Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

Diabetes mortality: trends and multi-country analysis of the Americas from 2000 to 2019.

BACKGROUND: Diabetes has been increasing worldwide and is now among the 10 leading causes of death globally. Diabetic kidney disease (DKD), a complication of poorly managed diabetes, is related to high mortality risk. To better understand the situation in the Americas region, we evaluated diabetes and DKD mortality trends over the past 20 years. METHODS: We analysed diabetes and DKD mortality for 33 countries in the Americas from 2000 to 2019. Data were extracted from the World Health Organization (WHO) Global Health Estimates and the World Population Prospects, 2019 Revision, estimating annual age-standardized mortality rates (ASMR) and gaps in the distribution of diabetes and DKD mortality by sex and country. Trend analyses were based on the annual average percentage of change (AAPC). RESULTS: From 2000 to 2019, the overall mortality trend from diabetes in the Americas remained stable [AAPC: -0.2% (95% CI: -0.4%-0.0%]; however, it showed important differences by sex and by country over time. By contrast, DKD mortality increased 1.5% (1.3%-1.6%) per year, rising faster in men than women, with differences between countries. Central America, Mexico and the Latin Caribbean showed significant increases in mortality for both diseases, especially DKD. In contrast in North America, diabetes mortality decreased whereas DKD mortality increased. CONCLUSIONS: The increase in DKD mortality is evidence of poorly controlled diabetes in the region. The lack of programmes on prevention of complications, self-care management and gaps in quality health care may explain this trend and highlight the urgent need to build more robust health systems based on primary care, prioritizing diabetes prevention and control.

Multimorbidity and social determinants of health in the US prior to the COVID-19 pandemic and implications for health outcomes: a cross-sectional analysis based on NHANES 2017-2018.

Multimorbidity increases the risk of all-cause mortality, and along with age, is an independent risk factor for severe disease and mortality from COVID-19. Inequities in the social determinants of health contributed to increased mortality from COVID-19 among disadvantaged populations. This study aimed to evaluate the prevalence of multimorbid conditions and associations with the social determinants of health in the US prior to the pandemic.Methods Data from the 2017-18 cycle of NHANES were used to determine the prevalence of 13 chronic conditions, and the prevalence of having 0, 1, or 2 or more of those conditions, among the US adult population aged ≥ 20 years. Multimorbidity was defined as having 2 or more of these conditions. Data were stratified according to demographic, socioeconomic and indicators of health access, and analyses including logistic regression, performed to determine the factors associated with multimorbidity.Results The prevalence of multimorbidity was 58.4% (95% CI 55.2 to 61.7). Multimorbidity was strongly associated with age and was highly prevalent among those aged 20-29 years at 22.2% (95% CI 16.9 to 27.6) and continued to increase with older age. The prevalence of multimorbidity was highest in those defined as Other or multiple races (66.9%), followed in decreasing frequency by rates among non-Hispanic Whites (61.2%), non-Hispanic Blacks (57.4%), Hispanic (52.0%) and Asian (41.3%) groups.Logistic regression showed a statistically significant relationship between multimorbidity and age, as expected. Asian race was associated with a reduced likelihood of 2 or more chronic conditions (OR 0.4; 95% CI 0.35 to 0.57; P < 0.0001). Socioeconomic factors were related to multimorbidity. Being above the poverty level (OR 0.64; 95% CI 0.46 to 0.91, p = 0.013); and a lack of regular access to health care (OR 0.61 (95% CI 0.42 to 0.88, p = 0.008) were both associated with a reduced likelihood of multimorbidity. Furthermore, there was a borderline association between not having health insurance and reduced likelihood of multimorbidity (OR 0.63; 95% CI 0.40 to 1.0; p = 0.053).Conclusions There are high levels of multimorbidity in the US adult population, evident from young adulthood and increasing with age. Cardiometabolic causes of multimorbidity were highly prevalent, especially obesity, hyperlipidemia, hypertension, and diabetes; conditions subsequently found to be associated with severe disease and death from COVID-19. A lack of access to care was paradoxically associated with reduced likelihood of comorbidity, likely linked to underdiagnosis of chronic conditions. Obesity, poverty, and lack of access to healthcare are factors related to multimorbidity and were also relevant to the health impact of the COVID-19 pandemic, that must be addressed through comprehensive social and public policy measures. More research is needed on the etiology and determinants of multimorbidity, on those affected, patterns of co-morbidity, and implications for individual health and impact on health systems and society to promote optimal outcomes. Comprehensive public health policies are needed to tackle multimorbidity and reduce disparities in the social determinants of health, as well as to provide universal access to healthcare.

