Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI.

OBJECTIVE: Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population. SUBJECTS: Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models. RESULTS: We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10-7). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue. CONCLUSION: Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.

A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.

STUDY QUESTION: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study? SUMMARY ANSWER: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry. WHAT IS KNOWN ALREADY: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations. STUDY DESIGN, SIZE, DURATION: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM. MATERIALS, SETTING, METHODS: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses. MAIN RESULTS AND THE ROLE OF CHANCE: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends. LIMITATIONS, REASONS FOR CAUTION: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings. WIDER IMPLICATIONS OF THE FINDINGS: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.

The use of phenome-wide association studies (PheWAS) for exploration of novel genotype-phenotype relationships and pleiotropy discovery.

The field of phenomics has been investigating network structure among large arrays of phenotypes, and genome-wide association studies (GWAS) have been used to investigate the relationship between genetic variation and single diseases/outcomes. A novel approach has emerged combining both the exploration of phenotypic structure and genotypic variation, known as the phenome-wide association study (PheWAS). The Population Architecture using Genomics and Epidemiology (PAGE) network is a National Human Genome Research Institute (NHGRI)-supported collaboration of four groups accessing eight extensively characterized epidemiologic studies. The primary focus of PAGE is deep characterization of well-replicated GWAS variants and their relationships to various phenotypes and traits in diverse epidemiologic studies that include European Americans, African Americans, Mexican Americans/Hispanics, Asians/Pacific Islanders, and Native Americans. The rich phenotypic resources of PAGE studies provide a unique opportunity for PheWAS as each genotyped variant can be tested for an association with the wide array of phenotypic measurements available within the studies of PAGE, including prevalent and incident status for multiple common clinical conditions and risk factors, as well as clinical parameters and intermediate biomarkers. The results of PheWAS can be used to discover novel relationships between SNPs, phenotypes, and networks of interrelated phenotypes; identify pleiotropy; provide novel mechanistic insights; and foster hypothesis generation. The PAGE network has developed infrastructure to support and perform PheWAS in a high-throughput manner. As implementing the PheWAS approach has presented several challenges, the infrastructure and methodology, as well as insights gained in this project, are presented herein to benefit the larger scientific community.

An excess of rare genetic variation in ABCE1 among Yorubans and African-American individuals with HIV-1.

Signatures of natural selection occur throughout the human genome and can be detected at the sequence level. We have re-sequenced ABCE1, a host candidate gene essential for HIV-1 capsid assembly, in European- (n=23) and African-descent (Yoruban; n=24) reference populations for genetic variation discovery. We identified an excess of rare genetic variation in Yoruban samples, and the resulting Tajima's D was low (-2.27). The trend of excess rare variation persisted in flanking candidate genes ANAPC10 and OTUD4, suggesting that this pattern of positive selection can be detected across the 184.5 kb examined on chromosome 4. Owing to ABCE1's role in HIV-1 replication, we re-sequenced the candidate gene in three small cohorts of HIV-1-infected or resistant individuals. We were able to confirm the excess of rare genetic variation among HIV-1-positive African-American individuals (n=53; Tajima's D=-2.34). These results highlight the potential importance of ABCE1's role in infectious diseases such as HIV-1.

Suitability of electrosurgical analysers for routine maintenance testing of electrosurgery units - a technical note.

PRIMARY OBJECTIVE: To evaluate the use of electrosurgical analysers in testing power output and leakage current from an electrosurgery unit and compare this to the manufacturer recommendations for routine testing. METHOD: Two electrosurgical analysers were compared to reference measurements (carried out using non-inductive resistors, a current transformer and oscilloscope) over a range of tests described in IEC 60601-2-2: 1998 measuring power output and leakage currents in different conditions. The analysers used were Metron QA-ES and Fluke 454A. OUTCOMES: Both analysers gave similar results to the reference measurements for power output. The Metron QA-ES gave similar results to the reference measurements for leakage current testing; however the Fluke 454A gave substantially different results when used as described in the manual. CONCLUSIONS: Electrosurgical analysers can be a valuable tool in the workshop, enabling rapid, accurate testing of electrosurgery equipment without needing additional equipment and setting up times. Not all analysers can perform all the tests that may be needed and in some cases the accuracy of the results is questionable. Users must be certain of the capabilities and limitations of the analyser before making decisions based on the results.

