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bioRxiv2017

Estimating Effects Of Second Line Therapy For Type 2 Diabetes Mellitus: Retrospective Cohort Study

ObjectiveMetformin is the recommended initial drug treatment in type 2 Diabetes Mellitus, but there is no clearly preferred choice for an additional drug when indicated. We use electronic health records to infer the counterfactual drug effectiveness in reducing HbA1c levels and effect on body-mass index (BMI) of four second line diabetes drug classes.\n\nStudy design and settingRetrospective analysis of the electronic health records of US-based patients in the Explorys database using causal inference methodology to adjust for censored patients and confounders.\n\nParticipants and ExposuresOur cohort consisted of roughly 25,000 patients with type 2 diabetes, prescribed metformin along with a drug out of four second line drug classes - sulfonylureas, thiazolidinediones, DPP-4 inhibitors and GLP-1 agonists, during the years 2000-2013.\n\nMain outcome measuresGlycated hemoglobin (HbA1c) and BMI of these patients after six and twelve months of treatment.\n\nResultsWe show that all four drug classes reduce glycated hemoglobin levels, but the effect of sulfonylureas after 12 months of treatment is less pronounced compared to other classes. We also predict that thiazolidinediones increase body weight while DPP-4 inhibitors decrease it.\n\nConclusionOur results are in line with current knowledge on second line drug effectiveness and effect on BMI. They demonstrate that causal inference from Electronic health records is an effective way for conducting multi-treatment causal inference studies.

epidemiology↗

bioRxiv2017

Causal epigenome-wide association study identifies CpG sites that influence cardiovascular disease risk

The extent to which genetic influences on complex traits and disease are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits.\n\nWe identified 10 genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits (P < 3.83x10-08). Bivariate fine mapping suggested that the individual variants responsible for the observed effects on cardiovascular traits at the ABO, ADCY3, ADIPOQ, APOA1 and IL6R loci were likely mediated through changes in DNA methylation. Causal effect estimates on cardiovascular traits ranged between 0.109-0.992 per standard deviation change in DNA methylation and were replicated using results from large-scale consortia.\n\nFunctional informatics suggests that the causal variants and CpG sites identified in this study were enriched for histone mark peaks in adipose tissue and gene promoter regions. Integrating our results with expression quantitative trait loci data we provide evidence that variation at these regulatory regions is likely to also influence gene expression at these loci.

epidemiology↗

bioRxiv2017

Polymorphisms in the vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa

BackgroundVitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide cathelicidin. Deficiency of 25-hydroxyvitamin D and single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene may increase the risk of TB disease and decrease culture conversion rates in drug susceptible TB. Whether these VDR SNPs are found in African populations or impact multidrug-resistant (MDR) TB treatment has not been established. We aimed to determine if SNPs in the VDR gene were associated with sputum culture conversion among a cohort of MDR TB patients in South Africa.\n\nMethodsWe conducted a prospective cohort study of adult MDR TB patients receiving second-line TB treatment in KwaZulu-Natal province. Subjects had monthly sputum cultures performed. In a subset of participants, whole blood samples were obtained for genomic analyses. Genomic DNA was extracted and genotyped with Affymetrix Axiom Pan-African Array. Cox proportional models were used to determine the association between VDR SNPs and rate of culture conversion.\n\nResultsGenomic analyses were performed on 91 MDR TB subjects enrolled in the sub-study; 60% were female and median age was 35 years (interquartile range [IQR] 29-42). Smoking was reported by 21% of subjects and most subjects had HIV (80%), were smear negative (57%), and had cavitary disease (55%). Overall, 87 (96%) subjects initially converted cultures to negative, with median time to culture conversion of 57 days (IQR 17-114). Of 121 VDR SNPs examined, 10 were significantly associated (p<0.01) with rate of sputum conversion in multivariable analyses. Each additional risk allele on SNP rs74085240 delayed culture conversion significantly (adjusted hazard ratio 0.30, 95% confidence interval 0.14-0.67).\n\nConclusionsPolymorphisms in the VDR gene were associated with rate of sputum culture conversion in MDR TB patients in this high HIV prevalence setting in South Africa.\n\nAuthor contributionsMJM, YVS, JCMB, SS, and NRG conceived and designed the study and drafted the initial manuscript. MJM, YVS, YN, and QH performed the data analyses. All authors contributed to interpretation of the data, revised the manuscript, and approved the final version.\n\nThe findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention (CDC). The use of trade names and commercial sources is for identification only and does not imply endorsement by the CDC.

