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1.  An Analysis of Bone Donor Deferral Rates in Scotland – a 6-Year Study 
Background
The Scottish National Blood Transfusion Service (SNBTS) is the main provider of tissues in Scotland. Tissue collection programmes were established in the mid-1990s, and the range of tissues collected has increased progressively over the years.
Mathods
Whilst the majority of tissues are obtained from cadaveric donations, bone is collected only from living donors who are usually patients undergoing primary hip replacement surgery (surgical donors). The bone is collected in an operating theatre, and, once stored, no further processing takes place prior to issue. Bone that fails for any reason (quality, microbiology or virological nonnegative result) is discarded.
Results
The deferral rate amongst live surgical bone donors in Scotland is around 65%, and it has been slowly and progressively rising from around 55% over the past few years. This needed investigated, particularly because comparisons with blood donors show that the deferral rate amongst bone donors is more than double that of first-time blood donors (29.7%). Our processes and systems are standardised, and our cohort of bone bank nurses have all been similarly trained and competency assessed. Moreover our data collection was done in a uniform fashion. It was therefore possible to conduct a 6-year audit on bone donor deferrals. It was found that a history of transfusion (16%), history of malignancy (18%) and bone quality (26%) were the main reasons for bone donor deferrals, accounting for 60% of all deferrals.
Conclusions
When these are taken into account, the residual deferral rates become very similar numerically to blood donors. It is important to note however that there are significant differences between the blood and bone donor cohorts. This study also highlighted some of deferral reasons. Particularly malignancy is a cause of significant numbers of deferrals, and the evidence of transmissibility of malignancy through bone donation is not strong. More robust risk assessments should be undertaken prior to implementing deferral conditions.
doi:10.1159/000334892
PMCID: PMC3268000  PMID: 22403521
Living bone donors; Deferral rates; Tissue donation; Femoral head
2.  Generation Scotland: the Scottish Family Health Study; a new resource for researching genes and heritability 
BMC Medical Genetics  2006;7:74.
Background
Generation Scotland: the Scottish Family Health Study aims to identify genetic variants accounting for variation in levels of quantitative traits underlying the major common complex diseases (such as cardiovascular disease, cognitive decline, mental illness) in Scotland.
Methods/Design
Generation Scotland will recruit a family-based cohort of up to 50,000 individuals (comprising siblings and parent-offspring groups) across Scotland. It will be a six-year programme, beginning in Glasgow and Tayside in the first two years (Phase 1) before extending to other parts of Scotland in the remaining four years (Phase 2). In Phase 1, individuals aged between 35 and 55 years, living in the East and West of Scotland will be invited to participate, along with at least one (and preferably more) siblings and any other first degree relatives aged 18 or over. The total initial sample size will be 15,000 and it is planned that this will increase to 50,000 in Phase 2. All participants will be asked to contribute blood samples from which DNA will be extracted and stored for future investigation. The information from the DNA, along with answers to a life-style and medical history questionnaire, clinical and biochemical measurements taken at the time of donation, and subsequent health developments over the life course (traced through electronic health records) will be stored and used for research purposes. In addition, a detailed public consultation process will begin that will allow respondents' views to shape and develop the study. This is an important aspect to the research, and forms the continuation of a long-term parallel engagement process.
Discussion
As well as gene identification, the family-based study design will allow measurement of the heritability and familial aggregation of relevant quantitative traits, and the study of how genetic effects may vary by parent-of-origin. Long-term potential outcomes of this research include the targeting of disease prevention and treatment, and the development of screening tools based on the new genetic information. This study approach is complementary to other population-based genetic epidemiology studies, such as UK Biobank, which are established primarily to characterise genes and genetic risk in the population.
doi:10.1186/1471-2350-7-74
PMCID: PMC1592477  PMID: 17014726
3.  Pedigree and genotyping quality analyses of over 10,000 DNA samples from the Generation Scotland: Scottish Family Health Study 
BMC Medical Genetics  2013;14:38.
Background
Generation Scotland: Scottish Family Health Study (GS:SFHS) is a family-based biobank of 24,000 participants with rich phenotype and DNA available for genetic research. This paper describes the laboratory results from genotyping 32 single nucleotide polymorphisms (SNPs) on DNA from over 10,000 participants who attended GS:SFHS research clinics. The analysis described here was undertaken to test the quality of genetic information available to researchers. The success rate of each marker genotyped (call rate), minor allele frequency and adherence to Mendelian inheritance are presented. The few deviations in marker transmission in the 925 parent-child trios analysed were assessed as to whether they were likely to be miscalled genotypes, data or sample handling errors, or pedigree inaccuracies including non-paternity.
Methods
The first 10,450 GS:SFHS clinic participants who had spirometry and smoking data available and DNA extracted were selected. 32 SNPs were assayed, chosen as part of a replication experiment from a Genome-Wide Association Study meta-analysis of lung function.
Results
In total 325,336 genotypes were returned. The overall project pass rate (32 SNPs on 10,450 samples) was 97.29%. A total of 925 parent-child trios were assessed for transmission of the SNP markers, with 16 trios indicating evidence of inconsistency in the recorded pedigrees.
Conclusions
The Generation Scotland: Scottish Family Health Study used well-validated study methods and can produce good quality genetic data, with a low error rate. The GS:SFHS DNA samples are of high quality and the family groups were recorded and processed with accuracy during collection of the cohort.
doi:10.1186/1471-2350-14-38
PMCID: PMC3614907  PMID: 23521772
Genetics; SNP Genotyping; Parent-child trios; Error rate; Non paternity; Generation Scotland; Biobank
4.  Rhegmatogenous retinal detachment in Scotland: research design and methodology 
BMC Ophthalmology  2009;9:2.
Background
Rhegmatogenous retinal detachment (RRD) is a potentially blinding condition and a common cause of ocular morbidity. Establishing an accurate estimate of disease incidence and distribution is an important first step in assessing the healthcare burden related to this condition and in subsequent planning and provision of treatment strategies. The aim of this study is to obtain a first estimate incidence of RRD in Scotland, to estimate the incidence of familial RRD and to describe the known associations of RRD within the study population.
Methods/Design
We have established a national prospective observational study seeking to identify and recruit all incident cases of RRD in the Scottish population over a 2 year period. After fully informed consent, all participants will have a blood sample taken and a full medical history and clinical examination performed including visual acuity, refraction, slit-lamp examination, intra-ocular pressure measurement and detailed fundal examination. We describe the study design and protocol.
Conclusion
This study will provide the first estimate of the annual incidence of RRD in Scotland. The findings of this study will be important in estimating the burden of disease and in the planning of future health care policy related to this condition. This study will also establish a genetic resource for a genome wide association study to investigate if certain genetic variants predispose to RRD.
doi:10.1186/1471-2415-9-2
PMCID: PMC2666641  PMID: 19317907
5.  Recent genomic heritage in Scotland 
BMC Genomics  2015;16(1):437.
Background
The Generation Scotland Scottish Family Health Study (GS:SFHS) includes 23,960 participants from across Scotland with records for many health-related traits and environmental covariates. Genotypes at ~700 K SNPs are currently available for 10,000 participants. The cohort was designed as a resource for genetic and health related research and the study of complex traits. In this study we developed a suite of analyses to disentangle the genomic differentiation within GS:SFHS individuals to describe and optimise the sample and methods for future analyses.
Results
We combined the genotypic information of GS:SFHS with 1092 individuals from the 1000 Genomes project and estimated their genomic relationships. Then, we performed Principal Component Analyses of the resulting relationships to investigate the genomic origin of different groups. We characterised two groups of individuals: those with a few sparse rare markers in the genome, and those with several large rare haplotypes which might represent relatively recent exogenous ancestors. We identified some individuals with likely Italian ancestry and a group with some potential African/Asian ancestry. An analysis of homozygosity in the GS:SFHS sample revealed a very similar pattern to other European populations. We also identified an individual carrying a chromosome 1 uniparental disomy. We found evidence of local geographic stratification within the population having impact on the genomic structure.
