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bioRxiv2016

The impact of the newly licensed dengue vaccine in endemic countries

BackgroundWith approximately 3 billion people at risk of acquiring the infection, dengue fever is now considered the most important mosquito-borne viral disease in the world, with 390 million dengue infections occurring every year, of which 96 million manifest symptoms with any level of disease severity. Treatment of uncomplicated dengue cases is only supportive and severe dengue cases require hospital intensive care. A vaccine now licensed in several countries and developed by Sanofi Pasteur (CYD-TDV, named Dengvaxia), is able to protect, in the first 25 months of the two Phase III, 66% of a subset of 9 - 16 year old participants. However, a significantly lower efficacy (including negative vaccine efficacy) was noted for children younger than 9 years of age.\n\nMethodology/Principal FindingsAnalysis of year 3 results of phase III trials of Dengvaxia suggest high rates of protection of vaccinated partial dengue immunes but high rates of hospitalizations during breakthrough dengue infections of persons who were vaccinated when seronegative, with vaccine appearing to induce enhancing antibodies (ADE). An age structured model was developed based on Sanofis recommendation to vaccinate persons age 945 years in dengue endemic countries. The model was used to explore the clinical burden of two vaccination strategies: 1) Vaccinate 4 or 20% of individuals, ages 9 - 45 years, seropositives and seronegatives, and 2) vaccinate 4 or 20% of individuals, ages 9 - 45 years, who are dengue immune only.\n\nConclusions/SignificanceOur results show that vaccinating dengue monotypic immune individuals prevents dengue hospitalizations, but at the same time dengue infections of vaccine-sensitized persons increases hospitalizations. When the vaccine is given only to partial immune individuals, after immuno-logical screening of the population, disease burden decreases considerably.\n\nAuthor SummaryCaused by four antigenically related but distinct serotypes a tetravalent vaccine is needed to protect against the huge burden of dengue disease. Dengvaxia is a vaccine candidate now licensed in several countries for individuals 9 - 45 years of age living in endemic countries with least 70% of seroprevalence. Modelers from Sanofi Pasteur have predicted that this vaccine has the potential to reduce by about 50% the disease burden within 5 years when 20% of an endemic country population is vaccinated, thus achieving a World Health Organization dengue prevention goal.\n\nIn this paper, mathematical modeling is used to investigate the impact of the newly licensed dengue vaccine using different scenarios. Our results show that to achieve significant reduction in disease bur-den, the vaccination program is most effective if it includes only individuals that have been already exposed to at least one dengue virus. Immunological screening of the population prior to vaccination is advised and vaccination strategies must be planned based on epidemiological disease dynamics for each specific endemic region.

Epidemiology↗

bioRxiv2016

The Causal Effects of Education on Health, Mortality, Cognition, Well-being, and Income in the UK Biobank