The rising burden of non-communicable diseases in the Americas and the impact of population aging: a secondary analysis of available data.

Background: Public health progress in the Americas has reduced the burden of many infectious diseases, helping more people live longer lives. At the same time, the burden of non-communicable diseases (NCDs) is increasing. NCD prevention rightly focuses on lifestyle risk factors, social, and economic determinants of health. There is less published information on the importance of population growth and aging to the regional NCD burden. Methods: For 33 countries in the Americas, we used United Nations population data to describe rates of population growth and aging over two generations (1980-2060). We used World Health Organization estimates of mortality and disability (disability-adjusted life years, DALYs) to describe changes in the NCD burden between 2000 and 2019. After combining these data resources, we decomposed the change in the number of deaths and DALYs to estimate the percentage change due to population growth, due to population aging, and due to epidemiological advances, measured by changing mortality and DALY rates. In a supplement, we provide a summary briefing for each country. Findings: In 1980, the proportion of the regional population aged 70 and older was 4.6%. It rose to 7.8% by 2020 and is predicted to rise to 17.4% by 2060. Across the Americas, DALY rate reductions would have decreased the number of DALYs by 18% between 2000 and 2019 but was offset by a 28% increase due to population aging and a 22% increase due to population growth. Although the region enjoyed widespread reductions in rates of disability, these improvements have not been sufficiently large to offset the pressures of population growth and population aging. Interpretation: The region of the Americas is aging and the pace of this aging is predicted to increase. The demographic realities of population growth and population aging should be factored into healthcare planning, to understand their implications for the future NCD burden, the health system needs, and the readiness of governments and communities to respond to those needs. Funding: This work was funded in part by the Pan American Health Organization, Department of Noncommunicable Diseases and Mental Health.

COVID-19 and inequities in the Americas: lessons learned and implications for essential health services

[ABSTRACT]. The COVID-19 pandemic has exacerbated social, economic, and health-related disparities, which disproportionately affect persons living in conditions of vulnerability. Such populations include ethnic groups who face discrimination and experience barriers to accessing comprehensive health care. The COVID-19 pandemic has exposed these health disparities, and disruptions of essential health services have further widened the gaps in access to health care. Noncommunicable diseases are more prevalent among groups most impacted by poor social determinants of health and have been associated with an increased likelihood of severe COVID-19 disease and higher mortality. Disruptions in the provision of essential health services for noncommunicable diseases, mental health, communicable diseases such as HIV, tuberculosis, and malaria, and maternal and child health services (including sexual and reproductive health), are projected to also increase poor health outcomes. Other challenges have been an increased frequency of interpersonal violence and food insecurity. Countries in the Americas have responded to the disruptions caused by the pandemic by means of health service delivery through telemedicine and other digital solutions and stepping up social service support interventions. As vaccinations for COVID-19 create the opportunity to overcome the pandemic, countries must strengthen primary health care and essential health services with a view to ensuring equity, if the region is to achieve universal health coverage in fulfillment of the Sustainable Development Goals.

