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PurposeThe diabetic cohort (DC) was set up to study the determinants of complications in individuals with type 2 diabetes and examine the role of genetic, physiological and lifestyle factors in the development of complications in these individuals.ParticipantsA total of 14 033 adult participants with type 2 diabetes were recruited from multiple public sector polyclinics and hospital outpatient clinics in Singapore between November 2004 and November 2010. The first round of follow-up was conducted for 4131 participants between 2012 and 2016; the second round of follow-up started in 2016 and is expected to end in 2021. A questionnaire survey, physical assessments, blood and urine sample collection were conducted at recruitment and each follow-up visit. The data set also includes genetic data and linkage to medical and administrative records for recruited participants.Findings to dateData from the cohort have been used to identify determinants of diabetes and related complications. The longitudinal data of medical records have been used to analyse diabetes control over time and its related outcomes. The cohort has also contributed to the identification of genetic loci associated with type 2 diabetes and diabetic kidney disease in collaboration with other large cohort studies. About 25 scientific papers based on the DC data have been published up to May 2019.Future plansThe rich data in DC can be used for various types of research to study disease-related complications in patients with type 2 diabetes. We plan to further investigate disease progression and new biomarkers for common diabetic complications, including diabetic kidney disease and diabetic neuropathy.

Introduction : False-positive recall is an issue in national screening programmes. The aim of this study is to investigate the recall rate at first screen and to identify potential predictors of false-positive recall in a multi-ethnic Asian population-based breast cancer screening programme. Methods : Women aged 50–64 years attending screening mammography for the first time (n = 25,318) were included in this study. The associations between potential predictors (sociodemographic, lifestyle and reproductive) and false-positive recall were evaluated using multivariable logistic regression models. Results : The recall rate was 7.6% (n = 1,923), of which with 93.8% were false-positive. Factors independently associated with higher false-positive recall included Indian ethnicity (odds ratio [95% confidence interval]: 1.52 [1.25 to 1.84]), premenopause (1.23 [1.04 to 1.44]), nulliparity (1.85 [1.57 to 2.17]), recent breast symptoms (1.72 [1.31 to 2.23]) and history of breast lump excision (1.87 [1.53 to 2.26]). Factors associated with lower risk of false-positive recall included older age at screen (0.84 [0.73 to 0.97]) and use of oral contraceptives (0.87 [0.78 to 0.97]). After further adjustment of percent mammographic density, associations with older age at screening (0.97 [0.84 to 1.11]) and menopausal status (1.12 [0.95 to 1.32]) were attenuated and no longer significant. Conclusion : For every breast cancer identified, 15 women without cancer were subjected to further testing. Efforts to educate Asian women on what it means to be recalled will be useful in reducing unnecessary stress and anxiety. NRF (Natl Research Foundation, S’pore) Published version

Breast cancer patients commonly present with comorbidities which are known to influence treatment decisions and survival. We aim to examine agreement between self-reported and register-based medical records (National Patient Register [NPR]). Ascertainment of nine conditions, using individually-linked data from 64,961 women enrolled in the Swedish KARolinska MAmmography Project for Risk Prediction of Breast Cancer (KARMA) study. Agreement was assessed using observed proportion of agreement (overall agreement), expected proportion of agreement, and Cohen’s Kappa statistic. Two-stage logistic regression models taking into account chance agreement were used to identify potential predictors of overall agreement. High levels of overall agreement (i.e. ≥86.6%) were observed for all conditions. Substantial agreement (Cohen’s Kappa) was observed for myocardial infarction (0.74), diabetes (0.71) and stroke (0.64) between self-reported and NPR data. Moderate agreement was observed for preeclampsia (0.51) and hypertension (0.46). Fair agreement was observed for heart failure (0.40) and polycystic ovaries or ovarian cysts (0.27). For hyperlipidemia (0.14) and angina (0.10), slight agreement was observed. In most subgroups we observed negative specific agreement of >90%. There is no clear reference data source for ascertainment of conditions. Negative specific agreement between NPR and self-reported data is consistently high across all conditions.

Aim: Genetic factors have been found to affect warfarin maintenance dose and a key factor for the successful clinical implementation of warfarin pharmacogenetic testing (WPGT) is economic sustainability. We aimed to estimate the willingness-to-pay (WTP) and preferences for WPGT in Singaporean Chinese subjects. Methods & subjects: A total of 197 warfarin patients and 187 members of the public completed a questionnaire. The discrete choice methodology was used and the choice model was estimated using hierarchical Bayes. Marginal WTP, attribute importance and WTP for three hypothetical WPGTs were calculated from the estimated utilities. Results: Both patients and the public placed most emphasis on side effects, followed by cost, number of International Normalized Ratio tests and ‘nature of test’. WTP for WPGT ranged from S$160 to S$730. Conclusion: WPGTs are likely to be economically sustainable.

Background Community involvement is an important component of health programme development and implementation, including those focused on chronic condition treatment and management. Yet, few studies explore the manifestations of community involvement in chronic care programmes. Our review aims to examine the evidence on how communities are involved in planning and implementing chronic condition programmes in high and upper-middle income countries. Methods Eligible studies included those that involved the community in the planning, implementation, monitoring and evaluation of health services, policy or health interventions. We searched Medline, Embase, Global Health, Scopus, and LILACs from 2000 to 2016, independently screened articles for inclusion, conducted data extraction, and assessed studies for risk of bias. Results 27,232 records were identified and after screening, 32 met inclusion criteria. We conducted a narrative synthesis to report on the forms and processes of community involvement used across mental health programmes and contrast this with the paucity of evidence on comparable programmes addressing other chronic conditions. Challenges reported included user factors, organisational factors, and social challenges such as stigma. Conclusion Our review adds to the evidence supporting community involvement in chronic condition management and the processes that contribute to successful and sustainable involvement. We report on a model, derived from inductive analysis, that considers social and cultural components, organisational factors and stakeholder relationships as underpinning the development of community interventions across the care continuum.