Educated people are generally healthier, have fewer comorbidities and live longer than people with less education. Previous evidence about the effects of education come from observational studies many of which are affected by residual confounding. Legal changes to the minimum school leave age is a potential natural experiment which provides a potentially more robust source of evidence about the effects of schooling. Previous studies have exploited this natural experiment using population-level administrative data to investigate mortality, and relatively small surveys to investigate the effect on mortality. Here, we add to the evidence using data from a large sample from the UK Biobank. We exploit the raising of the school-leaving age in the UK in September 1972 as a natural experiment and regression discontinuity and instrumental variable estimators to identify the causal effects of staying on in school. Remaining in school was positively associated with 23 of 25 outcomes. After accounting for multiple hypothesis testing, we found evidence of causal effects on twelve outcomes, however, the associations of schooling and intelligence, smoking, and alcohol consumption may be due to genomic and socioeconomic confounding factors. Education affects some, but not all health and socioeconomic outcomes. Differences between educated and less educated people may be partially due to residual genetic and socioeconomic confounding.\n\nSignificance StatementOn average people who choose to stay in education for longer are healthier, wealthier, and live longer. We investigated the causal effects of education on health, income, and well-being later in life. This is the largest study of its kind to date and it has objective clinic measures of morbidity and aging. We found evidence that people who were forced to remain in school had higher wages and lower mortality. However, there was little evidence of an effect on intelligence later in life. Furthermore, estimates of the effects of education using conventionally adjusted regression analysis are likely to suffer from genomic confounding. In conclusion, education affects some, but not all health outcomes later in life.\n\nFundingThe Medical Research Council (MRC) and the University of Bristol fund the MRC Integrative Epidemiology Unit [MC_UU_12013/1, MC_UU_12013/9]. NMD is supported by the Economics and Social Research Council (ESRC) via a Future Research Leaders Fellowship [ES/N000757/1]. The research described in this paper was specifically funded by a grant from the Economics and Social Research Council for Transformative Social Science. No funding body has influenced data collection, analysis or its interpretations. This publication is the work of the authors, who serve as the guarantors for the contents of this paper. This work was carried out using the computational facilities of the Advanced Computing Research Centre -http://www.bris.ac.uk/acrc/ and the Research Data Storage Facility of the University of Bristol -- http://www.bris.ac.uk/acrc/storage/. This research was conducted using the UK Biobank Resource.\n\nData accessThe statistical code used to produce these results can be accessed here: (https://github.com/nmdavies/UKbiobankROSLA). The final analysis dataset used in this study is archived with UK Biobank, which can be accessed by contacting UK Biobank access@biobank.ac.uk.

Epidemiology↗

bioRxiv2016

A comparative analysis of Chikungunya and Zika transmission

The recent global dissemination of Chikungunya and Zika has fostered public health concern worldwide. To better understand the drivers of transmission of these two arboviral diseases, we propose a joint analysis of Chikungunya and Zika epidemics in the same territories, taking into account the common epidemiological features of the epidemics: transmitted by the same vector, in the same environments, and observed by the same surveillance systems. We analyse eighteen outbreaks in French Polynesia and the French West Indies using a hierarchical time-dependent SIR model accounting for the effect of virus, location and weather on transmission, and based on a disease specific serial interval. We show that Chikungunya and Zika have similar transmission potential in the same territories (transmissibility ratio between Zika and Chikungunya of 1.04 [95% credible interval: 0.97; 1.13]), but that detection and reporting rates were different (around 19% for Zika and 40% for Chikungunya). Temperature variations between 22{degrees}C and 29{degrees}C did not alter transmission, but increased precipitation showed a dual effect, first reducing transmission after a two-week delay, then increasing it around five weeks later. The present study provides valuable information for risk assessment and introduces a modelling framework for the comparative analysis of arboviral infections that can be extended to other viruses and territories.

Epidemiology↗

bioRxiv2017

Non-annual seasonality of influenza-like illness in a tropical urban setting

In temperate countries, influenza and other viral respiratory diseases often have distinct seasonal peaks occurring during colder, wintertime months. However, little is known about the dynamics of influenza and viral respiratory disease dynamics in the tropics, despite high morbidity and a clear epidemiological link between tropical and temperate countries. In temperate countries, the dynamics of influenza and other respiratory diseases are often analyzed using syndromic surveillance data describing influenza-like illness (ILI) as ILI is highly correlated with virological surveillance for influenza. To obtain a detailed picture of respiratory disease incidence patterns in a large tropical city, we established an mHealth study in community outpatient clinics in Ho Chi Minh City, Vietnam (11N latitude). From August 2009 through December 2015, clinics reported daily case numbers of ILI using standard mobile-phone SMS messaging. A subset of these clinics performed molecular diagnostics for influenza A and B viruses. Unlike the annual patterns seen in temperate countries, ILI activity in Ho Chi Minh City exhibited strong non-annual periodicity and was not correlated with PCR-confirmed influenza. The dominant periodicity in the data was approximately 200 days. This was confirmed by a time series decomposition, a step-wise regression analysis on annual and non-annual covariates, and a forecasting exercise showing that forecasting was 30% to 40% more accurate when a 200-day non-annual cycle was included in the forecast. This suggests, for the first-time, that a non-annual cycle may be an essential driver of ILI dynamics in the tropics. This raises new questions about the seasonality and drivers of respiratory disease transmission in tropical countries.