epidemiology↗

bioRxiv2017

Spatial distribution of extensively drug-resistant tuberculosis (XDR-TB) patients in KwaZulu-Natal, South Africa

BackgroundKwaZulu-Natal province, South Africa, has among the highest burden of XDR-TB worldwide with the majority of cases occurring due to transmission. Poor access to health facilities can be a barrier to timely diagnosis and treatment of TB, which can contribute to ongoing transmission. We sought to determine the geographic distribution of XDR-TB patients and proximity to health facilities in KwaZulu-Natal.\n\nMethodsWe recruited adults and children with XDR-TB diagnosed in KwaZulu-Natal. We calculated distance and time from participants home to the closest hospital or clinic, as well as to the actual facility that diagnosed XDR-TB, using tools within ArcGIS Network analyst. Speed of travel was assigned to road classes based on Department of Transport regulations. Results were compared to guidelines for the provision of social facilities in South Africa: 5km to a clinic and 30km to a hospital.\n\nResultsDuring 2011-2014, 1027 new XDR-TB cases were diagnosed throughout all 11 districts of KwaZulu-Natal, of whom 404 (39%) were enrolled and had geospatial data collected. Participants would have had to travel a mean distance of 2.9 km (CI 95%: 1.8-4.1) to the nearest clinic and 17.6 km (CI 95%: 11.4-23.8) to the nearest hospital. Actual distances that participants travelled to the health facility that diagnosed XDR-TB ranged from <10 km (n=143, 36%) to >50 km (n=109, 27%). The majority (77%) of participants travelled farther than the recommended distance to a clinic (5 km) and 39% travelled farther than the recommended distance to a hospital (30 km). Nearly half (46%) of participants were diagnosed at a health facility in eThekwini district, of whom, 36% resided outside the Durban metropolitan area.\n\nConclusionsXDR-TB cases are widely distributed throughout KwaZulu-Natal province with a denser focus in eThekwini district. Patients travelled long distances to the health facility where they were diagnosed with XDR-TB, suggesting a potential role for migration or transportation in the XDR-TB epidemic.

epidemiology↗

bioRxiv2017

Multiscale Modeling To Explore Ebola Vaccination Strategies

BackgroundTransmission in epidemics of infectious diseases is characterized by a high level of subject-specific elements. These include heterogeneous infection conditions, time-dependent transmission potential, and age-dependent contact structure. These insights are often lost in epidemic models using population data. Here we submit an approach that can capture these details, paving the way for studying epidemics in a more mechanistic and realistic way.\n\nMethodsUsing experimental data, we formulated mathematical models of a pathogen infection dynamics from which we can simulate its transmission potential mechanistically. The models were then embedded in our implement of an age-specific contact network structure that allows to express all elements relevant to the transmission process. This approach is illustrated here with an example of Ebola virus (EBOV).\n\nResultsThe results showed that within-host infection dynamics can capture EBOVs transmission parameters as good as approaches using population data. Population age-structure, contact distribution and patterns can also be captured with our network generating algorithm. This framework opens vast opportunities for the investigations of each element involved in the epidemic process. Here, estimating EBOVs reproduction number revealed a heterogeneous pattern among age-groups, prompting questions on current estimates which are not adjusted for this factor. Assessments of mass vaccination strategies showed that a time window from five months before to one week after the start of an epidemic appeared to be effective. Noticeably, compared to a non-intervention scenario, a low vaccination coverage of 33% could reduce number of cases by ten to hundred times as well as lessen the case-fatality rate.\n\nConclusionsThis is the first effort coupling directly within-host infection model into an age-structured epidemic network model, adding more realistic elements in simulating epidemic processes. Experimental data at the within-host infection are shown able to capture upfront key parameters of a pathogen; the applications of this approach will give us more time to prepare for potential epidemics. Population of interest in epidemic assessments could be modeled with an age-specific contact network without exhaustive amount of data. Further assessments and adaptations for different pathogens and scenarios are underway to explore multilevel aspects in infectious diseases epidemics.