Conclusions
These findings illuminate the history of the Scottish population and have implications for further analyses such as the study of the contributions of common and rare variants to trait heritabilities and the evaluation of genomic and phenotypic prediction of disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1605-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1605-2
PMCID: PMC4458001  PMID: 26048416
Generation Scotland; Principal component analysis; Genetic ancestry; Admixture; Rare variants; Population structure
6.  Stroke, multimorbidity and polypharmacy in a nationally representative sample of 1,424,378 patients in Scotland: implications for treatment burden 
BMC Medicine  2014;12:151.
Background
The prevalence of multimorbidity (the presence of two or more long-term conditions) is rising internationally. Multimorbidity affects patients by increasing their burden of symptoms, but is also likely to increase the self-care demands, or treatment burden, that they experience. Treatment burden refers to the effort expended in operationalising treatments, navigating healthcare systems and managing relations with healthcare providers. This is an important problem for people with chronic illness such as stroke. Polypharmacy is an important marker of both multimorbidity and burden of treatment. In this study, we examined the prevalence of multimorbidity and polypharmacy in a large, nationally representative population of primary care patients with and without stroke, adjusting for age, sex and deprivation.
Methods
A cross-sectional study of 1,424,378 participants aged 18 years and over, from 314 primary care practices in Scotland that were known to be demographically representative of the Scottish adult population. Data included information on the presence of stroke and another 39 long-term conditions, plus prescriptions for regular medications.
Results
In total, 35,690 people (2.5%) had a diagnosis of stroke. Of the 39 comorbidities examined, 35 were significantly more common in people with stroke. Of the people with a stroke, the proportion that had one or more additional morbidities present (94.2%) was almost twice that in the control group (48%) (odds ratio (OR) adjusted for age, sex and socioeconomic deprivation 5.18; 95% confidence interval (CI) 4.95 to 5.43). In the stroke group, 12.6% had a record of 11 or more repeat prescriptions compared with only 1.5% of the control group (OR adjusted for age, sex, deprivation and morbidity count 15.84; 95% CI 14.86 to 16.88). Limitations include the use of data collected for clinical rather than research purposes, a lack of consensus in the literature on the definition of certain long-term conditions, and the absence of statistical weighting in the measurement of multimorbidity, although the latter was deemed suitable for descriptive analyses.
Conclusions
Multimorbidity and polypharmacy were strikingly more common in those with a diagnosis of stroke compared with those without. This has important implications for clinical guidelines and the design of health services.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0151-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-014-0151-0
PMCID: PMC4220053  PMID: 25280748
7.  Hepatitis C virus among childbearing women in Scotland: prevalence, deprivation, and diagnosis 
Gut  2004;53(4):593-598.
Objectives: (A) To examine the prevalence and demographic characteristics of hepatitis C virus (HCV) infection among childbearing women in Scotland; and (B) to determine the extent of maternal HCV infection diagnosed prior to birth.
Methods: (A) Residual dried blood spot samples from routine neonatal screening, collected throughout Scotland during March-October 2000, were unlinked from identifiers and tested anonymously for HCV antibodies; and (B) electronic record linkage of Scotland’s databases of births and diagnosed HCV infections was performed.
Results: (A) Of 30 259 samples, 121 were enzyme linked immunosorbent assay repeat reactive and 88 of these were confirmed as anti-HCV positive in the recombinant immunoblot assay, representing a seroprevalence of 0.29–0.40%. HCV seroprevalence was high among 25–29 year olds (0.4–0.57%), in high deprivation areas (0.92–1.07%), and in Greater Glasgow (0.83–0.96%) and Grampian (0.38–0.62%). Adjusted relative risk for HCV infection was highest among residents in high deprivation areas of Glasgow (7.2 (95% confidence interval 2.0–25.5)). (B) Of 121 HCV infections found among women at delivery, 24% and 46% were estimated to have been diagnosed prior to pregnancy and birth, respectively.
Conclusions: HCV prevalence among Scottish childbearing women is consistent with that expected from injecting drug use. Based on reported rates of mother to child transmission, 8–11 paediatric infections are expected per annum. Diagnosis in only 24% of infected women prior to pregnancy indicates the extent to which HCV goes unrecognised in the injecting community. The current HCV screening approach—to test only those with a history of injecting drug use (or other risk factors for infection)—identifies approximately a quarter of previously undetected infections among pregnant women.
doi:10.1136/gut.2003.027383
PMCID: PMC1774001  PMID: 15016757
hepatitis C; pregnancy; deprivation; antenatal screening
8.  Modelling the participation decision and duration of sporting activity in Scotland 
Economic Modelling  2010;27(4):822-834.
Motivating individuals to actively engage in physical activity due to its beneficial health effects has been an integral part of Scotland's health policy agenda. The current Scottish guidelines recommend individuals participate in physical activity of moderate vigour for 30 min at least five times per week. For an individual contemplating the recommendation, decisions have to be made in regard of participation, intensity, duration and multiplicity. For the policy maker, understanding the determinants of each decision will assist in designing an intervention to effect the recommended policy. With secondary data sourced from the 2003 Scottish Health Survey (SHeS) we statistically model the combined decisions process, employing a copula approach to model specification. In taking this approach the model flexibly accounts for any statistical associations that may exist between the component decisions. Thus, we model the endogenous relationship between the decision of individuals to participate in sporting activities and, amongst those who participate, the duration of time spent undertaking their chosen activities. The main focus is to establish whether dependence exists between the two random variables assuming the vigour with which sporting activity is performed to be independent of the participation and duration decision. We allow for a variety of controls including demographic factors such as age and gender, economic factors such as income and educational attainment, lifestyle factors such as smoking, alcohol consumption, healthy eating and medical history. We use the model to compare the effect of interventions designed to increase the vigour with which individuals undertake their sport, relating it to obesity as a health outcome.
doi:10.1016/j.econmod.2009.10.003
PMCID: PMC2890861  PMID: 20640033
Sport; Sample selection; Participation; Duration; Copula
9.  A Novel Diagnostic Target in the Hepatitis C Virus Genome 
PLoS Medicine  2009;6(2):e1000031.
Background
Detection and quantification of hepatitis C virus (HCV) RNA is integral to diagnostic and therapeutic regimens. All molecular assays target the viral 5′-noncoding region (5′-NCR), and all show genotype-dependent variation of sensitivities and viral load results. Non-western HCV genotypes have been under-represented in evaluation studies. An alternative diagnostic target region within the HCV genome could facilitate a new generation of assays.
Methods and Findings
In this study we determined by de novo sequencing that the 3′-X-tail element, characterized significantly later than the rest of the genome, is highly conserved across genotypes. To prove its clinical utility as a molecular diagnostic target, a prototype qualitative and quantitative test was developed and evaluated multicentrically on a large and complete panel of 725 clinical plasma samples, covering HCV genotypes 1–6, from four continents (Germany, UK, Brazil, South Africa, Singapore). To our knowledge, this is the most diversified and comprehensive panel of clinical and genotype specimens used in HCV nucleic acid testing (NAT) validation to date. The lower limit of detection (LOD) was 18.4 IU/ml (95% confidence interval, 15.3–24.1 IU/ml), suggesting applicability in donor blood screening. The upper LOD exceeded 10−9 IU/ml, facilitating viral load monitoring within a wide dynamic range. In 598 genotyped samples, quantified by Bayer VERSANT 3.0 branched DNA (bDNA), X-tail-based viral loads were highly concordant with bDNA for all genotypes. Correlation coefficients between bDNA and X-tail NAT, for genotypes 1–6, were: 0.92, 0.85, 0.95, 0.91, 0.95, and 0.96, respectively; X-tail-based viral loads deviated by more than 0.5 log10 from 5′-NCR-based viral loads in only 12% of samples (maximum deviation, 0.85 log10). The successful introduction of X-tail NAT in a Brazilian laboratory confirmed the practical stability and robustness of the X-tail-based protocol. The assay was implemented at low reaction costs (US$8.70 per sample), short turnover times (2.5 h for up to 96 samples), and without technical difficulties.
Conclusion
This study indicates a way to fundamentally improve HCV viral load monitoring and infection screening. Our prototype assay can serve as a template for a new generation of viral load assays. Additionally, to our knowledge this study provides the first open protocol to permit industry-grade HCV detection and quantification in resource-limited settings.
Christian Drosten and colleagues develop, validate, and make openly available a prototype hepatitis C virus assay based on the conserved 3' X-tail element, with potential for clinical use in developing countries.
Editors' Summary
Background.