epidemiology↗

bioRxiv2017

DNA methylation differences at regulatory elements are associated with the cancer risk factor age in normal breast tissue

BackgroundThe underlying biological mechanisms through which epidemiologically defined breast cancer risk factors contribute to disease risk remain poorly understood. Identification of the molecular changes associated with cancer risk factors in normal tissues may aid in determining the earliest events of carcinogenesis and informing cancer prevention strategies.\n\nResultsHere we investigated the impact cancer risk factors have on the normal breast epigenome by analyzing DNA methylation genome-wide (Infinium 450K array) in cancer-free women from the Susan G. Komen Tissue Bank (n = 100). We tested the relation of established breast cancer risk factors: age, body mass index, parity, and family history of disease with DNA methylation adjusting for potential variation in cell-type proportions. We identified 787 CpG sites that demonstrated significant associations (Q-value < 0.01) with subject age. Notably, DNA methylation was not strongly associated with the other evaluated breast cancer risk factors. Age-related DNA methylation changes are primarily increases in methylation enriched at breast epithelial cell enhancer regions (P = 7.1E-20), and binding sites of chromatin remodelers (MYC and CTCF). We validated the age-related associations in two independent populations of normal breast tissue (n = 18) and normal-adjacent to tumor tissue (n = 97). The genomic regions classified as age-related were more likely to be regions altered in cancer in both pre-invasive (n = 40, P=3.0E-03) and invasive breast tumors (n = 731, P=1.1E-13).\n\nConclusionsDNA methylation changes with age occur at regulatory regions, and are further exacerbated in cancer suggesting that age influences breast cancer risk in part through its contribution to epigenetic dysregulation in normal breast tissue.

epidemiology↗

bioRxiv2017

The social and spatial ecology of dengue presence and burden during an outbreak in Guayaquil, Ecuador, 2012

Dengue fever, a mosquito-borne viral disease, is an ongoing public health problem in Ecuador and throughout the tropics, yet we have a limited understanding of the disease transmission dynamics in these regions. The objective of this study was to characterize the spatial dynamics and social-ecological risk factors associated with a recent dengue outbreak in Guayaquil, Ecuador. We examined georeferenced dengue cases (n = 4,248) and block-level census data variables to identify potential social-ecological variables associated with the presence and burden of dengue fever in Guayaquil in 2012. We applied LISA and Morans I tests to analyze hotspots of dengue cases and used multimodel selection in R computing language to identify covariates associated with dengue incidence at the census zone level. Significant hotspots of dengue transmission were found near the North Central and Southern portions of Guayaquil. Significant risk factors for presence of dengue included poor housing conditions (e.g., poor condition of ceiling, floors, and walls), access to paved roads, and receipt of remittances. Counterintuitive positive correlations with dengue presence were observed with several municipal services such as garbage collection and access to piped water. Risk factors for the increased burden of dengue included poor housing conditions, garbage collection, receipt of remittances, and sharing a property with more than one household. Social factors such as education and household demographics were negatively correlated with increased dengue burden. Our findings elucidate underlying differences with dengue presence and burden and indicate the potential to develop dengue vulnerability and risk maps to inform disease prevention and control - information that is also relevant for emerging epidemics of chikungunya and zika.\n\nHighlightsO_LIIn 2012, Guayaquil, Ecuador had a large outbreak of dengue cases\nC_LIO_LIDengue case presence and burden exhibited spatial heterogeneity at the census block level\nC_LIO_LISocial-ecological drivers of case presence and burden differed in this outbreak, highlighting the need to model both types of epidemiological data\nC_LIO_LIAccess to municipal resources such as garbage collection and piped water had counterintuitive relationships with dengue presence, but poor housing, garbage collection and remittances correlated to dengue burden.\nC_LIO_LIOur findings inform risk mapping and vector control and surveillance allocation, relevant to this and other concurrent emergent epidemics such as chikungunya and zika\nC_LI