[RESUMEN]. La pandemia de COVID-19 ha acentuado las desigualdades sociales, económicas y relacionadas con la salud, que afectan desproporcionadamente a las personas en situación de vulnerabilidad. Esta población incluye grupos étnicos que se enfrentan a la discriminación y obstáculos para el acceso a la atención integral de salud. La pandemia de COVID-19 ha expuesto estas desigualdades de salud, y las interrupciones de los servicios esenciales de salud han ampliado aún más las brechas en el acceso a la atención de salud. Las enfermedades no transmisibles son más prevalentes en los grupos que han sufrido un mayor impacto de los determinantes sociales de la salud deficientes y se han asociado con una mayor probabilidad de presentar un cuadro grave de COVID-19 y una mayor mortalidad. Asimismo, se proyecta que las interrupciones en la prestación de servicios esenciales de salud para las enfermedades no transmisibles, la salud mental, las enfermedades transmisibles como la infección por el VIH, la tuberculosis y la malaria, y los servicios de salud maternoinfantil (como la salud sexual y reproductiva) incrementen los resultados deficientes en materia de salud. Otros retos son una mayor frecuencia de la violencia interpersonal y la inseguridad alimentaria. Los países de la Región de las Américas han respondido a las interrupciones causadas por la pandemia con la prestación de servicios de salud mediante la telemedicina y otras soluciones digitales, y la aceleración de las intervenciones de apoyo de los servicios sociales. A medida que la vacunación contra la COVID-19 crea la oportunidad de superar la pandemia, los países deben fortalecer su atención primaria de salud y sus servicios de salud esenciales a fin de garantizar la equidad, para que la Región logre la cobertura universal de salud en cumplimiento de los Objetivos de Desarrollo Sostenible.

[RESUMO]. A pandemia de COVID-19 exacerbou as disparidades sociais, econômicas e as relacionadas à saúde, que afetam de maneira desproporcional as pessoas que vivem em situação de vulnerabilidade. Essas populações incluem grupos étnicos que enfrentam discriminação e barreiras para o acesso à atenção integral à saúde. A pandemia de COVID-19 expôs essas disparidades, e as interrupções nos serviços essenciais de saúde ampliaram ainda mais as lacunas no acesso aos cuidados de saúde. As doenças não transmissíveis são mais prevalentes entre os grupos mais afetados por determinantes sociais da saúde deficientes e estão associadas a um aumento na probabilidade de doença grave pela COVID-19 e mortalidade mais elevada. Prevê-se que as interrupções na prestação de serviços essenciais de saúde para doenças não transmissíveis, saúde mental, doenças transmissíveis como HIV, tuberculose e malária, bem como dos serviços de saúde materno-infantil (incluindo saúde sexual e reprodutiva) também aumentem os desfechos adversos de saúde. Outros desafios são o aumento da frequência da violência interpessoal e insegurança alimentar. Os países das Américas responderam às interrupções causadas pela pandemia com a prestação de serviços de saúde por meio da telemedicina e outras soluções digitais, e a aceleração de intervenções de apoio dos serviços sociais. À medida em que a vacinação contra a COVID-19 oferece a oportunidade de superar a pandemia, os países devem fortalecer a atenção primária à saúde e os serviços essenciais de saúde com o objetivo de garantir a equidade, para que a região atinja a cobertura universal de saúde em cumprimento aos Objetivos de Desenvolvimento Sustentável.

Anthropometric cut-offs to identify hyperglycemia in an Afro-Caribbean population: a cross-sectional population-based study from Barbados.