Which thermometer? Factors influencing best choice for intermittent clinical temperature assessment.

The objectives of this study are (a) to review the current technologies, (b) to examine comparative costing data for six selected representative devices, and (c) to discuss the clinical factors related to selection of devices for intermittent temperature measurement. Financial estimates indicate that mercury-in-glass thermometers are the cheapest devices. Compact electronic and chemical (phase change) thermometers are cheaper alternatives than multi-patient contact thermometers requiring probe covers and infrared sensing models, which are commonly adopted in hospitals and clinical practice. However, time required to obtain readings will influence overall costs. Rigorous independent clinical research studies are now needed to establish which of these alternative technologies are 'fit for purpose'. As a minimum they should offer comparable clinical accuracy and reliability to mercury-in-glass and be suitable for most clinical measurement situations. Furthermore any additional costs should bring demonstrable benefits to the patient, user and healthcare system.

Pulmonary atresia in prenatal life.

Seven cases of pulmonary atresia with intact ventricular septum were detected in prenatal life. In two of these cases, there was a small hypertrophied right ventricle of the type commonly seen postnatally. In the remaining five cases, the right atrium and right ventricle were grossly dilated to a degree that caused lung compression. The resulting impairment of lung development appeared to be an important factor contributing to death in all five cases. Decompression of the right ventricle by intrauterine surgery to allow normal lung development in the last weeks of pregnancy may be the only way of changing this outcome.

Development and validation of an in vivo analysis tool to identify changes in carotid plaque tissue types in serial 3-D ultrasound scans.

We have developed a three-dimensional (3-D) B-mode acquisition system suitable for imaging carotid plaques in vivo. A texture classification system using 157 statistical and textural algorithms, previously developed in our laboratory and shown to predict the contents of in vitro carotid plaques, was applied to in vivo 3-D image sets obtained from patients with both symptomatic and asymptomatic carotid artery plaques. Delineation of plaque boundaries is more difficult using in vivo images than in vitro images of excised plaques embedded in agar. This study has examined inter- and intraobserver variability studies to assess the degree of selectivity of the plaque region-of-interest (ROI) and assess the degree of repeatability for potential use in comparing serial scans. An interobserver limit of agreement of +/-12.9% and an intraobserver limit of repeatability of <2% were obtained. These results show that the plaque ROI selection is subjective, but is repeatable within acceptable limits.

Medical device evaluation in the United Kingdom: past, present and future.

The evaluation of medical devices in the UK has been through many changes since the early hospital equipment assessments in the 1960s. The range of medical devices evaluated has increased and the evaluation reports published have changed, but the evaluation programme continues to be a respected service for the NHS and social care. This review documents the history of the Device Evaluation Service, from its beginnings to the present day, and looks forward to its future. Following an independent strategic review and the Healthcare Industries Task Force (HITF) recommendations, the Device Evaluation Service is now entering a new and exciting developmental phase.

Effect of angiotensin II blockade on the fibroproliferative response to phenylephrine in the rat heart.

In this study we infused phenylephrine into adult Wistar rats and used losartan to test for a possible role of angiotensin II in the phenylephrine-induced fibrosis. Phenylephrine, given by Alzet minipumps at a rate of 25 mg.kg-1.d-1, produced a rapid and striking fibrotic response that was obvious after 1 day and progressed throughout a 3-day infusion period. Northern and Western blot analyses showed large increases in cardiac fibronectin expression and atrial natriuretic peptide mRNA, corresponding to fibroblast proliferation and myocyte hypertrophy, respectively. Cardiac fibrosis, fibronectin mRNA, and atrial natriuretic peptide mRNA were blocked by prazosin (7 mg.kg-1.d-1). Administration of losartan (10 mg.kg-1.d-1) resulted in a threefold decrease in interstitial and perivascular fibroblast proliferation, as measured by proliferating cell nuclear antigen immunoreactivity (p < .05), a marked reduction of fibronectin mRNA in the heart, and a moderate reduction of cardiac atrial natriuretic peptide mRNA. The data suggest that effects mediated by a1-adrenergic and angiotensin type 1 receptors may promote cardiac fibrosis.

Angiotensin II alters aortic fibronectin independently of hypertension.