epidemiology↗

bioRxiv2017

Exponential Growth Of The USA Overdose Epidemic

Introduction Introduction Methods Discussion References The USA is experiencing an epidemic of drug overdose deaths 1-3. This epidemic has been attributed in part to increases in opioid prescribing that began in the late 1990s, which led to increasing substance use disorders and overdose deaths4-7. In an effort to understand and forecast trends in the epidemic, we examined data on reported accidental poisoning deaths from 1979 through 2015. We present our preliminary findings here.\n\nMethods Introduction Methods Discussion References All reported accidental poisoning deaths were abstracted for the period 1979 to 2015 from the deat ...

epidemiology↗

bioRxiv2017

Epigenome-Wide Association Study Of Asthma And Wheeze In Childhood And Adolescence

Asthma heritability has only been partially explained by genetic variants and is known to be sensitive to environmental factors, implicating epigenetic modifications such as DNA methylation in its pathogenesis.\n\nUsing data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC), we assessed associations of asthma and wheeze with DNA methylation at 7.5 years and 16.5 years, at over 450,000 CpG sites in DNA from the peripheral blood of approx. 1000 participants. We used Mendelian randomization (MR), a method of causal inference that uses genetic variants as instrumental variables, to infer the direction of association between DNA methylation and asthma.\n\nWe identified 302 CpGs associated with current asthma status (FDR-adjusted P-value <0.05) and 445 with current wheeze status at 7.5 years, with substantial overlap between the two. Genes annotated to the 302 associated CpGs were enriched for pathways related to movement of cellular/subcellular components, locomotion, interleukin-4 production and eosinophil migration. All associations attenuated when adjusted for eosinophil and neutrophil cell count estimates. At 16.5 years, two sites were associated with current asthma after adjustment for cell counts. The CpGs mapped to the AP2A2 and IL5RA genes, with a -2.32 [95% CI -1.47,-3.18] and -2.49 [95% CI -1.56,-3.43] change in percentage methylation in asthma cases respectively. Two-sample bi-directional MR indicated a causal effect of asthma on DNA methylation at several CpG sites at 7.5 years. However, associations did not persist after adjustment for multiple testing. There was no evidence of a causal effect of asthma on DNA methylation at either of the two CpG sites at 16.5 years.\n\nThe majority of observed associations are driven by higher eosinophil cell counts in asthma cases, acting as an intermediate phenotype, with important implications for future studies of DNA methylation in atopic diseases.

epidemiology↗

bioRxiv2017

HIV Transmission Efficiency Through Contaminated Injections In Roka, Cambodia

A nosocomial HIV outbreak recognized in late 2014 in Roka commune, Cambodia, demonstrates the potential for rapid transmission through skin-piercing healthcare procedures. Information reported from the investigation of the Roka commune outbreak is sufficient to estimate the transmission efficiency of HIV through contaminated injection equipment. With conservative assumptions, two estimates are 4.6% and 9.2%. These estimates are much greater than widely disseminated and influential low estimates of risk from unsafe injections, estimates which have encouraged low estimates of the contribution of unsafe healthcare to Africas generalized HIV epidemics. More information about nosocomial risks in Roka commune could improve the estimates in this paper and advise HIV prevention programs, particularly in countries with unreliably sterile healthcare and high HIV prevalence.

epidemiology↗

bioRxiv2017

Fitness, Physical Activity, And Cardiovascular Disease: Longitudinal And Genetic Analyses In The UK Biobank Study