About 3% of the world's population (170 million people) harbor long-term (chronic) infections with the hepatitis C virus (HCV) and about 3–4 million people are newly infected with this virus every year. HCV—a leading cause of chronic hepatitis (inflammation of the liver)—is spread through contact with the blood of an infected person. Globally, the main routes of transmission are the use of unscreened blood for transfusions and the reuse of inadequately sterilized medical instruments, including needles. In affluent countries, where donated blood is routinely screened for the presence of HCV, most transmission is through needle sharing among drug users. The risk of sexual and mother-to-child transmission of HCV is low. Although HCV infection occasionally causes an acute (short-lived) illness characterized by tiredness and jaundice (yellow eyes and skin), most newly infected people progress to a symptom-free, chronic infection that can eventually cause liver cirrhosis (scarring) and liver cancer. HCV infections can be treated with a combination of two drugs called interferon and ribavirin, but these drugs are expensive and are ineffective in many patients.
Why Was This Study Done?
An effective way to limit the global spread of HCV might be to introduce routine screening of the blood that is used for transfusions in developing countries. In developed countries, HCV screening of blood donors use expensive, commercial “RT-PCR” assays to detect small amounts of HCV ribonucleic acid (RNA; HCV stores the information it needs to replicate itself—its genome—as a sequence of “ribonucleotides”). All the current HCV assays, which can also quantify the amount of viral RNA in the blood (the viral load) during treatment, detect a target sequence in the viral genome called the 5′-noncoding region (5′-NCR). However, there are several different HCV “genotypes” (strains). These genotypes vary in their geographical distribution and, even though the 5′-NCR sequence is very similar (highly conserved) in the common genotypes (HCV genotypes 1–6), the existing assays do not detect all the variants equally well. This shortcoming, together with their high cost, means that 5′-NCR RT-PCR assays are not ideal for use in many developing countries. In this study, the researchers identify an alternative diagnostic target sequence in the HCV genome—the 3′-X-tail element—and ask whether this sequence can be used to develop a new generation of tests for HCV infection that might be more appropriate for use in developing countries.
What Did the Researchers Do and Find?
The researchers determined the RNA sequence of the 3′-X-tail element in reference samples of the major HCV genotypes and showed that this region of the HCV genome is as highly conserved as the 5′-NCR. They then developed a prototype X-tail RT-PCR assay and tested its ability to detect small amounts of HCV and to measure viral load in genotype reference samples and in a large panel of HCV-infected blood samples collected in Germany, the UK, Brazil, South Africa, and Singapore. The new assay detected low levels of HCV RNA in all of the genotype reference samples and was also able to quantify high RNA concentrations. The viral load estimates it provided for the clinical samples agreed well with those obtained using a commercial assay irrespective of the sample's HCV genotype. Finally, the X-tail RT-PCR assay gave similar results to a standard assay at a fraction of the cost when used to measure viral loads in a Brazilian laboratory in an independent group of 127 patient samples collected in Brazil.
What Do These Findings Mean?
These findings suggest that the HCV 3′-X-tail element could provide an alternative target for screening blood samples for HCV infection and for monitoring viral loads during treatment, irrespective of HCV genotype. In addition, they suggest that X-tail RT-PCR assays may be stable and robust enough for use in laboratories in emerging countries. Overall, these findings should stimulate the development of a new generation of clinical HCV assays that, because the protocol used in the X-tail assay is freely available, could improve blood safety in developing countries by providing a cheap and effective alternative to existing proprietary HCV assays.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000031.
The World Health Organization has a fact sheet about hepatitis C (in English and French)
The US Centers for Disease Control and Prevention provides information on hepatitis C for the public and for health professionals (information is also available in Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides basic information on hepatitis C (in English and Spanish)
The MedlinePlus Encyclopedia has a page on hepatitis C; MedlinePlus also provides links to further information on hepatitis C (in English and Spanish)
doi:10.1371/journal.pmed.1000031
PMCID: PMC2637920  PMID: 19209955
10.  Anticipated regret to increase uptake of colorectal cancer screening in Scotland (ARTICS): study protocol for a randomised controlled trial 
BMC Public Health  2013;13:849.
Background
Colorectal cancer is the second leading cause of cancer deaths in the UK. Screening is key to early detection. The Scottish programme of colorectal cancer screening is running successfully, and involves all adults aged between 50 and 74 years being invited to post back a faecal sample for testing every 2 years. However, screening uptake is sub-optimal: for example rates for the period November 2009 to October 2011 ranged from just 39% for males living in the most deprived areas to 67% for least deprived females. Recent research has shown that asking people to consider the emotional consequences of not participating in screening (anticipated regret) can lead to a significant increase in screening uptake.
Methods/Design
We will test a simple anticipated regret manipulation, in a large randomised controlled trial with 60,000 members of the general public. They will be randomly allocated to one of 3 arms, no questionnaire, control questionnaire or anticipated regret questionnaire. The primary outcome will be screening test kit return. Results will also be examined by demographic variables (age, gender, deprivation) as these are currently related to screening kit return.
Discussion
If this anticipated regret intervention leads to a significant increase in colorectal cancer screening kit returns, this would represent a rare example of a theoretically-driven, simple intervention that could result in earlier detection of colorectal cancer and many more lives saved.
Trial registration
Current Controlled trials: ISRCTN74986452
doi:10.1186/1471-2458-13-849
PMCID: PMC3847804  PMID: 24041309
Colorectal cancer; Screening; Anticipated regret; Health locus of control; ‘Ick’ factor
11.  Impact of Scotland's Smoke-Free Legislation on Pregnancy Complications: Retrospective Cohort Study 
PLoS Medicine  2012;9(3):e1001175.
An analysis of pregnancy data for the whole of Scotland demonstrates a reduction in small-for-gestational-age births and preterm delivery since the introduction of legislation banning smoking in enclosed public spaces.
Background
Both active smoking and environmental tobacco smoke exposure are associated with pregnancy complications. In March 2006, Scotland implemented legislation prohibiting smoking in all wholly or partially enclosed public spaces. The aim of this study was to determine the impact of this legislation on preterm delivery and small for gestational age.
Methods and Findings
We conducted logistic regression analyses using national administrative pregnancy data covering the whole of Scotland. Of the two breakpoints tested, 1 January 2006 produced a better fit than the date when the legislation came into force (26 March 2006), suggesting an anticipatory effect. Among the 716,941 eligible women who conceived between August 1995 and February 2009 and subsequently delivered a live-born, singleton infant between 24 and 44 wk gestation, the prevalence of current smoking fell from 25.4% before legislation to 18.8% after legislation (p<0.001). Three months prior to the legislation, there were significant decreases in small for gestational age (−4.52%, 95% CI −8.28, −0.60, p = 0.024), overall preterm delivery (−11.72%, 95% CI −15.87, −7.35, p<0.001), and spontaneous preterm labour (−11.35%, 95% CI −17.20, −5.09, p = 0.001). In sub-group analyses, significant reductions were observed among both current and never smokers.
Conclusions
Reductions were observed in the risk of preterm delivery and small for gestational age 3 mo prior to the introduction of legislation, although the former reversed partially following the legislation. There is growing evidence of the potential for tobacco control legislation to have a positive impact on health.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The risks of smoking during pregnancy, both on mother and fetus, are well established: women who smoke during pregnancy are more likely to have a miscarriage. Smoking can cause placental problems, such as placental abruption, which can result in heavy bleeding during pregnancy, which is dangerous for both mother and baby. Other dangers of smoking during pregnancy include the baby being born too early (premature birth), the baby being below average weight (small for gestational age), birth defects, and infant death. Because of the serious damage to health caused by smoking, in 2005, under the auspices of the World Health Organization, countries adopted the Framework Convention on Tobacco Control to protect present and future generations from the devastating health, social, environmental, and economic consequences of tobacco consumption and exposure to tobacco smoke. Article 8 of the treaty obliges member states who have ratified the treaty—168 so far—to protect all people from exposure to tobacco smoke in indoor workplaces, public transport, and indoor public places. As a result, many countries around the world have banned smoking in public places.
Why Was This Study Done?
