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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.  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
4.  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
5.  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
6.  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
7.  THE ROLE OF RACE AND TRUST IN TISSUE/BLOOD DONATION FOR GENETIC RESEARCH 
Background
Public willingness to donate tissue samples is critical to genetic research. Prior work has linked minority status and mistrust with less willingness to provide specimens. Some have suggested recruitment of prior research participants to address these barriers. We present data from a genetic epidemiology study with a request for blood and/or saliva specimens to: 1) measure willingness to donate tissue/blood samples, 2) identify demographic, trust, and other factors associated with willingness to donate samples, and 3) measure willingness to participate in future genetic research.
Methods
We surveyed participants in the North Carolina Colorectal Cancer Study (NCCCS), which included biologic sample collection from consenting participants. Participants were later asked about sample provision; trust in researchers, and future research participation.
Results
African Americans were less likely to give a blood sample when compared to whites (21% vs. 13%, p<0.05). After controlling for “trust,” this difference was no longer statistically significant (17% vs. 13%, p=0.27). Those who had given samples were more likely to express willingness to participate in future research.
Conclusion
Despite prior participation in a genetic epidemiology study, factors associated with provision of tissue samples reflected many previously identified demographic factors (race, trust). Interventions to improve and demonstrate the trustworthiness of the research team as well as recruitment of subjects with a record of sample donation might enhance future study participation.
doi:10.1097/GIM.0b013e3181cd6689
PMCID: PMC3114600  PMID: 20098329
Trust; Research Participation; Biologic samples; Genetics
8.  Stroke, multimorbidity and polypharmacy in a nationally representative sample of 1,424,378 patients in Scotland: implications for treatment burden 
BMC Medicine  2014;12(1):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
9.  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
10.  Biobanking research on oncological residual material: a framework between the rights of the individual and the interest of society 
BMC Medical Ethics  2013;14:17.
Background
The tissue biobanking of specific biological residual materials, which constitutes a useful resource for medical/scientific research, has raised some ethical issues, such as the need to define which kind of consent is applicable for biological residual materials biobanks.
Discussion
Biobank research cannot be conducted without considering arguments for obtaining the donors’ consent: in this paper we discuss to what extent consent in biobank research on oncological residual materials has to be required, and what type of consent would be appropriate in this context, considering the ethical principles of donation, solidarity, protection of the donors’ rights and the requirements of scientific progress. Regarding the relationship between informed consent and tissue collection, storage and research, we have focused on two possible choices related to the treatment of data and samples in the biobank: irreversible and reversible anonymization of the samples, distinguishing between biobank research on residual materials for which obtaining consent is necessary and justified, and biobank research for which it is not. The procedures involve different approaches and possible solutions that we will seek to define. The consent for clinical research reported in the Helsinki Declaration regards research involving human beings and for this reason it is subordinate to specific and detailed information on the research projects.
Summary
An important ethical aspect in regard to the role of Biobanks is encouraging sample donation. For donors, seeing human samples being kept rather than discarded, and seeing them become useful for research highlights the importance of the human body and improves the attitude towards donation. This process might also facilitate the giving of informed consent more willingly, and with greater trust.
doi:10.1186/1472-6939-14-17
PMCID: PMC3616854  PMID: 23547565
Biobanks; Consent; Oncological residual material; Cancer biobanks; Residual materials biobanks; Informed consent; Ethics; Research; Solidarity
11.  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
12.  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
13.  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
14.  Patient Characteristics and Participation in a Genetic Study: A Type 2 Diabetes Cohort 
Background
Recruitment of large, diverse populations into genetic studies remains challenging. Potential strategies to overcome limitations include leveraging electronic health data and minimizing patient burden. We sought to describe the overall participation rate and identify characteristics associated with participation in a genetic substudy of patients with type 2 diabetes mellitus, in which patients were identified via electronic hospital data and asked to participate by providing DNA samples by mail.