BackgroundExercise is inversely related with cardiovascular disease (CVD), but large-scale studies of incident CVD events are lacking. Moreover, little is known about genetic determinants of fitness and physical activity, and modifiable effects of exercise in individuals with elevated genetic risk of CVD. Finally, causal analyses of exercise traits are limited.\n\nMethodsWe estimated associations of grip strength, physical activity, and cardiorespiratory fitness with CVD and all-cause death in up to 502,635 individuals from the UK Biobank. We also examined these associations in individuals with different genetic burden on coronary heart disease (CHD) and atrial fibrillation (AF). Finally, we performed genome-wide association study (GWAS) of grip strength and physical activity, as well as Mendelian randomization analysis to assess the causal role of grip strength in CHD.\n\nFindingsGrip strength, physical activity, and cardiorespiratory fitness showed strong inverse associations with incident cardiovascular events and all-cause death (for composite CVD; HR, 0.78, 95% CI, 0.77-0.80; HR, 0.94, 95% CI, 0.93-0.95, and HR, 0.67, 95% CI, 0.63-0.71, per SD change, respectively). We observed stronger associations of grip strength with CHD and AF for individuals in the lowest tertile of genetic risk (Pinteraction = 0.006, Pinteraction = 0.03, respectively), but the inverse associations were present in each category of genetic risk. We report 27 novel genetic loci associated with grip strength and 2 loci with physical activity, with the strongest associations in FTO (rs56094641, P=3.8x10-24) and SMIM2 (rs9316077, P=1.4x10-8), respectively. By use of Mendelian randomization, we provide evidence that grip strength is causally related to CHD.\n\nInterpretationMaintaining physical strength is likely to prevent future cardiovascular events, also in individuals with elevated genetic risk for CVD.\n\nFundingNational Institutes of Health (1 R01 HL135313-01), Knut and Alice Wallenberg Foundation (2013.0126), and the Finnish Cultural Foundation.

epidemiology↗

bioRxiv2017

Social-Ecological Factors And Preventive Actions Decrease The Risk Of Dengue Infection At The Household-Level: Results From A Prospective Dengue Surveillance Study In Machala, Ecuador

BackgroundIn Ecuador, dengue virus (DENV) infections transmitted by the Aedes aegypti mosquito are among the greatest public health concerns in urban coastal communities. Community- and household-level vector control is the principal means of controlling disease outbreaks. This study aimed to assess the impact of knowledge, attitudes, and practices (KAPs) and social-ecological factors on the presence or absence of DENV infections in the household..\n\nMethodsIn 2014 and 2015, individuals with DENV infections from sentinel clinics were invited to participate in the study, as well as members of their household and members of four neighboring households located within 200 meters. We conducted diagnostic testing for DENV on all study participants; we surveyed heads of households (HOHs) regarding demographics, housing conditions and KAPs. We compared KAPs and social-ecological factors between households with (n=139) versus without (n=80) DENV infections, using bivariate analyses and multivariate logistic regression models with and without interactions.\n\nResultsSignificant risk factors in multivariate models included proximity to abandoned properties, interruptions in piped water, and shaded patios (p<0.05). Significant protective factors included use of mosquito bed nets, fumigation inside the home, piped water inside the home (p<0.05). In bivariate analyses (but not multivariate modeling), DENV infections was positively associated with HOHs who were male, employed, and of younger age than households without infections (p<0.05). DENV infections were not associated with knowledgeattitude, or reported barriers to prevention activities.\n\nDiscussionSpecific actions that can be considered to decrease the risk of DENV infections in the household include targeting vector control in highly shaded properties, fumigating inside the home, and use of mosquito bed nets. Community-level interventions include clean-up of abandoned properties, daily trash pick-up, and reliable piped water inside houses. These findings can inform interventions to reduce the risk of other diseases transmitted by the Ae. aegypti mosquito, such as chikungunya and Zika fever.\n\nAuthor summaryDengue, chikungunya and Zika viruses are transmitted to people primarily by the Aedes aegypti mosquitoes in tropical and subtropical regions. Diseases transmitted by the Ae. aegypti mosquito are a growing public health concern. Mosquito control is the principal means of preventing and controlling disease outbreaks. In this study, we compared the characteristics of households with and without DENV infections in the city of Machala, Ecuador. We found that risk factors for DENV infection included proximity to abandoned properties, interruptions in the piped water supply, and a highly shaded patio. Protective factors included the use of mosquito bed nets, fumigation inside the home, and piped water inside the home. These findings can be used to inform targeted vector control interventions by the public health sector at the household and community levels.

epidemiology↗

bioRxiv2017

Genome-wide Association Study Of Plasma Proteins Identifies Putatively Causal Genes, Proteins, And Pathways For Cardiovascular Disease