We performed these studies to assess the potential role of hemodynamic forces in mediating the changes in aortic fibronectin mRNA expression that occur in the rat in response to angiotensin II administration. With the use of an acute hypertensive model involving a 3-day infusion with a pressor dose of angiotensin II given by osmotic minipump, a selective increase in fibronectin mRNA expression but not of several other extracellular matrix genes was documented. This change was inhibited by losartan, indicating the importance of angiotensin receptors in the response. Prazosin, hydralazine, or L-arginine added to the drinking water all lowered the angiotensin II-induced increase in blood pressure but did not attenuate the increase in fibronectin mRNA expression. Angiotensin-converting enzyme inhibition using trandolapril did reduce fibronectin mRNA in the angiotensin II-infusion model, despite an inability to reduce blood pressure, whereas when angiotensin I was infused, quinapril lowered both blood pressure and fibronectin expression even at doses that did not completely normalize blood pressure. These studies suggest that angiotensin II induced an increase in aortic fibronectin mRNA that was not dependent solely on blood pressure.

Familial recurrence of congenital heart disease in a prospective series of mothers referred for fetal echocardiography.

Fetal echocardiography can ascertain, at an early stage in pregnancy, recurrences of congenital heart disease (CHD) in mothers with a family history of CHD. In 1,021 mothers referred for this reason, 20 recurrences were found; 17 occurred when there had been 1 previously affected child, and 3 when there had been 2 previously affected children. No recurrences were found in the 41 cases in which a parent had CHD. The overall recurrence rate was 1 in 52 with a previously affected child and 1 in 10 with 2 previously affected children. However, certain forms of CHD recurred much more frequently than others. Aortic valve atresia was associated with a recurrence rate of 1 in 28, coarctation of the aorta at a rate of 1 in 15, complex CHD at a rate of 1 in 11 and truncus arteriosus at 1 in 13. These findings are inconsistent with previous family studies; this may be due to more complete ascertainment, particularly of major lesions, possibly overlooked by postnatal family studies because of fetal loss. Alternatively, the availability of prenatal diagnosis may be producing an increase in family size after major CHD. The results support current doubts on the polygenic theory of inheritance for all forms of CHD.

Classification of reflectance spectra from pigmented skin lesions, a comparison of multivariate discriminant analysis and artificial neural networks.

Successful treatment of skin cancer, especially melanoma, depends on early detection, but diagnostic accuracy, even by experts, can be as low as 56% so there is an urgent need for a simple, accurate, non-invasive diagnostic tool. In this paper we have compared the performance of an artificial neural network (ANN) and multivariate discriminant analysis (MDA) for the classification of optical reflectance spectra (320 to 1100 nm) from malignant melanoma and benign naevi. The ANN was significantly better than MDA, especially when a larger data set was used, where the classification accuracy was 86.7% for ANN and 72.0% for MDA (p < 0.001). ANN was better at learning new cases than MDA for this particular classification task. This study has confirmed that the convenience of ANNs could lead to the medical community and patients benefiting from the improved diagnostic performance which can be achieved by objective measurement of pigmented skin lesions using spectrophotometry.

Spectrophotometric assessment of pigmented skin lesions: methods and feature selection for evaluation of diagnostic performance.

This study documents the optical reflectance characteristics of pigmented skin lesions and evaluates their potential for improving the differential diagnosis of malignant melanoma from benign pigmented skin lesions. Optical reflectance spectra in the wavelength range 320-1100 nm were obtained from 121 lesions already selected by expert dermatologists as suspicious of malignancy. Characteristic differences in spectra from benign and malignant lesions were studied. Feature extraction showed significant differences between lesion groups classified by histology. Seven of the most relevant features were used in the discriminant analysis of reflectance spectra from 15 melanoma and 32 compound naevi which resulted in a sensitivity of 100% and specificity of 84.4% when compared with histology. This simple objective technique appears to perform as well as the expert dermatologist and may improve the diagnostic accuracy of non-specialists such as trainees and GPs. Further prospective clinical study of reflectance spectrophotometry in a larger patient group is now required.

The accuracy of fetal echocardiography in the diagnosis of congenital heart disease.