INTRODUCTION: Body mass index (BMI) and waist circumference (WC) cut-offs associated with hyperglycemia may differ by ethnicity. We investigated the optimal BMI and WC cut-offs for identifying hyperglycemia in the predominantly Afro-Caribbean population of Barbados. RESEARCH DESIGN AND METHODS: A cross-sectional study of 865 individuals aged ≥25 years without known diabetes or cardiovascular disease was conducted. Hyperglycemia was defined as fasting plasma glucose ≥5.6 mmol/L or hemoglobin A1c ≥5.7% (39 mmol/mol). The Youden index was used to identify the optimal cut-offs from the receiver operating characteristic (ROC) curves. Further ROC analysis and multivariable log binomial regression were used to compare standard and data-derived cut-offs. RESULTS: The prevalence of hyperglycemia was 58.9% (95% CI 54.7% to 63.0%). In women, optimal BMI and WC cut-offs (27 kg/m2 and 87 cm, respectively) performed similarly to standard cut-offs. In men, sensitivities of the optimal cut-offs of BMI ≥24 kg/m2 (72.0%) and WC ≥86 cm (74.0%) were higher than those for standard BMI and WC obesity cut-offs (30.0% and 25%-46%, respectively), although with lower specificity. Hyperglycemia was 70% higher in men above the data-derived WC cut-off (prevalence ratio 95% CI 1.2 to 2.3). CONCLUSIONS: While BMI and WC cut-offs in Afro-Caribbean women approximate international standards, our findings, consistent with other studies, suggest lowering cut-offs in men may be warranted to improve detection of hyperglycemia. Our findings do, however, require replication in a new data set.

COVID-19 and inequities in the Americas: lessons learned and implications for essential health services.

The COVID-19 pandemic has exacerbated social, economic, and health-related disparities, which disproportionately affect persons living in conditions of vulnerability. Such populations include ethnic groups who face discrimination and experience barriers to accessing comprehensive health care. The COVID-19 pandemic has exposed these health disparities, and disruptions of essential health services have further widened the gaps in access to health care. Noncommunicable diseases are more prevalent among groups most impacted by poor social determinants of health and have been associated with an increased likelihood of severe COVID-19 disease and higher mortality. Disruptions in the provision of essential health services for noncommunicable diseases, mental health, communicable diseases such as HIV, tuberculosis, and malaria, and maternal and child health services (including sexual and reproductive health), are projected to also increase poor health outcomes. Other challenges have been an increased frequency of interpersonal violence and food insecurity. Countries in the Americas have responded to the disruptions caused by the pandemic by means of health service delivery through telemedicine and other digital solutions and stepping up social service support interventions. As vaccinations for COVID-19 create the opportunity to overcome the pandemic, countries must strengthen primary health care and essential health services with a view to ensuring equity, if the region is to achieve universal health coverage in fulfillment of the Sustainable Development Goals.

La pandemia de COVID-19 ha acentuado las desigualdades sociales, económicas y relacionadas con la salud, que afectan desproporcionadamente a las personas en situación de vulnerabilidad. Esta población incluye grupos étnicos que se enfrentan a la discriminación y obstáculos para el acceso a la atención integral de salud. La pandemia de COVID-19 ha expuesto estas desigualdades de salud, y las interrupciones de los servicios esenciales de salud han ampliado aún más las brechas en el acceso a la atención de salud. Las enfermedades no transmisibles son más prevalentes en los grupos que han sufrido un mayor impacto de los determinantes sociales de la salud deficientes y se han asociado con una mayor probabilidad de presentar un cuadro grave de COVID-19 y una mayor mortalidad. Asimismo, se proyecta que las interrupciones en la prestación de servicios esenciales de salud para las enfermedades no transmisibles, la salud mental, las enfermedades transmisibles como la infección por el VIH, la tuberculosis y la malaria, y los servicios de salud maternoinfantil (como la salud sexual y reproductiva) incrementen los resultados deficientes en materia de salud. Otros retos son una mayor frecuencia de la violencia interpersonal y la inseguridad alimentaria. Los países de la Región de las Américas han respondido a las interrupciones causadas por la pandemia con la prestación de servicios de salud mediante la telemedicina y otras soluciones digitales, y la aceleración de las intervenciones de apoyo de los servicios sociales. A medida que la vacunación contra la COVID-19 crea la oportunidad de superar la pandemia, los países deben fortalecer su atención primaria de salud y sus servicios de salud esenciales a fin de garantizar la equidad, para que la Región logre la cobertura universal de salud en cumplimiento de los Objetivos de Desarrollo Sostenible.