Background Type 2 Diabetes Mellitus (T2DM) is reported to affect one in 11 adults worldwide, with over 80% of T2DM patients residing in low-to-middle-income countries. Health systems play an integral role in responding to this increasing global prevalence, and are key to ensuring effective diabetes management. We conducted a systematic review to examine the health system-level factors influencing T2DM awareness, treatment, adherence, and control. Methods and findings A protocol for this study was published on the PROSPERO international prospective register of systematic reviews (PROSPERO 2016: CRD42016048185). Studies included in this review reported the effects of health systems factors, interventions, policies, or programmes on T2DM control, awareness, treatment, and adherence. The following databases were searched on 22 February 2017: Medline, Embase, Global health, LILACS, Africa-Wide, IMSEAR, IMEMR, and WPRIM. There were no restrictions on date, language, or study designs. Two reviewers independently screened studies for eligibility, extracted the data, and screened for risk of bias. Thereafter, we performed a narrative synthesis. A meta-analysis was not conducted due to methodological heterogeneity across different aspects of included studies. 93 studies were included for qualitative synthesis; 7 were conducted in LMICs. Through this review, we found two key health system barriers to effective T2DM care and management: financial constraints faced by the patient and limited access to health services and medication. We also found three health system factors that facilitate effective T2DM care and management: the use of innovative care models, increased pharmacist involvement in care delivery, and education programmes led by healthcare professionals. Conclusions This review points to the importance of reducing, or possibly eliminating, out-of-pocket costs for diabetes medication and self-monitoring supplies. It also points to the potential of adopting more innovative and integrated models of care, and the value of task-sharing of care with pharmacists. More studies which identify the effect of health system arrangements on various outcomes, particularly awareness, are needed.

Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size = −0.045 mm, P = 8.17×10−9). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06–1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45×10−9; 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions., Author Summary The anterior chamber is the space within the eye which is bound by the cornea, and the anterior surfaces of the iris and lens. Anterior chamber depth (ACD) is the distance measured along the eye's optical axis, from the cornea to the lens surface. ACD is an important risk factor for primary angle closure glaucoma (PACG), a major cause of irreversible blindness worldwide, and in particular, individuals of Asian ethnicity. In order to identify the genes that underlie PACG susceptibility, we conducted a two-staged study. We first conducted a large scale genetic study on a total of 5,308 population-based individuals of Asian descent to identify the genetic variants that influence ACD. This was followed by testing for associations between the identified genetic variant and PACG in another independent collection of 4,276 PACG cases and 18,801 controls. We found that a genetic variant within ABCC5 was associated with an increased risk of having PACG. Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants that influence the anterior chamber dimensions of the eye.

This study aims to determine the risk factors associated with glycaemic control of ambulatory patients with type 2 diabetes mellitus (T2DM) who are managed in primary care.The data was retrieved from a primary care site within the Singapore Consortium of Cohort Studies-Diabetes Cohort (SCCS-DC). Demographic and clinical variables were described, in association with the risk of having a deteriorating glycaemic control (defined as an absolute increase of at least 1% HbA1c from one year to a subsequent year). Next, multivariate model was performed to define the independent effect of each factor. The longitudinal analysis of the HbA1c was performed using Generalised Estimating Equation (GEE).The 5 year longitudinal data of 1256 patients (54% Chinese, 25% Malays, 12% Indians, 9% others) were analysed. Their mean HbA1c decreased by0.1% in the initial 3 years, but increased thereafter. 12% of them had absolute HbA1c increment of ≥1% in the first year, and 22% over 5 years. Based on GEE analysis, insulin, was associated with an increase of HbA1c (≥1%) from one year to another (all p0.05). Compared with Chinese patients, Malays had higher HbA1c (+0.3%), Indians (+0.3%), and others (+0.2%), (all p0.01). Patients with retinopathy had higher HbA1c (+0.2%) and those with cataract had lower mean HbA1c (-0.2%) (p0.01).Most cohort patients achieved glycaemic control within the initial 3 years. Patients of Malay and Indian ethnicity and those with retinopathy were associated with subsequent risk of glycaemic control deterioration. Those with cataract were associated with trend towards improved glycaemic control.

There has been limited success in identifying causal variants underlying association signals observed in genome-wide association studies (GWAS). The use of 1000 Genomes Project (1KGP) allows the imputation to estimate the genetic information at untyped variants. However, long stretches of high linkage disequilibrium within the genome prevent us from differentiating between causal variants and perfect surrogates, thus limiting our ability to identify causal variants. Transethnic strategies have been proposed as a possible solution to mitigate this. However, these studies generally rely on imputing genotypes from multiple ancestries from 1KGP but not against population-specific reference panels. Here, we perform the first transethnic fine-mapping study across three Asian cohorts from diverse ancestries at the loci implicated with eye and blood lipid traits, using population-specific reference panels that have been generated by whole-genome sequencing samples from the same ancestry groups. Our study outlines several challenges faced in a fine-mapping exercise where one simply aims to meta-analyse existing GWAS that have been imputed against reference haplotypes from the 1KGP.

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1. ispartof: Nature Genetics vol:47 issue:4 pages:373-80 ispartof: location:United States status: published

The Pittsburgh Sleep Quality Index (PSQI) is a widely used measure for assessing sleep impairment. Although it was developed as a unidimensional instrument, there is much debate that it contains multidimensional latent constructs. We examined the dimensionality of the underlying factor structure of PSQI in Singapore, a rapidly industrialising Asian country with multi-ethnicities representing the Chinese, Malays and Indians.The PSQI was administered through an interviewer-based questionnaire in two separate population-based cross-sectional surveys. An explanatory factor analysis (EFA) was first used to explore the underlying construct of the PSQI in both studies. Then, a confirmatory factor analysis (CFA) was conducted to evaluate an optimal factor model by comparing against other possible models identified in EFA.There are three correlated yet distinguishable factors that account for an individual's sleep experience from the same best-fit model obtained in both studies: perceived sleep quality, daily disturbances and sleep efficiency. Our three-factor structure of PSQI is superior to the originally intended unidimensional model. Our model also shows the best-fit indices when compared to the previously reported single-factor, two-factor and three-factor (by Cole et al.) models in a multi-ethnic Asian population.There is strong evidence that the PSQI contains a three-factor rather than a unidimensional structure in a multi-ethnic Asian population. Scoring the PSQI along their multidimensional perspectives may provide a more accurate understanding of the relationship between sleep impairment and health conditions rather than using a single global score.

