Development and evaluations of the ancestry informative markers of the VISAGE Enhanced Tool for Appearance and Ancestry.

The VISAGE Enhanced Tool for Appearance and Ancestry (ET) has been designed to combine markers for the prediction of bio-geographical ancestry plus a range of externally visible characteristics into a single massively parallel sequencing (MPS) assay. We describe the development of the ancestry panel markers used in ET, and the enhanced analyses they provide compared to previous MPS-based forensic ancestry assays. As well as established autosomal single nucleotide polymorphisms (SNPs) that differentiate sub-Saharan African, European, East Asian, South Asian, Native American, and Oceanian populations, ET includes autosomal SNPs able to efficiently differentiate populations from Middle East regions. The ability of the ET autosomal ancestry SNPs to distinguish Middle East populations from other continentally defined population groups is such that characteristic patterns for this region can be discerned in genetic cluster analysis using STRUCTURE. Joint cluster membership estimates showing individual co-ancestry that signals North African or East African origins were detected, or cluster patterns were seen that indicate origins from central and Eastern regions of the Middle East. In addition to an augmented panel of autosomal SNPs, ET includes panels of 85 Y-SNPs, 16 X-SNPs and 21 autosomal Microhaplotypes. The Y- and X-SNPs provide a distinct method for obtaining extra detail about co-ancestry patterns identified in males with admixed backgrounds. This study used the 1000 Genomes admixed African and admixed American sample sets to fully explore these enhancements to the analysis of individual co-ancestry. Samples from urban and rural Brazil with contrasting distributions of African, European, and Native American co-ancestry were also studied to gauge the efficiency of combining Y- and X-SNP data for this purpose. The small panel of Microhaplotypes incorporated in ET were selected because they showed the highest levels of haplotype diversity amongst the seven population groups we sought to differentiate. Microhaplotype data was not formally combined with single-site SNP genotypes to analyse ancestry. However, the haplotype sequence reads obtained with ET from these loci creates an effective system for de-convoluting two-contributor mixed DNA. We made simple mixture experiments to demonstrate that when the contributors have different ancestries and the mixture ratios are imbalanced (i.e., not 1:1 mixtures) the ET Microhaplotype panel is an informative system to infer ancestry when this differs between the contributors.

Solar insolation in springtime influences age of onset of bipolar I disorder.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Psychiatric morbidity in Chinese women after cervical cancer treatment in a regional gynaecology clinic.

OBJECTIVES: To identify the prevalence and factors associated with psychiatric disorders in Chinese cervical cancer survivors. METHODS: A cross-sectional study was conducted from May 2011 to April 2012 at the specialist gynaecology outpatient clinic at Pamela Youde Nethersole Eastern Hospital, Hong Kong. All cervical cancer patients who had completed treatment were consecutively recruited. They were interviewed using the Chinese-Bilingual Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Research version. Socio-demographic data and clinical information were collected from the patients and their hospital records were reviewed. RESULTS: A total of 113 patients were recruited into the study. The point prevalence of psychiatric disorders as a group in cervical cancer survivors was 37%. The point prevalence of depressive disorders, anxiety disorders, and schizophrenia were 31%, 16%, and 2%, respectively. Major depressive disorder was the most common mood disorder and generalised anxiety disorder the most common anxiety disorder. Younger age, a history of psychiatric illness, fatigue, menopausal symptoms, and pain were independent predictors of current psychiatric disorders. CONCLUSION: Psychiatric disorders, predominantly depressive and anxiety disorders, are common in Chinese cervical cancer survivors. Identification of independent predictors can help gynaecologists detect these disorders earlier and arrange appropriate interventions.

Discriminative value of FRAX for fracture prediction in a cohort of Chinese postmenopausal women.

