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1.  The Sexunzipped Trial: Young People’s Views of Participating in an Online Randomized Controlled Trial 
Background
Incidence of sexually transmitted infections (STIs) among young people in the United Kingdom is increasing. The Internet can be a suitable medium for delivery of sexual health information and sexual health promotion, given its high usage among young people, its potential for creating a sense of anonymity, and ease of access. Online randomized controlled trials (RCTs) are increasingly being used to evaluate online interventions, but while there are many advantages to online methodologies, they can be associated with a number of problems, including poor engagement with online interventions, poor trial retention, and concerns about the validity of data collected through self-report online. We conducted an online feasibility trial that tested the effects of the Sexunzipped website for sexual health compared to an information-only website. This study reports on a qualitative evaluation of the trial procedures, describing participants’ experiences and views of the Sexunzipped online trial including methods of recruitment, incentives, methods of contact, and sexual health outcome measurement.
Objective
Our goal was to determine participants’ views of the acceptability and validity of the online trial methodology used in the pilot RCT of the Sexunzipped intervention.
Methods
We used three qualitative data sources to assess the acceptability and validity of the online pilot RCT methodology: (1) individual interviews with 22 participants from the pilot RCT, (2) 133 emails received by the trial coordinator from trial participants, and (3) 217 free-text comments from the baseline and follow-up questionnaires. Interviews were audio-recorded and transcribed verbatim. An iterative, thematic analysis of all three data sources was conducted to identify common themes related to the acceptability and feasibility of the online trial methodology.
Results
Interview participants found the trial design, including online recruitment via Facebook, online registration, email communication with the researchers, and online completion of sexual health questionnaires to be highly acceptable and preferable to traditional methods. Incentives might assist in recruiting those who would not otherwise participate. Participants generally enjoyed taking part in sexual health research online and found the questionnaire itself thought-provoking. Completing the sexual health questionnaires online encouraged honesty in responding that might not be achieved with other methods. The majority of interview participants also thought that receiving and returning a urine sample for chlamydia testing via post was acceptable.
Conclusions
These findings provide strong support for the use of online research methods for sexual health research, emphasizing the importance of careful planning and execution of all trial procedures including recruitment, respondent validation, trial related communication, and methods to maximize follow-up. Our findings suggest that sexual health outcome measurement might encourage reflection on current behavior, sometimes leading to behavior change.
Trial Registration
International Standard Randomized Controlled Trial Number (ISRCTN): 55651027; http://www.controlled-trials.com/isrctn/pf/55651027 (Archived by WebCite at http://www.webcitation.org/6LbkxdPKf).
doi:10.2196/jmir.2647
PMCID: PMC3868966  PMID: 24334198
Internet; randomized controlled trials; qualitative research; outcome assessment (health care); sexual health; chlamydia trachomatis
2.  The Sexunzipped Trial: Optimizing the Design of Online Randomized Controlled Trials 
Background
Sexual health problems such as unwanted pregnancy and sexually transmitted infection are important public health concerns and there is huge potential for health promotion using digital interventions. Evaluations of digital interventions are increasingly conducted online. Trial administration and data collection online offers many advantages, but concerns remain over fraudulent registration to obtain compensation, the quality of self-reported data, and high attrition.
Objective
This study addresses the feasibility of several dimensions of online trial design—recruitment, online consent, participant identity verification, randomization and concealment of allocation, online data collection, data quality, and retention at 3-month follow-up.
Methods
Young people aged 16 to 20 years and resident in the United Kingdom were recruited to the “Sexunzipped” online trial between November 2010 and March 2011 (n=2036). Participants filled in baseline demographic and sexual health questionnaires online and were randomized to the Sexunzipped interactive intervention website or to an information-only control website. Participants were also randomly allocated to a postal request (or no request) for a urine sample for genital chlamydia testing and receipt of a lower (£10/US$16) or higher (£20/US$32) value shopping voucher compensation for 3-month outcome data.
Results
The majority of the 2006 valid participants (90.98%, 1825/2006) were aged between 18 and 20 years at enrolment, from all four countries in the United Kingdom. Most were white (89.98%, 1805/2006), most were in school or training (77.48%, 1545/1994), and 62.81% (1260/2006) of the sample were female. In total, 3.88% (79/2036) of registrations appeared to be invalid and another 4.00% (81/2006) of participants gave inconsistent responses within the questionnaire. The higher value compensation (£20/US$32) increased response rates by 6-10%, boosting retention at 3 months to 77.2% (166/215) for submission of online self-reported sexual health outcomes and 47.4% (118/249) for return of chlamydia urine samples by post.