epidemiology↗

bioRxiv2017

Genetic characterization of the Zika virus epidemic in the US Virgin Islands

Here we release draft genome sequences of Zika virus (ZIKV) that were sequenced from PCR-positive diagnostic specimens collected by the United States Virgin Islands Department of Health (USVI DoH) as part of their ongoing response to the ZIKV outbreak. We will use these sequences to conduct a genomic epidemiological study of ZIKV transmission in the USVI. We are releasing these genomes in the hope that they are useful for those individuals involved in the public health response to ZIKV and to other groups working to understand Zika virus transmission and evolution.

epidemiology↗

bioRxiv2017

External introductions helped drive and sustain the high incidence of HIV-1 in rural KwaZulu-Natal, South Africa

Despite increasing access to antiretroviral therapy, HIV incidence in rural KwaZulu-Natal communities remains among the highest ever reported in Africa. While many epidemiological factors have been invoked to explain this high incidence, widespread human mobility and movement of viral lineages between geographic locations have implicated high rates of transmission across communities. High rates of crosscommunity transmission call into question how effective increasing local coverage of antiretroviral therapy will be at preventing new infections, especially if many new cases arise from external introductions. To help address this question, we use a new phylodynamic modeling approach to estimate both changes in epidemic dynamics through time and the relative contribution of local transmission versus external introductions to overall incidence from HIV-1 subtype C phylogenies. Our phylodynamic estimates of HIV prevalence and incidence are remarkably consistent with population-based surveillance data. Our analysis also reveals that early epidemic dynamics in this population were largely driven by a wave of external introductions. More recently, we estimate that anywhere between 20-60% of all new infections arise from external introductions from outside the local community. These results highlight the power of using phylodynamic methods to study generalized HIV epidemics and the growing need to consider larger-scale regional transmission dynamics above the level of local communities when designing and testing prevention strategies.

epidemiology↗

bioRxiv2017

Can Zika Account For The Missing Babies?

The Zika virus (ZIKV) spread rapidly in Brazil in 2015 and 2016. Rio de Janeiro was among the Brazilian cities which were hit the hardest, with more that a hundred thousand confirmed cases up to the end of 2016. Given the severity of the neurological damage caused by ZIKV on fetuses, we wondered whether it would also cause an increase in the number of miscarriages, especially very early ones. As early miscarriages are unlikely to be recorded as a health event, this effect - if it occurred - would only show up as a reduction in the number of live births. In this paper we show that there was a 15% drop in live births between September and December 2016 compared to the previous year, and that this sharp drop from epidemiological week 33 onward is strongly correlated with the number of recorded cases of Zika about 40 weeks earlier. We postulate that ZIKV is directly responsible for this drop in the birth rate. Further work is required to ascertain whether other factors such the fear of having a microcephaly baby or the economic crisis are having a significant effect.