Characterization of genetic alterations in tumor biopsies serves as useful biomarkers in prognosis and treatment management. Circulating tumor cells (CTCs) obtained non-invasively from peripheral blood could serve as a tumor proxy. Using a label-free CTC enrichment strategy that we have established, we aimed to develop sensitive assays for qualitative assessment of tumor genotype in patients. Blood consecutively obtained from 44 patients with local and advanced colorectal cancer and 18 healthy donors were enriched for CTCs using a size-based microsieve technology. To screen for CTC mutations, we established high-resolution melt (HRM) and allele-specific PCR (ASPCR) KRAS-codon 12/13- and BRAF-codon 600- specific assays, and compared the performance with pyrosequencing and Sanger sequencing. For each patient, the resulting CTC genotypes were compared with matched tumor and normal tissues. Both HRM and ASPCR could detect as low as 1.25% KRAS- or BRAF-mutant alleles. HRM detected 14/44 (31.8%) patients with KRAS mutation in CTCs and 5/44 (11.3%) patients having BRAF mutation in CTCs. ASPCR detected KRAS and BRAF mutations in CTCs of 10/44 (22.7%) and 1/44 (2.3%) patients respectively. There was an increased detection of mutation in blood using these two methods. Comparing tumor tissues and CTCs mutation status using HRM, we observed 84.1% concordance in KRAS genotype (p = 0.000129, Fishers' exact test; OR = 38.7, 95% CI = 4.05-369) and 90.9% (p = 0.174) concordance in BRAF genotype. Our results demonstrate that CTC enrichment, coupled with sensitive mutation detection methods, may allow rapid, sensitive and non-invasive assessment of tumor genotype.

Objective: To estimate the excess hospitalization expenses attributable to type 2 diabetes mellitus (T2DM) in a high-income Asian country from the health system perspective and the patient perspective. Methods: Electronic medical records from a tertiary academic hospital in Singapore from 2012 to 2013 were used to create propensity score–matched cohorts with and without T2DM on the basis of their entry characteristics. A two-part model was then used to control for remaining differences between the cohorts. Excess cost due to diabetes was defined as the difference in hospital expenses between a patient with diabetes and a matched patient without diabetes. As part of the sensitivity analysis, a two-part model without matching and different matching algorithms were used to obtain the range of hospitalization expenses attributable to patients with T2DM. Balance of covariates after matching was investigated. All costs were presented in 2013 US dollars. Results: Mean adjusted excess hospital expense of one hospital visit attributable to diabetes was approximately $1007 and $113 from the health system perspective and the patient perspective, respectively. For the cohort of patients with T2DM in Singapore, this amounts to a total average expenditure of $117 million and $13 million from the health system perspective and the patient perspective, respectively. Conclusions: Hospitalization expenses from diabetes result in a significant cost to the health care system in Singapore. Nevertheless, the excess burden of hospitalization on patients is mitigated significantly by cost sharing, which may reduce financial incentives to avert admissions through preventative care, which is largely out-of-pocket.

In line with the recent adoption of the Sustainable Development Goals, global health has grown increasingly relevant in Southeast Asia (SEA), with the proliferation of new actors and growing interest in global health issues. In SEA, Singapore has emerged as a developed nation with the capabilities and resources to be a powerful force of change for progress in global health. The aim of this paper is to explore the perceptions of global health actors in SEA on Singapore’s role and contributions to the global health landscape. Twenty-five semi-structured interviews were conducted with participants from the SEA region with global health expertise and experience. Key-informants were recruited from a range of international and local health institutions across public and private sectors. Thematic analysis was conducted to identify emergent themes. Findings suggest that Singapore is perceived as being successful in achieving the Millennium Development Goals (MDGs), in its progress in healthcare and in its ability to exercise good governance. Obstacles that hampered Singapore’s ability to do more in global health were linked to its pragmatic priorities focusing on domestic health. The findings suggest a myriad of ways in which Singapore can expand its role in health globally by leveraging the strength of its academic institutions, good structures of governance, and influence in the region. Such efforts are perceived to yield practical benefits in bolstering Singapore’s security, economy and foreign relations, while enabling the state to contribute towards more charitable goals in reducing the global burden of disease. Drawing on our findings and supporting literature, a more comprehensive multidisciplinary research project examining Singapore’s existing global health footprint in various sectors and its potential to contribute more in global health could be beneficial.

Background Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. Methods and findings We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35–85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (–0.46 cm [95% CI: −0.53, −0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was −0.24 cm (95% CI: −0.34, −0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (−0.38 cm [95% CI: −0.44, −0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. Conclusions Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction., Valerie McCormack and colleagues reveal reduced breast density with increased age in women from different ethnic groups; however increased breast density in young women is a cancer risk., Author summary Why was this study done? Breast density, a measure of the amount of dense to fatty tissue in the breast, is a strong marker of breast cancer risk. Breast density determinants have been studied in high-income countries, but not in women worldwide. What did the researchers do and find? We studied how breast density differed by age and menopausal status in diverse groups of women from 22 countries worldwide. For over 11,000 women, mammograms were read centrally and risk factor data harmonised. We found that, regardless of the country and ethnic group of women, breast density was much lower in postmenopausal than in premenopausal women of the same age. Additionally, as a relative proportion of breast area, breast density was lower in older women both among premenopausal and postmenopausal women. Among premenopausal women, breast density changed with age without an increase in breast area, but among postmenopausal women, the latter also increased. What do these findings mean? That this change in breast density with age is seen internationally suggests that the change is due to a universal biological mechanism inherent to all women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.

In response to a growing chronic disease burden and ageing population, Singapore implemented Regional Health Systems (RHS) in 2008. In January 2017, the MOH announced that the six RHS clusters would be reorganised into three in 2018. This qualitative study sought to identify the health system challenges, opportunities, and ways forward for the implementation of the RHS. We conducted semi-structured interviews with 35 key informants from RHS clusters, government, academia, and private and voluntary sectors. Integration, innovation, and people-centeredness were identified as the key principles of the RHS. The RHS was described as an opportunity to holistically care for a person across the care continuum, address social determinants of health, develop new models of care, and work with social and community partners. Challenges to RHS implementation included difficulties aligning the goals, values, and priorities of multiple actors, the need for better integration across clusters, differing care capabilities and capacities across partners, healthcare financing structures that may not reflect RHS goals, scalability and evaluation of pilot programmes, and disease-centricity, provider-centricity, and medicalisation in health and healthcare. Suggested ways forward included building relationships between actors to facilitate integration; exploring innovative new models of care; clear long-term/scale-up plans for successful pilots; healthcare financing reforms to meet changing patient and population needs; and developing evaluation systems reflective of RHS principles and priorities.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P

Differences in the frequency of pharmacogenomic variants may influence inter-population variability in drug efficacy and risk of adverse drug reactions (ADRs). We investigated the diversity of ∼ 4500 genetic variants in key drug-biotransformation and -response genes among three South East Asian populations compared with individuals of European ancestry. We compared rates of reported ADRs in these Asian populations to determine if the allelic differentiation corresponded to an excess of the associated ADR. We identified an excess of ADRs related to clopidogrel in Singaporean Chinese, consistent with a higher frequency of a known risk variant in CYP2C19 in that population. We also observed an excess of ADRs related to platinum compounds in Singaporean CHS, despite a very low frequency of known ADR risk variants, suggesting the presence of additional genetic and non-genetic risk factors. Our results point to substantial diversity at specific pharmacogenomic loci that may contribute to inter-population variability in drug response phenotypes.