Conclusions
It was quick and efficient to recruit young people to this online trial. Our procedures for obtaining online consent, verifying participant identity, automated randomization, and concealment of allocation worked well. The optimal response rate for the online sexual health outcome measurement was comparable to face-to-face trials. Multiple methods of participant contact, requesting online data only, and higher value compensation increased trial retention at 3-month follow-up.
Trial Registration
International Standard Randomized Controlled Trial Number (ISRCTN): 55651027; http://www.controlled-trials.com/ISRCTN55651027 (Archived by WebCite at http://www.webcitation.org/6LbkxdPKf).
doi:10.2196/jmir.2668
PMCID: PMC3868980  PMID: 24334216
Internet; randomized controlled trials as topic; outcome assessment (health care); sexual health; sexually transmitted diseases; behavioral research
3.  Effects on promoter activity of common SNPs in 5′ region of GABRB3 exon 1A 
Epilepsia  2012;53(8):1450-1456.
Purpose
The β3 subunit of the γ-aminobutyric acid type A receptors (GABAA–Rs) is an essential component of GABAA–Rs in fetal, perinatal and adult mammalian brain. Various transcripts of the β3 subunit gene (GABRB3) produce various proteins with different N-termini. Rare variants in this N-terminus (exon 1A and exon 2) of GABRB3 protein segregate in affected family members of two multigeneration-multiplex families with remitting childhood absence epilepsy (rCAE), suggesting GABRB3 is a major Mendelian epilepsy gene for rare families with CAE. Thus the N-terminus of GABRB3 could be important for GABRB3 regulation in development and its alteration could produce rCAE. Here we determine if SNPs within the 1148 bp region upstream from exon1a influence the expression of GABRB3.
Methods
We studied luciferase reporter expression for promoter activity, 1148 bp upstream from exon 1A, using human embryonic kidney 293 cells. We generated constructs of the promoter region and compared different SNP haplotypes in 48 patients with rCAE. Then, we compared frequencies of rs20317, located in the core promoter region and rs4906902 located in the enhancer region between 48 patients with rCAE and more than 500 healthy controls matched for ethnicity and ancestral origin.
Key Findings
Highest luciferase expression occurred 230 bp upstream of exon 1A. The construct which excluded this region lost luciferase activity. Thus, this region contains the core promoter of exon1A. Allele C but not allele G (rs20317) significantly increased luciferase expression activity. Allele C creates binding motifs for cMYB and EGR-3. Longer constructs overlapping this region have a binding motif for REST (RE1-silencing transcription factor), a critical epigenetic modulator for neuronal genes. REST represses expression of neuronal genes in non-neuronal tissues, resulting in reduced luciferase expression activity. Even in the suppressed condition, the longer construct enhanced luciferase expression activity of the shorter construct, which excluded the distal end containing rs4906902. However allele frequencies of rs20317 and rs4906902 were not significantly associated with 48 rCAE patients in comparison to > 500 controls matched for ethnicity and ancestral origin.
Significance
Common SNPs in the promoter region increase luciferase expression activity. An epigenetic modulator, REST specifically alters expression of GABRB3 exon 1A transcripts, suggesting epigenetic regulation by REST dominantly controls the expression of GABRB3 variant2 transcript in early life GABAA signaling. Abnormal epigenetic regulation could be involved in absence seizures.
doi:10.1111/j.1528-1167.2012.03572.x
PMCID: PMC3418397  PMID: 22765836
luciferase activity; rs20317; rs4906902; epigenetic modulator; REST; Childhood absence epilepsy
4.  Integrating Psychological Theory Into the Design of an Online Intervention for Sexual Health: The Sexunzipped Website 
JMIR Research Protocols  2012;1(2):e16.
Background
The Internet can provide a confidential and convenient medium for sexual health promotion for young people.
Objective
This paper describes the development of an interactive, theory-based website (Sexunzipped) aimed at increasing safe sexual behavior of young people, as well as an outline of the evaluation protocol.
Methods
The website focuses on safer sex, relationships, and sexual pleasure. An overview of the site is provided, including a description of the theoretical constructs which form the basis of the site development. An integrated behavioral model was chosen as the guiding theory for the Sexunzipped intervention. A randomized trial design will be used to evaluate the site quantitatively.