UNLABELLED: We followed 2,266 postmenopausal Chinese women for 4.5 years to determine which model best predicts osteoporotic fracture. A model that contains ethnic-specific risk factors, some of which reflect frailty, performed as well as or better than the well-established FRAX model. INTRODUCTION: Clinical risk assessment, with or without T-score, can predict fractures in Chinese postmenopausal women although it is unknown which combination of clinical risk factors is most effective. This prospective study sought to compare the accuracy for fracture prediction using various models including FRAX, our ethnic-specific clinical risk factors (CRF) and other simple models. METHODS: This study is part of the Hong Kong Osteoporosis Study. A total of 2,266 treatment naïve postmenopausal women underwent clinical risk factor and bone mineral density assessment. Subjects were followed up for outcome of major osteoporotic fracture and receiver operating characteristic (ROC) curves for different models were compared. The percentage of subjects in different quartiles of risk according to various models who actually fractured was also compared. RESULTS: The mean age at baseline was 62.1 ± 8.5 years and mean follow-up time was 4.5 ± 2.8 years. A total of 106 new major osteoporotic fractures were reported, of which 21 were hip fractures. Ethnic-specific CRF with T-score performed better than FRAX with T-score (based on both Chinese normative and National Health and Nutrition Examination Survey (NHANES) databases) in terms of AUC comparison for prediction of major osteoporotic fracture. The two models were similar in hip fracture prediction. The ethnic-specific CRF model had a 10% higher sensitivity than FRAX at a specificity of 0.8 or above. CONCLUSION: CRF related to frailty and differences in lifestyle between populations are likely to be important in fracture prediction. Further work is required to determine which and how CRF can be applied to develop a fracture prediction model in our population.

Fibrinogen γ' levels in patients with intracerebral hemorrhage.

BACKGROUND: The fibrinogen γ' variant (γ') has both antithrombotic and prothrombotic properties when compared to normal fibrinogen. It may therefore be of relevance in intracerebral hemorrhage and intraventricular extension of the bleeding. OBJECTIVE: To study the role of γ' in intracerebral hemorrhage, and in intraventricular extension of the hemorrhage. PATIENTS/METHODS: We performed a case-control study in 156 controls and 55 patients with intracerebral hemorrhage, with and without intraventricular extension. Levels of fibrinogen γ' and the γ'/total fibrinogen ratio were measured in all participants. RESULTS: Levels of γ' were increased in patients with intracerebral hemorrhage when compared with controls (0.40 vs 0.32g/l, p<0.001). The γ'/total fibrinogen ratio was similar in patients and controls (0.092 vs 0.096 p=0.42). There was evidence for an unfavorable outcome in patients with fibrinogen levels in the highest tertile compared with the lowest tertile (OR 4.0, 95%CI 1.1-15.2), and a nonsignificant trend toward unfavorable outcome with higher levels of γ' (p-value for trend=0.06). CONCLUSIONS: Our study shows that absolute levels of fibrinogen γ' are increased in patients with intracerebral hemorrhage, but relative levels are similar in patients and controls, suggesting that the absolute rise in γ' is an acute phase response.

Haplotypes of the fibrinogen gene and cerebral small vessel disease: the Rotterdam scan study.

OBJECTIVE: Fibrinogen levels and fibrinogen clot structure have been implicated in the pathogenesis of vascular disease. We examined fibrinogen levels and variation in fibrinogen genes (fibrinogen gamma (FGG), alpha (FGA) and beta (FGB)), which have been associated with fibrin clot structure and fibrinogen levels, in relation to cerebral small vessel disease (SVD). METHODS AND RESULTS: This study was performed as part of the Rotterdam Scan Study, a population based study in 1077 elderly patients undergoing cerebral MRI. Plasma fibrinogen levels and haplotypes were determined. We examined the association between fibrinogen levels and haplotype with silent brain infarcts and white matter lesions using logistic regression models. We constructed seven haplotypes (frequency >0.01) that describe the total common variation in the FGG and FGA genes. Haplotype 2 (GATAGTG) was associated with the presence of silent brain infarcts compared with the most frequent haplotype (GGTGGTA) (OR 1.41, 95% CI 1.03 to 1.94). Haplotype 3 (GGCGATA) was associated with periventricular white matter lesions in the highest tertile of the distribution (OR 1.40, 95% CI 1.01 to 1.92). No association was found between plasma fibrinogen levels and SVD. CONCLUSIONS: Our study provides evidence for an association of common variation in the FGG and FGA genes with cerebral SVD. It is possible that the structure of the fibrin clot rather than plasma fibrinogen levels plays a role in the pathogenesis of cerebral SVD.

Determinants of bone mineral density in Chinese men.