OBJECTIVE To compare the prevalence of common medical conditions (including mental health and self-rated health) and lifestyle risk factors for disease of the Singapore workforce with the nonworking population, and evaluate the association of these factors with occupation class. METHODS Data were obtained from a population-representative cross-sectional survey in 2010. Adjusted prevalence ratios (PRs) were obtained by modified Breslow-Cox proportional hazards regression model. RESULTS Within the workforce, after adjustment for age, sex, and ethnicity, daily smoking (PR = 1.87; 95% confidence interval [CI], 1.40 to 2.51; P < 0.001), no regular exercise (PR = 1.13; 95% CI, 1.07 to 1.20; P < 0.001), and poor self-rated health (PR = 1.46, 95% CI, 1.22 to 1.76; P < 0.001) were more prevalent in the lower-skilled occupation classes. CONCLUSIONS Lower-skilled occupation classes in Singapore are associated with lifestyle risk factors, and tailored workplace health promotion programs addressing their specific health needs are needed.

The major histocompatibility complex (MHC) containing the classical human leukocyte antigen (HLA) Class I and Class II genes is among the most polymorphic and diverse regions in the human genome. Despite the clinical importance of identifying the HLA types, very few databases jointly characterize densely genotyped single nucleotide polymorphisms (SNPs) and HLA alleles in the same samples. To date, the HapMap presents the only public resource that provides a SNP reference panel for predicting HLA alleles, constructed with four collections of individuals of north-western European, northern Han Chinese, cosmopolitan Japanese and Yoruba Nigerian ancestry. Owing to complex patterns of linkage disequilibrium in this region, it is unclear whether the HapMap reference panels can be appropriately utilized for other populations. Here, we describe a public resource for the Singapore Genome Variation Project with: (i) dense genotyping across ∼ 9000 SNPs in the MHC; (ii) four-digit HLA typing for eight Class I and Class II loci, in 96 southern Han Chinese, 89 Southeast Asian Malays and 83 Tamil Indians. This resource provides population estimates of the frequencies of HLA alleles at these eight loci in the three population groups, particularly for HLA-DPA1 and HLA-DPB1 that were not assayed in HapMap. Comparing between population-specific reference panels and a cosmopolitan panel created from all four HapMap populations, we demonstrate that more accurate imputation is obtained with population-specific panels than with the cosmopolitan panel, especially for the Malays and Indians but even when imputing between northern and southern Han Chinese. As with SNP imputation, common HLA alleles were imputed with greater accuracy than low-frequency variants.

To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413

Introduction: Genetic factors affecting warfarin maintenance dose have been well established, but patient acceptance is a necessary consideration for the successful clinical implementation of warfarin pharmacogenetic testing (WPGT). In this study, we aimed to determine the attitudes toward WPGT among Singaporean Chinese.Methods: A total of 194 warfarin patients and 187 members of the public completed a structured survey on paper and the Internet, respectively. Attitudes were expressed as willingness to undergo WPGT (single item with 5-point response) and expectations and concerns about WPGT (two multi-item scales). Relationships between attitudes and socio-demographic and clinical variables were explored using Fisher's exact test, Student's t-test, one-way analysis of variance or Pearson's correlation.Results: Majority of respondents were willing to or neutral about undergoing WPGT. Both patients and public had relatively high expectations (mean [SD]: 3.77 [0.63], and 3.97 [0.55], respectively) and moderately high concerns (mean [SD]: 3.30 [0.69] and 3.33 [0.68], respectively) about WPGT. Willingness to undergo WPGT was associated with gender, educational status, length of warfarin treatment, and number of chronic diseases among warfarin patients, and with history of adverse drug reactions and number of chronic diseases among the public. Higher expectation of WPGT was associated with higher willingness (p < .001 in both populations), while higher concern was associated with lower willingness to undergo WPGT among the public (p = .004) but not among patients (p = .072).Conclusion: Patient acceptance is not a major barrier to clinical implementation of WPGT but patient education is necessary and the ethical, social, and legal issues should be addressed.

Introduction: Type 2 Diabetes Mellitus (T2DM) is a growing problem in England, with approximately 3.1 million (6.7%) people living with T2DM and a further 5 million at high risk of developing T2DM as of 2017. England’s National Health Service is undergoing rapid transformation aimed at improving population health through multi-sectoral partnerships to align and integrate needs, priorities, and goals across healthcare, public health, prevention, and social care. This qualitative study sought to understand the impact of healthcare transformation on T2DM prevention and care in England. Theory and Methods: This study is underpinned by the understanding that health systems are complex adaptive systems characterised by continuing self-organisation, non-linear interactions, interdependent and dynamic relationships, and multiple feedback loops. With this in mind, we conducted 38 semi-structured in-depth interviews with 11 persons with T2DM (PWDs), 14 healthcare professionals/providers (HCPs), and 13 health policymakers/decision-makers (PDMs). Participants were purposively and snowball sampled. We conducted thematic analysis in QSR NVIVO11 to inductively identify themes and subthemes from the data, drawing on grounded theory techniques including line-by-line analysis and the constant comparative method. Results: Three key themes emerged. All interviewees (across PWDs, HCPs, and PDMs) emphasised the urgency of England’s growing T2DM burden and its contributors, including obesity, socio-economic deprivation, and unhealthy food environments, as a key driver of transformation. Increased awareness of T2DM at population-level was mentioned as a parallel development. Additionally, participants highlighted how a person-centred, holistic approach is crucial to the transformation of T2DM prevention and care. Within this theme, each interviewee group highlighted contrasting, yet overlapping, subthemes. PWDs noted their preferences for empathetic, joined-up care that considers their cultural and ethnic differences and backgrounds. HCPs described shared care planning, cultivating patient-provider relationships, and multidisciplinary teams as characteristics of high-quality, holistic care provision. PDMs pointed to population-level needs driving development of policies and initiatives to tackle T2DM, especially in health and social care integration. Participants also identified system-level barriers to transformation and integration. Participants across all groups reported funding and human resource limitations as key challenges impacting the care continuum, from primary prevention to acute hospital-based care. PWDs observed that the health system, especially primary care, was under strain as a result. HCPs explained how organisational and change management factors, namely strategic leadership and national and local priority-setting, were critical drivers of transformation. HCPs and PDMs noted the impact of factors outside the health system, particularly democratic cycles and political agendas, on sustainability and scalability of transformation efforts. Discussion: This study offers insights into the multi-layered factors that impact healthcare transformation on T2DM prevention and care in England. From a complex adaptive systems viewpoint, these factors span systems hardware (e.g. organisational restructuring, capital investments) and software (e.g. cultural shifts, clinical practice improvements), and bottlenecks to meaningful, sustainable transformation often occur at the nexus of the two (e.g. mindset and practice change aligned to strategic priorities and resource allocation). This study also demonstrates that the health system is an open system affected by a multitude of external factors, including inequality, structural environment, and socio-political climate.