Results
The content of the site is described in detail with examples of the main content types: information pages, quizzes, and decision-making activities. We describe the protocol for quantitative evaluation of the website using a randomized trial design and discuss the principal challenges involved in developing the site, including the challenge of balancing the requirements of theory with young people’s views on website content and design.
Conclusions
Considerations for future interventions are discussed. Developing an online behavior-change intervention is costly and time consuming. Given the large public health potential, the cost involved in developing online interventions, and the need for attractive design, future interventions may benefit from collaborating with established sites that already have a user base, a brand, and a strong Internet presence. It is vital to involve users in decisions about intervention content, design, and features, paying attention to aspects that will attract and retain users’ interest. A central challenge in developing effective Internet-based interventions for young people is to find effective ways to operationalize theory in ways that address the views and perspectives of young people.
doi:10.2196/resprot.2114
PMCID: PMC3626157  PMID: 23612122
Internet; sex education; adolescents; young adults; health behavior; psychological theory
5.  What Young People Want From a Sexual Health Website: Design and Development of Sexunzipped 
Background
Sexual health education in the United Kingdom is of variable quality, typically focusing on the biological aspects of sex rather than on communication, relationships, and sexual pleasure. The Internet offers a unique opportunity to provide sexual health education to young people, since they can be difficult to engage but frequently use the Internet as a health information resource.
Objectives
To explore through qualitative research young people’s views on what elements of a sexual health website would be appealing and engaging, and their views on the content, design, and interactive features of the Sexunzipped intervention website.
Methods
We recruited 67 young people aged 16–22 years in London, UK. We held 21 focus groups and 6 one-to-one interviews to establish sexual health priorities, views on website look and feel, and what features of a sexual heath website would attract and engage them. Two researchers facilitated the focus groups, using a semistructured topic guide to lead the discussions and asking open questions to elicit a range of views. The discussions and interviews were audio recorded and detailed notes were made on key topics from the audio recording. Young people’s views influenced design templates for the content and interactive features of Sexunzipped.
Results
Young people particularly wanted straightforward information on sexual pleasure, sexually transmitted infections and pregnancy, how to communicate with partners, how to develop skills in giving pleasure, and emotions involved in sex and relationships. Focus group participants wanted social interaction with other young people online and wanted to see themselves reflected in some way such as through images or videos.
Conclusions
While it is challenging to meet all of young people’s technological and design requirements, consultation with the target audience is valuable and necessary in developing an online sexual health intervention. Young people are willing to talk about sensitive issues, enjoy the discussions, and can offer key insights that influence intervention development.
doi:10.2196/jmir.2116
PMCID: PMC3510764  PMID: 23060424
Sex education; adolescents; young adults; qualitative research
6.  Heritability and Genetic Correlation of Hair Cortisol in Vervet Monkeys in Low and Higher Stress Environments 
Psychoneuroendocrinology  2011;36(8):1201-1208.
Summary
Chronic activation of the hypothalamic-pituitary adrenal (HPA) system is a risk factor for a variety of physical and mental disorders, and yet the complexity of the system has made it difficult to define the role of genetic and environmental factors in producing long term individual differences in HPA activity. Cortisol levels in hair have been suggested as a marker of total HPA activation over a period of several months. This study takes advantage of a pedigreed nonhuman primate colony to investigate genetic and environmental influences on hair cortisol levels before and after an environmental change. A sample of 226 adult female vervet monkeys (age 3–18) living in multigenerational, matrilineal social groups at the Vervet Research Colony were sampled in a stable low stress baseline environment and 6 months after the entire colony was moved to a new facility with more frequent handling and group disturbances (higher stress environment). Variance components analysis using the extended colony pedigree was applied to determine heritability of hair cortisol levels in the two environments. Bivariate genetic correlation assessed degree of overlap in genes influencing hair cortisol levels in the low and higher stress environments. The results showed that levels of cortisol in hair of female vervets increased significantly from the baseline to the post-move environment. Hair cortisol levels were heritable in both environments (h2 = 0.31), and there was a high genetic correlation across environments (rhoG = 0.79), indicating substantial overlap in the genes affecting HPA activity in low and higher stress environments. This is the first study to demonstrate that the level of cortisol in hair is a heritable trait. It shows the utility of hair cortisol as a marker for HPA activation, and a useful tool for identifying genetic influences on long term individual differences in HPA activity. The results provide support for an additive model of the effects of genes and environment on this measure of long term HPA activity.
doi:10.1016/j.psyneuen.2011.02.013
PMCID: PMC3125414  PMID: 21411232
HPA axis; hair cortisol; heritability; genetic correlation; environmental stress; nonhuman primate; vervet monkey
7.  Environmental stress alters genetic regulation of novelty seeking in vervet monkeys 
Genes, brain, and behavior  2011;10(6):683-688.