A pandemia de COVID-19 exacerbou as disparidades sociais, econômicas e as relacionadas à saúde, que afetam de maneira desproporcional as pessoas que vivem em situação de vulnerabilidade. Essas populações incluem grupos étnicos que enfrentam discriminação e barreiras para o acesso à atenção integral à saúde. A pandemia de COVID-19 expôs essas disparidades, e as interrupções nos serviços essenciais de saúde ampliaram ainda mais as lacunas no acesso aos cuidados de saúde. As doenças não transmissíveis são mais prevalentes entre os grupos mais afetados por determinantes sociais da saúde deficientes e estão associadas a um aumento na probabilidade de doença grave pela COVID-19 e mortalidade mais elevada. Prevê-se que as interrupções na prestação de serviços essenciais de saúde para doenças não transmissíveis, saúde mental, doenças transmissíveis como HIV, tuberculose e malária, bem como dos serviços de saúde materno-infantil (incluindo saúde sexual e reprodutiva) também aumentem os desfechos adversos de saúde. Outros desafios são o aumento da frequência da violência interpessoal e insegurança alimentar. Os países das Américas responderam às interrupções causadas pela pandemia com a prestação de serviços de saúde por meio da telemedicina e outras soluções digitais, e a aceleração de intervenções de apoio dos serviços sociais. À medida em que a vacinação contra a COVID-19 oferece a oportunidade de superar a pandemia, os países devem fortalecer a atenção primária à saúde e os serviços essenciais de saúde com o objetivo de garantir a equidade, para que a região atinja a cobertura universal de saúde em cumprimento aos Objetivos de Desenvolvimento Sustentável.

Sodium and potassium excretion in an adult Caribbean population of African descent with a high burden of cardiovascular disease.

BACKGROUND: High sodium diets with inadequate potassium and high sodium-to-potassium ratios are a known determinant of hypertension and cardiovascular disease (CVD). The Caribbean island of Barbados has a high prevalence of hypertension and mortality from CVD. Our objectives were to estimate sodium and potassium excretion, to compare estimated levels with recommended intakes and to identify the main food sources of sodium in Barbadian adults. METHODS: A sub-sample (n = 364; 25-64 years) was randomly selected from the representative population-based Health of the Nation cross-sectional study (n = 1234), in 2012-13. A single 24-h urine sample was collected from each participant, following a strictly applied protocol designed to reject incomplete samples, for the measurement of sodium and potassium excretion (in mg), which were used as proxy estimates of dietary intake. In addition, sensitivity analyses based on estimated completeness of urine collection from urine creatinine values were undertaken. Multiple linear regression was used to examine differences in sodium and potassium excretion, and the sodium-to-potassium ratio, by age, sex and educational level. Two 24-h recalls were used to identify the main dietary sources of sodium. All analyses were weighted for the survey design. RESULTS: Mean sodium excretion was 2656 (2488-2824) mg/day, with 67% (62-73%) exceeding the World Health Organization (WHO) recommended limit of 2000 mg/d. Mean potassium excretion was 1469 (1395-1542) mg/d; < 0.5% met recommended minimum intake levels. Mean sodium-to-potassium ratio was 2.0 (1.9-2.1); not one participant had a ratio that met WHO recommendations. Higher potassium intake and lower sodium-to-potassium ratio were independently associated with age and tertiary education. Sensitivity analyses based on urine creatinine values did not notably alter these findings. CONCLUSIONS: In this first nationally representative study with objective assessment of sodium and potassium excretion in a Caribbean population in over 20 years, levels of sodium intake were high, and potassium intake was low. Younger age and lower educational level were associated with the highest sodium-to-potassium ratios. These findings provide baseline values for planning future policy interventions for non-communicable disease prevention.

Managing acute ischaemic stroke in a small island developing state: meeting the guidelines in Barbados.