Importance: Asia is home to the largest diabetic populations in the world. However, limited studies have quantified the association of diabetes with all-cause and cause-specific mortality in Asian populations. Objectives: To evaluate the association of diabetes with all-cause and cause-specific mortality in Asia and to investigate potential effect modifications of the diabetes-mortality associations by participants' age, sex, education level, body mass index, and smoking status. Design, Setting, and Participants: This pooled analysis incorporated individual participant data from 22 prospective cohort studies of the Asia Cohort Consortium conducted between 1963 and 2006. A total of 1 002 551 Asian individuals (from mainland China, Japan, South Korea, Singapore, Taiwan, India, and Bangladesh) were followed up for more than 3 years. Cohort-specific hazard ratios and 95% confidence intervals for all-cause and cause-specific mortality were estimated using Cox regression models and then pooled using random-effects meta-analysis. Analysis was conducted between January 10, 2018, and August 31, 2018. Exposures: Doctor-diagnosed diabetes, age, sex, education level, body mass index, and smoking status. Main Outcomes and Measures: All-cause and cause-specific mortality. Results: Of 1 002 551 participants (518 537 [51.7%] female; median [range] age, 54.0 [30.0-98.0] years), 148 868 deaths were ascertained during a median (range) follow-up of 12.6 (3.0-38.9) years. The overall prevalence of diabetes reported at baseline was 4.8% for men and 3.6% for women. Patients with diabetes had a 1.89-fold risk of all-cause death compared with patients without diabetes (hazard ratio [HR], 1.89; 95% CI, 1.74-2.04), with the highest relative risk of death due to diabetes itself (HR, 22.8; 95% CI, 18.5-28.1), followed by renal disease (HR, 3.08; 95% CI, 2.50-3.78), coronary heart disease (HR, 2.57; 95% CI, 2.19-3.02), and ischemic stroke (HR, 2.15; 95% CI, 1.85-2.51). The adverse diabetes-mortality associations were more evident among women (HR, 2.09; 95% CI, 1.89-2.32) than among men (HR, 1.74; 95% CI, 1.62-1.88) (P for interaction

Importance Understanding birth cohort–specific tobacco smoking patterns and their association with total and cause-specific mortality is important for projecting future deaths due to tobacco smoking across Asian populations. Objectives To assess secular trends of tobacco smoking by countries or regions and birth cohorts and evaluate the consequent mortality in Asian populations. Design, Setting, and Participants This pooled meta-analysis was based on individual participant data from 20 prospective cohort studies participating in the Asia Cohort Consortium. Between September 1, 2017, and March 31, 2018, a total of 1 002 258 Asian individuals 35 years or older were analyzed using Cox proportional hazards regression analysis and random-effects meta-analysis. The pooled results were presented for mainland China; Japan; Korea, Singapore, and Taiwan; and India. Exposures Tobacco use status, age at starting smoking, number of cigarettes smoked per day, and age at quitting smoking. Main Outcomes and Measures Country or region and birth cohort–specific mortality and the population attributable risk for deaths from all causes and from lung cancer. Results Of 1 002 258 participants (51.1% women and 48.9% men; mean [SD] age at baseline, 54.6 [10.4] years), 144 366 deaths (9158 deaths from lung cancer) were ascertained during a mean (SD) follow-up of 11.7 (5.3) years. Smoking prevalence for men steadily increased in China and India, whereas it plateaued in Japan and Korea, Singapore, and Taiwan. Among Asian male smokers, the mean age at starting smoking decreased in successive birth cohorts, while the mean number of cigarettes smoked per day increased. These changes were associated with an increasing relative risk of death in association with current smoking in successive birth cohorts of pre-1920, 1920s, and 1930 or later, with hazard ratios for all-cause mortality of 1.26 (95% CI, 1.17-1.37) for the pre-1920 birth cohort, 1.47 (95% CI, 1.35-1.61) for the 1920s birth cohort, and 1.70 (95% CI, 1.57-1.84) for the cohort born in 1930 or later. The hazard ratios for lung cancer mortality were 3.38 (95% CI, 2.25-5.07) for the pre-1920 birth cohort, 4.74 (95% CI, 3.56-6.32) for the 1920s birth cohort, and 4.80 (95% CI, 3.71-6.19) for the cohort born in 1930 or later. Tobacco smoking accounted for 12.5% (95% CI, 8.4%-16.3%) of all-cause mortality in the pre-1920 birth cohort, 21.1% (95% CI, 17.3%-24.9%) of all-cause mortality in the 1920s birth cohort, and 29.3% (95% CI, 26.0%-32.3%) of all-cause mortality for the cohort born in 1930 or later. Tobacco smoking among men accounted for 56.6% (95% CI, 44.7%-66.3%) of lung cancer mortality in the pre-1920 birth cohort, 66.6% (95% CI, 58.3%-73.5%) of lung cancer mortality in the 1920s birth cohort, and 68.4% (95% CI, 61.3%-74.4%) of lung cancer mortality for the cohort born in 1930 or later. For women, tobacco smoking patterns and lung cancer mortality varied substantially by countries and regions. Conclusions and Relevance In this study, mortality associated with tobacco smoking continued to increase among Asian men in recent birth cohorts, indicating that tobacco smoking will remain a major public health problem in most Asian countries in the coming decades. Implementing comprehensive tobacco-control programs is warranted to end the tobacco epidemic.