Osteoporotic fractures are increasing among Asian populations in both genders, but the risk factors for low bone mineral density (BMD) in Asian men is unclear. To determine the hormonal and lifestyle risk factors for low BMD in Asian men, we studied 407 community-dwelling southern Chinese men aged 50 years and above. Medical history and lifestyle habits were obtained with a structured questionnaire. Dietary calcium and phytoestrogen intake were assessed by a semi-quantitative questionnaire. BMD at the spine and hip were measured by dual-energy X-ray absorptiometry (DXA). Fasting blood was analyzed for 25(OH)D, parathyroid hormone (PTH), total and bioavailable estradiol (bio-E) and testosterone (bio-T). The mean age of the cohort was 68.42+/-10.4 (50-96) years. In the linear regression model, weight, age, body mass index (BMI), bio-E, PTH, cigarette smoking and weight-bearing exercise were significant determinants of total hip BMD. Together they explained 55% of the total variance of hip BMD, with body weight being the most important determining factor. With age and weight adjustment, height, bio-T and flavonoid intake were identified as additional determinants of total hip BMD. Strategies to prevent bone loss and osteoporosis in Asian men should include lifestyle modification and maintenance of hormonal sufficiency.

Causes of childhood blindness in a school for the visually impaired in Hong Kong.

OBJECTIVE: To identify the causes of blindness in children attending a school for the blind in Hong Kong. DESIGN: Cross-sectional observational study. SETTING: School for blind children in Hong Kong. PARTICIPANTS: Eighty-two blind students at the Ebenezer School and Home for the Visually Impaired were examined between December 1998 and August 1999. MAIN OUTCOME MEASURES: Demographic data were obtained from students and a questionnaire assessment made of their medical and ocular history. Visual acuity was assessed and visual loss classified according to the World Health Organization classification of visual impairment. Complete ophthalmic assessments were performed in all students including slit-lamp examination and dilated binocular indirect ophthalmoscopy. RESULTS: The mean age of the students was 12.2 years. Ten (12.2%) had a family history of eye disease. Major past medical illnesses were reported in 50% with prematurity and diseases of the central nervous system found in 26.8% and 11.0% of students, respectively. The most common anatomical site for visual impairment was the retina (47.6%), followed by diseases of the optic nerve (14.6%), and diseases of the anterior segment and the lens (14.6%). CONCLUSIONS: The pattern of childhood blindness in Hong Kong is similar to that seen in other developed countries. Preventable causes of childhood blindness, such as prematurity and birth asphyxia, were responsible for a large proportion of cases. Early diagnosis and treatment of such conditions may reduce the incidence of childhood blindness in Hong Kong.

Astigmatism in Chinese preschool children: prevalence, change, and effect on refractive development.

AIM: To study the prevalence, type, and progression of astigmatism in Chinese preschool children, and its effect on refractive development. METHODS: A cross sectional study of preschool children was carried out in two randomly selected kindergartens. A cohort study was performed on a subset of children, five years after initial examination. Refractive error (measured by cycloplegic autorefraction) and axial ocular dimensions (measured by ultrasonography) were the main study outcomes. RESULTS: 522 children participated in the study; the mean age was 55.7 months (SD 10.9; range 27 to 77). Mean cylinder reading was -0.65 D (SD 0.58; range 0.00 to -4.75), and with the rule astigmatism was predominant (53%). In the 108 children studied longitudinally, the mean cylinder reading reduced from -0.62 D to -0.50 D (p = 0.019). The presence of astigmatism in initial examination predisposed the eyes towards greater myopisation (p<0.001). In addition, children with increased astigmatism had greater myopic progression (p<0.001) and axial length growth (p = 0.002). CONCLUSIONS: This study reports a high prevalence of astigmatism in Chinese preschool children. The presence of astigmatism, and particularly with increasing astigmatism, appears to predispose the children to progressive myopia. Further studies are warranted.

Myopia progression among preschool Chinese children in Hong Kong.

