNVs ≥400 kb including known pathogentic CNVs along with replicating the literature finding that cases with SCZ had greater enrichment for genic CNVs. Our data confirm the association of SCZ with 16p11.2 duplications and 22q11.2 deletions and suggest a novel association with deletions at 11q12.2. Our results suggest the utility of exome focused arrays in surveying large genic CNVs in very large samples; and thereby open the door for new opportunities such as conducting well-powered CNV assessment and comparisons between different diseases. The use of a single platform also minimizes potential confounding factors that could impact accurate detection.
PMCID: PMC3966073  PMID: 23938935
schizophrenia; copy number variation; structural variation; genotyping; Illumina; exome array
15.  Excess Burden of Depression among HIV-Infected Persons Receiving Medical Care in the United States: Data from the Medical Monitoring Project and the Behavioral Risk Factor Surveillance System 
PLoS ONE  2014;9(3):e92842.
With increased life expectancy for HIV-infected persons, there is concern regarding comorbid depression because of its common occurrence and association with behaviors that may facilitate HIV transmission. Our objectives were to estimate the prevalence of current depression among HIV-infected persons receiving care and assess the burden of major depression, relative to that in the general population.
Methods and Findings
We used data from the Medical Monitoring Project (MMP) and the Behavioral Risk Factors Surveillance System (BRFSS). The eight-item Patient Health Questionnaire was used to identify depression. To assess the burden of major depression among HIV-infected persons receiving care, we compared the prevalence of current major depression between the MMP and BRFSS populations using stratified analyses that simultaneously controlled for gender and, in turn, each of the potentially confounding demographic factors of age, race/ethnicity, education, and income. Each unadjusted comparison was summarized as a prevalence ratio (PR), and each of the adjusted comparisons was summarized as a standardized prevalence ratio (SPR). Among HIV-infected persons receiving care, the prevalence of a current episode of major depression and other depression, respectively, was 12.4% (95% CI: 11.2, 13.7) and 13.2% (95% CI: 12.0%, 14.4%). Overall, the PR comparing the prevalence of current major depression between HIV-infected persons receiving care and the general population was 3.1. When controlling for gender and each of the factors age, race/ethnicity, and education, the SPR (3.3, 3.0, and 2.9, respectively) was similar to the PR. However, when controlling for gender and annual household income, the SPR decreased to 1.5.
Depression remains a common comorbidity among HIV-infected persons. The overall excess burden among HIV-infected persons receiving care is about three-times that among the general population and is associated with differences in annual household income between the two populations. Relevant efforts are needed to reduce this burden.
PMCID: PMC3963963  PMID: 24663122
16.  Heterogeneous HIV Testing Preferences in an Urban Setting in Tanzania: Results from a Discrete Choice Experiment 
PLoS ONE  2014;9(3):e92100.
Efforts to reduce Human Immunodeficiency Virus (HIV) transmission through treatment rely on HIV testing programs that are acceptable to broad populations. Yet, testing preferences among diverse at-risk populations in Sub-Saharan Africa are poorly understood. We fielded a population-based discrete choice experiment (DCE) to evaluate factors that influence HIV-testing preferences in a low-resource setting.
Using formative work, a pilot study, and pretesting, we developed a DCE survey with five attributes: distance to testing, confidentiality, testing days (weekday vs. weekend), method for obtaining the sample for testing (blood from finger or arm, oral swab), and availability of HIV medications at the testing site. Cluster-randomization and Expanded Programme on Immunization (EPI) sampling methodology were used to enroll 486 community members, ages 18–49, in an urban setting in Northern Tanzania. Interviewer-assisted DCEs, presented to participants on iPads, were administered between September 2012 and February 2013.
Nearly three of five males (58%) and 85% of females had previously tested for HIV; 20% of males and 37% of females had tested within the past year. In gender-specific mixed logit analyses, distance to testing was the most important attribute to respondents, followed by confidentiality and the method for obtaining the sample for the HIV test. Both unconditional assessments of preferences for each attribute and mixed logit analyses of DCE choice patterns suggest significant preference heterogeneity among participants. Preferences differed between males and females, between those who had previously tested for HIV and those who had never tested, and between those who tested in the past year and those who tested more than a year ago.
The findings suggest potentially significant benefits from tailoring HIV testing interventions to match the preferences of specific populations, including males and females and those who have never tested for HIV.
PMCID: PMC3958474  PMID: 24643047
17.  From (Un)Willingness to InvolveMENt: Development of a Successful Study Brand for Recruitment of Diverse MSM to a Longitudinal HIV Research 
HIV continues to be a major concern among MSM, yet Black MSM have not been enrolled in HIV research studies in proportionate numbers to White MSM. We developed an HIV prevention research brand strategy for MSM.