BACKGROUND: We describe hospital-based management of acute ischaemic stroke patients in 2010-2013 in Barbados, by comparing documented treatment given in the single tertiary public hospital with international guideline recommendations. METHODS: Evidence-based stroke management guidelines were identified through a systematic literature search. Comparisons were made between these guidelines and documented diagnostic practice (all strokes) and prescribed medication (ischaemic stroke only), using a combination of key informant interviews and national stroke registry data for 2010-2013. RESULTS: Several published international guidelines for the acute management of ischaemic stroke recommended patient management in a dedicated stroke unit or nearest hospital specialised in stroke care. Further, patients should receive clinical diagnosis, CT brain scan, specialist evaluation by a multidisciplinary team and, if eligible, thrombolysis with alteplase within 3-3.5 h of symptom onset. Subsequent secondary prophylaxis, with a platelet aggregation inhibitor and a statin was advised. Barbados had no stroke unit or stroke team, and no official protocol for acute stroke management during the study period. Most of the 1735 stroke patients were managed by emergency physicians at presentation; if admitted, they were managed on general medical wards. Most had a CT scan (1646; 94.9%). Of 1406 registered ischaemic stroke patients, only 6 (0.4%) had been thrombolysed, 521 (37.1%) received aspirin within 24 h of admission and 670 (47.7%) were prescribed aspirin on discharge. CONCLUSIONS: Acute ischaemic stroke diagnosis was consistent with international recommendations, although this was less evident for treatment. While acknowledging the difficulty in implementing international guidelines in a low-resource setting, there is scope for improvement in acute ischaemic stroke management and/or its documentation in Barbados. A stroke unit was established in August 2013 and written clinical protocols for acute stroke care were in development at the time of the study; future registry data will evaluate their impact. Our findings have implications for other low-resource settings with high stroke burden.

Educational Health Disparities in Cardiovascular Disease Risk Factors: Findings from Jamaica Health and Lifestyle Survey 2007-2008.

OBJECTIVES: Socioeconomic disparities in health have emerged as an important area in public health, but studies from Afro-Caribbean populations are uncommon. In this study, we report on educational health disparities in cardiovascular disease (CVD) risk factors (hypertension, diabetes mellitus, hypercholesterolemia, and obesity), among Jamaican adults. METHODS: We analyzed data from the Jamaica Health and Lifestyle Survey 2007-2008. Trained research staff administered questionnaires and obtained measurements of blood pressure, anthropometrics, glucose and cholesterol. CVD risk factors were defined by internationally accepted cut-points. Educational level was classified as primary or lower, junior secondary, full secondary, and post-secondary. Educational disparities were assessed using age-adjusted or age-specific prevalence ratios and prevalence differences obtained from Poisson regression models. Post-secondary education was used as the reference category for all comparisons. Analyses were weighted for complex survey design to yield nationally representative estimates. RESULTS: The sample included 678 men and 1,553 women with mean age of 39.4 years. The effect of education on CVD risk factors differed between men and women and by age group among women. Age-adjusted prevalence of diabetes mellitus was higher among men with less education, with prevalence differences ranging from 6.9 to 7.4 percentage points (p < 0.05 for each group). Prevalence ratios for diabetes among men ranged from 3.3 to 3.5 but were not statistically significant. Age-specific prevalence of hypertension was generally higher among the less educated women, with statistically significant prevalence differences ranging from 6.0 to 45.6 percentage points and prevalence ratios ranging from 2.5 to 4.3. Similarly, estimates for obesity and hypercholesterolemia suggested that prevalence was higher among the less educated younger women (25-39 years) and among more educated older women (40-59 and 60-74 years). There were no statistically significant associations for diabetes among women, or for hypertension, high cholesterol, or obesity among men. CONCLUSION: Educational health disparities were demonstrated for diabetes mellitus among men, and for obesity, hypertension, and hypercholesterolemia among women in Jamaica. Prevalence of diabetes was higher among less educated men, while among younger women the prevalence of hypertension, hypercholesterolemia, and obesity was higher among those with less education.

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

BACKGROUND: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. METHODS: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. RESULTS: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. IMPACT: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.