Scotland was the first country in the United Kingdom to ban smoking in public places, which was implemented as part of the Smoking, Health and Social Care (Scotland) Bill on 26 March 2006. Previous studies have shown that the introduction of the legislation led directly to a reduction in smoking and also a reduction in environmental tobacco smoke exposure in adults and children. Furthermore, the Scottish legislation has been accompanied by significant reductions in both cardiovascular and respiratory disease. Because of the known risks of smoking during pregnancy, the researchers wanted to investigate whether the change in policy on smoking in public places had positive benefits on the health of mothers and babies. They evaluated this by measuring the rates of preterm delivery and small for gestational age before and after the Scottish legislation went into effect.
What Did the Researchers Do and Find?
The researchers collected information on preterm delivery and small for gestational age in all single babies born live at 22–44 weeks gestation between 1 January 1996 and 31 December 2009 by using the Scottish Morbidity Record (SMR2), which collects relevant information on all women discharged from Scottish maternity hospitals, including maternal and infant characteristics and pregnancy complications. The researchers categorized preterm delivery into mild, moderate, and extreme depending on how much before 37 weeks the baby was born. They defined small for gestational age as the smallest 10% (below the 10th centile) for sex-specific birth weight at delivery, and very small for gestational age as the smallest 3% (below the 3rd centile), for all deliveries in Scotland over the study period. As some people may have stopped smoking in anticipation of the smoking ban, in their statistical model, the researchers included two possible breakpoints for the effect of the legislation—the actual date of implementation and 1 January 2006.
The researchers found that of the 716,968 pregnancies (the number eligible for inclusion in the study), 99.9% of women had their smoking status recorded, and among these 23.9% were current smokers, 57.6% never smokers, and 8.7% former smokers. However, following implementation of the legislation the researchers noted that there was a significant reduction in current smokers to 18.8%. In their statistical model, the researchers found that following 1 January 2006, there was a significant drop in overall preterm deliveries, which remained after adjustment for potential confounding factors. Likewise, there was a significant decrease in the number of infants born small, and very small, for gestational age after 1 January 2006. Furthermore, the researchers found that these significant reductions occurred in both mothers who smoked and those who had never smoked.
What Do These Findings Mean?
These findings suggest that the introduction of national, comprehensive smoke-free legislation in Scotland was associated with significant reductions in preterm delivery and babies being born small for gestational age. These findings are plausible and add to the growing evidence of the wide-ranging health benefits of smoke-free legislation, and support the adoption of such legislation in other countries that have yet to implement smoking bans.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001175.
More information is available on the World Health Organization's Framework Convention for Tobacco Control
More information on the Smoking, Health and Social Care (Scotland) Bill is available
The US Centers for Disease Control and Prevention has more information about the risks of smoking in pregnancy, as does the UK National Health Service's smokefree web page
NHS Health Scotland has a website that summarises all the studies to date evaluating the Scottish smoke-free legislation
doi:10.1371/journal.pmed.1001175
PMCID: PMC3295815  PMID: 22412353
12.  The Effect of Changing Patterns of Obstetric Care in Scotland (1980–2004) on Rates of Preterm Birth and Its Neonatal Consequences: Perinatal Database Study 
PLoS Medicine  2009;6(9):e1000153.
Jane Norman and colleagues analyzed linked perinatal surveillance data in Scotland and find that between 1980 and 2004 increases in spontaneous and medically induced preterm births contributed equally to the rising rate of preterm births.
Background
Rates of preterm birth are rising worldwide. Studies from the United States and Latin America suggest that much of this rise relates to increased rates of medically indicated preterm birth. In contrast, European and Australian data suggest that increases in spontaneous preterm labour also play a role. We aimed, in a population-based database of 5 million people, to determine the temporal trends and obstetric antecedents of singleton preterm birth and its associated neonatal mortality and morbidity for the period 1980–2004.
Methods and Findings
There were 1.49 million births in Scotland over the study period, of which 5.8% were preterm. We found a percentage increase in crude rates of both spontaneous preterm birth per 1,000 singleton births (10.7%, p<0.01) and medically indicated preterm births (41.2%, p<0.01), which persisted when adjusted for maternal age at delivery. The greater proportion of spontaneous preterm births meant that the absolute increase in rates of preterm birth in each category were similar. Of specific maternal complications, essential and pregnancy-induced hypertension, pre-eclampsia, and placenta praevia played a decreasing role in preterm birth over the study period, with gestational and pre-existing diabetes playing an increasing role. There was a decline in stillbirth, neonatal, and extended perinatal mortality associated with preterm birth at all gestation over the study period but an increase in the rate of prolonged hospital stay for the neonate. Neonatal mortality improved in all subgroups, regardless of obstetric antecedent of preterm birth or gestational age. In the 28 wk and greater gestational groups we found a reduction in stillbirths and extended perinatal mortality for medically induced but not spontaneous preterm births (in the absence of maternal complications) although at the expense of a longer stay in neonatal intensive care. This improvement in stillbirth and neonatal mortality supports the decision making behind the 34% increase in elective/induced preterm birth in these women. Although improvements in neonatal outcomes overall are welcome, preterm birth still accounts for over 66% of singleton stillbirths, 65% of singleton neonatal deaths, and 67% of infants whose stay in the neonatal unit is “prolonged,” suggesting this condition remains a significant contributor to perinatal mortality and morbidity.
Conclusions
In our population, increases in spontaneous and medically induced preterm births have made equal contributions to the rising rate of preterm birth. Despite improvements in related perinatal mortality, preterm birth remains a major obstetric and neonatal problem, and its frequency is increasing.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last about 40 weeks but increasing numbers of babies are being born preterm, before they reach 37 weeks of gestation (gestation is the period during which a baby develops in its mother). Nowadays in the US, for example, more than half a million babies arrive earlier than expected every year (1 in 8 babies). Although improvements in the care of newborn babies (neonatal care) mean that preterm babies are more likely to survive than in the past, preterm birth remains the single biggest cause of infant death in many developed countries, and many preterm babies who survive have long-term health problems and disabilities, particularly those born before 32 weeks of gestation. Preterm births can be spontaneous or medically induced. At present, it impossible to predict which mothers will spontaneously deliver early and there is no effective way to prevent these preterm births; medically induced early labor is undertaken when either the unborn baby or mother would be at risk if the pregnancy continued to full term.
Why Was This Study Done?
Preterm birth rates need to be reduced, but before this can be done it is important to know how the causes of preterm birth, the numbers of preterm stillbirths, and the numbers of preterm babies who die at birth (neonatal deaths) or soon after (perinatal deaths) are changing with time. If, for example, the rise in preterm births is mainly due to an increase in medically induced labor and if this change in practice has reduced neonatal deaths, it would be unwise to try to reduce the preterm birth rate by discouraging medically induced preterm births. So far, data from the US and Latin America suggest that the increase in preterm births in these countries is solely due to increased rates of medically induced preterm births. However, in Europe and Australia, the rate of spontaneous preterm births also seems to be increasing. In this study, the researchers examine the trends over time and causes of preterm birth and of neonatal death and illness in Scotland over a 25-year period.
What Did the Researchers Do and Find?
By searching a Scottish database of linked maternity records and infant health and death records, the researchers identified 1.49 million singleton births that occurred between 1980 and 2004 of which nearly 90,000 were preterm births. Over the study period, the rates of spontaneous and of medically induced preterm births per 1,000 births increased by 10.7% and 41.2%, respectively, but because there were more spontaneous preterm births than medically induced preterm births, the absolute increase in the rates of each type of birth was similar. Several maternal complications including preeclampsia (a condition that causes high blood pressure) and placenta previa (covering of the opening of the cervix by the placenta) played a decreasing role in preterm births over the study period, whereas gestational and preexisting diabetes played an increasing role. Finally, there was a decline in stillbirths and in neonatal and perinatal deaths among preterm babies, although more babies remained in the hospital longer than 7 days after birth. More specifically, after 28 weeks of gestation, stillbirths and perinatal deaths decreased among medically induced preterm births but not among spontaneous preterm births.
What Do These Findings Mean?