Identifying genetic variants associated with circulating protein concentrations (pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteomes causal role in disease and bridge a GWAS knowledge gap for hitherto unexplained SNP-disease associations. We conducted GWAS of 71 high-value proteins for cardiovascular disease in 6,861 Framingham Heart Study participants followed by external replication. We comprehensively mapped thousands of pQTLs, including functional annotations and clinical-trait associations, and created an integrated plasma-protein-QTL searchable database. We next identified 15 proteins with pQTLs coinciding with coronary heart disease (CHD)-related variants from GWAS or tested causal for CHD by Mendelian randomization; most of these proteins were associated with new-onset cardiovascular disease events in Framingham participants with long-term follow-up. Identifying pQTLs and integrating them with GWAS results yields insights into genes, proteins, and pathways that may be causally associated with disease and can serve as therapeutic targets for treatment and prevention.

epidemiology↗

bioRxiv2017

Are Your Covariates Under Control? How Normalization Can Re-introduce Covariate Effects

Many statistical tests rely on the assumption that the residuals of a model are normally distributed. Rank-based inverse normal transformation (INT) of the dependent variable is one of the most popular approaches to satisfy the normality assumption. Studies regularly adjust for covariates and then normalize the residuals. This study investigated the effect of regressing covariates against the dependent variable and then applying rank-based INT to the residuals. The correlation between the dependent variable and covariates at each stage of processing was assessed. An alternative approach was tested of applying rank-based INT to the dependent variable before regressing covariates was tested. Analyses based on both simulated and real data examples demonstrated that applying rank-based INT to the dependent variable residuals after regressing out covariates re-introduces a linear correlation between the dependent variable and covariates in almost all situations. This will increase type-1 errors and reduce power. Our proposed alternative approach, where rank-based INT was applied prior to controlling for covariate effects, gave residuals that were normally distributed and linearly uncorrelated with covariates. This approach is therefore recommended.

epidemiology↗

bioRxiv2017

Reproductive Period, Endogenous Estrogen Exposure And Dementia Incidence Among Women In Latin America And China; A 10/66 Population-Based Cohort Study

BackgroundExposure to endogenous estrogen may protect against dementia, but evidence remains equivocal. Such effects may be assessed more precisely in settings where exogenous estrogen administration is rare. We aimed to determine whether reproductive period (menarche to menopause), and other indicators of endogenous estrogen exposure are inversely associated with dementia incidence\n\nMethodsPopulation-based cohort studies, of women aged 65 years and over in urban sites in Cuba, Dominican Republic Puerto Rico and Venezuela, and rural and urban sites in Peru, Mexico and China. Sociodemographic and risk factor questionnaires were administered to all participants, including ages at menarche, birth of first child, and menopause, and parity, with ascertainment of incident 10/66 dementia, and mortality, three to five years later.\n\nResults9,428 women participated in the baseline phase, with response rates of 72-98% by site. The at risk cohort comprised 8,466 dementia-free women. Mean age at baseline varied from 72.0 to 75.4 years, lower in rural than urban sites and in China than in Latin America. Mean parity was 4.1, generally higher in rural than urban sites and ranging from 2.4-7.2 by site. 6,854 women with baseline reproductive period data were followed up for 26,463 person years. There were 692 cases of incident dementia, and 895 dementia free deaths. Pooled meta-analysed fixed effects, per year, for reproductive period (Adjusted Sub-Hazard Ratio [ASHR] 1.001, 95% CI 0.988-1.015) did not support any association with dementia incidence, with no evidence also for any interaction between APOE genotype and reproductive period (ASHR 0.993, 95% CI 0.947-1.041, I2=39.3%). Similarly no association was observed between incident dementia and; ages at menarche, birth of first child, and menopause: nulliparity; or index of cumulative endogenous estrogen exposure. Greater parity was positively associated with incident dementia (ASHR 1.030, 95% CI 1.002-1.059, I2=0.0%).\n\nConclusionsWe found no evidence to support the theory that natural variation in cumulative exposure to endogenous oestrogens across the reproductive period influences the incidence of dementia in late life.

epidemiology↗

bioRxiv2017

The Oropharynx As A Distinct Colonization Site For Staphylococcus aureus In The Community

BackgroundS. aureus is a frequent cause of hospital and community associated infections and colonization is known to increase the risk of infection, with the nares considered the most important colonization site.\n\nMethodsWe compared the prevalence of nasal and oropharyngeal carriage in a yearlong, prospective cohort study of people from the community as well as assessed risk factors for nares-only and oropharynx-only colonization.\n\nResultsColonization at both anatomical sites was correlated; however, oropharynx only carriage occurred and oropharyngeal swabs were more sensitive than nasal swabs at detecting carriage (77.27% and 72.725 respectively). Non-Caucasian race, having a greater number of people living in your home and more children in your home all significantly increased the odds of oropharynx-only carriage. Having S. aureus present on home environmental sites, exercising in a fitness center, and sharing bath towels all increased the odds of nares-only carriage.\n\nConclusionsOropharyngeal swabs increase the detection of S. aureus colonization in community embers.