Considerable attention has been paid to identifying genetic influences and gene-environment interactions that increase vulnerability to environmental stressors, with promising but inconsistent results. A nonhuman primate model is presented here that allows assessment of genetic influences on response to a stressful life event for a behavioral trait with relevance for psychopathology. Genetic and environmental influences on free choice novelty seeking behavior were assessed in a pedigreed colony of vervet monkeys before and after relocation from a low stress to a higher stress environment. Heritability of Novelty Seeking scores, and genetic correlations within and between environments, were conducted using variance components analysis. The results showed that Novelty Seeking was markedly inhibited in the higher stress environment, with effects persisting across a two year period for adults but not for juveniles. There were significant genetic contributions to Novelty Seeking scores in each year (h2 = .35–.43), with high genetic correlations within each environment (rhoG > .80), and a lower genetic correlation (rhoG = .35, ns) between environments. There were also significant genetic contributions to individual change scores from before to after the move (h2 = .48) These results indicate that genetic regulation of novelty seeking was modified by the level of environmental stress, and they support a role for gene-environment interactions in a behavioral trait with relevance for mental health.
doi:10.1111/j.1601-183X.2011.00707.x
PMCID: PMC3150611  PMID: 21631727
Environment; stress; novelty seeking; heritability; bivariate genetic correlation; vervet monkey
8.  Population-based and Family-based Designs to Analyze Rare Variants in Complex Diseases 
Genetic Epidemiology  2011;35(Suppl 1):S41-S47.
Genotyping of rare variants on a large scale is now possible using next-generation sequencing. The sample selection is a crucial step in designing the genetic study of a complex disease and knowledge of the efficiency and limitations of the population-based and family-based designs can help making the appropriate choice.
The 9 contributions to the Group 5 of the Genetic Analysis Workshop 17 evaluated the population-based and family-based designs by comparing the results obtained with various methods applied on the mini-exome simulations. These simulations consisted of 200 replicates comprising unrelated individuals and 8 extended pedigrees with genotypes and various phenotypes. The methods tested for association with a population-based and/or a family-based design, tested for linkage with a family-based design or estimated heritability.
In this paper, we summarize the strength and weaknesses of both designs. While a population-based design seems more suitable to detect the effect of multiple rare variants, a family-based design can potentially enrich the sample in very rare variants, for which the effect would be concealed at the population level. However, as of today, the main limitation is still the expensive cost of next-generation sequencing.
doi:10.1002/gepi.20648
PMCID: PMC3393851  PMID: 22128057
Genetic Analysis Workshop; 1000 genome project; next-generation sequencing; linkage; association; aggregation; familial relatedness; population stratification; heritability
9.  Identifying rare variants from exome scans: the GAW17 experience 
BMC Proceedings  2011;5(Suppl 9):S1.
Genetic Analysis Workshop 17 (GAW17) provided a platform for evaluating existing statistical genetic methods and for developing novel methods to analyze rare variants that modulate complex traits. In this article, we present an overview of the 1000 Genomes Project exome data and simulated phenotype data that were distributed to GAW17 participants for analyses, the different issues addressed by the participants, and the process of preparation of manuscripts resulting from the discussions during the workshop.
doi:10.1186/1753-6561-5-S9-S1
PMCID: PMC3287821  PMID: 22373325
10.  Identification of brain transcriptional variation reproduced in peripheral blood: an approach for mapping brain expression traits 
Human Molecular Genetics  2009;18(22):4415-4427.