Methods
During a phone interview, participants (n = 455) were asked to take part in a genetic substudy. Subjects verbally consenting were mailed saliva collection kits and written consent forms. We examined demographic and clinical variables associated with verbal consent and DNA kit return using logistic regression.
Results
Overall, 90% (n = 410) verbally consented to the genetic substudy during interviews. However, of those consenting, only 70% returned the DNA kit (n = 287). Among those consenting, after covariate adjustment, male sex (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.09–2.65), African American race (OR, 0.61; 95% CI, 0.39–0.95), hemoglobin A1c (HbA1c) (OR, 0.87; 95% CI, 0.75–1.00), and physical activity (OR, 0.58; 95% CI, 0.37–0.91) were significantly associated with DNA kit return.
Conclusions
To our knowledge, we are the first to demonstrate an inverse association between HbA1c and participation in genetic research, potentially indicating a compliance-related trait needing further exploration. The DNA kit return rate being notably lower than the verbal consent rate suggests that the greater convenience of a telephone/mail-in process did not drastically enhance full participation. Direct comparison to in-person donation may be warranted.
doi:10.231/JIM.0000000000000022
PMCID: PMC3978128  PMID: 24379022
genetics; type 2 diabetes; race; recruitment
15.  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
16.  Insights into the Management of Emerging Infections: Regulating Variant Creutzfeldt-Jakob Disease Transfusion Risk in the UK and the US 
PLoS Medicine  2006;3(10):e342.
Background
Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case.
Methods and Findings
A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall of blood products for possible vCJD contamination in the UK, contributed to a greater sense of urgency and a speedier implementation of regulations in that country. Third, while the results of scientific studies played a prominent role in the construction of regulations in both nations, this role was shaped by existing social and professional networks. In the UK, early focus on a European study implicating B-lymphocytes as the carrier of prion infectivity in blood led to the introduction of a policy that requires universal leukoreduction of blood components. In the US, early focus on an American study highlighting the ability of plasma to serve as a reservoir of prion infectivity led the FDA and its advisory panel to eschew similar measures.
Conclusions
The results of this study yield three important theoretical insights that pertain to the global management of emerging infectious diseases. First, because the perception and management of disease may be shaped by previous experience with disease, especially catastrophic experience, there is always the possibility for over-management of some possible routes of transmission and relative neglect of others. Second, local specificities within a given nation may influence the temporality of decision making, which in turn may influence the choice of disease management policies. Third, a preference for science-based risk management among nations will not necessarily lead to homogeneous policies. This is because the exposure to and interpretation of scientific results depends on the existing social and professional networks within a given nation. Together, these theoretical insights provide a framework for analyzing and anticipating potential conflicts in the international management of emerging infectious diseases. In addition, this study illustrates the utility of qualitative methods in investigating research questions that are difficult to assess through quantitative means.
A qualitative study of US and UK governmental policy statements on the topic of vCJD and blood transfusion transmission identified factors responsible for differences in the policies adopted.
Editors' Summary
Background.
In 1996 in the UK, a new type of human prion disease was seen for the first time. This is now known as variant Creutzfeldt-Jakob disease (vCJD). Prion diseases are rare brain diseases passed from individual to individual (or between animals) by a particular type of wrongly folded protein, and they are fatal. It was suspected that vCJD had passed to humans from cattle, and that the agent causing vCJD was the same as that causing bovine spongiform encephalopathy (or “mad cow disease”). Shortly after vCJD was recognized, authorities in many countries became concerned about the possibility that it could be transmitted from one person to another through contaminated blood supplies used for transfusion in hospitals. Even though there wasn't any evidence of actual transmission of the disease through blood before December 2003, authorities in the UK, US, and elsewhere set up regulations designed to reduce the chance of that happening. At this early stage in the epidemic, there was little in the way of scientific information about the transmission properties of the disease. Both the UK and US, however, sought to make decisions in a scientific manner. They made use of evidence as it was being produced, often before it had been published. Despite this, the UK and US decided on very different changes to their respective regulations on blood donation. Both countries chose to prevent certain people (who they thought would be at greater risk of having vCJD) from donating blood. In the UK, however, the decision was made to remove white blood cells from donated blood to reduce the risk of transmitting vCJD, while the US decided that such a step was not merited by the evidence.