The accuracy of the echocardiographic diagnosis of fetal heart disease in an experienced centre was evaluated by analysing the results achieved during 1987 at the Perinatal Cardiology Unit, Guy's Hospital. In this one year, 978 high-risk patients were referred for fetal echocardiography. Of these, 74 cases were found to have cardiac malformation, 69 of which were predicted from the prenatal study. Of the 69, the autopsy specimen was available for correlative purposes in 41 cases. A postnatal echocardiogram was performed by us in a further 15 cases. The result of autopsy or of a postnatal echocardiogram was obtained from another hospital in 7 cases. Postmortem was refused in 5 cases, while one further case remains alive but has not had a postnatal echocardiogram. Close correlation was achieved between the predicted echocardiographic diagnosis and the anatomical results. Some minor errors in the complete interpretation of a defect were found, particularly in those fetuses in whom image quality was poor, due to early (less than 20 weeks) or late (greater than 34 weeks) gestation or to maternal obesity. Difficulty in echocardiographic interpretation was also experienced in unusual defects. There was one false positive prediction of coarctation of the aorta. One major (total anomalous pulmonary venous drainage) and 5 minor abnormalities (two atrial and three ventricular septal defects) detected after birth were overlooked on the fetal study. Although the echocardiogram in prenatal life is not as accurate as it can be postnatally, with suitable experience a high degree of precision can now be achieved.

Compensation for the signal processing characteristics of ultrasound B-mode scanners in adaptive speckle reduction.

A systematic method to compensate for nonlinear amplification of individual ultrasound B-scanners has been investigated in order to optimise performance of an adaptive speckle reduction (ASR) filter for a wide range of clinical ultrasonic imaging equipment. Three potential methods have been investigated: (1) a method involving an appropriate selection of the speckle recognition feature was successful when the scanner signal processing executes simple logarithmic compressions; (2) an inverse transform (decompression) of the B-mode image was effective in correcting for the measured characteristics of image data compression when the algorithm was implemented in full floating point arithmetic; (3) characterising the behaviour of the statistical speckle recognition feature under conditions of speckle noise was found to be the method of choice for implementation of the adaptive speckle reduction algorithm in limited precision integer arithmetic. In this example, the statistical features of variance and mean were investigated. The third method may be implemented on commercially available fast image processing hardware and is also better suited for transfer into dedicated hardware to facilitate real-time adaptive speckle reduction. A systematic method is described for obtaining ASR calibration data from B-mode images of a speckle producing phantom.

Relationship between ultrasound texture classification images and histology of atherosclerotic plaque.

Structure and content of atherosclerotic plaque varies between patients and may be indicative of their risk for embolisation. This study aimed to construct parametric images of B-scan texture and assess their potential for predicting plaque morphology. Sequential transverse in vitro scans of 10 carotid plaques, excised during endarterectomy, were compared with macrohistology maps of plaque content. Multidiscriminant analysis combined the output of 157 statistical and textural algorithms into five separate texture classes, displayed as ultrasound (US) texture classification images (UTCI). Visual comparison between corresponding UTCI and histology maps found the five texture classes matched with the location of fibrin, elastin, calcium, haemorrhage or lipid. However, histology preparation removes calcium and lipid and, so, can affect the structural integrity of atherosclerotic plaques. Soft tissue regions smaller than the UTCI kernel, (0.87 mm x 0.85 mm x 3.9 mm), such as blood clots, are also difficult to detect by UTCI. These factors demonstrate limitations in the use of histology as a "gold standard" for US tissue characterisation.

What might echography learn from image science?

We review the current state of knowledge of the processes by which the information content of ultrasonic pulse-echo images is transferred to an observer, to the point of contributing to diagnostic judgments. As systematic knowledge in this specific field is rather sparse, we present relevant information and techniques derived from other areas of image science, both medical and otherwise. Quantitative measures both of the information content of ultrasonic and other images and of their characteristic noise content are first considered. An account is then given of the relevant aspects of human visual psychophysics, with particular reference to perception of contrast and detail, image texture, movement and colour, again with emphasis on documenting quantitative aspects of such behaviour. Against this background, we consider the efficiency, in current practice, of image information transfer to a human observer, how and to what extent this could be improved by changes in practice and, in particular, in what situations substantial innovations in machine processing of image data would be expected to improve human performance. It is suggested that several problems in the field may provide a worthwhile and challenging scope for future research.