epidemiology↗

bioRxiv2017

Enhancing Ebola Virus Disease Surveillance And Prevention In Counties Without Confirmed Cases In Rural Liberia: Experiences From Sinoe County During The Flare-Up In Monrovia, April To June, 2016

IntroductionDuring the flare-ups of Ebola virus disease (EVD) in Liberia, Sinoe County reactivated the multi-sectorial EVD control strategy in order to be ready to respond to the eventual reintroduction of cases.\n\nThis paper describes the impacts of the interventions implemented in Sinoe County during the last flare-up in Monrovia, from April 1 to June 9, 2016, using the resources provided during the original outbreak that ended one year back.\n\nMethodsWe conducted a descriptive study to describe the key interventions implemented in Sinoe County, the capacity available, the implications for the reactivation of the multi-sectoral EVD control strategy, and the results of the same. We also conducted a cross-sectional study to analyze the impact of the interventions on the surveillance and on infection prevention and control (IPC).\n\nResultsThe attrition of the staff trained during the original outbreak was low, and most of the supplies, equipment, and infrastructure from the original outbreak remained available.\n\nWith an additional US$1755, improvements were observed in the IPC indicators of triage, which increased from a mean of 60% during the first assessment to 77% (P=0.002). Additionally, personal/staff training improved from 78% to 89% (P=0.04).\n\nThe percentage of EVD death alerts per expected deaths investigated increased from 26% to 63% (P<0.0001).\n\nDiscussionThe small attrition of the trained staff and the availability of most of the supplies, equipment, and infrastructure made the reactivation of the multi-sectoral EVD control strategy fast and affordable. The improvement of the EVD surveillance was possibly affected by the community engagement activities, awareness and mentoring of the health workers, and improved availability of clinicians in the facilities during the flare-up. The community engagement may contribute to the report of community-based events, specifically community deaths. The mentoring of the staff during the supportive supervisions also contributed to improve the IPC indicators.

epidemiology↗

bioRxiv2017

Thoracolumbar Intervertebral Disc Area Morphometry In Elderly Chinese Men And Women: Radiographic Quantifications At Baseline And Changes At Year-4 Follow-Up

The manuscript submitted does not contain information about medical device(s)/drug(s). No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.\n\nStudy DesignA population-based radiographic study with longitudinal follow-up.\n\nObjectiveTo develop a quantitative index for lumbar disc space narrowing (DSN) evaluation in elderly subjects; to determine how DSN in the elderly is influenced by osteoporosis and gender.\n\nSummary of Background DataThere is paucity of research on quantitative classification of lumbar DSN based on disc areal morphometry.\n\nMethodsWith the database of Osteoporotic Fractures in Men (Hong Kong) and Osteoporotic Fractures in Women (Hong Kong) Studies and those who attended the year-4 follow-up (n = 1519 for men and n = 1546 for women), data of 491 women and 592 men were randomly selected. The anterior, middle, and posterior heights, anteroposterior diameter and area of intervertebral discs (T4T5 to L4L5) were measured on lateral radiographs. Disc Area Index for Lumbar Spine (DAIL, disc area divided by the mean of the sum of square of the adjacent upper and lower vertebrae mid-height anterior-posterior diameter) was developed and compared with semi-quantitative DSN expert grading.\n\nResultsDAIL correlated with semi-quantitative grading, with sensitivity and specificity varying from 87.3% to 96.8% for grade-1 DSN (<30% reduction in disc height), and 92.9 % to 100% for grade-3 DSN (>60% reduction in disc height). The thoracolumbar disc area loss among men and women during 4-years follow-up period varied between 1.32% and 3.56%, and it was greater for women (mean: 2.44%) than for men (mean: 1.90%, p=0.044). Majority of lumbar DSN progressions during 72 to 76 years old were progression from normal disc space to grade-1DSN. Osteoporosis was associated with greater disc area decrease, both for thoracic and lumbar discs.\n\nConclusionLumbar DSN can be quantified using DAIL. In elderly Chinese, intervertebral disc narrowing over a 4-year period was greater in women than men, and associated with the presence of osteoporosis.