These findings indicate that in Scotland between 1980 and 2004, increases in spontaneous and medically induced preterm births contributed equally to the rising rate of preterm births. Importantly, they also show that the increase in induced preterm births helped to reduce stillbirths and neonatal and perinatal deaths, a finding that supports the criteria that clinicians currently use to decide whether to induce an early birth. Nevertheless, preterm births still account for two-thirds of all stillbirths, neonatal deaths, and extended neonatal stays in hospital and thus cause considerable suffering and greatly increase the workload in neonatal units. The rates of such births consequently need to be reduced and, for Scotland at least, ways will have to be found to reduce the rates of both spontaneous and induced preterm births to achieve this goal while continuing to identify those sick babies who need to be delivered early to give them the best chance of survival.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000153
Tommys is a nonprofit organization that funds research and provides information on the causes and prevention of miscarriage, premature birth, and stillbirth
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on maternal and infant health (in English and Spanish)
The US National Women's Health Information Center has detailed information about pregnancy, including a section on pregnancy complications
MedlinePlus provides links to other information on premature babies and to information on pregnancy (in English and Spanish)
doi:10.1371/journal.pmed.1000153
PMCID: PMC2740823  PMID: 19771156
13.  Evidence of deteriorating semen quality in the United Kingdom: birth cohort study in 577 men in Scotland over 11 years. 
BMJ : British Medical Journal  1996;312(7029):467-471.
OBJECTIVE: To determine whether the quality of semen has changed in a group of over 500 Scottish men born between 1951 and 1973. DESIGN: Retrospective review of data on semen quality collected in a single laboratory over 11 years and according to World Health Organisation guidelines. SETTING: Programme of gamete biology research funded by Medical Research Council. SUBJECTS: 577 volunteer semen donors. Of these, 171 were born before 1959, 120 were born in 1960-4, 171 in 1965-9, and 115 in 1970-4. MAIN OUTCOME MEASURES: Conventional criteria of semen quality including semen volume (ml), sperm concentration (10(6)/ml), overall motility (% motile), total number of sperm in the ejaculate (10(6)), and total number of motile sperm in the ejaculate (10(6)). RESULTS: When the four birth cohort groups were compared a later year of birth was associated with a lower sperm concentration, a lower total number of sperm in the ejaculate, and a lower number of motile sperm in the ejaculate. The median sperm concentration fell from 98x10(6)/ml among donors born before 1959 to 78x10(6)/ml among donors born after 1970 (P=0.002). The total number of sperm in the ejaculate fell from 301x10(6) to 214x10(6) (P=0.0005), and the total number of motile sperm in the ejaculate fell from 169.7x10(6) to 129.0x10(6) (P=0.0065). CONCLUSION: This study provides direct evidence that semen quality is deteriorating, with a later year of birth being significantly associated with a reduced number of sperm in adult life.
PMCID: PMC2349950  PMID: 8597676
14.  The Pakistan Risk of Myocardial Infarction Study: a resource for the study of genetic, lifestyle and other determinants of myocardial infarction in South Asia 
European journal of epidemiology  2009;24(6):329-338.
The burden of coronary heart disease (CHD) is increasing at a greater rate in South Asia than in any other region globally, but there is little direct evidence about its determinants. The Pakistan Risk of Myocardial Infarction Study (PROMIS) is an epidemiological resource to enable reliable study of genetic, lifestyle and other determinants of CHD in South Asia. By March 2009, PROMIS had recruited over 5,000 cases of first-ever confirmed acute myocardial infarction (MI) and over 5,000 matched controls aged 30–80 years. For each participant, information has been recorded on demographic factors, lifestyle, medical and family history, anthropometry, and a 12-lead electrocardiogram. A range of biological samples has been collected and stored, including DNA, plasma, serum and whole blood. During its next stage, the study aims to expand recruitment to achieve a total of about 20,000 cases and about 20,000 controls, and, in subsets of participants, to enrich the resource by collection of monocytes, establishment of lymphoblastoid cell lines, and by resurveying participants. Measurements in progress include profiling of candidate biochemical factors, assay of 45,000 variants in 2,100 candidate genes, and a genomewide association scan of over 650,000 genetic markers. We have established a large epidemiological resource for CHD in South Asia. In parallel with its further expansion and enrichment, the PROMIS resource will be systematically harvested to help identify and evaluate genetic and other determinants of MI in South Asia. Findings from this study should advance scientific understanding and inform regionally appropriate disease prevention and control strategies.
doi:10.1007/s10654-009-9334-y
PMCID: PMC2697028  PMID: 19404752
Myocardial Infarction; Case-control study; South Asia; Pakistan; MI; Risk factors
15.  Designing and implementing sample and data collection for an international genetics study: the Type 1 Diabetes Genetics Consortium (T1DGC) 
Clinical Trials (London, England)  2010;7(1_supplement):S5-S32.
Background and Purpose The Type 1 Diabetes Genetics Consortium (T1DGC) is an international project whose primary aims are to: (a) discover genes that modify type 1 diabetes risk; and (b) expand upon the existing genetic resources for type 1 diabetes research. The initial goal was to collect 2500 affected sibling pair (ASP) families worldwide.
Methods T1DGC was organized into four regional networks (Asia-Pacific, Europe, North America, and the United Kingdom) and a Coordinating Center. A Steering Committee, with representatives from each network, the Coordinating Center, and the funding organizations, was responsible for T1DGC operations. The Coordinating Center, with regional network representatives, developed study documents and data systems. Each network established laboratories for: DNA extraction and cell line production; human leukocyte antigen genotyping; and autoantibody measurement. Samples were tracked from the point of collection, processed at network laboratories and stored for deposit at National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repositories. Phenotypic data were collected and entered into the study database maintained by the Coordinating Center.
Results T1DGC achieved its original ASP recruitment goal. In response to research design changes, the T1DGC infrastructure also recruited trios, cases, and controls. Results of genetic analyses have identified many novel regions that affect susceptibility to type 1 diabetes. T1DGC created a resource of data and samples that is accessible to the research community.
Limitations Participation in T1DGC was declined by some countries due to study requirements for the processing of samples at network laboratories and/or final deposition of samples in NIDDK Central Repositories. Re-contact of participants was not included in informed consent templates, preventing collection of additional samples for functional studies.
Conclusions T1DGC implemented a distributed, regional network structure to reach ASP recruitment targets. The infrastructure proved robust and flexible enough to accommodate additional recruitment. T1DGC has established significant resources that provide a basis for future discovery in the study of type 1 diabetes genetics.
doi:10.1177/1740774510373497
PMCID: PMC2917852  PMID: 20603248
16.  Why Do Males in Scotland Die Younger than Those in England? Evidence from Three Prospective Cohort Studies 
PLoS ONE  2012;7(7):e38860.
Background
To examine explanations for the higher rates of male mortality in two Scottish cohorts compared with a cohort in south-east England for which similar data were collected.
Methodology/Principal Findings
We compared three cohort studies which recruited participants in the late 1960s and early 1970s. A total of 13,884 men aged 45–64 years at recruitment in the Whitehall occupational cohort (south-east England), 3,956 men in the Collaborative occupational cohort and 6,813 men in the Renfrew & Paisley population-based study (both central Scotland) were included in analyses of all-cause and cause-specific mortality. All-cause mortality was 25% (age-adjusted hazard ratio 1.25, 95% confidence interval (CI)1.21 to 1.30) and 41% (hazard ratio 1.41 (95% CI 1.36 to 1.45) higher in the Collaborative and Renfrew & Paisley cohorts respectively compared to the Whitehall cohort. The higher mortality rates were substantially attenuated by social class (to 8% and 17% higher respectively), and were effectively eliminated upon the further addition of the other baseline risk factors, such as smoking habit, lung function and pre-existing self-reported morbidity. Despite this, coronary heart disease mortality remained 11% and 16% higher, stroke mortality 45% and 37% higher, mortality from accidents and suicide 51% and 70% higher, and alcohol-related mortality 46% and 73% higher in the Collaborative and Renfrew & Paisley cohorts respectively compared with the Whitehall cohort in the fully adjusted model.
Conclusions/Significance
The higher all-cause, respiratory, and lung cancer male mortality in the Scottish cohorts was almost entirely explained by social class differences and higher prevalence of known risk factors, but reasons for the excess mortality from stroke, alcohol-related causes, accidents and suicide remained unknown.
doi:10.1371/journal.pone.0038860
PMCID: PMC3394776  PMID: 22808017
17.  Haemochromatosis gene mutations and risk of coronary heart disease: a west of Scotland coronary prevention study (WOSCOPS) substudy 
Heart  2004;90(3):304-306.