Accuracy and Usefulness of Select Methods for Assessing Complete Collection of 24-Hour Urine: A Systematic Review.

Twenty-four-hour urine collection is the recommended method for estimating sodium intake. To investigate the strengths and limitations of methods used to assess completion of 24-hour urine collection, the authors systematically reviewed the literature on the accuracy and usefulness of methods vs para-aminobenzoic acid (PABA) recovery (referent). The percentage of incomplete collections, based on PABA, was 6% to 47% (n=8 studies). The sensitivity and specificity for identifying incomplete collection using creatinine criteria (n=4 studies) was 6% to 63% and 57% to 99.7%, respectively. The most sensitive method for removing incomplete collections was a creatinine index <0.7. In pooled analysis (≥2 studies), mean urine creatinine excretion and volume were higher among participants with complete collection (P<.05); whereas, self-reported collection time did not differ by completion status. Compared with participants with incomplete collection, mean 24-hour sodium excretion was 19.6 mmol higher (n=1781 specimens, 5 studies) in patients with complete collection. Sodium excretion may be underestimated by inclusion of incomplete 24-hour urine collections. None of the current approaches reliably assess completion of 24-hour urine collection.

Predicting the burden of acute myocardial infarction in a country with limited resources: combining data from routine sources.

BACKGROUND: Prior to implementation of a national surveillance system for cardiovascular disease in Barbados, a small island state with limited health resources, the national burden of acute myocardial infarction (MI) was unknown. METHODS: We retrospectively estimated national acute MI incidence rates (IRs) per 100,000 during the decade before registry implementation (1999-2008), using easily accessible routine data from different sources, assessing changes over time through Poisson regression. Future events (2009-2013) were estimated using simple sensitivity analysis to incorporate prediction uncertainty. Model predictions were compared with actual IRs from initial years of the registry. RESULTS: In 2000, crude IR was 85.5 (95% CI: 74.9-97.2), rising to 92.1 (81.2-103.9) in 2008. Accounting for population ageing, the model anticipated IR of 115.9 in 2010 (99.7-132.1), vs actual crude IR 129.7 (115.9-144.6). CONCLUSIONS: Despite no electronic medical record system in Barbados, data were simple to collect, and provided a rough baseline for acute MI burden. We show that, in countries with small populations, limited resources and in absence of surveillance, national mortality statistics and routine hospital data can be combined to adequately model national estimates of acute MI incidence. This cheap and simple, yet fairly accurate method could be a key tool for other low-resource countries with ageing populations and increasing cardiovascular disease levels.

Disparities in hypertension among black Caribbean populations: a scoping review by the U.S. Caribbean Alliance for Health Disparities Research Group (USCAHDR).

BACKGROUND: Despite the large body of research on racial/ethnic disparities in health, there are limited data on health disparities in Caribbean-origin populations. This scoping review aimed to analyze and synthesize published and unpublished literature on the disparities in hypertension and its complications among Afro-Caribbean populations. METHODS: A comprehensive protocol, including a thorough search strategy, was developed and used to identify potentially relevant studies. Identified studies were then screened for eligibility using pre-specified inclusion/exclusion criteria. An extraction form was developed to chart data and collate study characteristics including methods and main findings. Charted information was tagged by disparity indicators and thematic analysis performed. Disparity indicators evaluated include ethnicity, sex, socioeconomic status, disability, sexual orientation and geographic location. Gaps in the literature were identified and extrapolated into a gap map. RESULTS: A total of 455 hypertension related records, published between 1972 and 2012, were identified and screened. Twenty-one studies met inclusion criteria for detailed analysis. The majority of studies were conducted in the United Kingdom and utilized a cross-sectional study design. Overall, studies reported a higher prevalence of hypertension among Caribbean blacks compared to West African blacks and Caucasians. Hypertension and its related complications were highest in persons with low socioeconomic status. Gap analysis showed limited research data reporting hypertension incidence by sex and socioeconomic status. No literature was found on disability status or sexual orientation as it relates to hypertension. Prevalence and morbidity were the most frequently reported outcomes. CONCLUSION: The literature on hypertension health disparities in Caribbean origin populations is limited. Future research should address these knowledge gaps and develop approaches to reduce them.