epidemiology↗

bioRxiv2017

Components Of Alcohol Use And All-Cause Mortality

ImportanceCurrent recommendations for low-risk drinking are based on drinking quantity: up to one drink daily for women and two drinks daily for men. Drinking frequency has not been independently examined for its contribution to mortality.\n\nObjectiveTo evaluate the impact of drinking frequency on all-cause mortality after adjusting for drinks per day and binge drinking behavior.\n\nDesignTwo independent observational studies with self-reported alcohol use and subsequent all-cause mortality: the National Health Interview Survey (NHIS), and data from Veterans Health Administration clinics (VA).\n\nSettingEpidemiological sample (NHIS) and VA outpatient database (VA Corporate Data Warehouse).\n\nParticipants208,661 individuals from the NHIS interviewed between 1997 and 2009 at the age of 30 to 70 with mortality follow-up in the last quarter of 2011; 75,515 VA outpatients born between 1948 and 1968 who completed an alcohol survey in 2008 with mortality follow-up in June 2016.\n\nExposuresQuantity of alcohol use when not binging (1-2 drinks on typical day, 3-4 drinks on typical day), frequency of non-binge drinking (never, weekly or less, 2-3 times weekly, 4 or more times weekly), and frequency of binge drinking (never, less than weekly, 1-3 times weekly, 4 or more times weekly). Covariates included age, sex, race, and comorbidity.\n\nMain Outcomes and MeasuresAll-cause mortality.\n\nResultsAfter adjusting for binge drinking behavior, survival analysis showed an increased risk for all-cause mortality among people who typically drink 1-2 drinks four or more times weekly, relative to people who typically drink 1-2 drinks at a time weekly or less (NHIS dataset HR=1.15, 95% CI 1.06-1.26; VA dataset HR=1.31, 95% CI 1.15-1.49).\n\nConclusions and RelevanceDrinking four or more times weekly increased risk of all-cause mortality, even among those who drank only 1 or 2 drinks daily. This was seen in both a large epidemiological database and a large hospital-based database, suggesting that the results can be generalized.

epidemiology↗

bioRxiv2017

Estimating Time Of HIV-1 Infection From Next-Generation Sequence Diversity

Estimating the time since infection (TI) in newly diagnosed HIV-1 patients is challenging, but important to understand the epidemiology of the infection. Here we explore the utility of virus diversity estimated by next-generation sequencing (NGS) as novel biomarker by using a recent genome-wide longitudinal dataset obtained from 11 untreated HIV-1-infected patients with known dates of infection. The results were validated on a second dataset from 31 patients.\n\nVirus diversity increased linearly with time, particularly at 3rd codon positions, with little inter-patient variation. The precision of the TI estimate improved with increasing sequencing depth, showing that diversity in NGS data yields superior estimates to the number of ambiguous sites in Sanger sequences, which is one of the alternative biomarkers. The full advantage of deep NGS was utilized with continuous diversity measures such as average pairwise distance or site entropy, rather than the fraction of polymorphic sites. The precision depended on the genomic region and codon position and was highest when 3rd codon positions in the entire pol gene were used. For these data, TI estimates had a mean absolute error of around 1 year. The error increased only slightly from around 0.6 years at a TI of 6 months to around 1.1 years at 6 years.\n\nOur results show that virus diversity determined by NGS can be used to estimate time since HIV-1 infection many years after the infection, in contrast to most alternative biomarkers. We provide the regression coefficients as well as web tool for TI estimation.\n\nAuthor summaryHIV-1 establishes a chronic infection, which may last for many years before the infected person is diagnosed. The resulting uncertainty in the date of infection leads to difficulties in estimating the number of infected but undiagnosed persons as well as the number of new infections, which is necessary for developing appropriate public health policies and interventions. Such estimates would be much easier if the time since HIV-1 infection for newly diagnosed cases could be accurately estimated. Three types of biomarkers have been shown to contain information about the time since HIV-1 infection, but unfortunately, they only distinguish between recent and long-term infections (concentration of HIV-1-specific antibodies) or are imprecise (immune status as measured by levels of CD4+ T-lymphocytes and viral sequence diversity measured by polymorphisms in Sanger sequences).\n\nIn this paper, we show that recent advances in sequencing technologies, i.e. the development of next generation sequencing, enable significantly more precise determination of the time since HIV-1 infection, even many years after the infection event. This is a significant advance which could translate into more effective HIV-1 prevention.

epidemiology↗

bioRxiv2017

Diagnostic, Infection Timing and Incidence Surveillance Applications of High Dynamic Range Chemiluminescent HIV Immuno-Assay Platforms