INTRODUCTION: Myopia is the most common eye disorder especially in Asia. However, the information on myopic progression and ocular growth among preschool children, who undergo rapid changes, is limited. The aim of this study was to determine the prevalence, incidence of myopia and myopic progression among preschool children in Hong Kong. MATERIALS AND METHODS: A kindergarten was randomly chosen in Hong Kong, China. Preschool children aged 2 to 6 years attending the selected kindergarten were invited to participate. One hundred and eight children completed the 5-year cohort study. Refractive error and axial ocular dimensions were the main outcome measures. RESULTS: A total of 255 preschool children with a mean age of 4.96 (SD, 0.90) years were examined in the initial examination. Only 4.6% children had myopia of at least -0.50 D. The prevalence of myopia increased almost 10-fold to 43.5% after 5 years in the final examination. The annual incidence of myopia was 8.2%. The mean increase in axial length was 1.72 mm (SD, 0.80 mm) over the 5-year period (P < 0.001). The lens thickness decreased significantly from 3.80 mm (SD, 0.37 mm) to 3.74 mm (SD, 0.51 mm) whereas the vitreous chamber depth increased significantly from 15.01 mm (SD, 0.68 mm) to 16.42 mm (SD, 0.88 mm) (both P < 0.001). Children who were younger or were less hypermetropic at the initial examination was having greater myopic progression (P = 0.015, P < 0.001 respectively). CONCLUSION: This is the first prospective study to investigate the myopic progression and ocular growth among preschool children. Hong Kong has a high prevalence of myopia even in preschool children. They also experience a significant myopic shift and ocular growth. Further studies on the prevention of myopic development or progression should be targeted on this population.

Identification by 16S ribosomal RNA gene sequencing of an Enterobacteriaceae species with ambiguous biochemical profile from a renal transplant recipient.

Traditional ways of identification of bacteria by phenotypic characteristics cannot be used for non-cultivable organisms and organisms with unusual biochemical profiles. In this study, an Enterobacteriaceae was isolated in pure growth from the mid-stream urine of a 67-year old renal transplant recipient with urinary tract infection. Conventional biochemical tests did not reveal a pattern resembling any known member of the Enterobacteriaceae family. The Vitek system (GNI+) showed that it was 18% Leclercia adecarboxylata and 55% Klebsiella ozaenae; whereas the API system (20E) showed that it was 99.8% Rahnella aquatilis. 16S ribosomal RNA gene sequencing showed that there was 7 base differences between the isolate and Enterobacter cloacae, 18 base differences between the isolate and Enterobacter asburiae, 17 base differences between the isolate and Enterobacter cancerogenus, 35 base differences between the isolate and K. ozaenae, 27 base differences between the isolate and L. adecarboxylata, and 72 base differences between the isolate and R. aquatilis, indicating that the isolate most closely resembled a strain of E. cloacae. Identification of the organism in this study is important, as the choice of antibiotics would be radically different. In this case, cephalosporins should be avoided regardless of in-vitro susceptibility as cephalosporins are well-known to select for AmpC derepressed mutants in Enterobacter, and previous administration of third-generation cephalosporins is more likely to be associated with multidrug resistant Enterobacter isolates than is administration of antibiotics that do not include a third-generation cephalosporin.

Evaluation of combined commercial enzyme-linked immunosorbent assay for detection of rota and adenoviruses for automation.

219 stools were examined by direct electron microscopy (EM), culture and 'combined' commercial enzyme-linked immunosorbent assay kits (CELISA). The specificity of the combined ELISA for rotavirus was 100% as compared with EM, and 100% for adenovirus when both culture in addition to EM were carried out. ELISA appeared to be more sensitive than EM for both viruses. There was no cross-reaction between the 2 'combined' antisera. This technique may be useful for automation of viral diagnosis with ELISA using a 'panel' of selected viruses for a variety of specimens.

Comparison of Rotazyme and direct electron microscopy for detection of rotavirus in human stools.

A total of 115 stools were examined for Rotavirus, using direct electron microscopy (EM) and Rotazyme. The overall agreement was 88.7%. Of the negative results, there was 91.95% agreement. Rotazyme reactions of three-plus or more gave a 100% agreement with EM. The Rotazyme test is a useful diagnostic aid in laboratories not capable of performing EM.

Resistance to aminoglycoside antibiotics of gram-negative bacilli isolated in Canadian hospitals.

A survey was made of the frequency of resistance to amikacin, gentamicin and tobramycin among aerobic gram-negative bacilli isolated over a 4-week period in 1979 at six large, geographically separated Canadian hospitals. In the entire series of 4407 isolates the frequency of resistance was 2.5% to amikacin, 8.1% to gentamicin, 5.9% to tobramycin and 1.7% to all three. Most (81%) of the resistant bacteria were acquired by the patients after admission to hospital. The frequency of resistance to the three aminoglycoside antibiotics in each hospital largely reflected the local rate of cross-infection by endemic strains of resistant bacteria.