Premature Mortality from Cardiovascular Disease in the Americas - Will the Goal of a Decline of "25% by 2025" be Met?

BACKGROUND: Cardiovascular diseases (CVD) are the underlying cause 1.6 million deaths per year in the Americas, accounting for 30% of total mortality and 38% of by non-communicable deaths diseases (NCDs). A 25% reduction in premature mortality due four main NCDs was targeted by the 2011 High-level Meeting of the General Assembly on the Prevention and Control of NCDs. While overall CVD mortality fell in the Americas during the past decade, trends in premature CVD mortality during the same period have not been described, particularly in the countries of Latin America and the Caribbean. METHODS: This is a population-based trend-series study based on a total of 6,133,666 deaths to describe the trends and characteristics of premature mortality due to CVD and to estimates of the average annual percentage of change during the period 2000-2010 in the Americas. FINDINGS: Premature mortality due to CVD in the Americas fell by 21% in the period 2000-2010 with a -2.5% average annual rate of change in the last 5 year-a statistically significant reduction of mortality-. Mortality from ischemic diseases, declined by 25% - 24% among men and 26% among women. Cerebrovascular diseases declined by 27% -26% among men and 28% among women. Guyana, Trinidad and Tobago, the Dominican Republic, Bahamas, and Brazil had CVD premature mortality rates over 200 per 100,000 population, while the average for the Region was 132.7. US and Canada will meet the 25% reduction target before 2025. Mexico, Costa Rica, Venezuela, Dominican Republic, Panama, Guyana, and El Salvador did not significantly reduce premature mortality among men and Guyana, the Dominican Republic, and Panama did not achieve the required annual reduction in women. CONCLUSIONS: Trends in premature mortality due to CVD observed in last decade in the Americas would indicate that if these trends continue, the Region as a whole and a majority of its countries will be able to reach the goal of a 25% relative reduction in premature mortality even before 2025.

Disparities in cardiovascular disease among Caribbean populations: a systematic literature review.

BACKGROUND: Cardiovascular diseases (CVD) are the predominant cause of death globally. The large health disparities in the distribution of the burden of disease seen in developed and developing countries are of growing concern. Central to this concern is the poor outcome which is seen disproportionately in socially disadvantaged groups and racial/ethnic minorities. The aim of the study was to conduct a systematic literature review to investigate the nature of cardiovascular disease health disparities among Afro-Caribbean origin populations and identify current knowledge gaps. METHODS: A systematic literature review including a detailed search strategy was developed to search MEDLINE and other research databases. Using an a priori protocol peer-reviewed publications and grey literature articles were retrieved and screened and relevant data extracted by two independent review authors. Thematic analysis was done according to CVD outcomes and measures of disparity including age, sex, ethnicity and socioeconomic status. RESULTS: The search retrieved 665 articles of which 22 met the inclusion criteria. Most studies were conducted in the United Kingdom and centered on the prevalence of CVD by ethnicity, age and sex. An important sub-theme identified was the disparities in health service utilization/hospital admission. Coronary Heart Disease (CHD) and Peripheral Arterial Disease (PAD) were less prevalent among Afro-Caribbeans compared to Caucasian and South East Asian ethnic groups. The prevalence of CHD ranged from 0-7% in Afro-Caribbean to 2-22% in Caucasians. Strokes were more common among Afro-Caribbeans. There are inadequate data on morbidity and mortality from CVD, particularly across the socio-economic gradient, in Afro-Caribbean populations. CONCLUSIONS: There are important differences in morbidity and mortality from CVD across ethnic groups. Important knowledge gaps remain in understanding the social determinants of these disparities in CVD. More research exploring these gaps by varying disparity indicators needs to be undertaken.

Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults.

Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.