BACKGROUND: More women of fertile age are long-term survivors of cancer. However, population-based data on birth rates of female cancer survivors are rare. METHODS: A total of 42,691 women ≤ 45 years with a history of cancer were identified from the Swedish Multi-Generation Register and the Swedish Cancer Register, for whom relative birth rates were calculated as compared to the background population, ie, standardized birth ratios (SBRs). Independent factors associated with reduced birth rates among cancer survivors were estimated using Poisson modeling. RESULTS: Compared to the background population, cancer survivors were 27% less likely to give birth (SBR = 0.73, 95% confidence interval [CI] = 0.72-0.75). Large difference in SBRs existed by cancer site, with high SBRs for survivors of melanoma skin, thoracic, head and neck, and thyroid cancers, and low SBRs for reproductive, breast, brain and eye, and hematopoietic cancer survivors. Parity status at diagnosis affected fertility: women who already had a child at the time of diagnosis were less likely to give birth (SBR = 0.50, 95% CI = 0.48-0.53) than were nulliparous women (SBR = 0.87, 95% CI = 0.85-0.90). Multivariate analysis showed that cancer site (reproductive organs), age at onset of cancer (< 12 years), and parity status were all significant and independent predictors of a reduced probability of giving birth after diagnosis. CONCLUSIONS: Cancer survivors are less likely to give birth compared with the background population. Large variations in the likelihood to give birth after diagnosis were seen according to age at onset, cancer site, and parity status at diagnosis. Cancer 2013. © 2013 American Cancer Society.

Asia is experiencing a type 2 diabetes epidemic, but prevalence differs by ethnicity and level of socioeconomic development. Singapore and Mauritius have implemented comprehensive campaigns to address this public health problem. We compared diabetes and obesity prevalence trends among Chinese and South Asians living in Singapore and Mauritius to determine the contribution of ethnicity and economic development to diabetes.Age-specific data from serial national population-based surveys in Singapore and Mauritius between 1987 and 2010 were used to estimate age-standardized diabetes and obesity prevalence. Modified Breslow-Cox proportional hazard models were used to obtain rate ratios for diabetes risk factors.In Singapore, the age-standardized prevalence of diabetes remained stable for Chinese (men: 14% in 1992, 13% in 2010; women: 12% in 1992, 10% in 2010), but increases were observed for South Asians (men: 20% in 1992, 26% in 2010; women: 18% in 1992, 20% in 2010). There were similar patterns in Mauritius. In both countries, obesity prevalence trends were stable for Chinese women, but increased for Chinese men and South Asians. Associations between obesity and diabetes were stronger in Chinese than South Asians regardless of country.Despite different socioeconomic settings in Singapore and Mauritius, we observed rising diabetes prevalence among South Asians but stable prevalence in Chinese in both countries. This provides further evidence that ethnicity contributes to the development of diabetes, and that there should be an increased emphasis on future prevention strategies targeting South Asian populations in these countries.

The last three decades have witnessed an epidemic rise in the number of people with diabetes, especially type 2 diabetes, and particularly in developing countries, where more than 80% of the people with diabetes live. The rise of type 2 diabetes in South Asia is estimated to be more than 150% between 2000 and 2035. Although aging, urbanization, and associated lifestyle changes are the major determinants for the rapid increase, an adverse intrauterine environment and the resulting epigenetic changes could also contribute in many developing countries. The International Diabetes Federation estimated that there were 382 million people with diabetes in 2013, a number surpassing its earlier predictions. More than 60% of the people with diabetes live in Asia, with almost one-half in China and India combined. The Western Pacific, the world’s most populous region, has more than 138.2 million people with diabetes, and the number may rise to 201.8 million by 2035. The scenario poses huge social and economic problems to most nations in the region and could impede national and, indeed, global development. More action is required to understand the drivers of the epidemic to provide a rationale for prevention strategies to address the rising global public health “tsunami.” Unless drastic steps are taken through national prevention programs to curb the escalating trends in all of the countries, the social, economic, and health care challenges are likely to be insurmountable.

is Table S4 presenting mean differences in MD measures between processed images and the corresponding raw digital image, by percent density and breast area categories. (DOC 30 kb)

is Table S1 presenting percent density, dense area and total breast area in raw–processed image pairs and in SFM–processed digital image pairs, by reader. (DOC 33 kb)

is Table S3 presenting correlation of MD measures in inter-reader repeats. (DOC 29 kb)

is Information 1 showing calibration equations for the conversion of raw vDA to processed vDA, and Information 2 showing calibration equations for the conversion of processed vDA to raw vDA. (DOC 41 kb)

BACKGROUND: Inter-women and intra-women comparisons of mammographic density (MD) are needed in research, clinical and screening applications; however, MD measurements are influenced by mammography modality (screen film/digital) and digital image format (raw/processed). We aimed to examine differences in MD assessed on these image types. METHODS: We obtained 1294 pairs of images saved in both raw and processed formats from Hologic and General Electric (GE) direct digital systems and a Fuji computed radiography (CR) system, and 128 screen-film and processed CR-digital pairs from consecutive screening rounds. Four readers performed Cumulus-based MD measurements (n = 3441), with each image pair read by the same reader. Multi-level models of square-root percent MD were fitted, with a random intercept for woman, to estimate processed-raw MD differences. RESULTS: Breast area did not differ in processed images compared with that in raw images, but the percent MD was higher, due to a larger dense area (median 28.5 and 25.4 cm2 respectively, mean √dense area difference 0.44 cm (95% CI: 0.36, 0.52)). This difference in √dense area was significant for direct digital systems (Hologic 0.50 cm (95% CI: 0.39, 0.61), GE 0.56 cm (95% CI: 0.42, 0.69)) but not for Fuji CR (0.06 cm (95% CI: -0.10, 0.23)). Additionally, within each system, reader-specific differences varied in magnitude and direction (p, published_or_final_version

is Table S2 presenting mean MD measures of inter-reader repeats, by reader and image type. (DOC 29 kb)

is Figure S2 showing Bland–Altman plots for within-system and within-reader standardized vDA measures. (DOCX 79 kb)

is Figure S1 showing Bland–Altman plots for vMD measures, by mammography system and reader for: (A) percent mammographic density, (B) dense area and (C) breast area. Y axes to the same scale for comparisons. (DOCX 138 kb)