Why Was This Study Done?
This researcher wanted to understand more clearly why the UK and US ended up with different policies: what role was played by science, and what role was played by non-scientific factors? She hoped that insights from this investigation would also be relevant to similar challenges in the future—for example, as many countries try to work out how to control the threat of avian flu.
What Did the Researcher Do and Find?
The researcher searched for all relevant official government documents from the US and UK, as well as scientific papers, published between the time vCJD was first identified (March 1996) and the first instance of vCJD carried through blood (December 2003). She also interviewed people who knew about vCJD management in the US and UK—for example, members of government agencies and the relevant advisory committees. From the documents and interviews, the researcher picked out and grouped shared ideas. Although these documents and interviews suggested that policy making was rooted in scientific evidence, many non-scientific factors were also important. The researcher found substantial uncertainty in the scientific evidence available at the time. The document search and interviews showed that policy makers felt guilty about a previous experience in which people had become infected with HIV/AIDS through contaminated blood and were concerned about repeating this experience. Finally, in the UK, the possibility of blood contamination was seen as a much more urgent problem than in the US, because BSE and vCJD were found there first and there were far more cases. This meant that when the UK made its decision about whether to remove white blood cells from donated blood, there was less scientific evidence available. In fact, the main study that was relied on at the time would later be questioned.
What Do These Findings Mean?
These findings show that for this particular case, science was not the only factor affecting government policies. Historical and social factors such as previous experience, sense of urgency, public pressure, and the relative importance of different scientific networks were also very important. The study predicts that in the future, infectious disease–related policy decisions are unlikely to be the same across different countries because the interpretation of scientific evidence depends, to a large extent, on social factors.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030342.
National Creutzfeldt-Jakob Disease Surveillance Unit, Edinburgh, UK
US Centers for Disease Control and Prevention pages about prion diseases
World Health Organization variant Creutzfeldt-Jakob disease fact sheet
US National Institute of Neurological Disorders and Stroke information about prion diseases
doi:10.1371/journal.pmed.0030342
PMCID: PMC1621089  PMID: 17076547
17.  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
18.  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
19.  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
20.  Psychiatric Brain Banking: Three Perspectives on Current Trends and Future Directions 
Biological psychiatry  2010;69(2):104-112.
Introduction
The study of postmortem human brain tissue is central to the advancement of the neurobiological studies of psychiatric illness, particularly for the study of brain-specific isoforms and molecules.
Methods
The state-of-the-art methods and recommendations for maintaining a successful brain bank for psychiatric disorders are discussed, using the convergence of viewpoints from three brain collections, the National Institute of Mental Health Brain Collection (NIMH), the Harvard Brain Tissue Resource Center (HBTRC), and the Mt. Sinai School of Medicine Brain Bank (MSSM-BB), with diverse research interests and divergent approaches to tissue acquisition.
Results
While the NIMH obtains donations from medical examiners for its collection, and places particular emphasis on clinical diagnosis, toxicology, and building lifespan control cohorts, the HBTRC is uniquely designed as a repository whose sole purpose is to collect large-volume, high quality brain tissue from community-based donors based on relationships across an expansive nationwide network, and places emphasis on the accessibility of its bank in disseminating tissue and related data to research groups worldwide. The MSSM-BB collection has shown that, with dedication, prospective recruitment is a successful approach to tissue donation, and places particular emphasis on rigorous clinical diagnosis through antemortem contact with donors. The MSSM-BB places great importance on stereological tissue sampling methods for neuroanatomical studies, and frozen tissue sampling approaches that enable multiple assessments (RNA, DNA, protein, enzyme activity, binding, etc.) of the same tissue block. Promising scientific approaches for elucidating the molecular and cellular pathways in brain that may contribute to schizophrenia and/or bipolar disorder, such as cell culture techniques and microarray-based gene expression and genotyping studies are briefly discussed.