Questionnaires and focus groups were conducted with 54 participants. Descriptive statistics and chi-square analyses were performed and qualitative data were transcribed and content analyzed to identify common themes.
Formative research results indicated that younger Black MSM (18–29 years) were less likely to think about joining prevention studies compared to older (≥30 years) Black MSM (x2 = 5.92, P = 0.015). Qualitative and quantitative results indicate four prominent themes related to brand development: (1) communication sources (message deliverer), (2) message (impact of public health messaging on perceptions of HIV research), (3) intended audience (underlying issues that influence personal relevance of HIV research), and (4) communication channels (reaching intended audiences).
The findings highlight the importance of behavioral communication translational research to effectively engage hard-to-reach populations. Despite reservations, MSM in our formative study expressed a need for active involvement and greater education to facilitate their engagement in HIV prevention research. Thus, the brand concept of “InvolveMENt” emerged.
PMCID: PMC3955100  PMID: 24639900
18.  A population-based twin study of functional somatic syndromes 
Psychological medicine  2008;39(3):497-505.
The mechanisms underlying the co-occurrence of the functional somatic syndromes are largely unknown. No empirical study has explicitly examined how genetic and environmental factors influence the comorbidity of these syndromes. We aimed to examine how the comorbidity of functional somatic syndromes is influenced by genetic and environmental factors that are in common to the syndromes.
A total of 31,318 twins in the Swedish Twin Registry aged 41–64 underwent screening interviews via a computer-assisted telephone system from 1998 to 2002. Four functional somatic syndromes (chronic widespread pain, chronic fatigue, irritable bowel syndrome, and recurrent headache) and 2 psychiatric disorders (major depression and generalized anxiety disorder) were assessed using structured questions based on standard criteria for each illness in a blinded manner.
Multivariate twin analyses revealed that a common pathway model with 2 latent traits that were shared by the 6 illnesses fit best to the women's data. One of the 2 latent traits loaded heavily on the psychiatric disorders, whereas the other trait loaded on all 4 of the functional somatic syndromes, particularly chronic widespread pain, but not on the psychiatric disorders. All illnesses except the psychiatric disorders were also affected by genetic influences that were specific to each.
The co-occurrence of functional somatic syndromes in women can be best explained by affective and sensory components in common to all these syndromes, as well as by unique influences specific to each of them. The findings clearly suggest a complex view of the multifactorial pathogenesis of these illnesses.
PMCID: PMC3947533  PMID: 18578896
19.  Understanding Racial HIV/STI Disparities in Black and White Men Who Have Sex with Men: A Multilevel Approach 
PLoS ONE  2014;9(3):e90514.
The reasons for black/white disparities in HIV epidemics among men who have sex with men have puzzled researchers for decades. Understanding reasons for these disparities requires looking beyond individual-level behavioral risk to a more comprehensive framework.
Methods and Findings
From July 2010-Decemeber 2012, 803 men (454 black, 349 white) were recruited through venue-based and online sampling; consenting men were provided HIV and STI testing, completed a behavioral survey and a sex partner inventory, and provided place of residence for geocoding. HIV prevalence was higher among black (43%) versus white (13% MSM (prevalence ratio (PR) 3.3, 95% confidence interval (CI): 2.5–4.4). Among HIV-positive men, the median CD4 count was significantly lower for black (490 cells/µL) than white (577 cells/µL) MSM; there was no difference in the HIV RNA viral load by race. Black men were younger, more likely to be bisexual and unemployed, had less educational attainment, and reported fewer male sex partners, fewer unprotected anal sex partners, and less non-injection drug use. Black MSM were significantly more likely than white MSM to have rectal chlamydia and gonorrhea, were more likely to have racially concordant partnerships, more likely to have casual (one-time) partners, and less likely to discuss serostatus with partners. The census tracts where black MSM lived had higher rates of poverty and unemployment, and lower median income. They also had lower proportions of male-male households, lower male to female sex ratios, and lower HIV diagnosis rates.
Among black and white MSM in Atlanta, disparities in HIV and STI prevalence by race are comparable to those observed nationally. We identified differences between black and white MSM at the individual, dyadic/sexual network, and community levels. The reasons for black/white disparities in HIV prevalence in Atlanta are complex, and will likely require a multilevel framework to understand comprehensively.
PMCID: PMC3946498  PMID: 24608176
20.  Actor-partner effects associated with experiencing intimate partner violence or coercion among male couples enrolled in an HIV prevention trial 
BMC Public Health  2014;14:209.