BackgroundCustom staging assays, including the Sedia HIV-1 Limiting Antigen Avidity EIA (LAg) and avidity modifications of the Ortho VITROS anti-HIV-1+2 and Abbott ARCHITECT HIV Ag/Ab Combo assays, are used to identify recent infections in clinical settings and for cross-sectional HIV incidence estimation. However, the high dynamic range of chemiluminescent platforms allows differentiating recent and longstanding infection on signal intensity, and this raises the prospect of using unmodified diagnostic assays for infection timing and surveillance applications.\n\nMethodsWe tested a panel of 2,500 well-characterised specimens with estimable duration of HIV infection with the three assays and the unmodified ARCHITECT. Regression models were used to estimate mean durations of recent infection (MDRI), context-specific false-recent rates (FRR) and correlation between signal intensity and LAg measurements. A hypothetical epidemiological scenario was constructed to evaluate utility in surveillance applications.\n\nResultsOver a range of MDRIs (reflecting recency discrimination thresholds), a diluted ARCHITECT-based RITA produced lower FRRs than the VITROS platform (FRR {approx} 0.5% and 1.5% respectively at MDRI of 200 days) and the unmodified diagnostic ARCHITECT produces incidence estimates with comparable precision to LAg (RSE {approx} 17.5% and 15% respectively at MDRI of 200 days). ARCHITECT S/CO measurements were highly correlated with LAg ODn measurements (r = 0.80) and values below 200 are strongly predictive of LAg recency and duration of infection less than one year.\n\nConclusionsLow quantitative measurements from the unmodified ARCHITECT obviate the need for additional recency testing and its use is feasible in clinical staging and incidence surveillance applications.

epidemiology↗

bioRxiv2017

Vaccination Can Drive An Increase In Frequencies Of Antibiotic Resistance Among Non-Vaccine Serotypes Of Streptococcus pneumoniae

The bacterial pathogen Streptococcus pneumoniae is a major public health concern, being responsible for more than 1.5 million deaths annually through pneumonia, meningitis and septicemia. In spite of vaccination efforts, pneumococcal carriage and disease remain high, since available vaccines target only a subset of serotypes and vaccination is often accompanied by a rise in non-vaccine serotypes. Epidemiological studies suggest that such a change in serotype frequencies is often coupled with an increase of antibiotic resistance among non-vaccine serotypes. Building on previous multi-locus models for bacterial pathogen population structure, we have developed a theoretical framework incorporating variation in serotype and antibiotic resistance to examine how their associations may be affected by vaccination. Using this framework, we find that vaccination can result in rapid increase in frequency of pre-existing resistant variants of non-vaccine serotypes due to the removal of competition from vaccine serotypes.

epidemiology↗

bioRxiv2017

Fetal death certificate data quality: A tale of two US counties

PurposeDescribe the relative frequency and joint effect of missing and misreported fetal death certificate (FDC) data and identify variations by key characteristics.\n\nMethodsStillbirths were prospectively identified during 2006-2008 for a multi-site population-based case-control study. For this study, eligible mothers of stillbirths were not incarcerated residents of DeKalb County, Georgia, or Salt Lake County, Utah, aged > 13 years, with an identifiable FDC. We identified the frequency of missing and misreported (any departure from the study value) FDC data by county, race/ethnicity, gestational age, and whether the stillbirth was antepartum or intrapartum.\n\nResultsData quality varied by item, and was highest in Salt Lake County. Reporting was generally not associated with maternal or delivery characteristics. Reasons for poor data quality varied by item in DeKalb County: some items were frequently missing and misreported; however, others were of poor quality due to either missing or misreported data.\n\nConclusionsFDC data suffer from missing and inaccurate data, with variations by item and county. Salt Lake County data illustrate that high quality reporting is attainable. The overall quality of reporting must be improved to support consequential epidemiologic analyses for stillbirth, and improvement efforts should be tailored to the needs of each jurisdiction.\n\nAbbreviations and Acronyms

epidemiology↗

bioRxiv2017

Could The Recent Zika Epidemic Have Been Predicted?