Objectives: To measure the frequency of genotypes of the HFE (haemochromatosis) gene in patients recruited to the west of Scotland coronary prevention study (WOSCOPS), and relate them to the subsequent occurrence of coronary clinical events.
Design: Nested case–control study, drawing samples of DNA from the biological bank of a cohort study.
Patients: Men aged 45–64 years in 1989, with moderate hypercholesterolaemia and no evidence of coronary heart disease at baseline.
Interventions: Follow up for a mean period of 4.9 years. Typing for C282Y and H63D mutations of the HFE gene in 482 subjects with a subsequent coronary event and 1104 without an event.
Results: The C282Y mutation was present in 81 of 482 cases (16.8%) and 182 of 1104 controls (16.5%). Comparing the prevalence of gene mutations in the cases and controls, there were no significant differences. The hazard ratio for C282Y heterozygotes was 1.03 (95% confidence interval (CI) 0.77 to 1.36) and for C282Y/H63D compound heterozygotes 1.04 (95% CI 0.50 to 2.14). Prespecified subgroup analyses of the pravastatin, placebo, smoking, and non-smoking groups showed no significant differences between cases and controls. Repeating the analyses after adjusting for possible confounding factors produced no change in the results.
Conclusions: In a population of moderately hypercholesterolaemic middle aged Scottish men who did not have any evidence of coronary heart disease at baseline, the presence of a C282Y mutation in the HFE gene did not predict the occurrence of coronary events over a mean follow up of 4.9 years.
doi:10.1136/hrt.2003.015149
PMCID: PMC1768115  PMID: 14966054
haemochromatosis; genetics; coronary heart disease; iron
18.  Covert observation in practice: lessons from the evaluation of the prohibition of smoking in public places in Scotland 
BMC Public Health  2007;7:204.
Background
A ban on smoking in wholly or substantially enclosed public places has been in place in Scotland since 26th March 2006. The impact of this legislation is currently being evaluated in seven studies, three of which involve direct observation of smoking in bars and other enclosed public places. While the ethical issues around covert observation have been widely discussed there is little practical guidance on the conduct of such research. A workshop was therefore convened to identify practical lessons learned so far from the Scottish evaluation.
Methods
We convened a workshop involving researchers from the three studies which used direct observation. In addition, one of the fieldwork managers collected written feedback on the fieldwork, identifying problems that arose in the field and some solutions.
Results
There were four main themes identified: (i) the difficulty of achieving and maintaining concealment; (ii) the experience of being an observer; (iii) the risk of bias in the observations and (iv) issues around training and recruitment. These are discussed.
Conclusion
Collecting covert observational data poses unique practical challenges, in particular in relation to the health and safety of the researcher. The findings and solutions presented in this paper will be of value to researchers designing similar studies.
doi:10.1186/1471-2458-7-204
PMCID: PMC2034551  PMID: 17692118
19.  Human metabolic profiles are stably controlled by genetic and environmental variation 
A comprehensive variation map of the human metabolome identifies genetic and stable-environmental sources as major drivers of metabolite concentrations. The data suggest that sample sizes of a few thousand are sufficient to detect metabolite biomarkers predictive of disease.
We designed a longitudinal twin study to characterize the genetic, stable-environmental, and longitudinally fluctuating influences on metabolite concentrations in two human biofluids—urine and plasma—focusing specifically on the representative subset of metabolites detectable by 1H nuclear magnetic resonance (1H NMR) spectroscopy.We identified widespread genetic and stable-environmental influences on the (urine and plasma) metabolomes, with (30 and 42%) attributable on average to familial sources, and (47 and 60%) attributable to longitudinally stable sources.Ten of the metabolites annotated in the study are estimated to have >60% familial contribution to their variation in concentration.Our findings have implications for the design and interpretation of 1H NMR-based molecular epidemiology studies. On the basis of the stable component of variation quantified in the current paper, we specified a model of disease association under which we inferred that sample sizes of a few thousand should be sufficient to detect disease-predictive metabolite biomarkers.
Metabolites are small molecules involved in biochemical processes in living systems. Their concentration in biofluids, such as urine and plasma, can offer insights into the functional status of biological pathways within an organism, and reflect input from multiple levels of biological organization—genetic, epigenetic, transcriptomic, and proteomic—as well as from environmental and lifestyle factors. Metabolite levels have the potential to indicate a broad variety of deviations from the ‘normal' physiological state, such as those that accompany a disease, or an increased susceptibility to disease. A number of recent studies have demonstrated that metabolite concentrations can be used to diagnose disease states accurately. A more ambitious goal is to identify metabolite biomarkers that are predictive of future disease onset, providing the possibility of intervention in susceptible individuals.
If an extreme concentration of a metabolite is to serve as an indicator of disease status, it is usually important to know the distribution of metabolite levels among healthy individuals. It is also useful to characterize the sources of that observed variation in the healthy population. A proportion of that variation—the heritable component—is attributable to genetic differences between individuals, potentially at many genetic loci. An effective, molecular indicator of a heritable, complex disease is likely to have a substantive heritable component. Non-heritable biological variation in metabolite concentrations can arise from a variety of environmental influences, such as dietary intake, lifestyle choices, general physical condition, composition of gut microflora, and use of medication. Variation across a population in stable-environmental influences leads to long-term differences between individuals in their baseline metabolite levels. Dynamic environmental pressures lead to short-term fluctuations within an individual about their baseline level. A metabolite whose concentration changes substantially in response to short-term pressures is relatively unlikely to offer long-term prediction of disease. In summary, the potential suitability of a metabolite to predict disease is reflected by the relative contributions of heritable and stable/unstable-environmental factors to its variation in concentration across the healthy population.
Studies involving twins are an established technique for quantifying the heritable component of phenotypes in human populations. Monozygotic (MZ) twins share the same DNA genome-wide, while dizygotic (DZ) twins share approximately half their inherited DNA, as do ordinary siblings. By comparing the average extent of phenotypic concordance within MZ pairs to that within DZ pairs, it is possible to quantify the heritability of a trait, and also to quantify the familiality, which refers to the combination of heritable and common-environmental effects (i.e., environmental influences shared by twins in a pair). In addition to incorporating twins into the study design, it is useful to quantify the phenotype in some individuals at multiple time points. The longitudinal aspect of such a study allows environmental effects to be decomposed into those that affect the phenotype over the short term and those that exert stable influence.
For the current study, urine and blood samples were collected from a cohort of MZ and DZ twins, with some twins donating samples on two occasions several months apart. Samples were analysed by 1H nuclear magnetic resonance (1H NMR) spectroscopy—an untargeted, discovery-driven technique for quantifying metabolite concentrations in biological samples. The application of 1H NMR to a biological sample creates a spectrum, made up of multiple peaks, with each peak's size quantitatively representing the concentration of its corresponding hydrogen-containing metabolite.
In each biological sample in our study, we extracted a full set of peaks, and thereby quantified the concentrations of all common plasma and urine metabolites detectable by 1H NMR. We developed bespoke statistical methods to decompose the observed concentration variation at each metabolite peak into that originating from familial, individual-environmental, and unstable-environmental sources.
We quantified the variability landscape across all common metabolite peaks in the urine and plasma 1H NMR metabolomes. We annotated a subset of peaks with a total of 65 metabolites; the variance decompositions for these are shown in Figure 1. Ten metabolites' concentrations were estimated to have familial contributions in excess of 60%. The average proportion of stable variation across all extracted metabolite peaks was estimated to be 47% in the urine samples and 60% in the plasma samples; the average estimated familiality was 30% for urine and 42% for plasma. These results comprise the first quantitative variation map of the 1H NMR metabolome. The identification and quantification of substantive widespread stability provides support for the use of these biofluids in molecular epidemiology studies. On the basis of our findings, we performed power calculations for a hypothetical study searching for predictive disease biomarkers among 1H NMR-detectable urine and plasma metabolites. Our calculations suggest that sample sizes of 2000–5000 should allow reliable identification of disease-predictive metabolite concentrations explaining 5–10% of disease risk, while greater sample sizes of 5000–20 000 would be required to identify metabolite concentrations explaining 1–2% of disease risk.