Motivation: Analysing next-generation sequencing (NGS) data for copy number variations (CNVs) detection is a relatively new and challenging field, with no accepted standard protocols or quality control measures so far. There are by now several algorithms developed for each of the four broad methods for CNV detection using NGS, namely the depth of coverage (DOC), read-pair, split-read and assembly-based methods. However, because of the complexity of the genome and the short read lengths from NGS technology, there are still many challenges associated with the analysis of NGS data for CNVs, no matter which method or algorithm is used. Results: In this review, we describe and discuss areas of potential biases in CNV detection for each of the four methods. In particular, we focus on issues pertaining to (i) mappability, (ii) GC-content bias, (iii) quality control measures of reads and (iv) difficulty in identifying duplications. To gain insights to some of the issues discussed, we also download real data from the 1000 Genomes Project and analyse its DOC data. We show examples of how reads in repeated regions can affect CNV detection, demonstrate current GC-correction algorithms, investigate sensitivity of DOC algorithm before and after quality control of reads and discuss reasons for which duplications are harder to detect than deletions. Contact: g0801862@nus.edu.sg or agus_salim@nuhs.edu.sg Supplementary information: Supplementary data are available at Bioinformatics online.

Background: The aims of the present study were to estimate the rate of progression from newly diagnosed impaired fasting glycemia (IFG) to type 2 diabetes mellitus (T2DM) in Singapore and to identify factors associated with the progression to T2DM in individuals with newly diagnosed IFG. Methods: The present study was a retrospective cohort study of newly diagnosed IFG from the National Healthcare Group Diabetes Registry between 1 January 2006 and 31 December 2007 to estimated the rate of progression to T2DM. Univariate survival analysis, followed by multivariate survival analysis, was performed and interactions were tested in the final model. Results: Over a mean follow-up period of 1.65 ± 0.13 years, 85 of 490 participants with newly diagnosed IFG developed T2DM, giving an annual progression rate of 6.8%. The factors associated with the development of T2DM were higher fasting plasma glucose level in the year of IFG diagnosis (hazard ratio [HR] = 14.6; 95% confidence interval [CI] 5.66–37.5), Chinese race (HR = 2.70; 95% CI 1.44–5.06), and body mass index (HR = 1.11; 95% CI, 1.06–1.15). Conclusions: The progression rate to T2DM is high in subjects with newly diagnosed IFG. Intensive lifestyle modification can be incorporated into their current yearly follow-up to prevent progression to T2DM, which is a growing problem in Singapore.

Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk. The population-based epidemiology of MD has revealed genetic, lifestyle and societal/environmental determinants, but studies have largely been conducted in women with similar westernized lifestyles living in countries with high breast cancer incidence rates. To benefit from the heterogeneity in risk factors and their combinations worldwide, we created an International Consortium on Mammographic Density (ICMD) to pool individual-level epidemiological and MD data from general population studies worldwide. ICMD aims to characterize determinants of MD more precisely, and to evaluate whether they are consistent across populations worldwide. We included 11755 women, from 27 studies in 22 countries, on whom individual-level risk factor data were pooled and original mammographic images were re-read for ICMD by a core team to obtain standardized comparable MD data. In the present article, we present (i) the rationale for this consortium; (ii) characteristics of the studies and women included; and (iii) study methodology to obtain comparable MD data from original re-read films. We also highlight the risk factor heterogeneity captured by such an effort and, thus, the unique insight the pooled study promises to offer through wider exposure ranges, different confounding structures and enhanced power for sub-group analyses.

The genomes of outbred populations were first shown in 2006 to contain regions of homozygosity (ROHs) of several megabases. Further studies have also investigated the characteristics of ROHs in healthy individuals in various populations but there are no studies on Singapore populations to date. This study aims to identify and investigate the characteristics of ROHs in three Singapore populations. A total of 268 samples (96 Chinese, 89 Malays and 83 Indians) are genotyped on Illumina Human 1 M Beadchip and Affymetrix Genome-Wide Human SNP Array 6.0. We use the PennCNV algorithm to detect ROHs. We report an abundance of ROHs (≥500 kb), with an average of more than one hundred regions per individual. On average, the Indian population has the lowest number of ROHs and smallest total length of ROHs per individual compared with the Chinese and Malay populations. We further investigate the relationship between the occurrence of ROHs and haplotype frequency, regional linkage disequilibrium (LD) and positive selection. Based on the results of this data set, we find that the frequency of occurrence of ROHs is positively associated with haplotype frequency and regional LD. The majority of regions detected for recent positive selection and regions with differential LD between populations overlap with the ROH loci. When we consider both the location of the ROHs and the allelic form of the ROHs, we are able to separate the populations by principal component analysis, demonstrating that ROHs contain information on population structure and the demographic history of a population.

Genome-wide association studies (GWAS) have become the preferred experimental design in exploring the genetic etiology of complex human traits and diseases. Standard SNP-based meta-analytic approaches have been utilized to integrate the results from multiple experiments. This fundamentally assumes that the patterns of linkage disequilibrium (LD) between the underlying causal variants and the directly genotyped SNPs are similar across the populations for the same SNPs to emerge with surrogate evidence of disease association. We introduce a novel strategy for assessing regional evidence of phenotypic association that explicitly incorporates the extent of LD in the region. This provides a natural framework for combining evidence from multi-ethnic studies of both dichotomous and quantitative traits that (i) accommodates different patterns of LD, (ii) integrates different genotyping platforms and (iii) allows for the presence of allelic heterogeneity between the populations. Our method can also be generalized to perform gene-based or pathway-based analyses. Applying this method on real GWAS data in type 2 diabetes (T2D) boosted the association evidence in regions well-established for T2D etiology in three diverse South-East Asian populations, as well as identified two novel gene regions and a biologically convincing pathway that are subsequently validated with data from the Wellcome Trust Case Control Consortium.