Given knowledge at the time, the recent 2015-2016 zika virus (ZIKV) epidemic probably could not have been predicted. Without the prior knowledge of ZIKV being already present in South America, and given the lack of understanding of key epidemiologic processes and long-term records of ZIKV cases in the continent, the best related prediction was for potential risk of an Aedes-borne disease epidemic. Here we use a recently published two-vector capacity model to assess the predictability of the conditions conducive to epidemics of diseases like zika, chikungunya or dengue, transmitted by the independent or concurrent presence of Aedes aegypti and Aedes albopictus. We compare the potential risk of transmission forcing the model with the observed climate and with state-of-the-art operational forecasts from the North American Multi Model Ensemble (NMME), finding that the predictive skill of this new seasonal forecast system is highest for multiple countries in Latin America and the Caribbean during the December-February and March-May seasons, and slightly lower -but still of potential use to decision-makers- for the rest of the year. In particular, we find that above-normal suitable conditions for the occurrence of the zika epidemic at the beginning of 2015 could have been successfully predicted for several zika hotspots, and in particular for Northeast Brazil: the heart of the epidemic. Nonetheless, the initiation and spread of an epidemic depends on the effect of multiple factors beyond climate conditions, and thus this type of approach must be considered as a guide and not as a formal predictive tool of vector-borne epidemics.

epidemiology↗

bioRxiv2017

Software Application Profile: mrrobust - A Tool For Performing Two-Sample Summary Mendelian Randomization Analyses

MotivationIn recent years Mendelian randomization analysis using summary data from genome-wide association studies has become a popular approach for investigating causal relationships in epidemiology. The mrrobust Stata package implements several of the recently developed methods.\n\nImplementationmrrobust is freely available as a Stata package.\n\nGeneral FeaturesThe package includes inverse variance weighted estimation, as well as a range of median and MR-Egger estimation methods. Using mrrobust, plots can be constructed visualising each estimate either individually or simultaneously. The package also provides statistics such as [Formula] which are useful in assessing attenuation bias in causal estimates.\n\nAvailabilityThe software is freely available from GitHub [https://raw.github.com/remlapmot/mrrobust/master/].

epidemiology↗

bioRxiv2017

Large Meta-Analysis Provides Evidence For An Association Of Serum Vitamin D With Pulmonary Function