1H Nuclear Magnetic Resonance spectroscopy (1H NMR) is increasingly used to measure metabolite concentrations in sets of biological samples for top-down systems biology and molecular epidemiology. For such purposes, knowledge of the sources of human variation in metabolite concentrations is valuable, but currently sparse. We conducted and analysed a study to create such a resource. In our unique design, identical and non-identical twin pairs donated plasma and urine samples longitudinally. We acquired 1H NMR spectra on the samples, and statistically decomposed variation in metabolite concentration into familial (genetic and common-environmental), individual-environmental, and longitudinally unstable components. We estimate that stable variation, comprising familial and individual-environmental factors, accounts on average for 60% (plasma) and 47% (urine) of biological variation in 1H NMR-detectable metabolite concentrations. Clinically predictive metabolic variation is likely nested within this stable component, so our results have implications for the effective design of biomarker-discovery studies. We provide a power-calculation method which reveals that sample sizes of a few thousand should offer sufficient statistical precision to detect 1H NMR-based biomarkers quantifying predisposition to disease.
doi:10.1038/msb.2011.57
PMCID: PMC3202796  PMID: 21878913
biomarker; 1H nuclear magnetic resonance spectroscopy; metabolome-wide association study; top-down systems biology; variance decomposition
20.  The prevalence of sight‐threatening uveitis in Scotland 
Aim
To identify and quantify the prevalence of patients with uveitis receiving systemic immunosuppression in Scotland.
Methods
Anonymised data were prospectively collected on all patients with uveitis requiring systemic immunosuppression. Seven health boards participated over a 4‐month period between 1 August 2005 and 30 November 2005.
Results
373 patients were identified, of whom 205 (55%) were female. The mean age was 46.4 (range 7–97 years). Using the data from the seven participating health boards, an estimated Scottish prevalence of 9 per 100 000 was calculated. Prevalence varied between 2 and 59 per 100 000. In National Health Service Grampian, all patients with uveitis, whether sight‐threatening or not, are followed up at a specialist clinic. Extrapolating this figure to Scotland gives a prevalence of 25 per 100 000.
Discussion
The data from National Health Service Grampian suggest that there is a significant shortfall in the number of patients identified by survey. If the “missing population” exists, then where are they? Some might be receiving appropriate treatment at non‐specialist clinics, although simple under‐reporting may play a part. Greater concern is for those patients receiving inappropriate treatment for their uveitis, or for those within the community who are either oblivious to or in self denial of their condition.
doi:10.1136/bjo.2006.101386
PMCID: PMC1857573  PMID: 16916876
21.  Barriers to uptake and use of pre-exposure prophylaxis (PrEP) among communities most affected by HIV in the UK: findings from a qualitative study in Scotland 
BMJ Open  2014;4(11):e005717.
Objectives
To explore the acceptability of pre-exposure prophylaxis (PrEP) among gay, bisexual and men who have sex with men (MSM) and migrant African communities in Scotland, UK.
Design
Consecutive mixed qualitative methods consisting of focus groups (FGs) and in-depth interviews (IDIs) explored PrEP acceptability. Data were digitally recorded, transcribed and analysed thematically to identify anticipated and emerging themes.
Setting
Participants were recruited through community sexual health and outreach support services, and from non-sexual health settings across Scotland.
Participants
Inclusion criteria included identification as either MSM and/or from migrant African communities; 18 years and older; living in Scotland at the time of participation. 7 FGs were conducted (n=33): 5 with MSM (n=22) and 2 mixed-sex groups with African participants (n=11, women=8), aged 18–75 years. 34 IDIs were conducted with MSM (n=20) and African participants (n=14, women=10), aged 19–60 years. The sample included participants who were HIV-positive and HIV-negative or untested (HIV-positive FG participants, n=22; HIV-positive IDI participants, n=17).
Results
Understandings of PrEP effectiveness and concerns about maintaining regular adherence were identified as barriers to potential PrEP uptake and use. Low perception of HIV risk due to existing risk management strategies meant few participants saw themselves as PrEP candidates. Participants identified risk of other sexually transmitted infections and pregnancy as a concern which PrEP did not address for either themselves or their sexual partners. PrEP emerged as a contentious issue because of the potentially negative implications it had for HIV prevention. Many participants viewed PrEP as problematic because they perceived that others would stop using condoms if PrEP was to become available.
Conclusions
PrEP implementation needs to identify appropriate communication methods in the context of diverse HIV literacy; address risk-reduction concerns and; demonstrate how PrEP can be part of a safe and comprehensive risk management strategy.
doi:10.1136/bmjopen-2014-005717
PMCID: PMC4244494  PMID: 25412863
QUALITATIVE RESEARCH; PUBLIC HEALTH
22.  A national survey of the prevalence, incidence, primary care burden and treatment of atrial fibrillation in Scotland 
Heart  2007;93(5):606-612.
Objective
To examine the epidemiology, primary care burden and treatment of atrial fibrillation (AF).
Design
Cross‐sectional data from primary care practices participating in the Scottish Continuous Morbidity Recording scheme between April 2001 and March 2002.
Setting
55 primary care practices (362 155 patients).
Participants
3135 patients with AF.
Results
The prevalence of AF in Scotland was 9.4/1000 in men and 7.9/1000 in women (p<0.001) and increased with age (to 71/1000 in individuals aged >85 years). The prevalence of AF decreased with increasing socioeconomic deprivation (9.2/1000 least deprived and 7.5/1000 most deprived category, p = 0.02 for trend). 71% of patients with AF received rate‐controlling medication: β‐blocker 28%, rate‐limiting calcium‐channel blocker 42% and digoxin 43%. 42% of patients received warfarin, 44% received aspirin and 78% receeved more than one of these. Multivariable analysis showed that men and women aged ⩾75 years were more likely (than those aged <75 years) to be prescribed digoxin (men OR 1.41, 95% CI 1.14 to 1.74; women OR 1.88, 95% CI 1.50 to 2.37) and aspirin (2.04, 1.66 to 2.51; 1.79, 1.42 to 2.25) and less likely to receive an antiarrhythmic drug (0.62, 0.48 to 0.81; 0.52, 0.39 to 0.70) or warfarin (0.74, 0.60 to 0.91; 0.58, 0.46 to 0.73). Adjusted analysis showed no socioeconomic gradient in prescribing.
Conclusions
AF is a common condition, more so in men than in women. Deprived individuals are less likely to have AF, a finding raising concerns about socioeconomic gradients in detection and prognosis. Recommended treatments for AF were underused in women and older people. This is of particular concern, given the current trends in population demographics and the evidence that both groups are at higher risk of stroke.
doi:10.1136/hrt.2006.107573
PMCID: PMC1955558  PMID: 17277353
23.  Strategies for Increasing Recruitment to Randomised Controlled Trials: Systematic Review 
PLoS Medicine  2010;7(11):e1000368.
Patrina Caldwell and colleagues performed a systematic review of randomized studies that compared methods of recruiting individual study participants into trials, and found that strategies that focus on increasing potential participants' awareness of the specific health problem, and that engaged them, appeared to increase recruitment.
Background
Recruitment of participants into randomised controlled trials (RCTs) is critical for successful trial conduct. Although there have been two previous systematic reviews on related topics, the results (which identified specific interventions) were inconclusive and not generalizable. The aim of our study was to evaluate the relative effectiveness of recruitment strategies for participation in RCTs.
Methods and Findings
A systematic review, using the PRISMA guideline for reporting of systematic reviews, that compared methods of recruiting individual study participants into an actual or mock RCT were included. We searched MEDLINE, Embase, The Cochrane Library, and reference lists of relevant studies. From over 16,000 titles or abstracts reviewed, 396 papers were retrieved and 37 studies were included, in which 18,812 of at least 59,354 people approached agreed to participate in a clinical RCT. Recruitment strategies were broadly divided into four groups: novel trial designs (eight studies), recruiter differences (eight studies), incentives (two studies), and provision of trial information (19 studies). Strategies that increased people's awareness of the health problem being studied (e.g., an interactive computer program [relative risk (RR) 1.48, 95% confidence interval (CI) 1.00–2.18], attendance at an education session [RR 1.14, 95% CI 1.01–1.28], addition of a health questionnaire [RR 1.37, 95% CI 1.14–1.66]), or a video about the health condition (RR 1.75, 95% CI 1.11–2.74), and also monetary incentives (RR1.39, 95% CI 1.13–1.64 to RR 1.53, 95% CI 1.28–1.84) improved recruitment. Increasing patients' understanding of the trial process, recruiter differences, and various methods of randomisation and consent design did not show a difference in recruitment. Consent rates were also higher for nonblinded trial design, but differential loss to follow up between groups may jeopardise the study findings. The study's main limitation was the necessity of modifying the search strategy with subsequent search updates because of changes in MEDLINE definitions. The abstracts of previous versions of this systematic review were published in 2002 and 2007.