Conclusions
Despite unique perspectives from three established brain collections, there is a consensus that (1) diverse strategies for tissue acquisition, (2) rigor in tissue and diagnostic characterization, (3) the importance of sample accessibility, and (4) continual application of innovative scientific approaches to the study of brain tissue are all integral to the success and future of psychiatric brain banking. The future of neuropsychiatric research depends upon in the availability of high quality brain specimens from large numbers of subjects, including non-psychiatric controls.
doi:10.1016/j.biopsych.2010.05.025
PMCID: PMC3105380  PMID: 20673875
21.  Genetic Predisposition to Increased Blood Cholesterol and Triglyceride Lipid Levels and Risk of Alzheimer Disease: A Mendelian Randomization Analysis 
PLoS Medicine  2014;11(9):e1001713.
In this study, Proitsi and colleagues use a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset Alzheimer's Disease (LOAD) and find that genetic predisposition to increased plasma cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk.
Please see later in the article for the Editors' Summary
Background
Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD.
Methods and Findings
We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n = 10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p<5×10−8 and trait specific scores using SNPs associated exclusively with each trait at p<5×10−8 were developed. We used logistic regression to investigate whether the GRSs were associated with LOAD in each study and results were combined together by meta-analysis. We found no association between any of the full GRSs and LOAD (meta-analysis results: odds ratio [OR] = 1.005, 95% CI 0.82–1.24, p = 0.962 per 1 unit increase in HDL-c; OR = 0.901, 95% CI 0.65–1.25, p = 0.530 per 1 unit increase in LDL-c; OR = 1.104, 95% CI 0.89–1.37, p = 0.362 per 1 unit increase in triglycerides; and OR = 0.954, 95% CI 0.76–1.21, p = 0.688 per 1 unit increase in total cholesterol). Results for the trait specific scores were similar; however, the trait specific scores explained much smaller phenotypic variance.
Conclusions
Genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 44 million people worldwide have dementia, a group of brain disorders characterized by an irreversible decline in memory, communication, and other “cognitive” functions. Dementia mainly affects older people and, because people are living longer, experts estimate that more than 135 million people will have dementia by 2050. The commonest form of dementia is Alzheimer disease. In this type of dementia, protein clumps called plaques and neurofibrillary tangles form in the brain and cause its degeneration. The earliest sign of Alzheimer disease is usually increasing forgetfulness. As the disease progresses, affected individuals gradually lose their ability to deal with normal daily activities such as dressing. They may become anxious or aggressive or begin to wander. They may also eventually lose control of their bladder and of other physical functions. At present, there is no cure for Alzheimer disease although some of its symptoms can be managed with drugs. Most people with the disease are initially cared for at home by relatives and other unpaid carers, but many patients end their days in a care home or specialist nursing home.
Why Was This Study Done?
Several lines of evidence suggest that lipid metabolism (how the body handles cholesterol and other fats) is altered in patients whose Alzheimer disease develops after the age of 60 years (late onset Alzheimer disease, LOAD). In particular, epidemiological studies (observational investigations that examine the patterns and causes of disease in populations) have found an association between high amounts of cholesterol in the blood in midlife and the risk of LOAD. However, observational studies cannot prove that abnormal lipid metabolism (dyslipidemia) causes LOAD. People with dyslipidemia may share other characteristics that cause both dyslipidemia and LOAD (confounding) or LOAD might actually cause dyslipidemia (reverse causation). Here, the researchers use “Mendelian randomization” to examine whether lifetime changes in lipid metabolism caused by genes have a causal impact on LOAD risk. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if dyslipidemia causes LOAD, genetic variants that affect lipid metabolism should be associated with an altered risk of LOAD.