Intimate partner violence (IPV) and coercion have been associated with negative health outcomes, including increased HIV risk behaviors, among men who have sex with men (MSM). This is the first study to describe the prevalence and factors associated with experiencing IPV or coercion among US MSM dyads using the actor-partner interdependence model (APIM), an analytic framework to describe interdependent outcomes within dyads.
Among MSM couples enrolled as dyads in an HIV prevention randomized controlled trial (RCT), two outcomes are examined in this cross-sectional analysis: 1) the actor experiencing physical or sexual IPV from the study partner in the past 3-months and 2) the actor feeling coerced to participate in the RCT by the study partner. Two multilevel APIM logistic regression models evaluated the association between each outcome and actor, partner, and dyad-level factors.
Of 190 individuals (95 MSM couples), 14 reported experiencing physical or sexual IPV from their study partner in the past 3 months (7.3%) and 12 reported feeling coerced to participate in the RCT by their study partner (6.3%). Results of multivariate APIM analyses indicated that reporting experienced IPV was associated (p < 0.1) with non-Black/African American actor race, lower actor education, and lower partner education. Reporting experienced coercion was associated (p < 0.1) with younger actor age and lower partner education.
These findings from an HIV prevention RCT for MSM show considerable levels of IPV experienced in the past 3-months and coercion to participate in the research study, indicating the need for screening tools and support services for these behaviors. The identification of factors associated with IPV and coercion demonstrate the importance of considering actor and partner effects, as well as dyadic-level effects, to improve development of screening tools and support services for these outcomes.
PMCID: PMC3942775  PMID: 24580732
Actor-partner interdependence model; Coercion; HIV; Intimate partner violence; MSM
21.  Acceptability and intended usage preferences for six HIV testing options among internet-using men who have sex with men 
SpringerPlus  2014;3:109.
Men who have sex with men (MSM) continue to be disproportionately impacted by the Human Immunodeficiency Virus (HIV) epidemic in the United States (US). Testing for HIV is the cornerstone of comprehensive prevention efforts and the gateway to early engagement of infected individuals in medical care. We sought to determine attitudes towards six different HIV testing modalities presented collectively to internet-using MSM and identify which options rank higher than others in terms of intended usage preference.
Between October and November 2012, we surveyed 973 HIV-negative or -unknown status MSM and assessed their acceptability of each of the following services hypothetically offered free of charge: Testing at a physician’s office; Individual voluntary counseling and testing (VCT); Couples’ HIV counseling and testing (CHCT); Expedited/express testing; Rapid home self-testing using an oral fluid test; Home dried blood spot (DBS) specimen self-collection for laboratory testing. Kruskal-Wallis tests were used to determine whether the stated likelihood of using each of these modalities differed by selected respondent characteristics. Men were also asked to rank these options in order of intended usage preference, and consensual rankings were determined using the modified Borda count (MBC) method.
Most participants reported being extremely likely or somewhat likely to use all HIV testing modalities except DBS self-collection for laboratory testing. Younger MSM indicated greater acceptability for expedited/express testing (P < 0.001), and MSM with lower educational levels reported being more likely to use CHCT (P < 0.001). Non-Hispanic black MSM indicated lower acceptability for VCT (P < 0.001). Rapid home self-testing using an oral fluid test and testing at a physician’s office were the two most preferred options across all demographic and behavioral strata.
Novel approaches to increase the frequency of HIV testing among US MSM are urgently needed. Combination testing packages could enable high risk MSM in putting together annual testing strategies personalized to their circumstances, and warrant due consideration as an element of combination HIV prevention packages.
PMCID: PMC3942559  PMID: 24600551
HIV testing preferences; Internet-using men who have sex with men; Combination prevention approaches; Rapid home HIV self-testing
22.  Genome-wide association study of patient and clinician rated global impression severity during antipsychotic treatment 
Pharmacogenetics and genomics  2013;23(2):69-77.
Examine the unique and congruent findings between multiple raters in a genome-wide association studies (GWAS) in the context of understanding individual differences in treatment response during antipsychotic therapy for schizophrenia.
We performed GWAS to search for genetic variation affecting treatment response. The analysis sample consisted of 738 patients with schizophrenia, successfully genotyped for ~492K SNPs from the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE). Outcomes included both clinician and patient report of illness severity on global impression scales, the CGI-S and PGI, respectively. Our criterion for genome-wide significance was a pre-specified threshold ensuring that, on average, only 10% of the significant findings are false discoveries.
Thirteen SNPs reached genome-wide significance. The top findings indicated three SNPs in PDE4D, 5q12.1 (p =4.2×10−8, p =1.6×10−7, p =1.8×10−7), mediated the effects of quetiapine on patient reported severity and an additional three SNPs in TJP1, 15q13.1 (p = 2.25×10−7, p = 4.86×10−7, p = 4.91×10−7), mediated the effects of risperidone on patient reported severity. For clinician reported severity, two SNPs in PPA2, 4q24 (p = 3.68×10−7, p = 5.05×10−7), were found to reach genome-wide significance.