epidemiology↗

bioRxiv2017

Side Effects And The Need For Secrecy: Characterising Discontinuation Of Modern Contraception And Its Causes In Ethiopia Using Mixed Methods

BackgroundContraceptive discontinuation is a major barrier to reducing global unmet needs for family planning, but the reasons why women discontinue contraception are poorly understood. Here we use data from Ethiopia to investigate (i) the magnitude of contraceptive discontinuation in 2005-2011, (ii) how the risk of discontinuation varies with method type and education level and (iii) the barriers to continuation. Our main hypothesis is that contraceptive discontinuation is driven by the experience of physiological side-effects associated with the use of hormonal contraception, rather than a lack of education.\n\nMethodsWe used a mixed methods explanatory sequential design to explain the quantitative results in more details through the qualitative data. First, we analysed quantitative data from the 2011 Ethiopian Demographic and Health Survey to study patterns of contraceptive discontinuation and method choice using multilevel multiprocess models. Second, we conducted semi-structured interviews and focus group discussions in the 3 most populated regions of Ethiopia with individuals of reproductive age and health professionals.\n\nResultsThe analysis of EDHS data shows that the rate of discontinuation has not reduced in the period 2005-2011 and remains high. Discontinuation mainly takes the form of abandonment, and is a function of method type and wealth but not of educational level. Interviews with women and health professionals reveal that the experience of debilitating physiological side effects, the need for secrecy and poverty are important barriers to continuation.\n\nConclusionsOur findings together suggest that physiological and social side-effects of contraceptive use, not education, are the root causes of contraceptive discontinuation in Ethiopia. We argue that to tackle discontinuation due to side-effects, dispelling misconceptions through educating women is not addressing the root causes of discontinuation, and that priority should be given to both engaging men and questioning the appropriateness of medical technology to the physiology of Ethiopian women, especially those living in poverty.

epidemiology↗

bioRxiv2017

Leg Length, Skull Circumference, And The Incidence Of Dementia In Latin America And China; A 10/66 Population-Based Cohort Study

BackgroundAdult leg length is influenced by nutrition in the first few years of life. Adult head circumference is an indicator of brain growth. Cross-sectional studies indicate inverse associations with dementia risk, but there have been few prospective studies.\n\nMethodsPopulation-based cohort studies in urban sites in Cuba, Dominican Republic Puerto Rico and Venezuela, and rural and urban sites in Peru, Mexico and China. Sociodemographic and risk factor questionnaires were administered to all participants, and anthropometric measures taken, with ascertainment of incident 10/66 dementia, and mortality, three to five years later.\n\nResultsOf the original at risk cohort of 13,587 persons aged 65 years and over, 2,443 (18.0%) were lost to follow-up; 10,540 persons with skull circumference assessments were followed up for 40,466 person years, and 10,400 with leg length assessments were followed up for 39,954 person years. There were 1,009 cases of incident dementia, and 1,605 dementia free deaths. The fixed effect pooled meta-analysed adjusted subhazard ratio (ASHR) for leg length (highest vs. lowest quarter) was 0.80 (95% CI, 0.66-0.97) and for skull circumference was 1.02 (95% CI, 0.84-1.25), with no heterogeneity of effect between sites (I2=0%). Leg length measurements tended to be shorter at follow-up, particularly for those with baseline cognitive impairment and dementia. However, leg length change was not associated with dementia incidence (ASHR, per cm 1.006, 95% CI 0.992-1.020), and the effect of leg length was little altered after adjusting for baseline frailty (ASHT 0.82, 95% CI 0.67-0.99). A priori hypotheses regarding effect modification by gender or educational level were not supported.\n\nConclusionsConsistent findings across settings provide quite strong support for an association between adult leg length and dementia incidence in late-life. Leg length is a relatively stable marker of early life nutritional programming, which may confer brain reserve and protect against neurodegeneration in later life through mitigation of cardiometabolic risk. Further clarification of these associations could inform predictive models for future dementia incidence in the context of secular trends in adult height, and invigorate global efforts to improve childhood nutrition, growth and development.

epidemiology↗