Genome-wide gene expression studies may provide substantial insight into gene activities and biological pathways differing between tissues and individuals. We investigated such gene expression variation by analyzing expression profiles in brain tissues derived from eight different brain regions and from blood in 12 monkeys from a biomedically important non-human primate model, the vervet (Chlorocebus aethiops sabaeus). We characterized brain regional differences in gene expression, focusing on transcripts for which inter-individual variation of expression in brain correlates well with variation in blood from the same individuals. Using stringent criteria, we identified 29 transcripts whose expression is measurable, stable, replicable, variable between individuals, relevant to brain function and heritable. Polymorphisms identified in probe regions could, in a minority of transcripts, confound the interpretation of the observed inter-individual variation. The high heritability of levels of these transcripts in a large vervet pedigree validated our approach of focusing on transcripts that showed higher inter-individual compared with intra-individual variation. These selected transcripts are candidate expression Quantitative Trait Loci, differentially regulating transcript levels in the brain among individuals. Given the high degree of conservation of tissue expression profiles between vervets and humans, our findings may facilitate the understanding of regional and individual transcriptional variation and its genetic mechanisms in humans. The approach employed here—utilizing higher quality tissue and more precise dissection of brain regions than is usually possible in humans—may therefore provide a powerful means to investigate variation in gene expression relevant to complex brain related traits, including human neuropsychiatric diseases.
doi:10.1093/hmg/ddp397
PMCID: PMC2766297  PMID: 19692348
11.  Discourse analysis: what is it and why is it relevant to family practice? 
Family Practice  2009;26(5):413-419.
This paper aims to illustrate what discourse analysis is and how it can contribute to our understanding of family practice. Firstly, we describe what ‘discourse analysis’ is, mapping the discourse analysis terrain by discussing four studies relevant to primary care to illustrate different methodological approaches and key concepts. We then address the practicalities of how to actually do discourse analysis, providing readers with a worked example using one particular approach. Thirdly, we touch on some common debates about discursive research. We conclude by advocating that researchers and practitioners take up the challenge of understanding, utilizing and extending the field of discourse studies within family practice.
doi:10.1093/fampra/cmp038
PMCID: PMC2743732  PMID: 19556336
Discourse analysis; family practice; methodology; primary health care; qualitative research
12.  Co-regulation and multilocus determinants of gene expression in humans 
BMC Proceedings  2007;1(Suppl 1):S88.
Background
The regulation of gene expression is an emerging area of investigation. Increased knowledge can deepen our understanding of the genetic contributions to variations in complex traits. The purpose of this study is to explore the feasibility of detecting regulatory elements of gene expression with multivariate analyses.
Methods
Peripheral blood lymphocyte expression levels of 30 genes on chromosome 5 and a single gene, DEAD, on chromosome 22 were analyzed in single-point variance-component linkage analyses in multiplex families to identify putative regulatory regions. To explore the possibility of regulatory regions having individual relationships with the expression levels of a single gene, we utilized stepwise regression. To explore the possibility of pleiotropy of a single regulatory locus for multiple genes, bivariate linkage analysis was applied.
Results
Twenty-one loci were linked to five expression levels. The two most significant were for the known region on chromosome 22 (LOD = 4.62). On chromosome 5 a LOD of 4.57 was found for the gene leukocyte-derived arginine aminopeptidase (LRAP) with a single-nucleotide polymorphism (SNP) within 5 Mb. Both genes showed evidence of linkage to multiple SNPs. When 194 family members were treated as independent, stepwise regression identified fewer single-nucleotide polymorphisms with significant predictive values (p < 0.05), providing evidence for multiple regulatory regions of unequal effect. However, when corrections for non-independence were applied these results could no longer be detected.
Conclusion
The complex nature of gene regulation can be explored by linkage analysis with single-nucleotide polymorphisms followed by multivariate methods to explore co-regulation.
PMCID: PMC2367586  PMID: 18466591
13.  Including endophenotypes as covariates in variance component heritability and linkage analysis 
BMC Genetics  2005;6(Suppl 1):S49.
The purpose of these analyses was to determine if incorporating or adjusting for covariates in genetic analyses helped or hindered in genetic analyses, specifically heritability and linkage analyses. To study this question, two types of covariate models were used in the simulated Genetic Analysis Workshop 14 dataset in which the true gene locations are known. All four populations of one replicate were combined for the analyses. The first model included typical covariates of sex and cohort (population) and the second included the typical covariates and also those related endophenotypes that are thought to be associated with the trait (phenotypes A, B, C, D, E, F, G, H, I, J, K, and L). A final best fit model produced in the heritability analyses was used for linkage. Linkage for disease genes D1, D3, and D4 were localized using models with and without the covariates. The use of inclusion of covariates did not appear to have any consistent advantage or disadvantage for the different phenotypes in regards to gene localization or false positive rate.
doi:10.1186/1471-2156-6-S1-S49
PMCID: PMC1866735  PMID: 16451660

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