We found evidence of both novel and consistent association when examining the results from the patient and clinician ratings suggesting that different raters may capture unique facets of schizophrenia. Although our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes that potentially mediate treatment response of antipsychotic medication.
PMCID: PMC3922978  PMID: 23241943
CATIE; CGI; pharmacogenomics; personalized medicine; schizophrenia; GWAS; single nucleotide polymorphism; PANSS
23.  MBD-seq as a cost-effective approach for methylome-wide association studies: demonstration in 1500 case–control samples 
Epigenomics  2012;4(6):605-621.
We studied the use of methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq) as a cost-effective screening tool for methylome-wide association studies (MWAS).
Materials & methods
Because MBD-seq has not yet been applied on a large scale, we first developed and tested a pipeline for data processing using 1500 schizophrenia cases and controls plus 75 technical replicates with an average of 68 million reads per sample. This involved the use of technical replicates to optimize quality control for multi- and duplicate-reads, an in silico experiment to identify CpGs in loci with alignment problems, CpG coverage calculations based on multiparametric estimates of the fragment size distribution, a two-stage adaptive algorithm to combine data from correlated adjacent CpG sites, principal component analyses to control for confounders and new software tailored to handle the large data set.
We replicated MWAS findings in independent samples using a different technology that provided single base resolution. In an MWAS of age-related methylation changes, one of our top findings was a previously reported robust association involving GRIA2. Our results also suggested that owing to the many confounding effects, a considerable challenge in MWAS is to identify those effects that are informative about disease processes.
This study showed the potential of MBD-seq as a cost-effective tool in large-scale disease studies.
PMCID: PMC3923085  PMID: 23244307
MBD; methylome-wide association studies; next-generation sequencing; principal component analysis; pyrosequencing
24.  Fine mapping of ZNF804A and genome wide significant evidence for its involvement in schizophrenia and bipolar disorder 
Molecular psychiatry  2010;16(4):429-441.
A recent genome wide association study reported evidence for association between rs1344706 within ZNF804A (encoding zinc finger protein 804A) and schizophrenia (P=1.61 ×10−7), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 ×10−9). Here we provide additional evidence for association through meta-analysis of a larger dataset (schizophrenia/schizoaffective disorder N = 18945, schizophrenia plus bipolar disorder N =21274, controls N =38675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high density LD mapping. Meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 ×10−11, OR=1.10, 95% CI 1.07–1.14) and schizophrenia and bipolar disorder combined (P=4.1 ×10−13, OR=1.11, 95% CI 1.07–1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.
PMCID: PMC3918934  PMID: 20368704
25.  Genome Wide Linkage Analysis of Multiple Measures of Neuroticism of two large cohorts from Australia and the Netherlands 
Archives of general psychiatry  2008;65(6):649-658.
People meeting diagnostic criteria for anxiety or depressive disorders tend to score high on the personality scale of neuroticism. Studying this personality dimension can give insights into the aetiology of these important psychiatric disorders.
To undertake a comprehensive genome-wide linkage study of neuroticism, using large study samples that have been measured multiple times. To compare the results between countries for replication and across time within countries for consistency.
Genome wide linkage scan.
Twin individuals and their family members from Australia (AU) and the Netherlands (NL).
19,635 sibling pairs completed self-report questionnaires for neuroticism up to five times over a period of up to 22 years. 5,069 sibling pairs were genotyped with microsatellite markers.
Non-parametric linkage analyses were conducted in Merlin-Regress for the mean neuroticism scores averaged across time. Additional analyses were conducted for the time specific measures of neuroticism from each country to investigate consistency of linkage results.
Three chromosomal regions exceeded empirically-derived thresholds for suggestive linkage using mean neuroticism scores: 10p 5 cM (NL), 14q 103 cM (NL) and 18q 117 cM (AU & NL combined), but only 14q retains significance after correction for multiple testing. These regions all showed evidence for linkage in individual time-specific measures of neuroticism and one (18q) showed some evidence for replication between countries. Linkage intervals for these regions all overlap with regions identified in other studies of neuroticism or related traits and/or in studies of anxiety in mice.
Our results demonstrate the value of the availability of multiple measures over time and add to the optimism reported in recent reviews for replication of linkage regions for neuroticism. These regions are likely to harbour causal variants for neuroticism and its related psychiatric disorders and can inform prioritisation of results from genome-wide association studies.
PMCID: PMC3912824  PMID: 18519823

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