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for the association of serum 25-hydroxyvitamin D [25(OH)D] and pulmonary function. We conducted the largest cross-sectional meta-analysis of the 25(OH)D- pulmonary function association to date, based on nine European ancestry (EA) cohorts (n=22,838) and five African ancestry (AA) cohorts (n=4,290) in the CHARGE Consortium. Data were analyzed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean (SD) serum 25(OH)D was 68 (29) nmol/L for EAs and 49 (21) nmol/L for AAs. For each 1 nmol/L higher 25(OH)D, forced expiratory volume in the first second (FEV1) was higher by 1.1 mL in EAs (95% CI: 0.9,1.3; P=2.5x10-21) and 1.8 mL (95% CI: 1.1,2.5; P=1.6x10-7) in Aas (Prace difference=0.06), and forced vital capacity (FVC) was higher by 1.3 mL in EAs (95% CI: 1.0,1.6; P=1.1x10-20) and 1.5 mL (95% CI: 0.8,2.3; P=1.2x10-4) in AAs (Prace difference=0.56). Among EAs, the 25(OH)D-FVC association was stronger in smokers: per 1nmol/L higher 25(OH)D, FVC was higher by 1.7 mL (95% CI: 1.1,2.3) for current smokers and 1.7 mL (95% CI: 1.2,2.1) for former smokers, compared to 0.8 mL (95% CI: 0.4,1.2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EAs, a stronger association was observed for smokers compared to never smokers, which supports the importance of vitamin D in vulnerable populations.\n\nCohort FundingThis work was supported by National Institutes of Health (NIH) grant number R21 HL125574 funded by the National Heart, Lung, and Blood Institute (NHLBI) and the NIH Office of Dietary Supplements (ODS) (co-Principal Investigators [co-PIs]: DBH and PAC). The corresponding author (PAC) had full access to the data for the meta-analysis, and had final responsibility for the decision to submit for publication. No funding source had any role in the analysis of the data, the writing of the manuscript, or the decision to submit it. This work was also supported in part by R01HL077612 (PI: RGB) and by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (ZO1 ES043012, PI: SJL). SJL is supported by the Intramural Research Program of NIH, National Institute of Environmental Health Sciences. Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01HL105756.\n\nThe Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study.\n\nThe Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C. 25(OH)D measurements were conducted with the support of R01 HL103706 from the NHLBI and R01 HL103706-S1 from the NIH ODS. The authors thank the staff and participants of the ARIC study for their important contributions.\n\nThis Cardiovascular Health Study (CHS) research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Vitamin D measurements were made possible by NHLBI (R01HL084443-01A2).\n\nThis work in Framingham Heart Study was supported by NHLBIs Framingham Heart Study contract (N01-HC-25195 and HHSN268201500001I). Vitamin D measurements in the Framingham study were made possible by NIA (R01 AG14759 to SLB.).\n\nThe Health Aging and Body Composition cohort study was supported by NIA contracts N01AG62101, N01AG2103, and N01AG62106, NIA grant R01-AG028050, NINR grant R01-NR012459, and in part by the Intramural Research Program of the NIA, NIH. This research was further supported by RC1AG035835, and the serum vitamin D assays were supported by R01AG029364.\n\nThe Multi-Ethnic Study of Atherosclerosis (MESA) study is conducted and supported by NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from NHLBI, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001881 from NCRR, and DK063491 from the NIDDK. The MESA Lung study was supported by grants R01 HL077612, RC1 HL100543 and R01 HL093081 from NHLBI. Support for the Mineral Metabolite dataset was provided by grant HL096875.\n\nThe Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands; the Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Dutch Ministry of Education, Culture, and Science; the Dutch Ministry for Health, Welfare, and Sports; the European Commission (DG XII), and the Municipality of Rotterdam. LL was a postdoctoral fellow of the Research Foundation--Flanders (FWO) in Brussels, Belgium. Part of this work was supported by a FWO-grant G035014N. DSM Nutritional Products AG, Kaiseraugst, Switzerland, sponsored the Vitamin D serum analyses. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists.\n\nThe Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005).\n\nAuthor DisclosureDr. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson.\n\nAll other authors have no conflicts of interest. There is no commercial support or financial interest from the tobacco industry for the research presented.\n\nThe study sponsors were not involved in study design, data collection, data analysis, data interpretation, report writing, or decisions to submit the paper for publication. PAC and DBH had final responsibility for the decision to submit for publication.\n\nOnline Supporting MaterialSupplemental table, figures, and methods are available.\n\nAbbreviation Footnote

epidemiology↗

bioRxiv2017

The Nasal And Oropharyngeal Microbiomes Of Healthy Livestock Workers

Little information exists on the microbiomes of livestock workers. A cross-sectional, epidemiological study was conducted enrolling 59 participants (26 of which had livestock contact) in Iowa. Participants were enrolled in one of four ways: from an existing prospective cohort study (n=38), from the Iowa Department of Natural Resources Animal Feeding Operations database (n=17), through Iowa county fairs (n=3), and through snowball sampling (n=1). We collected two sets of swabs from the nares and oropharynx of each participant. The first set of swabs was used to assess the microbiome via 16s rRNA sequencing and the second was used to culture S. aureus. We observed livestock workers to have greater diversity in their microbiomes compared to those with no livestock contact. In the nares, there were 26 operational taxonomic units found to be different between livestock workers and non-livestock workers with the greatest difference seen with Streptococcus and Proteobacteria. In the oropharynx, livestock workers with swine exposure were more likely to carry several pathogenic organisms. The results of this study are the first to characterize the livestock worker nasal and oropharyngeal microbiomes.

epidemiology↗