What Did the Researchers Do and Find?
The researchers investigated whether genetic predisposition to raised lipid levels increased the risk of LOAD in 10,578 participants (3,914 patients with LOAD, 1,675 elderly people without LOAD, and 4,989 population controls) using data collected in six genome wide studies looking for gene variants associated with Alzheimer disease. The researchers constructed a genotype risk score (GRS) for each participant using genetic risk markers for four types of blood lipids on the basis of the presence of single nucleotide polymorphisms (SNPs, a type of gene variant) in their DNA. When the researchers used statistical methods to investigate the association between the GRS and LOAD among all the study participants, they found no association between the GRS and LOAD.
What Do These Findings Mean?
These findings suggest that the genetic predisposition to raised blood levels of four types of lipid is not causally associated with LOAD risk. The accuracy of this finding may be affected by several limitations of this study, including the small proportion of lipid variance explained by the GRS and the validity of several assumptions that underlie all Mendelian randomization studies. Moreover, because all the participants in this study were white, these findings may not apply to people of other ethnic backgrounds. Given their findings, the researchers suggest that the observed epidemiological associations between abnormal lipid levels in the blood and variation in lipid levels for reasons other than genetics, or to LOAD risk could be secondary to variation in lipid levels for reasons other than genetics, or to LOAD, a possibility that can be investigated by studying blood lipid levels and other markers of lipid metabolism over time in large groups of patients with LOAD. Importantly, however, these findings provide new information about the role of lipids in LOAD development that may eventually lead to new therapeutic and public-health interventions for Alzheimer disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001713.
The UK National Health Service Choices website provides information (including personal stories) about Alzheimer's disease
The UK not-for-profit organization Alzheimer's Society provides information for patients and carers about dementia, including personal experiences of living with Alzheimer's disease
The US not-for-profit organization Alzheimer's Association also provides information for patients and carers about dementia and personal stories about dementia
Alzheimer's Disease International is the international federation of Alzheimer disease associations around the world; it provides links to individual associations, information about dementia, and links to World Alzheimer Reports
MedlinePlus provides links to additional resources about Alzheimer's disease (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001713
PMCID: PMC4165594  PMID: 25226301
22.  Prospective Swiss cohort study of living-kidney donors: study protocol 
BMJ Open  2011;1(2):e000202.
Background
Offering living kidney donation raised the concern that donors are exposed to unknown risks. All Swiss transplant centres therefore decided to start a prospective cohort study of living kidney donors in Switzerland. This paper describes the rationale for and implementation of this cohort study.
Methods/design
All kidney donors in Switzerland are registered and examined before donation and biennially after donation starting in the first year after nephrectomy. Before each follow-up visit, the study centre sends a package to the kidney donor containing the health questionnaire, blood and urine tubes and a prepaid envelope for sending the samples to the central laboratory. The donor makes an appointment with their family physician, who examines the donor and reports findings such as pain and other complaints, blood pressure, creatinine, albumin, all major health events and the state of mental and social well-being to the study centre. The family doctor draws the blood sample and mails it with the urine sample in the prepaid envelope. All data are centrally managed. All abnormal findings in the follow-up of individual donors are regularly discussed with the principal investigator, and necessary clinical changes made and recorded in the database. The health insurance of the recipient covers all costs of the donor follow-up. The main outcomes are the occurrence of albuminuria, hypertension and renal insufficiency. The secondary outcomes are major somatic and social events such as death, cardiovascular disease, stroke and depression.
Discussion
This prospective cohort offers unique opportunities to assess the risks of living kidney donation and will allow us to examine the risks associated with the methods used for nephrectomy in Switzerland (various forms of open surgery and laparoscopic nephrectomy). The prospective collection of all clinically relevant data and the regular monitoring of donors will allow timely interventions at early stages before serious kidney and general health problems occur.
Article summary
Article focus
To describe the rationale and set-up of the Swiss Living Kidney Donor Cohort Study.