Conclusion
Recruitment strategies that focus on increasing potential participants' awareness of the health problem being studied, its potential impact on their health, and their engagement in the learning process appeared to increase recruitment to clinical studies. Further trials of recruitment strategies that target engaging participants to increase their awareness of the health problems being studied and the potential impact on their health may confirm this hypothesis.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Before any health care intervention—a treatment for a disease or a measure such as vaccination that is designed to prevent an illness—is adopted by the medical community, it undergoes exhaustive laboratory-based and clinical research. In the laboratory, scientists investigate the causes of diseases, identify potential new treatments or preventive methods, and test these interventions in animals. New interventions that look hopeful are then investigated in clinical trials—studies that test these interventions in people by following a strict trial protocol or action plan. Phase I trials test interventions in a few healthy volunteers or patients to evaluate their safety and to identify possible side effects. In phase II trials, a larger group of patients receives an intervention to evaluate its safety further and to get an initial idea of its effectiveness. In phase III trials, very large groups of patients (sometimes in excess of a thousand people) are randomly assigned to receive the new intervention or an established intervention or placebo (dummy intervention). These “randomized controlled trials” or “RCTs” provide the most reliable information about the effectiveness and safety of health care interventions.
Why Was This Study Done?
Patients who participate in clinical trials must fulfill the inclusion criteria laid down in the trial protocol and must be given information about the trial, its risks, and potential benefits before agreeing to participate (informed consent). Unfortunately, many RCTs struggle to enroll the number of patients specified in their trial protocol, which can reduce a trial's ability to measure the effect of a new intervention. Inadequate recruitment can also increase costs and, in the worst cases, prevent trial completion. Several strategies have been developed to improve recruitment but it is not clear which strategy works best. In this study, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) of “recruitment trials”—studies that have randomly divided potential RCT participants into groups, applied different strategies for recruitment to each group, and compared recruitment rates in the groups.
What Did the Researchers Do and Find?
The researchers identified 37 randomized trials of recruitment strategies into real and mock RCTs (where no actual trial occurred). In all, 18,812 people agreed to participate in an RCT in these recruitment trials out of at least 59,354 people approached. Some of these trials investigated novel strategies for recruitment, such as changes in how patients are randomized. Others looked at the effect of recruiter differences (for example, increased contact between the health care professionals doing the recruiting and the trial investigators), the effect of offering monetary incentives to participants, and the effect of giving more information about the trial to potential participants. Recruitment strategies that improved people's awareness of the health problem being studied—provision of an interactive computer program or a video about the health condition, attendance at an educational session, or inclusion of a health questionnaire in the recruitment process—improved recruitment rates, as did monetary incentives. Increasing patients' understanding about the trial process itself, recruiter differences, and alterations in consent design and randomization generally had no effect on recruitment rates although consent rates were higher when patients knew the treatment to which they had been randomly allocated before consenting. However, differential losses among the patients in different treatment groups in such nonblinded trials may jeopardize study findings.
What Do These Findings Mean?
These findings suggest that trial recruitment strategies that focus on increasing the awareness of potential participants of the health problem being studied and its possible effects on their health, and that engage potential participants in the trial process are likely to increase recruitment to RCTs. The accuracy of these findings depends on whether the researchers identified all the published research on recruitment strategies and on whether other research on recruitment strategies has been undertaken and not published that could alter these findings. Furthermore, because about half of the recruitment trials identified by the researchers were undertaken in the US, the successful strategies identified here might not be generalizable to other countries. Nevertheless, these recruitment strategies should now be investigated further to ensure that the future evaluation of new health care interventions is not hampered by poor recruitment into RCTs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000368.
The ClinicalTrials.gov Web site is a searchable register of federally and privately supported clinical trials in the US and around the world, providing information about all aspects of clinical trials
The US National Institutes of Health provides information about clinical trials
The UK National Health Service Choices Web site has information for patients about clinical trials and medical research
The UK Medical Research Council Clinical Trials Units also provides information for patients about clinical trials and links to information on clinical trials provided by other organizations
MedlinePlus has links to further resources on clinical trials (in English and Spanish)
The Australian Government's National Health and Medical Research Council has information about clinical trials
WHO International Clinical Trials Registry Platform aims to ensure that all trials are publicly accessible to those making health care decisions
The Star Child Health International Forum of Standards for Research is a resource center for pediatric clinical trial design, conduct, and reporting
doi:10.1371/journal.pmed.1000368
PMCID: PMC2976724  PMID: 21085696
24.  Ophthalmic and visual profile of guide dog owners in Scotland 
BACKGROUND/AIMS—Out of an estimated 90 000 visually impaired people in Scotland, 509 make use of a guide dog. Initial research in Northern Ireland suggests that the ophthalmic profile of guide dog owners (GDOs) is highly specific. The aim of this study was to compare the ophthalmic and visual characteristics of Scottish GDOs with other groups of visually impaired people.
METHODS—A random sample of GDOs from central and northern Scotland (n=82) underwent a detailed assessment of residual vision (distance and near acuity, visual fields, contrast, and glare sensitivity). Comparative data were obtained from two populations of visually impaired non-GDOs—one group attending hospital ophthalmic and low vision clinics (n=50) the other social services rehabilitation clients (n=35). All participants completed a questionnaire to elicit ophthalmic history, age, and registration details.
RESULTS—GDOs were found to be significantly younger and more profoundly visually impaired than non-GDOs. The main causes of visual impairment were retinitis pigmentosa (23%), optic atrophy (15%), and retinopathy of prematurity (7%). Ninety nine per cent of GDOs were registered blind and had been visually impaired for an average of 39 years. Only 31% were totally blind.
CONCLUSION—GDOs represent a unique minority of the visually impaired population. Epidemiological registration trends would suggest that the numbers of young profoundly visually impaired people are unlikely to increase relative to their elderly counterparts. This has implications on the future demand for guide dog ownership.

 Keywords: ophthalmic profile; visual profile; guide dog owners; Scotland
PMCID: PMC1722993  PMID: 10434873
25.  Viral subtype and heterosexual acquisition of HIV infections diagnosed in Scotland 
Sexually Transmitted Infections  1999;75(6):392-395.
OBJECTIVE: As at December 1998, 87% of the estimated 33 million people living with HIV throughout the world resided in Africa and South East Asia. In Scotland (and the United Kingdom), a major public health concern has been that non-B subtypes of HIV which predominate in the regions above might enter the country and spread heterosexually among the indigenous population. The authors conducted an investigation to determine if, and to what extent, such transmission had occurred. METHODS: Stored blood samples from people who were diagnosed as HIV positive in central Scotland during 1995-7 and who were reported to have acquired their infection heterosexually, were identified. Sequence data were sought from each sample and, where obtained, viral subtype was assigned. For each case, viral subtype was linked to corresponding epidemiological details on heterosexual risk. RESULTS: Viral sequence was obtained from specimens for 53 of 59 cases. For 43 of the 53 cases, information on region of sexual contact was known. All 19 cases who had a sexual risk in Africa or Asia had a non-B subtype (A, C, or E) while 20 of 24 cases who did not report sexual contact in these regions had a B subtype (p < 0.0001). Of the remaining 10 cases, nine had a subtype B and one a subtype C virus. CONCLUSION: There is no evidence that non-B viral strains from developing countries have yet disseminated appreciably among indigenous heterosexual men and women within Scotland. Continuing to collect both demographic and molecular data from indigenous heterosexuals who are newly diagnosed with HIV would improve the chances of detecting rapidly any appreciable dissemination of non-B subtypes among this population if it were to occur. Such information would be helpful in informing HIV prevention strategies. 



PMCID: PMC1758257  PMID: 10754942

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