Children diagnosed with noncentral nervous system solid cancers (NCNSSC) experience several adverse late effects, including second malignant neoplasm. The aim of our study was to assess the risk of specific second malignancies after a childhood NCNSSC. Diagnosis and follow-up data on 10,988 cases of NCNSSC in children (0-14 years) were obtained from 13 registries. Standardized incidence ratios (SIRs) with 95% confidence intervals (CI) and cumulative incidence of second malignancies were computed. We observed 175 second malignant neoplasms, yielding a SIR of 4.6, 95% CI: 3.9-5.3. When considering second cancers with at least 10 occurrences, highest relative risks were found for second malignant bone tumors (SIR = 26.4, 16.6-40.0), soft tissue sarcomas (SIR = 14.1, 6.7-25.8) and myeloid leukemia (SIR = 12.7, 6.3-22.8). Significant increased risks for all malignancies combined were observed after sympathetic nervous system tumors (SIR = 11.4, 5.2-21.6), retinoblastomas (SIR = 7.3, 5.4-9.8), renal tumors (SIR = 5.7, 3.8-8.0), malignant bone tumors (SIR = 5.6, 3.7-8.2), soft tissue sarcomas (SIR = 4.7, 3.2-6.8), germ-cell, trophoblastic and other gonadal neoplasms (SIR = 2.5, 1.1-4.9), carcinomas and other malignant epithelial neoplasms (SIR = 2.2, 1.4-3.3). The highest risk of a second malignancy of any type occurred 5 to 9 years after NCNSSC (SIR = 9.9, 6.8-13.9). The cumulative incidence of second malignancies 10 years after the first neoplasm was eight times higher among NCNSSC survivors than in the general population, with the absolute difference between observed and expected cumulative incidence still increasing after 50 years of follow-up. Children who survived a NCNSSC experience a large increased risk of developing a new malignancy, even many years after their initial diagnosis. Copyright © 2011 UICC.

Corneal curvature (CC) is a key determinant of major eye diseases, such as keratoconus, myopia and corneal astigmatism. No prior studies have discovered the genes for CC. Here we report the findings from four genome-wide association studies of CC in 10 008 samples from three population groups in Singapore. Our discovery phase surveyed 2867 Chinese and 3072 Malays, allowing us to identify two loci that were associated with CC variation: FRAP1 on chromosome 1p36.2 and PDGFRA on chromosome 4q12. These findings were subsequently replicated in a validation study involving an additional 2953 Asian Indians and a further collection of 1116 Chinese children. The effect sizes of the identified variants were consistent across all four cohorts, with seven single nucleotide polymorphisms (SNPs) in FRAP1 (lead SNP: rs17036350, meta P-value = 4.06 × 10(-13)) and six SNPs in PDGFRA (lead SNP: rs2114039, meta P-value = 1.33 × 10(-9)) attaining genome-wide significance in the SNP-based meta-analysis of the four studies. This is the first genome-wide survey of CC variation and we have identified two implicated loci in three genetically diverse Asian populations, suggesting the presence of common genetic etiology across multiple populations.

The abundance of copy number variants (CNVs) and regions of homozygosity (ROHs) have been well documented in previous studies. In addition, their roles in complex diseases and traits have since been increasingly appreciated. However, only a limited amount of CNV and ROH data is currently available for the Swedish population. We conducted a population-based study to detect and characterize CNVs and ROHs in 87 randomly selected healthy Swedish individuals using the Affymetrix SNP Array 6.0. More than 600 CNV loci were detected in the population using two different CNV-detection algorithms (PennCNV and Birdsuite). A total of 196 loci were consistently identified by both algorithms, suggesting their reliability. Numerous disease-associated and pharmacogenetics-related genes were found to be overlapping with common CNV loci such as CFHR1/R3, LCE3B/3C, UGT2B17 and GSTT1. Correlation analysis between copy number polymorphisms (CNPs) and genome-wide association studies-identified single-nucleotide polymorphisms also indicates the potential roles of several CNPs as causal variants for diseases and traits such as body mass index, Crohn's disease and multiple sclerosis. In addition, we also identified a total of 14 815 ROHs 500 kb or 2814 ROHs 1M in the Swedish individuals with an average of 170 and 32 regions detected per individual respectively. Approximately 141 Mb or 4.92% of the genome is homozygous in each individual of the Swedish population. This is the first population-based study to investigate the population characteristics of CNVs and ROHs in the Swedish population. This study found many CNV loci that warrant further investigation, and also highlighted the abundance and importance of investigating ROHs for their associations with complex diseases and traits.

Motivation: With the expansion of whole-genome studies, there is rapid evolution of genotyping platforms. This leads to practical issues such as upgrading of genotyping equipment which often results in research groups having data from different platforms for the same samples. While having more data can potentially yield more accurate copy-number estimates, combining such data is not straightforward as different platforms show different degrees of attenuation of the true copy-number or different noise characteristics and marker panels. Currently, there is still a relative lack of procedures for combining information from different platforms. Results: We develop a method, called MPSS, based on a correlated random-effect model for the unobserved patterns and extend the robust smooth segmentation approach to the multiple-platform scenario. We also propose an objective criterion for discrete segmentation required for downstream analyses. For each identified segment, the software reports a P-value to indicate the likelihood of the segment being a true CNV. From the analyses of real and simulated data, we show that MPSS has better operating characteristics when compared to single-platform methods, and have substantially higher sensitivity compared to an existing multiplatform method. Availability: The methods are implemented in an R package MPSS, and the source is available from http://www.meb.ki.se/~yudpaw. Contact: agus_salim@nuhs.edu.sg Supplementary Information: Supplementary data are available at Bioinformatics online.

Genetic markers displaying highly significant statistical associations with complex phenotypes may not necessarily possess sufficient clinical validity to be useful. Understanding the contribution of these markers beyond readily available clinical biomarkers is particularly important in pharmacogenetics. We demonstrate the utility of genetic testing using the example of warfarin in a multi-ethnic setting comprising of three Asian populations that are broadly representative of the genetic diversity for half of the population in the world, especially as distinct interethnic differences in warfarin dose requirements have been previously established. We confirmed the roles of three well-established loci (CYP2C9, VKORC1 and CYP4F2) in explaining warfarin dosage variation in the three Asian populations. In addition, we assessed the relationship between ethnicity and the genotypes of these loci, observing strong correlations at VKORC1 and CYP4F2. Subsequently, we established the additional utility of these genetic factors in predicting warfarin dose beyond ethnicity and clinical biomarkers through performing a series of systematic cross-validation analyses of the relative predictive accuracies of various fixed-dose regimen, clinical and genetic models. Through a pharmacogenetics model for warfarin, we show the importance of genetic testing beyond readily available clinical biomarkers in predicting dose requirements, confirming the role of genetic profiling in personalized medicine.