Key messages
The question of whether kidney donation increases health risks such as hypertension and renal failure is still unsettled.
Data for this countrywide prospective cohort study over the period of at least 18 years will answer many still open questions concerning living kidney donor outcome.
Strengths and limitations of this study
This countrywide cohort study includes all consenting Swiss living kidney donors.
This is a long-term follow-up allowing the assessment of clinically relevant outcomes of donation such as hypertension and renal failure.
We cannot completely rule out residual confounding in this observational study.
doi:10.1136/bmjopen-2011-000202
PMCID: PMC3208897  PMID: 22080536
23.  Informing the ‘early years’ agenda in Scotland: understanding infant feeding patterns using linked datasets 
Background
Providing infants with the ‘best possible start in life’ is a priority for the Scottish Government. This is reflected in policy and health promotion strategies to increase breast feeding, which gives the best source of nutrients for healthy infant growth and development. However, the rate of breast feeding in Scotland remains one of the lowest in Europe. Information is needed to provide a better understanding of infant feeding and its impact on child health. This paper describes the development of a unique population-wide resource created to explore infant feeding and child health in Scotland.
Methods
Descriptive and multivariate analyses of linked routine/administrative maternal and infant health records for 731 595 infants born in Scotland between 1997 and 2009.
Results
A linked dataset was created containing a wide range of background, parental, maternal, birth and health service characteristics for a representative sample of infants born in Scotland over the study period. There was high coverage and completeness of infant feeding and other demographic, maternal and infant records. The results confirmed the importance of an enabling environment—cultural, family, health service and other maternal and infant health-related factors—in increasing the likelihood to breast feed.
Conclusions
Using the linked dataset, it was possible to investigate the determinants of breast feeding for a representative sample of Scottish infants born between 1997 and 2009. The linked dataset is an important resource that has potential uses in research, policy design and targeting intervention programmes.
doi:10.1136/jech-2013-202718
PMCID: PMC3888626  PMID: 24129609
CHILD HEALTH; BREAST FEEDING; RECORD LINKAGE; NUTRITION
24.  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
25.  New national Biobank of The Danish Center for Strategic Research on Type 2 Diabetes (DD2) 
Clinical Epidemiology  2012;4:37-42.
Long-term storage of biological samples from patients has become increasingly important in studies of disease control and treatment. The first nationwide Danish diabetes project, ie, The Danish Center for Strategic Research in Type II Diabetes (DD2), aims to improve treatment and the long-term outcome of patients with newly diagnosed type 2 diabetes (T2D). The DD2 project includes establishment of a biobank with samples from 50,000 patients with newly diagnosed T2D. This paper describes how blood and urine samples from 10,000 patients per year are collected, handled, and stored. The biobank includes whole blood, DNA, and plasma and urine samples, all frozen at −80°C. Sampling tubes have been standardized and are sent to hospital outpatient clinics and general practitioners where samples are taken, handled, aliquoted, and returned by mail overnight in standardized cryostorage tubes. When received at the biobank, samples are frozen without further treatment. From each patient, 24 cryostorage tubes are stored. Each tube is labeled with a barcode that links the data to other information available in a clinical databank registry. When patients are enrolled in DD2, a questionnaire is filled out and a quality monitoring system ensures that patients, samples, and questionnaires can be linked together at all times. The biobank is located at Vejle Hospital and the Danish National Biobank at Statens Serum Institut. As of the end of March 2012, samples from 1186 patients have been stored, and currently samples from 8–10 patients arrive per day. We have established the first national biobank in Denmark where blood, DNA, and plasma and urine samples from patients with newly diagnosed T2D are systematically collected and stored. This biobank enables sophisticated analysis of genetic variation and response to treatment, as well as disease marker studies that better classify disease status, progression, and complications.
doi:10.2147/CLEP.S33042
PMCID: PMC3470454  PMID: 23071400
DD2; biobank; type 2 diabetes; logistics; implementation; biorepository; data registration

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